Mc Lc

Phn I:M u..................................................................................................2 Phn II:MONOTERPENOID ............................................................................3 1.Phng php vt l & sinh tng hp ..........................................................3 2.Cc monoterpen mch h ...........................................................................5 3.Cc monoterpen mt vng ....................................................................... 15 4. Cc Monotecpen 2 vng .......................................................................... 38 5. Furanoid v Pyranoid monoterpenoid ...................................................... 52 Phn III:Ti Liu Tham Kho ......................................................................... 55 Phn IV:Kt Lun ........................................................................................... 62

Phn I:M u
T xa xa con ngi thch v quan tm ti du thm tch t thc vt. Nhng mi ti u th k XIX mi c nhng nghin cu u tin v thnh phn ho hc tinh du. Vo nm 1818 ngi ta tm c mt s hp cht v xc nh c rng t l nguyn t C:H tinh du l 5:8. Tip thep l mt s hp cht hidrocacbon khng no, khng vng hoc c vng c tch ra. Chng c cng chung l (C5H8),(n2) v c t tn l TECPEN. trong i sng ca chng lun c mt ca hp cht tecpen nhng c th bn cha bit v nhng sn phm hu ch cho cuc sng i thng nh du gi, nc hoa, hay l gip ch cho sc kho ca bn thn chng ta nh thuc bi b sc kho t du c heo, du gi cha cm,.. Vy tecpen c nhng loi no tnh cht vt l ho hc nh th no, nhng ng dng ca n trong i sng ca n ra sao? Chng ta s cng nhau tm hiu . M u cho nhng nghin cu v terpen, chng ta cng i tm hiu t nhng hp cht terpenoid c bn nhng cng khng km phn quan trng v gn gi vi chng ta, l phn m nhm 1 xin trnh by di y: Monoterpen

Phn II: MONOTERPENOID

1.Phng php vt l & sinh tng hp Thm mt nhm ph khi lng na ca cc hydrocacbon trong nhm Caran v Mtan c cng b.[1] S ng nht ca cc ru monoterpenoid trong nhng hn hp phc i khi l thi quen, vn s tr nn n gin hn nu chun b trifloacetat, v s dng ph F n.m.r.[2] Thuyt pht sinh sinh vt ca monoterpen nhn c nhiu ch . Bi bo u tin trong lot bo co c dnh ni v monoterpen (mt lng ln cc ng phn ca Thujone) ca Tanaceum vulgare (cy cc ngi).[3] Con ng tm ra Thujone c kim nghim da trn qui m kt hp ca phng x ca axetat [Cacbon C14 ] v n cho thy rng nhng terpen bit (v d menth-1-en-4-ol-sabinene) u tham gia trc tip vo con ng , trong khi nhng cht khc ( v d thujone ) l cc nhnh ca con ng chnh. Thm vo , bi bo ny cng c cuc tho lun th v v v tr hin ti ca thuyt pht sinh monoterpenoid. Mt cch tip cn hi khc c Zavarin s dng. Vi tinh du t Pinus v Abies, ng pht trin mt lot s liu phn tch thng k suy ra t thuyt pht sinh. T mt lng kh ln cc mu, ng nhn ra s lp li nht nh trong s c mt ca cc monoterpen,mt vi tnh cht nh tnh (c trong hai hoc nhiu hn nhng hp cht c cng loi) v mt vi tnh cht nh lng (nhng hp cht c trong quan h ton hc vi cht khc), v c nn tng c coi l ngun pht sinh ca cc cht nh pinen, camphan, bonyl axetat, terpinen, sabinen, v mt vi hydrocacbon terpen khc.[4] Nhng nghin cu t 3

phng th nghim da trn thuyt sinh tng hp tip tc xut hin. Mc d chng thng c ch v qu thc bt ngun t nhng nghin cu pht sinh, chng him khi ging vi nhiu hn 1 qu trnh ha hc. Mt v d nh s tng hp campho c m t di y, t dn xut bi-cyclo [2,2,1] heptan. S khc bit nh y l s tng hp ca cc terpen t geranyl pyrophotphat c thc hin bi Haley et al, ng th lm theo kh ging vi thuyt sinh tng hp c a ra. H kim tra s bin i trong nhng sn phm t neryl(1) v geranyl (2) diphenylphotphat (nhng m hnh sinh hc ca pyrophotphat) v tm ra nhiu sn phm ca terpen mch vng hn trong h neryl. Cc terpen mch vng c hnh thnh t geranyl diphenylphotphat nhng tc gi cho rng c th chng c sinh ra qua linalyl pyrophotphat (3), mc d n khng c tm thy trong hp cht (xem s 1).[5]

S 1 Lm vic vi cc ti nc cam, Potty v Bruemmer phn lp c mt enzym l geraniol dehydrogenase,[6] enzym ny duy tr tnh cn bng gia andehit v ancol. S c mt mt loi enzym th hai bo ha mt trong hai lin 4

kt bi trong h thng ny tr thnh citronellal v citronellol c kt lun. Cc tc gi cng chng minh s c mt cu cc enzym chuyn ha mevalonate thnh linalyl pyrophotphat, ng thi cho rng cc qu thuc h cam u tng hp cc terpenoid t mevalonate bng cch ny. Vai tr ca cc monoterpen cyclopentanoid trong sinh tng hp cc indol alkaloid c tho lun trong chng 6.

2.Cc monoterpen mch h 2,6-Dimethyloctane- Dembitskii et al.[8,9] bo co kh nng phn lp ca mt hydrocacbon khc thng, cis-2,6-dimethyloctan-1,4,7-triene (4), t loi cy Achilla filipendulina, cu hnh ni i dng cis c xc nh ch yu da trn c s quang ph i.r. iu ny gi nh v vic hymentherene c cng b l mt hp cht thin nhin [2,6-dimethylocta-2,4,7-triene, (5)] [10] nhng v sau cho thy l mt hp cht trong s cc monoterpen bit.[11] Cht achillen l mt hp cht thin nhin, tuy nhin li c cung cp t qu trnh tng hp ca olefin.[12] Nhm ngi Nga khc cng cng b ru achillenol (6)[13]

Dehydrolinalool (7), mt trong s nhng sn phm trung gian ca linalool v vitamin A, khng phn ng vi axit formic to sn phm ,-aldehit hay xeton khng no nh mong i, m thay vo hnh thnh tetrahydropyran (8), cng vi acetylcyclohexen (9)[14] 5

3,7-Dimethyl-1,5,7-octatrien-3-ol [(15)=R- ng phn] c tm thy t nhin trong c hai dng i xng. ng phn 3S-(+)-enantiomorph xut hin trong l cy Ho du Nht Bn ( tn thng gi ca n l hotrienol)[15] trong khi ng phn R- c phn lp t cy ch en[16] v ch xanh [17]. ng phn Rc tng hp t R-linalyl axetat bng cch brom ha vi N-bromosuccinimide, cho 3 hp cht allylically axetat c brom ha (11), (12) v (13), tt c u dn n hp cht axetat ca ancol mong mun trong phn ng ca dehydrobrom ha vi dietylanilin. Mt ru nh vy cng c tng hp, ngay c khi n c tm ra l mt hp cht thin nhin, bng cch hidrat ha vi axit sunfuric trong axeton, mt trong nhng glycol thu c bng cch tng nhy oxi ha nh sng ca linalool (16)[18]

Dihydrotagetone (25), xy ra trong cy Tagetes glandulifera (Com-positae), c tng hp bi ba tuyn ng mi (mc d khng phi l u tin), mt trong s cng dn n cc tagetone t nhin (24) [19] Teisseire v Corbier bt u t cc ete enol (18) v (19) ca 4-methylbutan-2-mt, m phn ng vi nhng-2-ynol c mt ca hir kali sunfat cung cp cho hai allenic xeton (22) v (23) bng cch phn ng Claisen ca cc ban u hnh thnh acetylenic ete (20) v (21). Khi hn hp ca allenones c x l vi c s, ch c mt mong mun (22), hin ti trong hn hp n mc 65%, sp xp li cho ra mt hn hp ca cis-v-tagetones xuyn (24) trong hiu sut khong 45% da trn cc butynol (cis tagetone-l sn phm ch yu t nhin). S dng crotyl ru thay cho ru acetylenic, Hai tng hp ca dihydrotagetone c b sung minh ha trong scheme2. Mt s lng nht nh cc phn ng ni ting trong lot bi ny c tng kt bi Sasaki et al tho lun v phn ng Diels-Alder 1,4-cycloaddition ca myrcene (27), so snh hot ng ca n vi dienes khc, c bit isoprene.[21]

Vic to vng v tr 1,3- ca benzoninitrile oxit (28) thnh myrcen (27) vi phn ng c 2 ni i lin hp, hnh thnh 2 sn phm cng (29) v (30). Cht km phn ng 1,3-dipoles, diazometan, diphenylnitrilmine, v phenyl-, v ptoluensulphonyl-azide, u khng phn ng.[22] Mt loi khc ca phn ng cng (bao gm mt phc h ) thnh 2 lin kt ca myrcen l phn ng ca triclorosilane, vi s c mt ca axit cloroplatinic, to 1,2- v 1,4- sn phm cng mono ca h lin kt i lin hp

(chim u th trc y), cng vi sn phm cng 1,2 : 3,4-. Lin kt bi th 3 ch phn ng 105C v p sut cao.[23]

S epoxy ha ca alloocimen (31) c chng t l mt peroxit trung gian cao phn t (32) v to ra cc peoxit bit nh (33) v (34) bng phn ng nhit, mt loi phn ng cng s to ra 4-metylhexa-2,4-dienal (35) v 6-metylhepta-3,5dien-2-one (36).[24]

Bi v s sn c v tinh khit ca geraniol (37) v nerol (40) nhng cht c cu hnh xc nh, Stork et al. s dng chng to cc olefin c cu dng hnh hc xc nh. Giai on u tin ph thuc vo vic cc axetat c th b ct bi ozon c bit cc lin kt i, to ra cc aldehit axetat,[25] nhng cht ny cng c c lp nh imetyl axetan (38) v (41). Cc axetat ca clo tng ng (39) v (42) th kh to ra hn khi khng c cc ng phn ca cc lin kt b, nhng khi c ru trong hexametyl photphramid (2:1) hay metyl-liti, cng vi p-toluen sunphonyl clo v Liti clo trong cng hn hp dung mi, nng sut tng ng ca hp cht ca clo (39) v (42) tng ln m khng cn ng phn ha.[26]

10

Cc monoterpenoid non-isoprenoid- c tnh hot ng trong s cc monoterpenoid c quan h vi axit chrysanthenic (43) v thuc v artemesyl (44), santolenyl (45), v lavandulyl (46) cc nhm m khng theo qui tc ni u vi ui ca n v isopren. Ru yomogi (47), hinhf thnh t allylically chuyn ha thnh ru cy ngi (51)[27,28] , c phn lp t Artemisia feddei. Lp santolinyl hin nay bao gm cc ru, lyratol (46) t Cyathocline lyrata v 2,5dimetyl-3-vinylpent-4-en-2-ol (49), t cy cc la m Moroccan, Ormenis multicaulis.[30] Ru cy ngi (51) c tng hp bng s sp xp li tuyn lin kt sigma ca ylided c dn xut t di-isopentenyl ete (50)[31,32] 1 phn ng xy ra s tch tr sinh tng hp ca cc terpen k l ny.

C kt lun cho rng c th tt c chng c rt ra t b khung ca axit chrysanthemic (43; R=H),[33,34] bi s m vng lin kt ca xyclopropan, c th to ra hoc (44), (45) hay (46), v qu thc mt vi chuyn ha ca khung chrysanthemyl thnh khung monoterpen l xut hin trong phng th nghim. Mi y nht khi chiu sng chrysanthemol (52) vi n thy ngn p sut cao sn phm thu c bao gm lavandulol (53) v 3-metyl-but-2-enol (54), mi cht vi 11

hiu sut khong 20%.[35] Phn ng sigmatropic ca thioeter vi ete (50) c pht hin, dn n suy on cc monoterpen ca cy ngi hng c th c hnh thnh bng cc qu trnh tng t. Trong nhng iu kin ny chuyn ha trc tip t chrysanthemyl thnh chrysantmethol khng cn phi dng n thy ngn p sut cao

Ru yomogi (47) c chuyn ha thnh hp cht ca nhm satonilyl, (57), (58) v (59), bng vic m vng ca epoxit (53)t khi c xc tc axit.[38]

Qu trnh tng hp ca ru yomogi (47) t c nh quang oxi ha hydro cacbon (61) thu c bng phn ng Wurtz (s dng xc tc Mg) ca 3metylbut-2-enyl clo (60). N cng hnh thnh t cht bit 2,2-dimetylbut-3-enal dng phn ng Wittig, cng b sau ny a ra qu trnh tng hp ca cu trc (62), tng c tin l c mt ru yomogi.[41] 12

Cc nghin cu v chrysanthemic axit v cc dn xut ca n thng nh hng tng hp este ca axit trans-chrysanthernic, mt s trong t nhin ang xy ra ( v do , c th phn hy sinh hc ) thuc tr su. Tng hp ca axit pyrethric hay mono - este ca n ( 65 ) t axit chrysanthemic c thc hin thnh hai th nghim. Ueda v Matsui so snh c bn cht ng phn hnh hc ca pyrethric acid bng cch bini cis v trans- metyl chrysanthemate vo anhyt tng ng [ e. g. ( 63 ; R = Me).Martel v Buenia 43 theo cng phng php, u tin khng c isome ha tm bt i[ ( lR, 2 R ) ], sau lp vo tng hp n metyl este ca axit chrysanthemic i hnh [ ( lS, 2 S ) ] ( 43a ; R = Me ), phn cn li t dung dch ca axit raxemic, i theo s 3. Crombie et al. cng s dng tuyn ging nhau t anhyt ( 63 ; R = Me ) kiu 14 clabelled metyl chrysanthemate do phn ng Wittig .

13

Vn v vic s dng ca axit chrysanthemic t [i.e. the (1S, 2S) isomer] cng c tng hp bi Ueda v Matsui[46]. H nhit phn axit chrysanthemic to ra pyrocine (66).Chuyn ha ca cis - chrysanthemate este thnh trans-esters d dng thc hin (cho este metyl ) bi s nhit phn ca cis este ti 240-260C.[47] S telomerise ha ca Isopren- Qu trnh tng hp ca cc monoterpenoid bng s telomerise ha ang c nghin cu, c bit l Nga v Nht Bn, v mt nh gi ( Nga) v s telemerise ha s dng isopren-hydro clo sn phm cng, c a ra. on bao gm C10 , di iu kin nht nh th 45% geranyl clo c th phn lp cho sn phm cng urotropin hoc cc phn ng xa hn. S telomerise ha axit photphoric ca isopren, mt khc, to ra hu ht l sn phm -terpinen v alloocimen nh cc hydrocacbon C10,[48] cng vi geraniol v terpineol. Khi c mt axit axetic, linalyl, geranyl, lavandulyl, v cc axetat khc c hnh thnh trong phn ng [49] ca axit photphoric vi nhiu monoterpen hydrocacbon. Ngi ta cng b rng mt nhm ancol C9 (67) xut hin trong hn hp to ra bi phn ng gia axit photphoric v isopren. Axit percloric c th hnh thnh di hiu sut thp ca 2,2,5-trimetyl-6-vinyltetrahydropyran (68).[52] 14

Vi s c mt ca lithi naphtalen a vo tetrahydrofuran, isoprene c nh trng hp to ra monoterpene, oxy ha hn hp bng oxy i qua cho 30 - 40% ru C10 v 30% C10 glicol. 10% nerol v 10% geraniol c to ra cng thm 5% ca 2,6-dimetylocta-1,7-dien-6-ol (69) ca cc ru hydric, v 55% 2,7dimetylocta-2,6-dien-1-ol (70), vi 20% sn phm khc. Cc glycol chim 50% trong mi hp cht 2,6- v 2,7-dimetyl-octa-2,6-dien-1,8-diol (71) v (72). [54]

3.Cc monoterpen mt vng Cyclobutan- Mt trong nhng cht mi th v nht mi y c khm ph l monoterpene cyclobutanes ( ngoi nhng h thng hai vng. cha ng cyclobutanes). Cht hp dn tnh dc ging c ( Anthonornus. grandis, Boheman) c xc nh l cis-substituted cyclobutane (73)[55] Cc Cyclopentan- Mt vi cht mi c phn lp gn y nh: theveside (74)[57] v cc metyl este ca n t nhng loi trc o, Thevetia peruviana (Pers.) K. Schum, v C9 iridoid glucoseide galiridoside (75)[58] t Galeopsis

15

tetrahit L. (labiatae). Mt ngun phong ph ca cc este glyco iridoid l loi cy n lang.

Glycozit mi nht l valerosidatum (76) c phn lp t Valeriana wallichii v V. officinalis. Mc d chng khng phi cc monoterpen cyclopentan, cc glucozit morronoside (77) v kingoside (78) c phn lp t qu Lonicera morrowii, A. Gray, v loniceroside (79) v cht sweroside (80) c bit trc y, c phn lp t l ca nhng loi thc vt ging nhau cng h. Mt bn tm tt ca loi glycozit ny c sp xp bi Bobbitt v Segebarth.[64]

16

Chng ta cng c bit rng 7-deoxyloganic axit (81) l mt tin cht ca nhiu iridoglucoside.[65] Kinh nghim thu c t nghin cu cc loi thc vt Gardinia jasminoides v Paederia scandens cho thy rng cc axit cng tc dng trong phn ng irridoglucoside ca cc cy ny. Gn y cc Iridoglucoside phn lp t cy Gardinia jasminoides l cc gardenoside (82) v geniposide (83), trong khi , t qu th phn lp ra genipingentiobioside. Gn y, lng nh ca deacetylasperulosidic metyl este (85), cng nh iridoglucoside shanzhiside (86), cng c tm thy trong cy ny[69] Thnh tu tng hp ca nm trong lnh vc ny chnh l s tng hp loganin penta-axetat (95) thc hin bi Bchi et al. S dng phng php m rng ca de Mayo cho tng hp cc -dixeton bng quang ha phn ng cng vng ca 17

enol ha -dixeton thnh cc olefin. Nhm ca Bchi xy dng c phn 2 vng trong phn ng quang ha n. T nguyn liu u l este axit 2formylmalonaldehit metyl (87), theo 2 bc t xeton v trimetyl dng orto, v 3cyclopentenyl tetrahydropyranyl ete (88). Bc x c dng sn phm du th vi Amberlite -120 trao i nha cation nhn c mt hn hp lng ca hydroxy acetan (89). S oxi ha gip chng ta phn lp c xeton (90) mong mun l sn phm chnh ca qu trnh kt tinh.

18

May mn l s hnh thnh ca dn xut butylthiometylen (91) xy ra chnh tren cnh nhm cacbonyl ni a vo nhm metyl. Niken Raney kh lu hunh dn n sai metyl epim ha (92), nhng cht ny c th ng phn ha da tr cht mong mun (93). Borohydrie gim i, axetyl ha v glocozit ha hnh thnh loganin penta-axetat (95). [70] 19

Cavill tm tt nhng ti liu trc v cc iridoid n gin hn. T chrysope- loi cy th v Actinidia polygama mt vi ete c to ra, mt vi trong s chng c tng hp t 2 nhm. S tng hp ca matatabiether tun theo phng php thc nghim c dng trong c 2 phng th nghim, nhng nhm ca Wolinsky m t chi tit hn qu trnh tng hp ca cc hp cht khc c a ra trong hnh, c bit l neonepentalacton (96) v cc ete (97) v (98) cng t nhin xut hin.

p-Menthanes.- (i) Hydrocarbons . Cc bin th ca p-menthadienes vi axit hoc baz theo iu kin khc nhau, c bit n t nhiu nm, nhng theo 20

nhng thng tin gn y , cng vi gp nht t cc ti liu tham kho , c tm thy trong mt bi bo ca Bates [ 75] v cng s cng tho lun v cc iu kin cn thit trnh thm ha qu mc ti p-cymene (103) . Nhng bt n nh ca chui pha isopropenyl so vi chui bo ha pha isopropyl lin tc c phn nh trong s lng cc phn ng ph tng thm , c bit s mt cn i nh hng , c th xy ra khi cc cht dn xut menthadiene c ch bin vi cc cht phn ng c tnh axit . Mt trong nhng v d mi nht l m t ca Kergomard et al v cng s v mt s gii thch v ng hc ca s axeto ha ca carveyl ete. Khi trans-p- menth-1(7)-en-2-y1ethyl ether (99) c x l bng vt ca axit percloric trong axit axetic, sn phm chnh d kin l phellandryl acetate (chy) , nhng trans-p-mentha-1(7),8-dien-2-1ethyl ether (101) di cng iu kin thu c 40% carvenone (102) v 30% p-cymene (103) , 1 du vt ca inter- mediate mentha-1(7),4(8)-dien-2-~1ethyl ether (104) cng c nhn dng [76]

21

T mentha-1,3,8-triene(107) c phn lp t rau mi ty, v nghi ng mt phn trch nhim v mi ca nh my, n c tng hp trong hai phng th nghim nhng trong thc t, c mi, mc d gi nh mi ty, Kh nng ca vt liu t nhin [79] . mt vn lm sch bt ngun t thc t l khi hnh thnh do nhit phn ca acetat (105) hoc (106) lun cho trine (107 ) trn vi cc ng phn (108 ) v (109) (Cc phng php c s dng bi Birch v Subba Rao dn n mt hn hp tng t ) hn hp ny yu cu sc k trn 2 ct khc nhau c c cht tinh khit . Mentha-1,5,8-triene (110) c m t ln th ba Hai n phm trc khng c n.r.m h tr cho cu trc

22

S oxi ha ca limonene (111) bi selen dioxit c nghin cu trong 3 th nghim , s dng dung mi hydroxy , sn phm ch yu l mentha- 1,8- dien-4-ol (112).[79,83,84] C th chp nhn vi kt qu khi oxi ha carvone (117) t selen dioxit , cng cho ra sn phm chnh l hp cht 4- hydroxy( 118) , vi s mt i ca i xng quang hc ( i xng bn tay ) C4 [88], c ch lm pht sinh cc cht i quang th yu trans-cameol (113) v mentha-1,8dien-10-ol c xc nh xy ra theo cc ca mt este selenite allylic. Cc phn ng rt ph thuc vo dung mi , nu thc hin trong anhydrite axetic , nh trong v d ny , sn phm 23

chnh l menthe 1,8 dien-10-yl acetate (119).[79,89] n cng xut hin trong t nhin trong du v ca citrus unshu , cam Valencia v citrus junos [86]

Cc sn phm ca qu trnh oxi hoa peracid cng c kim nh li . Wilde v Teulon a ch ra cch tt nht iu ch cis hoc tran- limonene 1,2 epoxides , mt hn hp ca chng thu c bng cch trc tip oxi ha peracid trong dung mi clo hidrocacbon , cho hn hp tc dng vi hidro clo trong ete , khi hai diaxal chlorohydrins (122) v (123) c to thnh m khng c ng phn quang hc . y , 2 ng phn (122) chuyn thnh mt p-nitrobenzoate, to iu kin chng ct (123) , cho Nitrobenzoate ca (122) tc dng vi methanolic potassium hydroxide dn ti cis epoxide (120) , lm tng t vi (123) s thu c trans epoxides (121)[ 91] . Nhng limonene epoxides hu dng khc l (124) v (125) c th to ra trc tip t limonene bi 1 phn ng ca hidrocacbon vi hidro peroxides trong s c mt ca benzonitril , [92] . Qu trnh u tin c thc hin bi Payne .[ 93] Mc d nng sut nh , sn phm to ra c ln benzonitril v 1,2-epoxides , trn thc t n vn l phng php tng hp 24

mt bc a ra sn phm c th d dng tch c bng cch chng ct lm cho n tr thnh con ng hu ch oxi ha menthanes trong nhm isopropyl . Phn ng ca limonene -1,2-epoxides , hoc tinh khit[ 91] hoc nh mt hn hp [94] ,vi bases nh aluminum alkoxides [95] , cho ru allylic c kim chng , v phn ng tng t vi propyl liti ca 1,2-epoxy-trans-pmenthane v menthane-2,3-epoxide (126), to ra (127) v (128) cng c tho lun .

S oxi ha allylic ca h thng menthadiene vn c quan tm , bi v tnh hu dng v mt kinh t c c mt phng php thc s r c c carvone t limonene. Mt trong nhng phng php hiu qu hn c m t gn y s dng phc crom trioxit-pyridine trong methylene chloride. Mt qu trnh oxi ha allylic khc c bo co trong lot bi ny s dng xc tc tristriphenylphosphinechlororhodium to ra carvotanacetone (1 33) v piperitone (134) m khng c i xng bn tay , c l l thng qua i xng khng gian (132) . [100]

25

Mt tc nhn oxi ha mi to ra oxi n c m t bi Murray v Kaplan

. Phosphite esters v zne cung cp cho hp cht ng tng t oxi n

kh nng phn

Qu trnh oxi ha ca P-cymene (103) thng cho carvacrol(139) c cha s lng khc nhau thymol (140) , nhng thallium trifluoroacetate trong trifluoroacetic acid li cho mt cht hu c cha thallium (137) , n c th c chuyn i bi Ch tetra-acetate tip theo bi triphenylphosphine vo carvacrol trifluoroacetate (138). Sodium hydroxide thy phn khi cho carvacrol (139) tinh khit mc cao , mc d ch t 39% sn lng .[102]

Cht quang ha xylene-sensitized c b sung vo hp cht cha hydroxylic ( nc hoc ru ) cho limonene c m t r hn bng cch 26

kropp . A 1.2 : 1 hn hp ca cis- v trans-fl-terpineol (142a,b; R = H) thu c khi chiu x mt dung dch nc khi c du vt ca xylen , hoc tng ng methyl ethers (142a,b; R = Me) khi dng dung mi l methanol . Mt du vt ca mentha1(7),8-diene (143) , v cng tm thy racemis limon mt cch rng ri . H tr tng cho rng phn ng i qua carbonium ion (141) i xng .[103]

(ii) Oxygenated p-Menthunes. Mt lot cc menthadien-l- v 2-ol c xc nh trong du cn ty ;iu ng ch l chng u l sn phm ca qu trnh quang oxi ha ca limon c cis- v trans- p-mentha-l(7),5-dien-2-0(144) dc pht hin t tinh du ca Cinnarnomurn japonicurn sieb v c gi l 'yabunikkeols' ( t tn ting nht ca loi cy ny ) nhng cha tm c cu trc n.m.r ca n. Mt trong nhng nim tin rng ri nht v cc hng v ca 7-oxygenated p-menthanes gn y ang c tho lun li . Mt trong nhng iu ng vng lu nht l tn ti hai oximes (syn v anti) ca perilla aldehyde (145) v ch c syn oxime l ngt . Acton ch ra rng trn thc t ch c 1 oxime ca perilla aldehyde ( v n l ngt ). [106] n c cho rng ging vi mi th l lin kt vi andehyt th l (146) trn thc t pht sinh t ht th l ai cp t dihydroaldehyde (147). Varo v Heinz ch ra loi hp cht trn khng n nh nh th no , a dihydroaldehyde (147) tinh khit vo mt sc k kh ba nh disproportionation cho tetrahydrocuminaldehyde (148) v cuminaldehyde t xy ra khi bay hi , h cho rng cc andehyt chnh t nhin trong th l ti c cha cc phn t dihydro (147) , cc dihydroandehyt (149) thay th trong ht ging ( n c thi gian lu cng trn hu ht cc g.l.c ct ng phn ca n (147) ) cng nh ru tng ng (150 ) .[107]

27

Mt aldehyde mi gn y c phn lp t du ca Rosa darnascena (Bungari du hoa hng), v th hin c menth-l-en-Pal, mt hn hp ca c hai diastereo-ng phn (152) v (153) hin din trong cc sn phm t nhin "Bi qu trnh oxy ha ca cc sn phm hydroboration (+)-limonene (111) (xem thm ref. [109], c hai c chun b, v mt lot cc dn xut lin quan n 9-oxy ha p-menthane l tng quan vi cc sn phm t nhin.[108]

28

Lp th ca phn ng khc nhau vi 2 - v 3-oxy ha p-menthanes c kimtra, trong mt s trng hp hu nh khng ln u tin. Sodium gim borohydride ca menthone (1 59, piperitone (1 34), piperitenone, v pulegone (1 54)[110] theo cc iu kin khc nhau c bo co lo methyl ha pulegone (154) a ra mt hn hp phc tp hn so vi suy ngh trc y, nhng khng. tt c cc sn phm c xc nh "quang lun chuyn phn tn v lng sc vng trn ca cc epoxit pulegone c trit tho lun '' Phn ng ca axetylen vi menthone (155) v carvomenthone (157) c hin th cung cp cho mi trng hp nh hn ca epimer c mt nhm trc hydroxy [57: 43 (1 56) trong trng hp ca menthone, 54: 46 (1 58) trong trng hp ca carvomenthone].[113]

Vic b sung cacben (t dimethyloxosulphonium methylide) carvone (130) n nng sut (159) c hin th lp th "4 trong ngha tng t nh phn ng b sung khc ca carvone.[114] Vic b sung ca brm carvone thy bromide sn lng xuyn carvone tribromide (1 Ma), tri qua mt cn bng t m vi bromide hydro trong axit acetic 0 C cung cp cho mt hn hp c cha 55% 29

cis-carvone tribromide (160b), n t m ch n lin quan n mt hydrohalide bt u loi b theo sau bi mt readdition hydrohalide-xc tc ca halogen, khng tin hnh mt-chloro-cht dn xut, v xy ra nhiu ln nhanh hn trong s hin din ca hydbromide hn so vi s hin din ca hydro clorua. "[115] Katsuhara tho lun v c ch opoxidation endocyclic / - xeton terpene khng bo ha v i n kt lun rng nguyn t oxy s stereoselectively gii thiu trong mt trng thi chuyn tip thun li nht lin quan n vic chng cho ln nhau n nh tt nht qu o. ng d on s hnh thnh ca lR, 4R, SR-menth4en-3-mt trong epoxide (161) t cc xeton khng bo ha, L6 mt d on rng sau c xc nhn.[117]

Mt s sp xp li bt ng xy ra khi palladium chloride (PdCl,) c php phn ng vi ally1 ru ca lot p-menthane trong s hin din ca carbon monoxide. n-Allylpalladium hp cht c hnh thnh, nhng sau 10 ngy, k t piperitol (l28) sp xp li 3,4,8-trihapto phc tp (162) thu c t pulegol (l63) sau 1 gi Menth-3-en-2-01 (127) dn n phc tp cng sau 9 ngy.[118] "Mt vng co th v (167) xy ra ti cng thi im vi s hnh thnh thng 30

thng ca menth-2-en-1-01 (164),[119] khi tt c cis-1-hydroxycarvomenthyl

Quang ca isopiperitenone (129) tit l mt phn ng mi. Isopiperitenone c v phi c trung gian trong s bc x ca verbenone (168),[120] Lz0 v n c chng minh rng n thc s l chuyn i nng sut 35-42% thnh 1,2-dimethyltricyclo [3,3,0,02 ~ 7] octan-6-mt (169) hexane. Trong methanol (170) cng thu c. Mt phn ng tng t c tm thy vi 4-isopiperitenoneacetoxy. "H thng chung hnh thnh tng t nh thu c t s bc x ca 31

carvone carvonecamphor lZ2 condensations ca xeton menthane khng bo ha vi ethyl acetate-aceto c lm r.[122] Carvone (130) phn ng vi s c mt ca mt lng nh cc c s nhit phng cung cp cho cc ester bicyclic (171), trong khi nng cao hn c s v 80 "C, C-thay th bicyclo [3,3, l] nonanone (1 72 ) c hnh thnh [123] trc y l tng ng vi mt y-pyran ngm nc ca cc loi (173) thu c trong cc phn ng xc tc clorua km pulegone (1 54) vi ethyl.[125]

Sp xp li ether 2-methylbutadienyl (174) carveol c kim tra xem nh th no n nay phn ng kp [UIA (175) (176) J xy ra vi gi lp th. N c bo co rng ch ether cis ca carveol phn ng, v l lp lun rng trong khi mt nhm isopropenyl xch o ti C-4

32

thc thi mt cu thuyn gi vo trung gian, cc ether xuyn s c lin kt vi mt cu gh gi s mang li cho cc proton trc C-4 khng thun li gn vi cc phn khc ca cc phn t tri qua s sp xp sigmatropic. [126]Trong mt nghin cu m rng cc nh my ca Gaillardia v Heleniurn loi, Bohlmann v cc ng nghip phn lp c mt s lng ln cc monoterpenoids b oxy ha cao, 33

hu ht trong s h c bt ngun trc tip t thymol bi qu trnh oxy ha ti mt hoc nhiu ca cc nhm methyl thit b u cui. [127,128] hp cht ca cc loi (181) cng c bo co trong Doronicum austriacurn Jacq. [129] Trong s cc hp cht (177) (1 83)], c l cui cng l th v nht, v Bohlmann bo co mt synthe sis ca ether methyl [128].

m-Menthane Mc d t lu ngi ta tin rng cc m-menthane xut hin mt cch t nhin l cc tp cht sinh ra t -carene, Bardyshev et al. (+)-mmenth-5-en-8-ol (184) c tch ra t vic un nng phn on nhit cao (tch nh cc thnh phn) du thng ca Nga, , m loi du ny cng c cha carene.[130]

34

o-Menthanes Cu trc ca carquejol(185), l cc cht bit t rt lu ca nhm, c sa i v c ngnh ha hc lp th chnh thc xc lp, v cng c h tr nghin cu c lp. Cc loi ru v xeton ng phn khc nhau trong cc chui o-menthane (tng ng vi menthol-tinh du bc h, v menthone) c m t.[132,133,134] Ngi ta ch ra rng nhit phn verbenene (186) s to ra mt o-menthatriene (188) cng vi nhiu hydrocacbon khc, c bit (189) l t vic phn on diradical (187)[135] m c to thnh t ban u

35

Cc cy Baccharis genistelloide, m carquejol c ly t , khng phi l loi Baccharis duy nht sn sinh c o-menthane. Bohlmann v Zdero tch 2 loi ete (190) t cy Baccharis timera.[136] Cc Tetramethylcyclohexane Dn xut 1,1,2,3-Tetramethylcyclohexane, hay cc pyronene, c th c c t vic nhit phn -pinene, v l i tng chnh ca mt lot cc xut bn t Balan, trong bn mi nht c cp ti hydroclo ha -pyronene sau hnh thnh hai hp cht (192) v (193).[137] Phn ng ca nhng hydrochloride ny c tho lun trong

Ete Karahana (196) c tch t cy hoa bia t Nht bn, [138] cng l mt dn xut 1,1,2,3-tetra-methylcyclohexane(C7H14), c tng hp bi Coates v Melvin theo mt phng php m h cho rng c th ging vi phn ng ha sinh gen sinh vt.[139] S tng hp cc cht ny bao gm vic ng mch vng geranyl acetate (194) vi benzoyl peroxit vi s tham gia ca mui ng v hydro ha hn hp thu c vi sn phm l cn diol (cn c 2 nhm hydroxin trong mi phn t) tng ng, t cis-diol (195) (c 2 nguyn t cng pha) c tch v bin i sang ether (hp cht c 2 nhm hidrocacbua lin kt vi nhau bi 1 nguyn t oxi) vi p-toluenesulphonyl chlorit()trong piridin (C5H5N) nhit phng.

36

T r ca Ferulu hispanica, Bohlmann v Zdero tch mt dn xut 1,1,2,5tetramethylcyclohexane, c th l 4-hydroxy-1,1,5-trimethyl-2 formylcyclohexa 25 diene, cc ester ca siu axit v axit -acetoxymethyl-cis-crotonic acid (197) v (198).[141] Cc Cycloheptane

Karahanaenone(200) c tng hp t linalool (16). Bromohydrin thu c t phn ng gia linalool vi N-bromosuccinimide (ng mch vng trong qu trnh phn ng) thng qua vic trng ct hi lu nha furan (199) trong collidine, xy ra vic mt i hydro bromua v ti sp xp li thnh cycloheptenone t vic t nng sn phm th.[142]

37

Hai sn phm mi (202) v (203) c tch ra t vic xem xt li ng phn quang hc ca eucarvone(201). Mt trong s ,(203) chuyn sang dehydrocamphor(204),do xp xp li nh nng lng quang hc.[143]

4. Cc Monotecpen 2 vng Bicyclo [3,2,0] heptan. Chng ta ngh rng filifolone (207) c th c to ra bi thm dimetylxeten vo vng t methylcyclopentadiene (205), nhng n c chng minh l phn ng ny ch yu cung cp cho hai ng phn (206a) v (206b), vi mt lng nh cha xc nh sn phm.[144] i vi vic chuyn i ca cc b khung pinen sang filifolone. xem di y. Bicyclo [3,1, O] hexanes[145,146] 38

Cc lp th ca cc dn xut thujane vn cn c tho lun v mt danh php sa i c xut. S pht hin ra 2-thujene (209) (cn c gi l alphathujene) c th d dng c to ra t xc tc K0Bu'-DMSO ng phn ca Sabinene (208). Cc boran ca Sabinene (208) v 2 thujene- xc nhn v n ch ra rng cc xc tc axit hydrat ha cc cht ny khng lin quan n ion cc loi, phn ng c phn ln chi phi bi hiu ng m rng phm vi hn l bi s sp xp cc phn t trong khng gian . [148] Mt hn hp ca cis-v trans-sabinene hydrat [(210A) v (210b)] c thc hin t sabinene bi cc qu trnh oxymercuration-demercuration.[149] y l phng php hiu qu u tin to ra ng phn cis-, trc phn ng Grignard ch yu l to ra cc ng phn khc.

Chuyn i thujone c sn d dng (211) sang 3-thujene (212) c thc hin theo hai th nghim. Nhit phn ca cc mui natri ca p toluenesulphonylhydrazone-thujone dn n t l 1: 1 ca hn hp d tip cn hn 2-thujene (210) v 3-thujene (212). [150] Baldwi v Krauss tng sn lng bng cch x l cng p toluenesulphonylhydrazone vi natri trong dung dch acetamide. Trong phn ng ny 97% cc hydrocacbon thu c, 80% trong s c 3-thujene v 20% l y-terpinene (213) [151]. "Phng php th hai c li th l khng sn xut 2-thujene, cht cc k kh tch ra khi thujene-3. 39

Hai phng php tng hp v c bn ging ht nhau v bn cht ca xeton Sabina (214), t hai th nghim khc nhau c m t, sau y l con ng th hin trong n [7] v s dng mt s b sung -ketocarbene-olefin ni phn t trong bc cui. [152,153]

Phn ng ca umbellulone (215) vi bromosuccinimide-N c kim tra,[154] LS4 Umbellulone b cn tr bi mt xeton v Wheeler v Chung ch ra rng trong khi sn lng lithium hirua nhm trong hn hp te d kin ca hai umbellulols (216) v (217) , mt nucleophile cng knh ging nh hydride trit-butoxyaluminium lithium kh lin kt i c (218).[155]

40

Bicyclo (2,2,] l heptanes. S ng gp tng hp th v nht i vi lnh vc ny ca monoterpenes c l l sinh hc di truyn' tng hp camphor (222) bi Money et al.[156]( +)Dihydrocarvone (219) c chuyn i thnh mt hn hp ca acetat enol (220) v (221) v iu tr ca mt trong nhng [(220)] vi trifluoride bo trong camphor lm sn lng methylene chloride (222) cao ;tuy nhin , n c tnh trit quang racemic .Cc acetate enol khc (221) cng cho carvenone (102) theo cc iu kin ny (223) v verbanone oxime (224)] [157] v ngoi ca halogenua aminoalkylmagnesium camphors khc nhau thay th. N lc gn y tng hp terpenoid c hot tnh dc bao gm vic kh cc sn phm sp xp li Beckmann [t epicamphoroxime][158]

41

Vic kh Clemmensen ca oxocamphor-6 (225), ngoi vic cung cp thng tin v cc c ch kh Clemmensen ca 1,3-diketones, dn n mt isocamphanone cu-hydroxy ha th v (226) c th c mt nhm exo-methyl, thng qua cc con ng c nu ra [159].

Mt s dn xut 7,7-dimethylnorbornane hin nay d dng tip cn bng camphenilone (227). Cc giai on ca qu trnh tng hp di nh l hn hp hydrocarbon c th hin trong hnh8, nhng cc kh khn chnh l vic tch apobornene (228) t cc hydrocarbon tricyclene (229), chngkhng phi l tch 42

bng cch chng ct hoc bng sc k trn ct ngm nitrat bc. Hydroboration cho cc organoborane (230) t apobornene, cho php cc hydrocarbon khc s c ct i. Apobornene sau c th c phc hi bng oxymercuration (thy ngn trong axit axetic acetate) tip theo bng deoxymercuration (lithium chloride trong dimethylformamide 50 C), hoc organoborane c th c chuyn i thnh apocamphor (231) v cc cht khc bng cc k thut thng thng[160]

Bicyclo (3,1,1) heptan. B khung pinane, theo quan im c sn v nhng pinan, thng l ch ca rt nhiu nghin cu. Gn y, s tnh ton ca my tnh cng s gip ca phng php gradient to c cu trc hnh hc l tng ca mt s dn xut apopinan (6,6-dimethylbicyclo-[3,1,1] heptan) c kt hp vi nng lng nh nht. Do kt qu m ngi c nn tham kho t ti liu gc, nhng 43

cng lu rng nhng tnh ton rt tn km khi mi ln s dng trn my tnh, v do tc ng vi cc phn t khc khng cha mt phng i xng nh apopinan(C, i xng), vn lm tng s phc tp. V mt sinh hc, tm ra rng mt s phn phn on ca du thng kch thch s tng hp ca caroten trong Bfakeslea tripora, tecpen bicyclic (c bit l nhng pinan v camphen) nhng khng c tecpen n vng.[162] Cc pinan ( -v -) c xy dng li t b khung axt pinic. Diethyl pinate (232) c th c chuyn i sang mt hn hp ca acyloins [v d nh (233)] do ngng t acyloin thng thng. Vic kh nhm Lithium hydride cho ptoluenesulphonates ca cc acyloin ny a ra mt hn hp ca ru, do hn hp ca xeton c th thu c bi qu trnh oxy ha vi oxit cromic trong axeton. Mt trong nhng xeton, nopinone (234), tch ra bng cch kt tinh phn on ca semicarbazone, c chuyn i thnh -hoc -pinen.[163]

S chun b 8-pinen c thc hin n gin theo phng php Shapiro, tc l phn ng toluenesulphonylhydrazone ca pinocamphone (235) vi lithiumbutin.[165] 44

Kropp lm mt nghin cu cn thn cc bc x trc tip vi pinen(237) cung cp cho mt hn hp ca cis- v trans-ocimenes (238) v (239)khng b lm bn bi [166] p-menthadien.

S t oxi ha quang ha ca -pinen trong s c mt ca cc anhydrid axetic c kim tra, v tm thy mt s phn ng phc tp. Oxy ha khng kh ca -pinen(237) c xc tc bi oxit cromic, tuy nhin, cho varbenone (240) hiu sut 30%, ci m c th d dng tch khi t cc nguyn liu ban u v cc sn phm.[168] S cng hp gc ha hc vo -pinen c nghin cu trong 2 phng th nghim. Gaiffe v Castanet tm thy rng vic b sung cc aldehyt khi c mt di-t-butyl peoxit dn n cu trc menth-1-ene; vng m cng c tm thy trong phn ng chnh ca Claisse, Davies, v Parfitt, ngoi tr trong trng hp cc thiol xy ra bn ngoi cc lin kt i. Cc phn ng ca Coxon c cp trong cc diu kin khc nhau, cng nh vi cc phn ng xy ra ban u 45

ti lin kt i ca -pinen (241), c bit l phn ng vi ixt lu hunh. C hai hydrocacbon v epoxit ca n cung cp cho cc sulphite cyclic (242), ri sp xp li to thnh dn xut ca myrtenol (243). Cc sulfit vng xut pht t pinen, mt khc, phi tri qua qu trnh m vng cung cp hp cht cho menthan. Hnh dng v tnh cht ha hc ca ru (243) v aldehit tng ng tng l ch ca cc lun n, v (-) axit-cis-permyrtanic (244) c m t l mt peracid hot ng quang hc rt thch hp cho tng hp bt i xng.[172] Cc dn xut xi ho pinen, cc quang ph N.M.R ca pinanol [2 hydroxypinanes, (245)] c tho lun bi Coxon, cc thuc tnh quang ph ca cc 3-hydroxypinan [(246) pinocampheols] c m t bi Teissire.

Bessiere-Chrttien[174] v Bras ch ra rng vic m vng phn ng ca pinane-epoxit (247; R = Me) thnh aldehit campholenic (248; R = Me) c tin hnh song song vi cc phn ng tng ng ca epoxit apopinene (247; R = H) thnh aldehyt apocampholenic (248; R = H), nhng orthodene epoxit l (249) phn ng khc nhau, phn ng chim u th vi km bromua c ng phn ha cho 46

ra cc ketone (250), c chuyn thnh, n nh hn ng phn nhit ng (251).[176] Mt phn ng bt ng trong lot orthodene l hydroboration ca ru (252), trong xy ra ti cui thay th nhiu hn cc lin kt i cung cp cho (253).[177]

Mt s phn ng ca nopinone (234) [179] c bo co. Coxon et al. xem xt cc phn ng Brom ha v dehydrobrom , do h hy vng lm ra bo co pin-3-en-2-one (254), nhng thy rng n khng phi l mt phn ng d dng nh suy ngh trc y. Bessiere-Chrttien v Meklati thc hin ng phn (255) v (256) ca pinocarvones v myrtenal t nopinone (234). Nhit phn nopinone (234) to ra mt hn hp ca mt chui xeton mch h [(257), 39%], mt cyclohexanone [(258), 27%], mt [cyclopentanone (259), cis 47

14% v 8% trans ], vi 11% cc hp cht khng xc nh, tt c cc cht c bt ngun t hai gc(260).[180] Verbenone epoxit (261) vi hydrogen peroxide kim tri qua qu trnh oxy ha mnh hn na thu c axit pinonomic (262), * cc c ch c Temple tho lun. Phn ng ca epoxit verbenone vi xc tc clorua nhm to ra (263) v sau p-mentha-1, 4 (8)-dien-2-01-3-one (264) cng c trnh by.[183]

Erman bo co v phn ng tip theo ca chrysanthenone (265); axit axetic 60C n cho filifolone (266) vi mt s vng m [(267) v (264)] km theo s sp xp. Cui cng, hai hp cht chim u th sau khi phn ng ko di vi trifluoride bo, khi mt s thymol v bicyclo khc [4,2,0] octan (268)[184] cng c to thnh. Xc tc baz phn ct, mt khc, cc kt qu trong vic hnh thnh cc axit (269) v (270) cho thy t l ph thuc vo cc iu kin ban u.[185]

48

S chun b ca nopadiene (272) t nopol (271)[186] v sp xp li khp vng Diels-Alder chnh n (273) cho ra dn xut fenchyl (274) v (275) di nh hng ca kh hydro bromide trong benzen 25 C.[187]

ng vng (276) t -pinen (241) tri qua qu trnh acrolein v cyclisation vi xc tc axit cho 6-isopropyltetralin v cc diol ba vng (277), sau ny thng hay s dng cc nng axit thp.[188] Cc enamines ca pinocamphone (278) 49

v verbanone (280) c th c alkyl ho, v khi methyl vinyl xeton c s dng, sn phm l mt xeton ba vng [v d: (279), t pinocamphone]

Bicyclo [4,1, O] heptanes. Qu trnh epoxit ha ca car-3-ene (281) xy ra t pha ca phn t i din vi cu cyclopropane, v thay th - epoxit (283) lun lun l kh khn hn c c. Hai th nghim to ra n tng i n gin, bng cch s dng Nbromosuccinimide hnh thnh bromohydrin (282) m sau c x l

[190,191] S phc tp ca qu trnh oxy ha oxit cromic ca car-3-ene c cp. Phn ng ca p-toluenesulphonylhydrazones vi cc hp cht organolithium c s dng to ra cis-car-4-ene (285) t carone tng ng (284), nu car5-one (286) c s dng, cc m-menthadiene (287) cng c s dng.[192] 50

N cng c sinh ra t qu trnh oxy ha bng selen ixt car-3-ene cho 42% diene oxabicyclic a thch (288), cng vi mt s carvacrol, carvone, v ,dimethylstyrene. Cc deamination ca caranamines khc nhau c tm thy vi hiu sut kh cao, trong trng hp ca 2- v 5-arnines, cc sn phm t cc ion tng ng cyclopropane carbonium kh n nh, nhng vi 4-amin (289) cho ra nhiu sn phm phc tp, bao gm c hai hp cht [ (290) v (291)] c hin th di y.[195] Vic b sung chloro-v cacben dichloro-ra xe xy ra t pha i din ca vng ca nhm dimethylcyclopropane, dn n vic hnh thnh 1-trans 4,4trimethyltricyc10 [5,1, 0,0 ~] octane (292).[196]

51

B sung methyl vinyl ketone cis-caran-4-mt c th tin hnh nh d kin mt cch tng t nh enamines ca pinocamphone.[197] 5. Furanoid v Pyranoid monoterpenoid Mt glycol mi, elsholtzidiol(293), c bo co t Esholtzia densa, Beuth. Qu trnh tng hp ca Perillene (295) c m t, i theo hng t 3furylmethanol (249) c nu Scheme 9.[199]

Bin th ca phn ng ng vng trong tng hp ca oxit hoa hng (299)[200] c m t bi Eschinazi[201] N bao gm s oxi ha cp lin kt i ca 52

citronelly axetat (296) vi axit perfomic, sau dng nhit ha hp cht axetyl sn xut axetat diene (298), ru tng ng ca n c tun hon theo chu k bi axit sunfuric. Oxit hoa hng v cc ete lin kt tun hon c th c m [(300) v (301)] vi NaNH3.

Mc d phn ng kh benzofuran-2-ones xy ra trong t nhin lin kt n terpenoid cao hn n mc m chng ging vi trimethyl-cyclohexan, chng c th xy ra nhiu hn lin kt ng ti nhng ionone v carotenoid.[202] Gn y n c tm ra,v d, dye-sensitised quang ha ca c inonol (302) v carotene(303) to ra dihydro-actinidiolide (304) v mt allene (305).[203] N 53

c tm thy trong mt s loi cy, v Demole et al. a ra danh sch cc ngun.[204]

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Phn III:Ti Liu Tham Kho

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61

Phn IV:Kt Lun

Trong s ng dng quan trng ca terpenoid trong i sng ca chng ta, cc monoterpen cng c s ng gp c trng khng nh trong . L thnh phn ch yu trong tinh du c tm thy trong hn 60 h thc vt, nhng monoterpen ch tp trung ch yu trong khong 10 h, do monoterpen cng l mt trong s nhng thnh phn quan trng trong ngnh hng liu. Khng nhng th, trong s monoterpen cn c nhiu cht c hot tnh sinh hc ng ch , c th k n nh p-menth-1-en-8-thiol c trong nc p v qu bi chm, hay campho t g cy Cinnamonum, hay menthol t menthapiperita Monoterpen ni ring, cng nh lp cht terpenoid ni chung lm a dng v phong ph thm ngun hp cht thin nhin mang li nhiu gi tr quan trng trong cuc sng. Trn y l bi vit ca chng em v Monotecpen, bi vit khng trnh khi nhng sai xt. Chng em rt mong c gio s cho kin bi vit ca chng em c hon thin hn. Chng em xin chn thnh cm n! 62

TRNG I HC BCH KHOA H NI VIN K THUT HA HC

B MN HA HU C

-------------------*------------------

TIU LUN
TI: CHNG 2: SESQUITERPENOIDS
GV : Nhm SV Thc Hin: Hng Dn
PGS. TS. Trn Thu Hng

MSSV

1. 2. 3. 4.

Nghim Xun Hng Nguyn Vn Minh Nguyn Vn Lm Ng Th Mn

20081 207 20081

63

758 20081 489 20081 717 Lp CN Hu C Ha Dc

K53

H ni, thng 11 nm 2011

MC LC
CHNG 2: SESQUITERPENOIDS ............................................................ 65 1. 2. 3. 4. 5. 6. Gii thiu. 65 Farnesane C15H32 66 Monocyclo -v Bicyclo-farnesanes Bisabolane, Curcumane 75 Caroten 78 Cadinane, Amorphane, Muurolane, Bulgarane, v cc hp cht dng 78 87 89 71

vng ca Sesquiterpenoids 7. 8. 9. 10. 11.

Santalane v Bergamotane

Cuparane, Thujopsane, Cedrane, Acorane, v Laurane Caryophyllane v Humulane Germacran 103 Elemane 114 97

64

12. 13. 14. 15.

Eremophilane, Valencane, Vetispiram, Tricyclovetivane, Guaiane 135 Aristolane, Aromadendrane, 140 Non-farnesyl Sesquiterpenoids 143

122

TI LIU THAM KHO ..............................................................................144

CHNG 2: SESQUITERPENOIDS
1. Gii thiu. Xt v mi gc th sesquiterpenoids vn l ti y thch thc ti tr v khe lo ca cc nh ha hc hu c.Thi gian qua chng ta c chng kin cc qu trnh tng hp xy dng cng thc mch cacbon cng nh cng thc ha hc lp th ca sesquiterpen. c bit vi phng php ng vng ni phn t olefin diazoxeton ca Fock v Finici [1] mang li nhiu tin trin mi. Secquiterpen c c bit ch v mt cc hot tnh sinh hc ca n trong lnh vc sinh tng hp. Secquiterpen c ly t cc ngun t nhin rt phong ph. ng ch nht phi k ti cc nghin cu ca Andersen v Yoshikoshi v du vetiver, ca Zavarin [2] trn cc hydrocarbon. Zvarin [3] s 65

dng phng php xc sut thng k tnh nh tnh v nh lng monoterpen, l mt phng php chng minh s tn ti ca n trong thc vt. Trong thc t, trng hp khng c cht ch th xc nh trc tip c th s dng k thut ny p dng cho mt s nhm secquiterpen. Cc nghin cu ca Geissman, Herz, v Mabry trn sesquiterpenoids lactons tip tc cung cp nhng hiu bit c gi tr vo cc vn lien quan ti chemotaxonomy [4] Trong nghin cu ca Henderson v cc cng s [5], ng s dng k thut phn tch siu vi sinh v in t cng vi chp nh siu hin vi xc nh hm lng secquiterpen, kt qu ch ra rng lng secquiterpen trong cp l mm ca cy Pgostemon cablin nhiu gp 12 ln so vi cc b phn khc ca cy. Cui cng phi cp n s pht trin ngy cng mnh ca phng php nghin cu nh hng hiu ng ni phn t. N khng ch h tr gii thch v cu trc mch cacbon m cn gip xc nh c cu trc lp th ca secquiterpen. 2. Farnesane C15H32 Trans-Farnesene (1) l sn phm chnh ca phn ng hyr ca nerolidol v farnesol vi xc tc l axit hoc baz, cng c th ng phn ha trans, trans- -farnesene vi hiu sut cao di tc dng ca roi clo tri hyrat [7], ng phn ca farnesene l thnh phn cu thnh nn nha ca to Granny Smith [8].

66

Kh nng quang ha ca Trans-Farnesene (1) c kim chng bng cch chiu x trc tip tia x ln hai ng phn bicyclo [2,1,1] hexan dn xut tng ng (3a) v (3b). Khi chiu x trc tip h pht hin ra hn hp ng phn phc tp hn ko ch gm 2 dn xut tng ng (3a),(3b) m cn gm c cyclobutene (4).White v Gupta chiu x ln bicyclo [3,2,0] heptane (5) (bo ha Me ti 0,72) th thy rng khng h c du vt ca cis-/-bergamotene(6) (xem di y). Tuy vy, Courtney v McDonald phn lp c mt mu hydrocarbon khng tinh khit m h cho rng c th thu c cis- B-bergamotene (6) trn c s N.M.R(bo ha Me ).

Cc este angelate khng bo ha (7) c phn lp t guatemuliensis Brichellia. Theo bo co ca Thomas, ngi p dng phng php ClaisenCope phn ng gia 1 diene ete v ru allylic tng hp cc -sinensal (8) hay phn ng ca ru allylic (9) vi 1-ethoxy -2-methylbuta-1,3-dien (10). Trost nghin cu gii thch cu trc, phng php phn lp, phng php tng hp hoocmon Juvenile t loi bm tm khng l Hyalophorace. 67

Ngoi 6 phng php tng hp trn cn c 3 phng php na c bo co. Cavil s dng mt cch tng hp n gin l tng hp methyl 10,l l-epoxy3,7,1l -trimethyl-2,6-dodecadienoatei, dung mi s dng l keto-acetonide (12,R =

Me) Van Tamelen v McCormick, trong mt cch tip cn hon ton khc, xy dng cc 6,7: 10, l ldiepoxide ca farnesol thnh ru tris-allylic (13). Bo v 68

nhm chc hydroxyl, chuyn i tng ng vi bis-allylic clorua, v sau tc dng vi liti ng dimethyl to ra triene te trityl (14) l mt hn hp ca bn ng phn hnh hc .

Loi b cc nhm bo v, xy dng cc nhm carbomethoxy cn thit, chit tch v hon thnh vic tng hp hormone juvenile (11). Mt phng php tng hp lp th mang tnh chn lc c Johnson v cc ng nghip s dng trong tng hp hormone juvenile, h dng ketal olefinic trong phn ng Claisen, phn ng ny cho hiu sut kh ln. Cc estehydroxy (15) phn ng vi cc olefinketal (16) trong mi trng axit to thnh este (17).Phn ng ngng t Claisen gia (17) v ru allylic vi xc tc l Natri borohydride to ra este-trienol (18). Tip tc phn ng th SN vi Clo sau tch Clo to thnh triene-este(19) v chuyn i thnh hormone juvenile(11).

69

Trong mt nghin cu sau ca h v phng php Claisen-Cope Thomas s dng phng php ny trong tng hp torreyal v dendrolasin.Sn phm phn ng ca furylmethanol-3 vi l-ethoxy-2-methylbuta-1 ,3-diene l ete (20), khi em nhit phn ete ny thu c aldehyde (21). Tin hnh phn ng tch loi vi clo allylic to ra torreyal (22, R = CHO) sau c chuyn i sang dendrolasin (22, R=Me).

(22, R = Me) 70

Trong mt tng hp thay th ca dendrolasin, Parker v Johnson s dng sp xp c chn lc i vi cyclopropylcarbinol (23) do t c chuyn ha vi hiu sut gp i to thnh bromide homoallylic (24). Chuyn i ca nhm-Brom vo mt nhm aldehydo, sau l thc hin phn ng Witting vi isopropylidenetriphenylphosphor to ra dendrolasin (22, R = Me).

Vic tng hp davanone (25) i t cht u l linalylacetate. Cc cng thc ng phn lp th tuyt i ca sesquiterpenoid n (-)-ngaione (26) c xc nh nh sau:

3. Monocyclo -v Bicyclo-farnesanes 'Cht chuyn ha C', xut pht t s chuyn ha ca acid (+)-abscisic c trong mng chua, xc nh c cu trc (27) v methyl ha sp xp li cc nhm methyl to ra este ca axit phaseic (28).

71

Vomifoliol (29) gn y c phn lp t RauwolJia uomitoria. Hai tng hp ca cc format-enol khc, v d nh luciferin Latia (30), l cht in hnh trong h thng luciferase ca loai c nc ngt cng c bo co, c hai s dng nguyn liu u l dihydro--ionone.. Cc allenic keto-diol (31), mt loi thuc chng kin tit ca chu chu ln, Rornalea microptera, gn nh chc chn khng phi l mt sesquiterpenoid nh ngha thc s t tn ca n. Ngun gc cu n c xc nh bi s suy thoi ca 1 sc t allenic nh neoxanthin(32) hoc fucoxanthin (33). C hai nh ha hc Meiwald v Weedon cng cc ng nghip ca h tng hp hp cht ny bng cch s dng cng mt phng php xy dng b khung v cc nhm chc nng. Nh vy, c hai phng php tng hp trn, ngoi s tham gia ca cc hp cht c lithi hoc c Magie cng vi s pht sinh ca but-3-yn-2-ol n mt nhm chc nng ph hp vi 2,2,6trimethylcyclohexanone sau hnh thnh cc allenic moiety bng cch kh bng lithium nhm hydride.

72

Hai th cu trc (34) hoc (35) c xc nh c ngun gc t nm Collybia maculata. Caparrapi oxit (36), cc sesquiterpenoid tng t ca monoterpene tng ng v oxit diterpene ( oxit v manoyl oxit tng ng), cng c ng phn ha. Mt s hp cht khc nh Cyclonerodiol (37) cng sinh t nerolidol c phn lp t cc loi nm Tricothecium. Oxit-diol tng ng

(38) ng xy ra trong cc loi nm.

73

Hon thnh chi tit bng cch c lp v xc nh cu trc ca su bicyclofamesanes lin quan cht ch thu c t fragrans Cinnamosma c c published, viz., cinnamolide (39), cinnamosmolide (40), cinnamodial (41), bemarivolide (42), bemadienolide (43), v fragrolide (44). Cinnamodial (41) v ugandensolide (45) cng c phn lp t ugandensis Wurburgia, mt loi m cng tm thy hai loi eremophilane (xem di y).

74

Vic ng vng tng i hiu qu ca acid monocyclofarnesic vi botrifluorideetherate to thnh methyl bicyclofarnesate (46) dn n mt tng hp thnh cng ca drimenin (48) qua vic lacton ha vi xc tc axit ca ru allylic (47), mt sn phm khc ca phn ng cng vi Oxi nguyn t to thnh (46). N cng c a ra rng vic hydride gim drimenin n diol allylic (49) tip theo l mt qu trnh oxy ha hai bc thu c cinnamolide (39) vi hiu sut cao. Mt cht chuyn ha khng nm mc C16 c xc nh c cu trc (50). Trong h thng, hp cht ny c th c xem nh l mt bicyclofarnesane khi thm mt nguyn t carbon hoc nhiu hn, hp cht ny c coi nh l mt diterpenoid b suy thoi.

4. Bisabolane, Curcumane Mt s bisabolane sesquiterpenes, gm c B-bisabolene (51), [34] isobisabolene (52), [35]v cryptomerion (53) [36] c con ngi tng hp v iu ch. Cu trc ca cryptomerion (54) c xc nh phn ln bng phng php n.m.r.spectra. [37] Trong mt khong thi gian ngn sau n lt nuciferal(55)

75

c xc nh bi Buchi and Wust. [38] Cng mt s nh khoa hc tng hp c bisabolane (56) t (+)-carvone [39] Hai hp cht mi ca juvenile hormone, juvabione (57a) [13b] c tng hp thnh cng. Cht u tin l [40] R-( +)-limonene t disiamyl- borane kt hp vi hai nguyn t oxi ca hai ancol (58a) v (58b), sn phm c tch ra khi hn hp bng phng php kt tinh phn vi dinitrobenzoat v em i thy phn. Cc ru c tch ri ra khi cho phn ng vi isobutyl-lithium khi c mt ca cc xeton cha C bt i xng. Tin hnh phn ng oxi ha ta c (+)juvabione (57a) v ( + )-epijuvabione (57b) tng ng.
O

(51) OH

(52) H O

(53) O

O OH CHO (54) (55) (56)

Mt s phn ng ca chuyn ha S-( - )-limonene thnh (- ) -juvabione v (-)-epijuvabione.

R R H R H O H

CO2Me

OH (a) R = (b) R = (58) Me Me

(a)R= Me (b)R= Me (57)

(a) R = Me (b) R = Me (59)

76

Phng php th hai da trn s hot ng ca axit ca phn ng DielsAlder (60) thay bng nhm th 4-cyclohexenone (61). Hn na qu trnh tng hp v chit tch bng phng php sc k cho ta cc este ( s n ng khng gian ca iso butylic khng c). Cht c cho phn ng vi Caxi trong mi trng ammoniac sau tin hnh oxi ha ta c ng phn quang hot.
OMe H H

O O (60) (61)

CO2Me

(62)

Gi thuyt mi c cng b mi nht l tng hp c sesquicarene (63) c ngun gc t nhin. V bn cht , tt c cc qu trnh tng hp ph thuc vo cc nhm th ca mch carbene-olefm, c th l (64, R = Me), [42,43] (64, R = H), [44] v (65). Ch nhng hp cht [35-45] c tng hp mi tn ti ng phn dng Trans. Gn y. Corey v Achiwa [47] nhn thy rng mui iot ca thy ca (65) (i.e. ngn khng ch l xc tc ca phn ng phn hy mui diazo

cispans) m cn tng gp i kh nng hnh thnh cu dng Trans,Trans ca (65). Nh vy, hin nay sesquicarene bn trn th trng c tng hp t farnesol (trans,trans : cis,truns, 1.5:1) vi t l chim khong 35%.

H N2 H O (63) (64) (65) R N2

77

Phn ng diazo c p dng trong qu trnh tng hp sirenin

(66,

R' = R2 = CH2OH ), cc ng ht dich c sn xut bng khun t Allornyces. Nhiu thit b hin i xc nh u cui ca allylic hydroxyl chc nng c s dng, nhng dn gin nht l chuyn dioxide-ethanol oxidation 51 ca este (66;R' =C02Me, R2 = Me) bng aldehydo-este CHO) khng c ng phn ca cis-isomer.
H O H , R R (67) CH(Me).NH3.Br O.(CO).

(66; R' = C02Me, R2 =

(66)

5. Caroten My phn tch X-quang [52] ca daucyl D, L-alaninate hydrobromide (67) khng nh cc cu hnh tng i trong daucol v cc dn xut ca carotol v daucene. 6. Cadinane, Amorphane, Muurolane, Bulgarane, v cc hp cht dng vng ca Sesquiterpenoids Vi nhng ng phn lp th c cu hnh tuyt i nh (+)--vlangene (68, i t trisubstituted olefin) xy dng nn tng v hiu bit v ha lp th ca nhng hp cht c lien quan, mt chng trnh nghin cu hot tnh sinh hc ca sesquiterpene c xut. 54-57 tt c c s lc trong ti 1. Cc kin ca cc nh nghin cu ca mt cation (70) c to r t mt cation (69) bng cch thay i 1,3 hydro. V vy cation (69) c th, ln lt, chuyn sang cc

78

dng t cis, trans farnesyl pyrophosphate v nerolidyl pyrophosphate. Hn th na c th gii thch c s tn ti ca copaane, ylangane v cubebane.

(69)

(70)

H Bulgarane

H Muulane

H Amorphane

H Cadinane

H H

H H Copaane H Cubebane Ylangane (68)

Gi thuyt 1

C hai

u c

bit n qua con ng tng hp (73,R = Et, ng phn quang hot) v (73, R =Me, racemic). 79

(-)- 2- Cadinene l mt v d ca nhm cht Cadinenes c s quay phn cc trong du cy vetiver pha bc n .
H H H

RO H (71) H (72)

H (73)

Cu trc v lp th ca Chiloscyphone (74) c xc nh v ph O.r.d v c.d cho thy ph hp vi khung steroid. 60 i t Taiwania cryptomerioides, ba hp cht muurolance thuc lp sesquiterpenoids c phn lp 61 viz, (75), (76), v(77).
OH H HO H O H OH OH H

H (75)

H (76)

H (77)

(74)

Mt trong nhng tinh du c trong du cy Reuion vetiver xc nh c cu trc (i). Trc ngi ta bit n nh zizanene, hp cht ny trong thc t ( + ) - amorphehe v bin th ca n c th tn ti di dng hp cht ca (70). Trong iu kin c nh sng , cc cht c ngun gc t nhin vi s c mt ca laevojuneol l sn phm c lien quan qu trnh chuyn ha t (i) (iii) ( cht quang hot fi - Ylangene) (iv) (v) (ii) Theo thong tin ca Gio s N.H.Andersen.

80

H (I)

H OH (II) (III)

H (IV) (V)

Theo ng phn lp th tuyt i ca lp cht sesquiterpenoids, Ohloff v Pawlak 6 thu c cc diol (75) trong sn phm ca catalysedrearrangement ca (-)--copaene epoxide (78) trong acit long . Ngoi diol ny, sn phm co 19% v 44% ca hai hp cht (79) v (80). Vi diol (75), qu trnh Oxi ha v loi nc cho ta sn phm l enone (81) [tng t qu trnh Oxh ha allylic cho ta sn phm l (79) c Ohta v Hirose[54] Oxi ha (-)--muurolene bng t-butyl chromate. Nhng pht hin ny chng minh cc hp cht i quang ca sterone c s chuyn ha vi nhau. Cui cng, sau nhiu ln tho lun cho ta cu trc ca (-)-torreyol (-cadiol) c gii quyt nh (82) l mt dang ca muurolol. [63]

81

H O H (78) O H

HO

HO

H (79) H

H (80) OH

H (81)

H (82)

Ba ng phn ha hc ca cubebane c tm thy l hp cht dng vng cyclopropane l mt hp cht mui diazoketone ca cyclopropane ln u tin c tng hp, et Yoshikoshi s dng (-)-Trans-caran-2-1 l nguyn liu u chuyn ha ba dng thnh Spiro-lactone(83). Pyrolytic c th chuyn ha cc acid-olefin (84) vi hiu sut khong 70%. S chuyn ha cc mui diazoketone, sau khi phn ng cho sn phm l cc xetone dng vng ba canh (85, R = O) v steroisomer ca n(86).

O O

CO2H

R H (85)

(83)

(84)

82

H (86)

H (87)

HO

H (88)

Qu trnh chuyn ha cc ketone (85, R = O) thnh -cubebene (86), cubebene (85, R=CH2 ) v cubebol (88). Piers v cc ng nghip tng hp thnh cng cubebene (85, R = CH2) thng qua qu trnh dehydro cc dn xut ca acid-olefin (84) (c hai dng hp cht ca isopropyl) i t menthone racemic v isomenthone. Cc phng php tng t cng c cc cng nhn n tm ra, tuy nhin sn phm tn ti dng hn hp ca stereoisomers [63]. Copacamphene (89), mc d c tm thy trong t nhin [i t Copaborneol (xem sau)], c tng hp theo phng php ca McMurry [67] hin nay ang c s dung, nh l mt bc quan trng, vic ph v cu ni C-O ca epoxit cisdecalone(90) thnh tricyclicketol(91). Qu trnh loi nc cho ta sn phm chnh ca Keto-olefin (92), trong Lithium hidrua nhm, Hydro mi sinh, v qu trnh Oxi ha, cho ta hn hp sn phm ca xetone epimeric (93).

83

OH

O (89)

H (90) (91) O

(92)

(93)

(94)

C nhm ca Zavarin v McMurry [67] c cc cng trnh nghin cu v cyclosativene synthesisof (95) t isomerisation ca sativene (94) vi acetate cupric trong acid acetic. Trong cng mt iu kin c s chuyn dich cn bng gia longicyclene v longifolene. ng phn th ba, isosativene (96), cng c mt trong hn hp trng thi cn bng. Phng php tng hp Copacamphene, McMurry [67] cho phn ng vi cupric acetate- acid acetic v c sn phm l mt hn hp hydrocacbon trang thi cn bng nh vi sativene. Nh vy, cn bng sau y (Gi thuyt 2) c thit lp. Lu qu trnh chuyn ha gia (89) thnh (94) c lin quan ti s quay ca nhm isopropyl theo mt phng quay phn cc.

(89)

(94)

(95)

(96)

(Gi thuyt 2)

84

Cc cng thc ha hc v phng php tng hp Copaborneol (97) theo phng php ca Kolbe-Haugwitz v Westfelt. Cc mu cht sch thng mi ca santalol c chuyn i thnh mt hn hp ca syn v anti Ketoeste(98) v (99), trong ch c ng phn syn(98) c th thc hin theo phn ng Michael to ra tricycle-Keto-esters(100).
MeO2C HO O O

(97)

(98) MeO2C O

(99)

CO2Me

(100)

S thay th mt nhm methyl bng mt nhm methoxycarbonyl v qu trnh phn ng ca hn hp Keto vi Natri trong mi trng ru cho ta sn phm l Copaborneol (97). Gn y, hai cp i quang ca hp cht (101, R=CH2OH [71,72] and R=CO2H [73] ), cc dn xut ca cycloCopacamphene, c phn lp t tinh du c Vetiver.
R H (101)

85

Mt s nh gi dc l v v ng ca cc sesquiterpenoid, picrotoxin tutin, Coriamyrtin l do cu trc ca cc nhm th nh vo khung ca cc lp cht. Cc hot tnh sinh hc ca Coriamytin (102, R=H) [74] v tutin (102, R=OH) [75,76] c tm thy trong men bia ca v

trong cc cy ca mt nh my Coriuriu japonica. Cc kt qu t sn phm phn hy phng x ph hp vi mt gi thuyt trc l s ct t cc lin kt bng qu trnh oxi ha ca khung ba vng nh Copaborneol (97).
O O O OC OH
(97) (102) OH O O HO O O O C OH HO O O C O O OH OH OH

(103)

(104)

Cn ch , hai nhm methyl ca nhm th iso-propenyl u c c nh, do bc b gi thuyt hnh thnh lin kt i ca nhm th iso-propenyl. Gn y, cc hp cht ca lp cht picrotoxin c phn lp nhiu hn t Hyaenunche globosa, c th l pre-toxin(103) v lambicin(104), v nhng hp cht tng t nhu Capenicin [77] . 86

7. Santalane v Bergamotane Cch tng hp n gin santalol (105) l i t aldehyde m trc c Corey v cc cng s tm thy vi tn l (106) . Trong gi thuyt mi v phn ng ca Witing (i) ethylidenetripheylphosphorane, (ii) n-butyl-lithium, v (iii) paraformaldehyde] cho ta cc ng phn cis- theo gi thuyt. Nhm nghin cu ca Erman tip tc pht trin cch tng hp ca santalols, l vic tng hp 8-santalol (107) t methylnorcamphor-3. Trc y, cc con ng cho ta mu sch ca cc ng phn dng trans- c coi l ng phn c ngun gc t nhin. Vic s dng cc mui borat esteres l nhm th bo v trong phn dihyro--santalol [80] nh gi thuyt 3. (Lu cc mui borat este bn trong mi trng acid khan hoc mi trng dung mi tr, nhng d thy phn trong mi trng nc).
CHO OH

(105)

(106)

(107)

OH

O Br

O
3

O via borater ester Ph3=CH2 OH (108) OH

(Gi thuyt 3) 87

Nh vy, vic tng hp (-)--cis-bergamotene v (+)--cis-bergamotene (110) c trnh by y trong mt bi bo [81] Cc hp cht chnh l Olefinic iodides (111,R=CH2I), c nhiu con ng tng hp i t (-)--pinene Sau khi thc hin chui phn ng ca mui iot cho nhm mtehtyl-pentenyl c sn phm l mt aldehyde [111,R=(CH2)2CHO]. So snh vi ph chun cho ta thy ng phn (109) trng vi ph ca -bergamotene c trong t nhin. Mt khc, (110) c ph khng trng vi -bergamotene trong t nhin, cn phi xen xt xc nh cu trc lp th ca (112).

(109) R

(110)

(111)

(112)

Theo mt s th nghim [82] cho thy qu trnh sinh tng hp khng sinh Fumagillin(113) c xc nh l c ngun gc t nhin sesquiterpenoid kt hp vi v acetic acid, kt hp s tt hn khi kt hp vi meva-lonic acid. Theo cng b, hai aciad acetic phng x c a vo phn t hon chnh (tc l trong hai phn t Terpenoid v polyketide) nhng mc khc nhau, mt hin tng m trc y c bit n. Ch mt phn Terpenoid c nh vi mavalonic acid phng x, v ozonolysis cho ta acetone vi mt phn ba tng s phng x. 88

OH O H

OMe O C(O) [CH=CH]4 CO2H (113) O (114)

Mt ht ging ny mn, cht kch thch rau dip, graphinone, c phn lp t nm Graphiurn c thnh lp t(114) [83]. Hp cht ny tng t nh Ovalicin, phn lp t Pseudeurotiurn. [84] 8. Cuparane, Thujopsane, Cedrane, Acorane, v Laurane Mt phng php tng hp -cuparenone (115) c cng b, trong ethyl p-tolylacetate c chuyn thnh hydroxyl-vinyl chloride(116) theo ba bc.

Xc tc ca phn ng l acid-catalysed c cho trc tip vi -cuparenone. Mt iu th v l qu trnh sinh tng hp cc sc t da, Heli-cobasidin(117, R = OH) v congener ca c th (117, R = H) v (118) c to ra thng qua thc n c cha nm. Cc t l 3H: mavalonic acid lactone (3H: 14C, 3:3) vi cc nc c s dng
14

C trong cc hp cht(117, R = H),(118), v Leuco-acetate

(119)( Ngun gc t Helicobasidin) tng ng l 2.2:3, 3.3:3, v 1.85:3. Trn c s v tr ca ba nguyn t Hydro c trong cu trc phn t (tc l lin kt i), kt qur ny cho ta thy s ng vng ca cyclopentane. Trong trng hp ny, gi 89

thuyt cho rng cuparane sesquiterpenesas c ngun gc t -bisabolene , nhng c th l cc cation c lin h cht ch vi nhau, trong c th xy ra qu trnh hydride. Cc v tr ca hai hydrogens trong cc hp cht ny ang c rt nhiu ngi ch .

Cch th ba tng hp Thujopsene (120,R = Me) c cng b, trong phn hy mui diazoketone ca (121) mt ln na chng minh l cc stepin rt quan trng trong tng hp. Qu trnh Oxi ha cc hp cht ca Thujopsenes [88] v Thujopsenol (120 R = CH2OH ) [89] tng ng vi s lng ca Thujopsadiene [90] (122, R = CH2 ) v Mayurone (122, R = O), cng vi mt s sn phm khc. Sau khi tm thy hai hp cht c tm thy trong t nhin, qu trnh tng hp trong phng th nghim ging vi qu trnh sinh tng hp trong c th sng.

Hai cng b mi nht v tng hp -cedrene (123) v Cedrol (124). C hai u c miu t trong sinh tng hp, v l dng bn nht ca cc cation (125), v nh th, tri qua qu trnh chuyn t acid-catalysed cyclisa-tion thnh -cedrene. Hai cch tng hp to nn cc cation khc nhau nhng cng din ra ng thi tao ra sn phm chnh l spiro-dienone (126, R = Me [91] v R = Et [92]). Trong Crall v Lawton [92] thnh cng trong vic tng hp t acid-fomic ca ru 90

(127), Corey v cc ng nghip [91] qu trnh tng hp t cc diol(128) cng cho ra sn phm l -cedrene, mc d vi hiu sut thp hn. Mc d vy [91], cc endiol (129) c kh nng chuyn ha thnh -cedrene c hiu sut cao hn so vi vic s dng fomic-acid, gim lng nhit v lng lithium-ethylamine ca cc phn ng vi diene (130) tip theo. Cui cng, Cedrol (124) thu c bng boron tri-fluoride phn ng vi enol-acetate (130), methyl-lithium l xc tc c s dng tip theo trong phn ng.

Ngay sau khi c nhng thng tin y , ru (127), tn gi l -cedrene, c tm thy trong than ca cy Juniperus rigidu v Tomita v Hirose cng cho ()-cedrene (123) trong mi trng formic-acid vi hiu sut ln hn 90%. Tng t nh vi diene(132), -acoradiene, v sn phm l (-)-cedrene, cng c tm thy t mt loi cy. Sau , Hirose v cc cng s [94] phn lp thnh cng 91

bn sesquiterpene khc t loi cy trn. Bao gm -acoradiene (133), (134), -acoradiene (135), v acorenol (136). Nhng nh nghin cu cng b mt ru ba vng (137) v nu quan im ca mnh v khung mch chnh v cu trc lp th t cation(138). Andersen v Syrdalg [95] cng b phn lp thnh cng - v -alaskenes trong tinh du ca l Nootkatensis Chamaecypnris. Ngoi ra, cn hai diene, trn thc t, ging vi - v -acoradiene.

Theo mt s nh khoa hc c th phn lp sesquiterpenoids t qu trinh thy phn ca lacresin, s hnh thnh Laccifer Luca, xut hin. Bao gm shelloic acid (139, ) [96] jalaric acid (139, ),[96] epishelloic acid (139, ) [97] laksholic acid (139, 92

) [97] epilaksholic acid (139, lacci-shellolic acid (139,

) [97] ) [98] Nhng

), [98] epilaccishellolic acid (139,

), [98] v laccijalaric acid (139,

hp cht c nhm aldehyde c coi l sn phm ban u, v trong cc phn ng n c s dng lm nguyn liu cho phn ng Cannizzra ca ru v acid tng ng trong qu trnh trch ly.

Cc hp cht ha hc [99] v X-quang [100] ca laurinterol (140) c cng b. Ngoi laurinterol, debromolaurinterol v isolaurinterol (141) cng c tm thy trong cy Lnurencia intermedia Yamada. Aplysin (142), c phn lp t Aplysiu kurodai Baba, c th l sn phm ca laurinterol phn ng vi xc tc acid. Mt cng b mi y, qu trnh tng hp aplysin v debromoaplysin, i t ancol (143) c s dung [101]. Cc alaskene tn thng gi l acoradiene t alaskane (i) khc vi acorane (ii) c cu hnh tuyt i cha nhm methyl trong vng cyclopentane. Theo bo co ca gio s NH.Andersen.

93

Tng hp methyl ether ca debromolaurinterol c thc hin bng cch ng vng diazoketone. T rt nhiu to, Laurencia nipponicu Yamada phn lp c mt bromo-sesquiterpen mi c tn l Laurenisol (145, R = Br, R1 = OH) khi ng vng hp cht ny th cho ra Laurene (145, R = R1= H).

Thm nh li hot tinh sinh hc ca sesquiterpene tricothecane c tin hnh cn thn bi Hanson v ng nghip. S kt hp ca [2-14C-4R, 4-3H ] mevalonic acid Cc loi Tricothecium roseum v Trichuderma cho thy: (a) m ch c hai trong ba loi c th c kt hp c trong tricothecin 146 [, R2 = 0, R '=C(O)-CH: CH.Me] v trichodermol (146, R1=H2, R2=H) v (b) cc nguyn t triti c t C-2 v C-10. Hn na, trn c s trng hp nghin cu vi [1,1-3 H
2

,2-14C] v [2-3H2, 2-14C]-farnesyl pyrophosphates, cc tc gi kt lun rng cis,

trans-farnesyl pyrophosphate l mt ng phn thch hp cho sinh tng hp.Gn y, Nozoe v Machida phn lp c hai hp cht, trichodiol (147) v trichodiene (148) t Tricothecium roseum l chttrung gian ca sesquiterpene tricothecane 94

Nh trong cc n phm gn y cho thy rng hin nay nhiu c t polyoxygenated ca cc loi tricothecane c trong nhiu loi Fusariurn . Hai thng tin rt th v ca Hayashi v cng s trong bo co v s c lp v c cu gii thch r cc bazzanene (149,R=H) v bazzanenol (149,R = OH) t Bazzania pornpeanu (Lac.) Mitt, l 1 trong 2 i din mt ch mang tnh cht xng sng mi trong lnh vc sesquiterpene, v sinh tng hp. Hin nay,tuy vic xc nh cu trc da ch yu vo IR,NMRv bng ph khi lng, cng vi thc t l bazzanene cho ra cuparene (150) cho nng sut tt da trn phn ng dehydrogenation t palladium-charcoal. Thch hpcho vic nghin cu ny l cc s kin sau y: (a): -himachalene(151) xut hin ging nh cuparene nhit (480- 4900C)nhng khng phi trn phn ng kh selen hoc kh lu hunh v (b): -chamigrene-(152)dn n cuparene mt trong nhng sn phm dehydrogenation ca n.

95

S xut hin ca bicyclo [5,3,1] trong xng bazzanene c th yu cu phi chng thc thm. Chi tit hon chnh ca qu trnh tng hp quang ha trn cc -himachalene (151) bo co bi Mayo c hon thnh chi tit. Isolongifolene (1 53), mt sn phm do s chuyn v ca longifolene vi xc tc axit, l chi tit trong su bo co ca Dev v cng tc vin ca ng. Mt tng hp ca khun cht chuyn ha culmorin (154) c m t bi Roberts, Poonian, v Welch. iu c bn trong tng hp ny l diketone bicyclic (155) thu c nng sut cao t tetrahydroeucarvone theo tiu chun annelation. Qua su bc diketone ny c chuyn i sang ketodiester (156) c ng vng v decarboxylated n diketone ba vng (157). Barton v Werstiuk 'L9 trc chuyn i cc (-)-diketone (157) culmorin bi gim vi natri trong n-propanol. Hon tt cc chi tit cui cng ca qu trnh tng hp quang ha da trn cc -himachalene (151) c de Mayo bo co. Cc lin kt ha hc m rng vi isolongifolene (153), vi xc tc axit thu c sn phm sp xp li cu trc ca longifolene, l chi tit quan trng trong su vn ca Dev v cng tc vin ca mnh. Mt tng hp n gin ca loi cht chuyn ha culmorin (154) c m t bi Roberts, Poonian, v Welch.Cc vn xy dng c bn trong tng hp ny l dixeton bicyclic (155) thu c vi hiu xut nh nhau t tetrahydroeucarvone bng phng php ammelation tiu chun. Trong su bc ca phng php dixeton ny c chuyn ha sang cc xeto-dieste (156) c ng vng v decarboxyl ha n dixetone ba vng (157). Barton v Werstiuk trc bin i cc (-)-dixeton (157) thnh culmorin bng cch kh ha vi natri trong n-propanol.

96

9. Caryophyllane v Humulane Hnh nh cc cu trc ca hai trong bn sn phm ng phn ca caryophyllene c xc nh bng phn tch tia-X. y l 2 hp cht photocaryophyllene A (158, R =-Me) v photocaryophyllene D (158, R =-Me). Hai norsesquiterpenoids c kh ha l kobusone (159) v isokobusone (160), cng c phn lp.

Naya v Kotake, trong mt xt nghim du ca cy ht b Nht Bn, c lp c ba loi hp cht humulane, l., Humuladienone (161, R = Me), humulenone II (161, R = = CH2), v humulol (162), ngoi ra cn c diol 3 vng(163, R=OH), nhit si 2700C. Diol ny c tch theo 2 cch khc nhau: (a) Sutherland em x l humulene (164) vi N-bromosuccinimide trong 97

dung dch axeton- nc sau bin i cc sn phm bromohydrin (163, R = Br) thu c diol (163, R = OH), nhit si 205-206C, bng cch thy phn, (b) McKervey v Wright c c cng mt diol,nhit si 201-203C, do chuyn v vi xc tc axit (20% axit sulfuric) vi humulene epoxit-1,2 (165), mt sn phm t nhin c bit n. Trn c s ca nhng pht hin ny v thc t l c hai caryophyllene (166) v humulene c th c bt ngun t bromohydrin trn hai bc trong ng nghim, McKervey v Wright mc nhin cng nhn rng cu t chnh 1,2-epoxide c th tham gia vo cc qu trnh sinh tng hp ca caryophyllene v caryophyllene diol.

K t khi pht hin ra cc sesquiterpenoids dng illudane, mt s hp cht lin quan c phn lp, l., axt illudalic (167),[126] illudinine (168), [126] v dihydroilludin S (169, R= -OH). [127] Cc lp th tuyt i ca illudin S (169, R = O) c xc nh.[128] Mt phn tip theo ca qu trnh tng hp lp th thnh cng ca M illudin (170) c trnh by bi Matsumoto v cng s [129]. Trong diacetate (171, R = Ac), m trc c chun b trong tng hp u tin, c chn lc thy phn cho cc monoacetate (171, R = H).Hp cht ny c chuyn i trong ba bc to diacetate (172), trong , sau mt 98

qu trnh thy phn chn lc, qu trnh oxy ha Jones, v thy phn acetate, mang li illudin M (170).

Ba hp cht, coriolin (173, R1 = H, R2 = =O), coriolin B[173, R1 = C (O).(CH2)6.Me, R2 = OH],[131] v coriolin C [173, R1 =C(O).CH(OH).(CH2)5 Me, R2=O],[131] c lin quan n illudol (174)[132] c phn lp t vic trao i trong nc ca Corilusconsors. Kagawa v cng s trnh by mt con ng tng hp kt hp b

99

khung protoilludane trong cu trc ca illudol.

Tng hp ny c lin quan n s hnh thnh hai bc ca -acetoxyenone (175) t 2,7,7-trimethylbicyclo[3,3,0] octan-3-one m, ln lt, c thu thp t cc 2-carbomethoxy-4,4-dimethylcyclopentanone bit bi mt phng php annelation tiu chun.Phn tch cu hnh ca enone (175) trong s c mt ca 1,1-diethoxyethylene mang li nhng cis,anti,cisxeton ba vng (176).S iu chnh tun t ca hp cht ny vi bromide magi ethyl, metaperiodate natri, v alumina c bn cho cc di xetonenolte (177) m, s gim bt natri borohydride v qu trnh oxy ha Jones, mang li cc di xeton (178). Cui cng, mt s ngng t nghch o intramolecular cho cc xeton ba vng (179) ci m l mt tin cht tim nng ca illudol (l74).

100

Mt thch thc ca vic tng hp cc b khung phc tp v cc tnh cht ca methyl marasmate (180) c gii quyt bi de Mayo v cc ng nghip khi s dng khng t hn bn qu trnh quang ha ring bit. Cc xeton tetracyclic (181) c hnh thnh bi s kt hp quang ha ca cyclopentane-1 ,2-dione enol acetate vi Spiro [2,4] hept-5-ene. Qu trnh ny c chuyn i qua bn bc t enone (182) sau c sp xp li c cc xeton ba vng (183). Sau tip tc qu trnh oxy ha tetra-acetate, este ha, v loi b methanol thu c cc este-enone (184, R = H). Ngoi vic cng Oxy nguyn t vo hp cht ny, cn phi kh bng hydroperoxide to ra cc hydroxy enone-ester (184, R = OH), sau c photolysed vi s c mt ca vinylene cacbonat to thnh cacbonat ba vng km n nh (1 85). Kh, este ha, v tch nc s cho dieste (186) m trong , qua qu trnh phn hy quang ha ca s chuyn ha pyrazoline tng ng, cho cc hp cht pentacyclic (187). Periodate c ph ct bng glycol formed ri thy phn v sau decacboxyl ha cho (188) l 1 ng phn ca methyl marasmate .

101

102

10. Germacran 103

Germacrane l m t loi sesquiterpenoids , m t kha c nh ang lu y trong h p ch t nay l cu trc vng 10 cnh. Kha cnh ny trc c tho lun v hiu ng i n t xuyn vng (c ph uv di thng ) v nhng phn ng ha hc xuyn vong (sp xp li i nh v ong vong ta o ra hai loa i eudesmane ho c guaian ). Gn y, sc mnh ca hai k thut quang ph c s dng nghin cu v vn ny. Vic u tin l s dng Nuclear Overhauser Effect (Noe) [135] v th hai l phn tch tia X ca mt dn xu t thch hp. Bhacca v Fischer,[136] trong mt nghin cu ph c ng hng t ha t nhn ca dihydrotamaulipin-A acetate, trnh by bng chng v cu trc ca phn t (189) bng cch quan st ca NOEs gia nhm C 4 methyl v C-6 hydro (15%) v C-2 hydro (10%). Nhm C -10 methyl cng cho thy mt NOE vi C-2 hydro (15%). Nhng quan st ny ph hp vi c u truc phn t NOE a c s dng trong s gii thch c u truc cu (189), trong nhm methyl vinyl l syn v hai lin kt i ang trong mt hng.K thu t a furanosesquiterpenoids,

zeylanone (190), linderalactone (1 9 1), v isofurano-dienone (192) [137] . Cc hp cht chnh c tm ra b ng phng phap NOE sau nay c chi ra di y .

104

Nhng nghin cu gn y cng nhn l sesquiterpenoids germacrane nht nh c th tn ti trong nhiu hn mt cu trc. V vy, Yoshioka v Mabry [138] chng minh bng cc nghin cu ph cng hng t ht nhn rng isabelin tn ti trong hai dng cu trc vi t l 10: 7 ti nhit phng.Tng ng vi cng thc (193) v (194). Trong lin kt c mt iu th v ng lu rng bc x ca isabelin [139] ti 253,7nm a n quang ho ca isabelin(195), cc sn phm cua s ph i h p 2+2 cyclo c bi t th hi n trong c u truc phn t (194). Mt khc, s phn cc nh sng ca dihydroisabelin (196), m tn ti nh mt gia i phap cho c u truc nay , dn n ta o ra hai ng phn quang ho c (197) v (198).Sn phm (199) c tnh i xng di tc dng nhit m vong ta o ra dihydrophotoisabelin (197) ngoi ra sn phm (200) khng mong mu n cung c to thnh. 105

T mt nghin cu ph c ng hng t ha t nhn ph thuc vo nhit v quang ph c.d ca neo- linderalactone, Tori et al. [140] kt lun rng hp cht ny tn ti hai da ng c u truc (201) v (202) vi t l 8: 2 nhit phng. Vi cc iu kin cn tr th c s chuyn dch, E l khong 10kcal/mol c tinh ton t d liu nghin cu ph cng hng t ht nhn , trong khi bin nhit quan st dn n mt gi tr l 0,6 + 0,2 kcal/mol cho G gia (201) v (202). Tuy nhin, mt v d khc c cu trc khng thay i c ghi li bi Halsall et a l 106

[141]. ngi a tach c c u truc ca urospennal (203) bng phng phap sc k.Hai c u truc nay xu t hi n hai da ng khac nhau va c n inh bi lin k t hydro.

Phn tch tia X s n ph m c ng cua ba c nitrate va costunolide ch ra r rng r ng phn t t n ta i da ng c u truc (204) vi cc nhm methyl trong mt mi quan h syn v lin k t i vi tri th ng goc . B ng cach ny ngi ta cng tm c c u truc ca pregeijerene (205) phc ba c nitrate v dn xut kim loa i n ng ca elephantol (206) v shiromodiol (207). [143]

S to vng ca mu i axit t chay trans ,trans-farnesyl hoc s ng phn ha lin k t i ca cc cation (69) v (70) c th dn n cc cation (69a) v (70A) m t lu c noi n trong thuy t ngu n g c v s s ng cua sesquiterpene.K thut chit tach va s c ky m t cach c n th n hi n a chng minh c r ng co 4 ng phn ca germacratrienes c phn lp . S dng cc quy 107

trnh , Morikawa v Hiose [144] phn lp c germacrene-C* (208) t cc loi tri cy kh ca Kadsura japonica .Xt v khi l ng trong thuyt v s sng , germacrene-C s tng ln b-Elemen (209) v nhit v Selina-4 ,6-diene (2 10) v Selina-4 (14), 6 - diene (21 1) trn c t silicsgel ng . T nhng nghin cu trn v cc nghin cu khc na , Hirose et al.145 cng a phn l p c germacrene-D (212), ci m c ng phn ha bi nhit hoc silica gel dn n mt lot cc sn phm bao gm (+)-y-muurolene, (-)-a-amorphene, a- muurolene -, (+)-6cadinene, v (+)-y cadinene -, trong khi ng phn quang ho c cho (-)-bbourbonene (213) cng vi lng nh hn a- bourbonene-v P-copaene. Mt ng phn khac la germacrene -B (214), c phn lp t du ca hoa bia cng vi Selina-4 (14), 7 (11)-diene (215) v Selina-3,7 (1 lt)-diene (216) [146,147]. Cu i cng, bng phng phap sc k rt cn thn , m t ch t r t kho g p germacrene -A (217) c tm thy trong san h sng, Eunicea mummosa Lamouroux [148]. Germacrene A l quay tri , k t qua (+)-B-Elemen (21 8 ) nhi t phn , v ng xy ra vi (-)-Selina-4 (14), 11 (12)-diene (B-selinene) (219).Hai ng phn tng ng i l p hoan toan c phn lp sau t cc ngun trn mt t v n c d on rng cc mu trn mt t ca germacrene -A s la quay pha i.

108

T thn r ca cy tha ch xng b .., Iguchi et al [149] phn l p c preiso calamendiol (220) cng vi bn hp cht lin quan, shyobunone (221), epishyobunone (222), isoshyobunone (223), v isocalamendiol (224). Cc nghin cu cho th y ng phn xeton (225) l tin cht chung ca tt c nm ch t trn la c v h p l.

109

Hai kt qu ang ghi nh n thu c khi nhi t phn shiromodiol acetate (226) [150] v cac germacratriene epoxit (227) [151] C hai sa n ph m s p x p la i to ra, vi (228) v (229), v (230) v (231) tng ng, v (228) v (230) c th c c hnh thnh do qu trnh cp electron chuyn ng trong vng v th hi n trong via (232). Nhng bin i c th l d u hi u v ngun gc ca

carabrone (233).

110

Jain v McCloskey [152] tm thy rng axit la xuc tac cho s on g vong ca costu-nolide (234) trn c t nha trao i cation Amberlite cho m t l ng ln a (235) v p-cyclocostunolides (236). Hn na, ng nay cung cho thy r ng dihydrocostunolide (237) khng chi co hi n t ng sp xp li cac inh m c n l to hp cht hai vng nhit cao nh (238), (239), v (240). -

111

Hin nay, mt nhm ln cc lp cht furanosesquiterpenoids c bi t l c ng thi trong loi Linderu v Neolitseu. Takeda [6] a ra m t s lng rt y ca a dng ha hc v cc vn v quang ph trong lin k t cua cac h p ch t nay . C cu trc xc nh, vic s dng ca NOE gn y ng m t vai tr quan trng trong vi c gii thch r v cu trc , c bit l trong ki n th c ca ha l p th v hnh hc. Nhng b sung gn y vo ca nhom furanogermacranes c lit k trong Bng 1. M t s l ng germacranolides mi t nhiu ngun khc nhau ang gia tng vi mt t c ham mu v by gi a gi m t vi tri quan tro ng , v d c th c tm thy trong c t nht mt , nu khng thi nhi u hn , ca tt c 15 nguyn t carbon vi m t nguyn t oxy chc nng , t epoxit tao ete v lactones . Vi vi c m rng chung loai va a dng c u truc trong khung carbon n gia n, mt s hiu bit t t hn v tnh cht ha hc v c tinh quang ph t c iu ny, n lt n , cho php sa i mt s cu trc trc v s tng quan gia cc hp cht hin c, va c phn lp. Bng 2 l d anh mc b sung mi vo nhm ny 112

Hai k thut c m t h tr vic xc nh ha l sesquiterpenoid. Trong mt nghin cu ph

p th ca

a-methylene-y-lacton (241) thng gp c lin quan vi nhm ca lactones c ng hng t ha t nhn ca mt s hp cht nh t i nh (v d germacranolides, eudesmanolides, guaianolides vv) Samek [176] Kt lun rng ni chung, (a) Jab v Jac (khong 3,5 Hz) trong trans lactones l ln hn trong cis lactones (khong 1,5 Hz), v (b) JAC > 3 Hz >Jab. Nhng "quy tc", lm th no bao gi, khng th p dng cho n khi phn tch mt cch cht ch hn na ph c ng hng t ha t nhn ca ra . S dng mt cch tip cn khc nhau, Geissman et al [177] nghin cu o.r.d v quang ph c.d ca mt lot cc loi sesquiterpenoid c cha a-methylene-y- lacton co mau . Vi rt t ngoi l, cc quy tc sau y lin quan cc du hiu ca hiu ng cotton (chuyn i t n ->ii*, khong 255 nm.) c th xy dng c : cis-6 ,12-olides, tch cc; cis-8 ,12-olides, khng c d hi; truns-6, 12 - olides, tiu cc; trans-8 ,12olides, tch cc. Nhng kt qu ny v ca Suchy et al. 163 cho pyrazolines c du hi u, trong tng lai, h tr vic ki m tra c u trc l p th ca s hp vng y lacton trong cc hp cht mi c c lp, ngoi tr trong nhng trng hp phn t c cha hai vng lactone.

113

11.

Elemane

Cc nghin cu gn y v sp xp li cac inh c a germacrane thu c loa i sesquiterpenoids cng b mt s kt qu ang chu y phan ng cua cac ch t ny c tnh thun nghch v phn t c cu trc (cn ) trong vi c . Jain et al [179] v cng s chng minh o ngc trong ba phn t co c u truc tng t nhom ny v i costunolide v dn xu t c a n [242, R = CH, a- Me, v CH2 N (Me)2]. Mt khc, Takeda et al [6,180] v cc cng s khng ch quan st cc o ngc ca vic sp xp li cac inh nhng cng th y rng cc da ng l p th tng i ca furanoelemadienes co th thay i trong tng qua trinh . Nh vy, linderalactone (191) v te (246) c mi quan h v c u truc l p th nn co nhng phn ng hoa ho a gi ng nhau ta o ra isolin -deralactone (243) [181] v (246a) tng ng, trong khi diol (244) c chuyn thnh (245). Vi gi nh c bn ca m t phn t thay i inh cua c u truc da ng gh , vic kim tra cc c u truc phn t ca cc furanogerma-cradienes (191), (244), v (246) l ph hp vi nhng kt qu ny c u truc c a (191) l suy lun t d liu NOE), trang 831. C mt iu c n lu y vi c s p x p cc inh cua phn t o ngc ph thuc vo mt c u trc ca elemane (tc l t c mt trng thi chuyn tip da ng gh ) v trong bi cnh ny c bi t khng th quan sat chuy n i nghich ao cua (244) vo (245) gi ng vi mt nghin cu NOE ca diol (245) [6].

114

S o ngc ca Cope sp xp li ph thuc vo mt cu kinca i tc elemane (tc l t c mt trng thi chuyn tip bn gh) vtrong bi cnh ny n l th v rng khng th quan st o ngc chuyn i ca (244) vo (245) tng thch vi mt nghin cu Noe ca diol (245).[6]

115

L lun tng t cng c th c vin dn gii thch isomerisation ca (-)--elemenol (247) n (+)-epi--elemenol (249) thng qua trng thi trung gian germacratriene(248).[183]

Corey v BrogerlS4 cng b mt tng hp rt hay ca elemol (250) lin quan n, nh l bc quan trng, cc niken cacbonyl gy ra cyclisation ca este dibromic (251). Theo on trc cng vic ca Corey v ng nghip phn ng ny c th dn n s hnh thnh (252) hoc l (253), ngoi cc ng phn hnh hc khc v epimeric. Trong cng on ny, tuy nhin, cc sn phm chnh lng phn iso elemadiene (253, 7-CO2Me) v khng c ng phn trans, transcyclodeca-1,5 -diene (252) c hnh thnh. Cc este (253) sau c chuyn i sang elemol bng cch x lvi methylmagnesium bromic.

Terpenoids v Steroids

116

Trong khi xy ra t nhin sesquiterpenoids elemane thng b b nghi ng l to ra ca c lp, Kupchan v ng nghip, trong tm kim ca h cho cc tc nhn chng ung th, c lp ba dng kh i dilactones elemane, viz.,vernolepin (254,R=H),[185] vernomenin (255) [185] v vernodalin [254,R=C(O). C(CH2).CH20H] [169]. S hnh thnh cc hp cht ny t mt tin thn germacradien-14,15-olide trong thi gian cch ly dng nh khng hay cho lm, mc d khng phi khng th.

Cc ng phn selinadienes c phn lp v y l nhng cp trong vn bn theo s xut hin ca h hp tc vi cc loi sesquiterpene khc. (+)--Eudesmol (256) c c lp di hnh thc mt O--Larabinopyranoside [186], v axit vachanic c th hin c trng vi acid ilicic (257) [187] -Cyclopyrethrosin (258), mt trong nhng xc tc axit sn phm sp xp li cc germacranolidepyrethrosin, c phn lp t mt ngun t nhin[188]. Cc cu trc ca pulchellin B(259, R1 = Ac, R2 = H), pulchellin C (259, R1 = R2 = H), pulchellin E (259, R1 = H, R2 = Ac), v pulchellin F(259, R1= angeloyl,R2 = H) c sa i; [176b] trc chng c coi lguaianolides gi.[189] Sa i ny c thc y phn ln bi mt thc t l

117

Sesquiterpenoids

Hp cht C-8 cis-hp nht lactones ca cc loi eudesmanolide trong s c mt cc khp ni c bit gia cc proton C-7 v 2 proton C-13 exomethylene (ca.1-1.5Hz). Mt quan st th v c thc hin lin quan n photolability ca11,13-dihydro-6-santonins (260) [190]. C nhng epimers c photodecarboxylated u tng t cc dn xut cyclopropane (261).

Sau khi chuyn i thnh cng [191] ca calantolactone (262) v isoalantolactone (263) vo artemisin (264) thng qua cc xeto-este (265), Nakazaki v Naemura [192] tng hp (+)-xeto-esteny mt cch rt k lngca vic racemic ha hydroxy-enone ( 266) v n s chuyn ha tip theo, do vy em li tt c cc tng hp ca (264).

118

B sung gn y vo nhm eudesman-6,12-olide c a vo trong Bng

3. Bng 3 Endesman-6, 12olides Tn 9 4 4; 6 Colartin 4 1 1 -OH Khc 4-Me ; 3,4-epoxy; l-angeloyl Arbusculin- A Arbusculin-B Arbusculin-E 4-Me 4,5 11-CO2H (khng phi lactonised) 11-Me (tc l khng c nhm exomethylene) Artecalin Reynosin 3-xeto; 4-Me 4,14 195 196 119 194 194 194 194 Ch thch 193

Epoxysantamarine Ludovicin-A Ludovicin-B 3 Ludovicin-C

1 1 1; 1

3,4-epoxy; 4-Me 3,4-epoxy; 4-Me 4,14 3-xeto; 4,5

196

197 197

197

C vi v d lin quan loi eudesmane sesquiterpenes trong ci m c s hp nht vng l cis.Hortmann [198] gi rng nhng loi c th xut pht bi mt s gia nhit kncho php ca tin thn gi (267) cung cp cho (268) hoc (269). Cu trc ca sesquiterpene xut hin trong t nhin,occidentalol, c trn thc t, c hiu chnh li bi Hortmann v De Roos [199] ng h (268).Gn y, Tomita v Hirose [200] c lp occidenol (trc ygi l occidiol) t cy tng bchkoraiensis.Trn c s cc bng chng ph v t thc t l c(-)occidenol v (-)-elemol (250) cho cng hydroxyxeto-este (270) vo qu trnh oxy ha v este ha (ti C-5 c v xy ra trong trng hp ca occidenol), cc tc gi chuyn cu trc (271) n occidenol.H ngh mt biogenesis lin quan n divinyloxiran 4,5-dihydrooxepin sp xp li ca tin thn gi (272).

Tht th v khi lu rng ngun gc ca miscandenin (273) cng c xut xy ra thng qua s sp xp li ny.Mt kim tra ca mt m hnh phn t ca cc gi thuyttin cht (273a) ca miscandenin s ngh cu hnh ngc li ng ba vng tc l C-10 nhm methyl v hydro C-5 nu trng thi chuyn 120

tip thun li cho vic sp xp li ging dng na-gh, cf. linderalactone (191).Ngoi ra, nu trng thi chuyn tip thng gp l thuyn ging nh lp th ti cc ng ba vng ca miscandenin slcis vi C-10methylv C-5 hydro trong mt cu hnh Lp th sau m tm thy trong occidenol (271) nhng hp l trong trng hp bng cch s dng mt sai st tng t. [200]

Cu trc ca acetylenic norsesquiterpene chamaecynenol (274) c xut pht bi phn tch X-quan.[201]. Cc lp th ca nhm C4-hydroxy trong t nhin hydroxyisochamaecynone (275) c thnh lp nh l bi tng hp ton b.[202] Cnhng epime c tng hp t xeton acetylenic bit (276) (thu c t mantonin) trong mt chu trnh nm bc.
Mt trong cc cu trc ny thay th cho miscandenin s thch ng vi n.m.r quan st ph, lin lc c nhn t Gio s W. Herz.

T mt nghin cu ca n.m.r. v d liu i.r., cc nhm steroid c chuyn thnh hp cht ny (275).

121

12. Eremophilane, Valencane, Vetispiram, Tricyclovetivane, Nhng chng trnh t thc vt c mc nhin cng nhn vo h thng sesquiterpene c th chnh thc lin quan n mt loi tin cht eudesmane thng qua mt di chuyn1,2-methyl(xem hnh 4).V vy, b khung lp th a ra bi cc loi eremophilane (281) sesquiterpene c th c hp l v tin thn nh l cation ca (278), tm thy t (277). Bi mt l do tng t, lp valencane (283) c th c chnh thc bt ngun t cc cation (280) (tc l mt loi 4-epi, 10-epi-eudesmane) m c th, ln lt, pht sinh t cng mt tin cht cyclodeca-1,6-diene di hnh thc khc ca mu gh (279), trong cc nhm methyl ln nhau syn nhng chng li vi cc nhm isopropylol.Tuy nhin, mt s hp cht (xem sau) m tng t nh cc lp valencane theo ngha l chngmang nhm 4,5 methyl nhng c mt trung tm sp2 ti C-7.Do , n c th c lp lun rng cc hp cht ny c bt ngun t mt tin cht eudesmane hon ton i cc mc d iu ny c v kh kh xy ra. Ngoi nhng thay i 1,2-methyl, n c ngh [56,95,203,204] m C-9,10 c chuyn i trong cc cation (278) v (280) c th to ra cc hp cht spiro (282, tc l, hinesol) v (284) (xem sau).

122

Hnh 4
*Khng xut hin c bt k l do thuyt phc ti sao trong hai hnh thc gh i ca cation (69a) khng th c s dng c trong gi thuyt ny.

Eremophila mitchelli l mt ngun giu eremophilane sesquiterpenoids [205] khc nhau v chng c bit l by gi c th c thm vo cc dienone (285).[206] Ha hc ca eremophilane lin quan n sesquiterpenoid bakkenolide-A (286) c cng b.[207]

123

Cu trc (287) ban u c chuyn thnh eremophilene c chng minh l sai trn 1 s lng nhiu. Trong nhng ni u tin, Piers v Keziere [208] hon thnh mt tng hp khung c chn lc ca diene ny v chng minhkhng ging vi eremophilene t nhin.Trn c s ca n.m.r. v thc t l eremoligenol (288) c th mt nc to eremophilene, chng thay i cu trc (289) to thnh sesquiterpene ny. Coates v Shaw [209] xc nhn vic ny bng cch tng hp ca c khung chn lc eremophilene v eremoligenol. Nhng tng hp tp trung vo mt quy trnh mi xy dng cho vic loi b cc nhm xeto xeto-este (290).Qu trnh chuyn i ny c lin quan n cc te tng ng methoxymethyl enol v gim tip theo vi lithium trong amoniac lng mang este t n nh trc (291). X l cc hp cht ny vi lithium-methyl mang li eremoligenol (288) trong , ln lt, to ra eremophilene (289) trn s loi nc.S dng phng thc annelation isoxazolec pht trin bi Stork v ng nghip, Ohashi [210] bo co mt s tng hp mang tnh kinh t v trong khung chn lc ca dehydrofukinone (292), trong cc bc quan trng l chuyn iisoxazole (293) thnh diketone (294).

124

Brown v Thornson [211] ch ra bng cch tng hp m cu trc ca maturinone norsesquiterpenoid cn c sa i (295) ci m l trong hu ht thc vt c chp nhn nhiu hn.Lin quan n hp cht ny l cacalol (296) (mt dng eremophilane vi mt s di chuyn methyl) v decompostin (297).[212,213b]

Gn y furanoeremophilanes c lit k trong Bng 4.

Bng 4:
Tn i V Furanoeremophilanes-OR tr -OH ca lin kt Khc hi ch G

125

Adenostylone

1,10

6C(O).CHMe2 6C(O).CHMe2 6-angeloyl

9-xeto 13 9-xeto;10-H 13 9-xeto 13

Isoadenostylone Neoadenostylone Warburgina

1,2

1,10

1,2; 9,10

1; 10 9 6;

3xeto;11CO2Me 14

Euryopsol

15 10-H 16 10-H;6,14olide 17

Hu ht Warburgiadione [eremophila-l,9,7 (11)-triene-3,8-Dione].

Marshall v Ruden [218] c bo co tng hp khung chn lc ca nootkatone (298), trong cc xeto-este (299) l annelated vi trans-pent-3-en-2-one cung cp cho cc bicyclic xeto-este (300).Cc phn na ethylidene c chuyn i thnh nhm 7-acetylbi s epoxy ha, sp xp li xc tcacid, v cn bng c bn.Sau khibis-ketalisation ca dixto-este (301) nhm carbomethyoxy c chuyn vo nhm 5-methyl trong ba bc v mt phn ng Wittig tip theo mang li racemicnootkatone (298).

126

Mt tng hp trc ca nootkatone bi Odom v Pinder [219] c rt li. Chi tit y ca cc cht ha hc dn n vic sa i cu trc ca vetivone (302) c cng b[220]. N ch ra

[221] rng nardostachone l i din chnh xc (303).Cc estebicyclic (304) s dng bi Coates v Shaw [209] trong tng hp ca eremophilene v eremoligenol cng c p dng cho cc tng hp ca valencene (305) v valerianol (306) [222]. Nh vy, cn bng c bn cho cc ng phn iso n nh hn (307) m x l vi lithium-methyl to ra valerianolv trn qu trnh mt nc tip theo, valencene. Andersen v cng s [204] gn y c lp mt s hydrocacbon lin quan t du c vetiver, thm vo cc hp cht t thc vt khc c lin quan (xem sau). Chng bao gm nootkatene (308), -vetivenene (309), v -vetivenene (310).

127

34, 593.

S gii thch s c lp v cu trc ca cun tiu thuyt tetracyclic sesquiterpeneishwarane (311, R = H2) [223] v ishwarone (311, R = O), [224] thu c t r ca Aristofochia indica, c bo co bi Govindachari v cng s.T quan im sinh hc thc vt cc hp cht ny, m kt hp mt tricyclo [3,2,1,02,7] h thng vng octane, thuc v mt nhm valencane trong congeners ca h l

aristolochene (312). Mt trong nhng sn phm thoi ha ca isoishwarane, ishwarone (313), c tng hp [225] thng qua quang ha thm voca allene to enone (314) mang n xeton ba vng (315).Chuyn i ny cho 128

hydroxyketal (316) v xc tc axit aldolisationlito (317) tip theo l loi nc v thu gnWolff-Kishner mang li isoishwarane (313).

Gn y cc thng tin ca Andersen,Yoshikoshi v ng nghip cho thy trn thnh phn ca du c vetiver c ngun gc khc nhau c minh ha bi cc cch thc da trn cc c s c t trn cc khi nim sinh hc di truyn trn c s cch ly cc stereochemically c tnh ng nht ca cc hp cht lin quan gi l: "quy tc configurational - absolute ". C hai nhm cho thy s phn lp ca vetiselinenol v vetiselinene (319), (-)selina4(14),7(1l)-diene (320) v (-)--selinene (321). Klein and Rojahn cng tm thy (-)-selinad,11(12)-diene (322) v (+)-selina-3,l l(12)-diene (323) trong thnh phn du ca Dipterocarpus alatus Roxb. Lin quan n nhng iu ny v cc loi valencane l hai ng phn vetispiranes: -vetispirene (324) & vetispirene (325).

129

Trn c s ca c hai nghin cu tng hp v suy thoi, Marshall v cc ng nghip ch ra rng cu trc ca -vetivone da trn mt b khung bicycle [5,3,0] decan l khng c c s v tip theo vic quyt nh cu trc (326) kt hp mt b khung spiro[4,5] decane v iu ny h xc nhn c mt s tng hp phc tp. Phng php lm vic c gii thiu c chn lc ca mt nhm isopropylidene trong mt s cht tng bc cho thy h bt u vi cc xetonolefin (327), c ly qua photolysis ca cht gi l dienone(328). Cc cu trc lp th tuyt i ca hinesol (282), c thit lp vng chc bng mt tng hp r rng c lin quan n cc dienone ba vng (329) sinh ra t 6-methoxy-1-tetralone. X l cc dienone vi dimethylcopper lithium to ra mt hn hp ca syn v anti enones (330). Bng mt lot cc phn ng stereoselective hp cht ny c chuyn i cc diol (331) tri qua giai on gy ra mono mesylate ct khai to ra Spiro [4,5] -xeton (332). Loi xeton ca hinesol c tng hp bng cc con ng thng thng.

130

131

Lin quan n l thuyt sinh hc di truyn l s pht hin ra -rotunol (333), m ng thi xy ra vi -rotunol-(334), sinh ra dienone (335) khi mt nc. Dienone ny cng c th c to thnh t hinesol trong ba bc. Ramage cho rng hinesol (282) c th c coi nh l mt tin thn ca cc loi sesquiterpene zizaane [v d, (342)] bi cyclisation n cation trung gian (336) tip theo l mt s thay i Wagner-Meerwein vi cation ba vng (337). Bc cui cng tm ra mt tin l trong phng th nghim solvolysis mono mesylate (338) to ra cc xeton ba vng (339).

132

Mc d xut ny gii thch c cu tng v lp th tuyt i ca loi ny (ngoi tr c th c ca hydro C-4), cc lp th tuyt i ca cc vetispiranes l v d in hnh (324), (325) v (326) m hp xy ra vi cc loi zizaane trong du c vetiver, l, trong thc t, i cc vi cc i ca (+)-- vetivone thu c t hinesol (282). Nh vy c v nh khng chc rng hinesol t n c th c xem xt trong biogenesis ca loi sesquiterpene zizaane. Mt s lng ng k ca cc sesquiterpene ba vng gi y c phn lp t cc loi du c vetiver khc nhau. Cc danh php v carbon nh s ca cc hp cht ny gy ra phn no kh hiu, mt phn do cch ly c lp v t tn v mt phn l do cu trc trc (v do tn) tri qua nhng sa i. Hin nay, cc mi quan h sau y l ng: khusenol = tricyclovetivenol = khusimol tricyclovetivene = khusene = khusimene = zizaene zizanoic acid = khusimic acid Trong thc t c th c bin minh cho cc tn tricyclovetivane nh b khung hydrocarbon gc vi vic nh s v lp th nh trong hnh (340), tc l ph hp vi h thng nh s c chp nhn cho vng hp nht.

* Trong mt nghin cu ca cc hydrocacbon t du c vetiver RCunion, mt hp cht ca cu trc (ii) c c lp, gi tt l prezizaene. Zizaene (iii) c th 133

c pht hin trong cc isomerisation acidcatalysed ca prezizaene, c hai u l sn phm cui cng isomerised ba hydrocacbon mi. Cc biogenesis ca sesquiterpene loi zizaane c coi l lin quan n cyclisation ca (+)-curcumene (i) nh c hin th cng vi thng tin c nhn gio s N.H.Andersen.

Ngoi cc sesquiterpene khc c tm thy trong du c vetiver, Andersen v Yoshikoshi c lp c [tricyclovetiv-3(14)-en-6 xu-ol] zizanol (341). Cu trc ha lp th ca khusimol (tricyclovetiv-3(14)-en-15-ol) (342) c lm sang t bi phn tch tia X ca 1 nguyn t nng pht ra v isokhusimol [tricyclovetiv-7(15)-en-14-ol]) ch nh c cu trc (343).

Yoshikoshi cng bo co mt tng hp cc acid epizizanoic (344) bt u t carboxylate (+)-methylcamphene (345). Vic chuyn i cc aldehyde tng ng v aldolisation vi acetone cho enone (346), c chuyn i sang cc 134

diketone-cyano (347) trong hai bc, v sau n este

ba vng (348).

Osmylation n cisdiol, sp xp li cc mono mesylate xut pht t hai hp cht epimeric ( C-4) xeton (339) trn c s cn bng ko di. Tng hp c hon thnh bi mt phn ng Wittig trn epimer 4/3-H (nh cc mui natri).

13. Guaiane Hai phng php tng hp ra bulnesol racemic(349) hin nay c bo co. Trong mt stereochemical, cc tnh nng c kt hp trong b khung bicyclo [5,3,0] decan ca bulnesol v encouraged do kt qu ca nghin cu m hnh, Marshall v Partridge s dng mt cch thch hp vi functionalised bicyclo [4,3,l] Decan precursor (350), m trong qu trnh solvolysis, cho cc olefinacetate (351). Hp cht ny c chuyn i sang bulnesol thng qua o hm tng ng 7-carbomethoxy (epimerised). Mt khc, Kato s dng 1 h thng hp nht cis-fused decalin ph hp thay th (352) trn solvolysis cho cng 1 este (353) m Marhall v Ptridge chun b.

135

Trong mt cch tip cn vi cc b khung guaiane, Piers v Cheng chun b trc enone (355) v photolysis ca dienone (354). Mt n lin quan tm bc c s dng chuyn i (355) cho mt bulnesene (356), cc sn phm kh nc ca bulnesol.

Guaioxide (357, R = -Me) v liguloxide (357, R = -Me) c th hin trn epimeric ti C-4 v cc dn xut ca hp cht ny v cc cht lin quan c m t y . Kato tng hp ra kessane (359) vi hiu sut 30% bng cch solvolysis ha mesylate (358) [cf: solvolysis ca hp cht (352) trn].

136

Ourisson v ng nghip cng b chi tit y ca s c lp v gii thch r cu trc ca c hai -gurjenene (360) v seychellene (361, R = CH2). Seychellene, m chnh thc c th c bt ngun t cy hoc hng ru (362) ca mt di dn 1,2-methyl (chuyn v mt m c, nh c nu ra, khng c thnh cng thc hin trong phng th nghim), c tng hp bi hai nhm. Tng hp bo co ca Piers tham gia xy dng b khung ba vng ca mt s chuyn i lc ht nhn bn trong tosylate trong cis-decalone (363) mang n cho xeton (361, R = 0).

S tng hp ca cis-decalone l mt v d tuyt vi v iu khin v thao tc vi nhm chc nng stereoselective. Cc xeton (361, R = 0) c chuyn i thnh seychellene vi hiu sut 85% bng methyllithium v tip theo l s tch nc. Vic tng hp khc, bo co ca Schmalzl v Mirrington, bt u t bicyclo [2,2,2] c bn, h thng ch s octan (364) c nhm exo acety c chuyn i trong mt s bc to thnh mt s chui isobutylol pha ngoi. 137

Cc cu ethylene cng c thay th c sn phm cui cng l ruxeton (365). iu chnh cc tosylate tng ng vi triphenylmethide kali mang li cc xeton ba vng (361, R = 0) trc y bi Piers. Cc phng php ha hc gn lin vi s gii thch cu trc ca torilin (366) c xut bn. Cc hemiketal, isocurcumol (367), c c lp.

Trn phng din formolysis, cyperene epoxit (368) a n mt s sn phm, hai trong s l (369) v (370), sau ny c tng quan vi mt cedrene v xc nhn bng phn tch tia X. Mt khc, s iu chnh ca sn lng clorua (368) vi stannic hai xeton (371) v (372), sau c mt ln na khng nh bng phn tch tia-X .

138

Cc tc ng c hc ca nhng s sp xp th v cc nhm th c tho lun. Mt xeton lin quan n cyperotundone, c th l scariodione (373), c c lp. Hon thnh cc chi tit trong vic tng hp thnh cng desacetoxymatricarin (374, R = H) v achillin (374, R = -OAC) c bo co. Nhiu guaianolides mi c phn lp t cc nhm Compositae, chng c lit k trong Bng 5.

139

Cc v d c bo co trong vng A ca b khung pseudoguaianolide guaianolide hoc c kh sa i. Chng bao gm enhydrin (375), canambrin (376), parthemollin (377), xanthanol (378,R'=OH, R2=OAC), v isoxanthanol (378,R'=O, R2=OH). Herz gn y xc nh c mt s pseudoguaianolides lin quan t cc loi Hymenoxys trong mt qu trnh oxy ha trong c th loi Baeyer-Villiger din ra trong vng A. Chng bao gm psilotropin (floribundin) (379) v 11,13-dihydro ca n phi sinh thm (11 -Me) themoidin, anthemoidin (380), greenein (38 l), hymenolide (382), v hymenoxynin (383).

14. Aristolane, Aromadendrane, Vic tng hp cc sesquiterpens vi mt vng gem-dimethyl cyclopropane c xem xt vi iu kin trc l (384). Hp cht ny Bicyclogermacrene c phn lp t tinh du v Cam, qut, cng vi germacrene-B, -D. bi-cycloelemene (385) trc bi phn lp, l mt sn phm. Cc cuc tho lun cho thy rng:hai cht trng thi cn bng nhit nhng khi tng nhit ln khng th gi nguyn hnh dng cu trc ban u m b chuyn thnh ng phn khc: iso bicyclogermacrene (386). Dng axit lm xc tc to nn s hon v ca (384) s cho ra ledrene (387) v -cadinene. Xy ra ng thi vi Bicyclogermacrene l spatulenol (388) v Globulol.

140

Ramage et al [203] ch ra rng (Homo allylic) tham gia ca cc lin kt i trong vic di chuyn cc nhm hydroxy trong mt hp cht (ging nh 390) c th mang li s hnh thnh ca cc sesquiterpene-aristolene-(391).Mt lp khc ngoi aristolane l Debilone (392) v c th l The novel peroxide nordocsinone (393) c phn lp t Nardostachys chinensis thuc v nhm ny. Pernelle v Teisseire xy dng mt qui trnh 4 bc cho cc ng phn ca aristolene c 1(10) (391) (calarene) n cc cht him aristolene-9 (394).

141

Piers v cc ng nghip

bn bo co tng hp rt chi tit v

aristolone (395) lin quan n ng vng ni phn t ca cc iazoketone (396) bt ngun t 2,3 dimethy cyclohexanone. Rt ngn mt s bc. Cyclisation ny, n cho c hai aristolone (395) v 6,7-epi-compound (397). cc cu trc tng i lp th ca aristolone r rng Piers v cc cng s tng hp c cu trc lp th ca Decalone Racemic (398) iu ch t (-) aristolone bit.

Ton b chi tit tng hp ca antipode, aromadendrene (+) v cht ng phn i quang lin quan c bo co bi Buchi et al [286]. Vic ny xc lp cu trc lp th tng i v tuyt i ca aromadendrene (399), allo-aromadendrene (400), globulod(389),viridoflorol (401) v ledol (402).

142

15. Non-farnesyl Sesquiterpenoids y l cc sesquiterpenoids tng i him m khng th xut pht t mt tin cht farnesyl trc tip hoc gin tip c. v d ca nhm ny l furoventalene (403), the keto-lactone(404), phenol (405), v cu trc sa i ca humbertiol (406). Phng n xut cho cc Biogenetic schemes lin quan n s kt hp ca 1 monoterpene C10 (mch vng hoc khng vng) vi mt C5 (v d: Dimethylally pyrophosphate).

143

Cui cng, cho thy rng : mt hp cht sesquiterpene, Bilobalid A, phn lp t l Cy Bch Qu, c cc cu trc tng ng vi cc ginkgolides diterpenoid bt thng trng 1 trong cc vng lacton c loi b.

TI LIU THAM KHO

1 2

G. Stork and J. Ficini, J. Amer. Chem. SOC., 1961,83,4678. L. A. Smedman, E. Zavarin, and R. Teranishi, Phytochern., 1969,8,1457; L. A. Smedman,

K. Snajberk, E. Zavarin, and T. R. Mon, Phytochem., 1969, 8, 1471.

3 4

E. Zavarin, Phytochem., 1970,9, 1049. W. Herz, Recent Advances in Phytochemistry, ed. T. J. Mabry, Vol. 1, p. 229, North-

Holland Publishing Co., Amsterdam, 1968; T. A. Geissman and M. A. Irwin, Pure Appl. Chem., 1970, 21, 167; W. Herz, G. Anderson, S. Gibaja, and D. Raulais, Phytochem., 1969, 8, 877.
5 6 6a 7 8 9 10 11

W. Henderson, J. W. Hart, P. How, and J. Judge, Phyrochem., 1970,9, 1219. K. Takeda, Pure Appl. Chem., 1970,21, 181. W. Parker, J. S. Roberts. and R. Ramage, Quart. Rev., 1967, 21, 331. G. Brieger, T. J. Nestrick, and C. McKenna, J. Org. Chem., 1969,34, 3789. K. E. Murray, Austral. J. Chem., 1969, 22, 197. J. D. White and D. N. Gupta, Tetrahedron, 1969,2!5, 3331. J. L. Courtney and S. McDonald, Austral. J. Chem., 1969, 22, 241 1. F. Bohlmann and C. Zdero, Tetrahedron Letters, 1969, 5109.

144

145

126 127 128

M. S. R. Nair, H. Takeshita, T. C. McMorris, v M. Anchel, J. Org. Chem., 1969,34, 240. A. Ichihara, H. Shirahama, v T. Matsumoto, Tetrahedron Letters, 1969, 3965. N. Harada v K. Nakanishi, Chem. Comm., 1970, 310.

146

129

T. Matsumoto, H. Shirahama, A. Ichihara, H. Shin, S. Kagawa, v F. Sakan,Tetrahedron Letters, 1970, 1171 .

130

S. Takahashi, H. linuma, T. Takita, K. Maeda, v H. Umezawa, Teiruhedron Letters, 1969, 4663.

131

S. Takahashi, H. Iinuma, T.Takita, K. Maeda, v H. Umezawa, Terruhedron Letters, 1970, 1637.

132 133

T. C. McMorris, M. S . R. Nair, v M. Anchel, J. Amer. Chem. SOC., 1967,89,4562. S. Kagawa, S. Matsumoto, S. Nishida, S. Yu, J. Morita, A. Ichihara, H. Shirahama, F. A. L. Anet va A. J. R., Bourn, J. Amer. Chem. SOC., 1965,87, 5250. N. S. Bhacca va N. H. Fischer, Chem. Comm., 1969, 68. H. Hikino, C. Konno, T. Takemoto, K. Tori, M. Ohtsuru, and I. Horibe, Chem.

v T. Matsumoto, Tetrahedron Letters, 1969, 3913.

135 136 137

Comm.,1969,662.
138 139 140 141

H. Yoshioka and T. J. Mabry, Tetrahedron, 1969, 25,4767. H. Yoshioka, T. J. Mabry, and A. Higo, J. Amer. Chem. Sac., 1970,92,923. K. Tori, I. Horibe, K. Kuriyama, and K. Takeda, Chem. Comm., 1970,957. R. K. Bentley, J.G.St.C. Buchanan, T. G. Halsall, and V. Thaller, Chem. Comm.,

1970,435.
145 146 147 148

K. Yoshihara. Y. Ohta, T. Sakai, and Y. Hirose, Tetrahedron Letters.1969, 2263. R. D. Hartley and C. H. Fawcett, Phyrochem., 1969,8, 1793. R. D. Hartley and C. H. Fawcett, Phytochem., 1969,8,637. A. J. Weinheimer, W. W. Youngblood, P. H. Washecheck, T. K. B. Karns, and L. S.

Ciereszko, Tetrahedron Letters, 1970, 497.

149

M. Iguchi, A. Nishiyama, H. Koyama, S. Yamamura, and Y. Hirata, Tetrahedron

Letters, 1969, 3729; M. Iguchi, A. Nishiyama, S. Yamamura, and Y. Hirata, ibid., 1969,4295; 1970,855.
150

K. Wada, Y. Enomoto, and K. Munakata, Tetrahedron Letters, 1969, 3357; Agric and

Biol. Chem. (Japan), 1970,34, 946.

151

E. D. Brown, T. W. Sam, and J. K. Sutherland, Tetrahedron Letters, 1969, 5025.

147

152

T. C. Jain and J. E. McCloskey, Tetrahedron Letters, 1969, 2917; cf: T. C. Jain. C. M.

Banks, and J. E. McCloskey, ibid., 1970, 2387.

153 154

T. C. Jain and J. E. McCloskey, Tetrahedron Letters, 1969, 4525. For a review of furanosesquiterpenes, see T. Kubota, in 'Cyclopentanoid Terpene

Derivatives', ed. W. I. Taylor and A. R. Battersby, Marcel Dekker, Inc., New York, 1969.
155 a b

K. Takeda, I. Horibe, M. Teraoka, and H. Minato, J. Chem. SOC. (C), 1969, 1491;

K. Takeda, I. Horibe, and H. Minato, J. Chem. Sac. (C), 1970, 1547; K. Takeda, K. Tori, I.
156 157 158 159

Horibe, H. Minato, N. Hayashi, S. Hayashi, and T. Matsuura, J. Chem. Soc. (C), 1970,985. K. Takeda, I. Horibe, M. Teraoka, and H. Minato, J. Chem. SOC (C), 1969, 2786. K. Takeda, I. Horibe, M. Teraoka, and H. Minato, J. Chern. SOC. (0, 1970,973. A. R. de Vivar, C. Guerrero, E. Diaz, and A. Ortega, Tetrahedron, 1970, 26, 1657. M. Holub, Z. Samek, D. P. Popa, V. Herout, and F. Sorm, Coll. Czech. Chem. Cornm.,

1970,35, 284.
160 161 162 163

S. J. Torrance, T. A. Geissman, and M. R. Chedekel, Phytochem., 1969,8,2381. M. A. Irwin, K. H. Lee, R. F. Simpson, and T. A. Geissman, Phytochem., 1969, 8, 2009. R. Toubiana, M.-J. Toubiana, and B. C. Das, Compt. rend., 1970,270, C, 1033. M. Suchy, L. DolejS, V. Herout, F. Sorm, G. Snatzke, and J. Himmelreich, Coff.

Czech. Chem. Comm., 1969, 34, 229; see also refs. 178, 272.
164 165 166

Z. Samek, M. Holub, V. Herout, and F. Sorm, Tetrahedron Lerrers, 1969,2931. R. W. Doskotch and F. S. El-Feraly, J. Org. Chem., 1970,35, 1928. T. H. Porter, T. J. Mabry, H. Yoshioka, and N. H. Fischer, Phytochem., 1970,9, 199; H.

Yoshioka, W. Renold, and T. J. Mabry, Chem. Comm., 1970,148.

167

S. M. Kupchan, Y. Aynehchi, J. M. Cassady, H. K. Schnoes, and A. L. Burlingame, J.

Org. Chem., 1969,34, 3867.

168

T. Kurokawa, K. Nakanishi, W. Wu, H. Y. Hsu, M. Maruyama, and S. M. Kupchan,

Tetrahedron Letters, 1970, 2863.

169

S. M. Kupchan, R. J. Hemingway, A. Karim, and D. Werner, J. Org. Chem., 1969,34,

3908.
170

W. Herz and S. V. Bhat, J. Org. Chem., 1970, 35, 2605.

148

171

M. F. LHomme, T. A. Geissman, H. Yoshioka, T. H. Porter, W. Renold, and T. J.

Mabry, Tetrahedron Letters, 1969, 3161.

172 173

C. M. Ho and R. Toubiana, Tetrahedron, 1970, 26, 941. M. N. Mukhametzhanov, V. I. Sheichenko, A. I. Bankovskii, K. S. Rybalko, and K. 1.

Boryaev, Khim. prirod. Soedinenii, 1969, 56.

174

R. Raghavan, K. R. Ravindranath, G. K. Trivedi, S. K. Paknikar, and S. C.

Bhattacharyya, Indian J. Chem., 1969,7, 310.

175

W. Hen, P. S. Subramaniam, P. S. Santhanam, K. Aota, and A. L. Hall, J. Org. Chem., Z. Samek, Tetrahedron Letters, 1970, 671; H. Yoshioka, T. J. Mabry, N. Dennis,

1970,35, 1453.
176

and W. Herz, J. Org. Chem., 1970, 35,627.

177

T. G. Waddell, W. Stocklin, and T. A. Geissman, Tetrahedron Letters, 1969, 1313;

Tetrahedron, 1970, 26, 2397.

178 179 180 181 182 183 184

G. Snatzke, Riechstofle, Aromen, Korperpflegemirrel, 1969, 19, 98. T. C. Jain, C. M. Banks, and J. E. McCloskey, Tetrahedron Letters, 1970, 841. K. Takeda, I. Horibe, and H. Minato, J. Chem. SOC. (0, 1970,1142. K. Tori and I. Horibe, Tetrahedron Letters, 1970, 281 I. D. J. Robinson v C. H. L. Kennard, J. Chern. SOC(. B), 1970, 965. K. Morikawa v Y . Hirose, Tetrahedron Letters, 1969, 869. E. J. Corey v E. A. Broger. Tetrahedron Letters, 1969, 1779.

* Xem thm cc phn tch X-quangbc nitrat ca geijerene182i vipregeijerene.143

185 186 187 188 189 190 191

S. M. Kupchan, R. J. Hemingway, D. Werner, v A. Karim, J. Org. Chem.,1969, 34, 3903 H. Yoshioka, T. J. Mabry, v A. Higo, J. Org. Chem., 1969, 34, 3697. T. C. Jain v C. M. Banks, Chem. v Ind., 1969, 378; see ref. 273. R. W. Doskotch v F. S. El-Feraly, Canad. J. Chem., 1969, 47, 1139. W. Herz v S. K. Roy, Phytochem., 1969, 8, 661. G. W. Perold v G. Ourisson, Tetrahedron Letters, 1969, 3871. K. Naemura v M. Nakazaki, Tetrahedron Letters, 1969, 33. M. Nakazaki v K. Naemura, Bull. Chem. SOC. Nht Bn, 1969, 42, 3366.

192 193

F. Bohlmann v M. Grenz, Tetrahedron Letrers, 1969, 5111.

149

194 195 196

M. A. Irwin v T. A. Geissman, Phytochem., 1969, 8, 2411. T. A. Geissman, T. S. Griffin, v M. A. Irwin, Phytochem., 1969, 8, 1297. H. Yoshioka, W. Renoid, N. H. Fischer, A. Higo, v T. J. Mabry, Phytochem., 1970, 9,

823.
197 198 199 200 201 202 203 204 205 206 207 208 209 210 211

K. H. Lee v T. A. Geissman, Phytochem., 1970, 9, 403. A. G. Hortmann, Tetrahedron Letters, 1969, 5785. A. G. Hortmann v J. B. De Roos, J. Org. Chem., 1969, 34, 736. B. Tomita v Y. Hirose, Tetrahedron Letters, 1970, 235. H. Shimanouchi v Y. Sasada, Bull. Chem. SOC. Nht Bn, 1969, 42, 334. M. Ando, T. Asao, v K. Takase, Tetrahedron Letters, 1969, 4689. D. F. MacSweeney, R. Ramage, v A. Sattar, Tetrahedron Letters, 1970, 557. N. H. Andersen, M. S. Falcone, v D. D. Syrdal. Tetrahedron Letters, 1970, 1759. F. Sorm, Pure Appl. Chem., 1970,21,263. G. L. Chetty, L. H. Zalkow, v R. A. Massy-Westropp, Tetrahedron Letters, 1969,307. K. Shirahata, T. Kato, Y. Kitahara, v N. Abe, Tetrahedron, 1969,25, 3179. E. Piers v R. J. Keziere, Canad. J. Chem., 1969, 47, 137. R. M. Coates v J. E. Shaw, J. Org. Chem., 1970, 35, 2597. M. Ohashi, Chem. Comm., 1969, 893. P. M. Brown v R. H. Thomson, J. Chem. SOC. (C), 1969, 1184; xem hu ht trong H.

Kakisawa, Y. Inouye, v J. Romo, Tetrahedron Letters, 1969. 1929.

212

J. Romo. Bol. Inst. Quim. Uniu. nac. auton. Mexico, 1969, 21, 92; P. Joseph-Nathan,

C. Negrete, v P. Gonzalez, Phytochem., 1970, 9, 1623.

213 a

J. Harmatha, Z. Samek, L. Novotny, V. Herout, v F. Sorm, Cofl. Czech. Chem.

Comm., 1969,34, 1739; b1969,34,2792.

214 215

C. J. W. Brooks v G. H. Draffan, Tetrahedron, 1969, 25, 2865. G. A. Eagle, D. E. A. Rivett, D. H. Williams, v R. G. Wilson, Tetrahedron, 1969,

25, 5227.
216

L. Novotny, Z.Samek, J. Harmatha, v F. Sorm, Coll. Czech. Chem. Comm., 1969,

34, 336.
217

Y. Ishizaki, Y. Tanahashi, T. Takahashi, v K. Tori, Chem. Comm., 1969, 551.

150

218 219 220 221 222 223 224

J. A. Marshall v R. A. Ruden, Tetrahedron Letters, 1970, 1239. H. C. Odom v A. R. Pinder, Chem. Comm., 1969,26; xemfootnote 1 ca ghi ch 218. K. Endo v P. de Mayo, Chem. and Pharm. Bull. (Nht Bn), 1969,17, 1324. A. R. Pinder, Tetrahedron Letters, 1970, 413. G. Jommi, J. Kfepinsky, V. Herout, v F. Sorm, Coil. Czech. Chem. Comm., 1969, T. R. Govindachari, P. A. Mohamed, v P. C. Parthasarathy, Tetrahedron, 1970,26, T. R. Govindachari, K. Nagarajan, v P. C. Parthasarathy, Chem. Comm., 1969,823;

A. K. Ganguly, K. W. Gopinath, T. R. Govindachari, K. Nagarajan, B. R. Pai, v P. C. Parthasarathy, Tetruheciron Letters, 1969, 133; H. Fuhrer, A. K. Ganguly, K. W. Gopinath, T. R. Govindachari, K. Nagarajan, B. R. Pai, v P. C. Parthasarathy, Tetrahedron, 1970, 26, 2371.
225

R. B. Kelly v J. Zamecnik, Chem. Comm., 1970, 1102.

151

152

153

154

MC LC
Chng 3: Diterpenoids 1. M u...2 2. Gii thiu .................................................................................................... 3 3. Diterpenoids hai vong ................................................................................ 3 Labdane ....................................................................................................... 3 Lerodane ...................................................................................................... 7 4. Diterpenoids ba vong ............................................................................... 10 Pimaranes................................................................................................... 10 155

Abietanes ................................................................................................... 10 Cassanes..................................................................................................... 12 Ha tnh vng A ......................................................................................... 13 Ha tnh vng B ......................................................................................... 15 Ha tnh vng C ......................................................................................... 16 5. Diterpenoids b n vong ............................................................................. 20 Kaurane-Phyllocladane .............................................................................. 20 Grayanotoxins ............................................................................................ 25 Gibberellins................................................................................................ 26 Diterpene Alkaloids ................................................................................... 28 6. Diterpenoids co s vong ln va s ta o vong cua chung .......................... 30 Phorbol va h p ch t cua no ........................................................................ 30 Taxane Diterpenes...................................................................................... 32 7. T ng h p Diterpenoids ............................................................................ 33 8. Ti Liu Tham Kho...42

L I M U

156

Diterpenoid l mt loi tecpen gm bn n vi isoprene. C cng thc ha hoc l C20H32 Chng xut pht t pyrophosphate geranylgeranyl. Diterpenes hnh thnh c s cho cc hp cht sinh hc quan trng nh retinol, vng mc, v phytol hay chng c bit n l cht khng khun v khng vim. Diterpenoid c tm thy trong thc vt v l cht c hot tnh sinh hc rt th v ti Diterpenoid. Di s hng dn t n tinh cua c giao cung nh s giup cua ba n be chung em a hoan thanh bai ti u lu n nay . N i dung ti u lu n cua chung em c chia thnh 8 ph n chinh da theo cac thanh ph n c u ta o chinh cua Diterpenoid . . Chnh v vy chng em c c gio giao cho tiu lu n mn ho c H p Ch t Thin Nhin vi

157

CHNG 3: DITERPENOIDS
1. Gii thiu Chng ny c chia thnh cc phn, da trn cu to chnh ca diterpenes. Mt bo co lu hnh rng ri trn 'Common and Systematic Nomenclature of Cyclic Diterpenes [1] ca Cyclic Diterpenes JW Rowe, xut vi I.U.P.A.C. t tn v nh s cho diterpenes. Mc d nhng xut ny cha c chnh thc chp nhn,nhng cng c p dng trong mt s n phm v c s dng trong ti liu ny .

2. Diterpenoids hai vng H Labdane. Cc loi cy l kim l mt ngun quan trng cha diterpenes, v mt s c nghin cu trong nm qua. Dacrydium colensoi c mt lng ln diterpenes ca oxit manoyl v sandaracopimara -diene cc loi. Phn 158

trung lp[2a] cha ng "mt lactonic bt thng homoditerpene (1) tng quan vi colensan-2-one (2). N.m.r c s dng to ra cc ha lp th ca vng lacton hp nht, v cc bng chng ha hc ch ra rng nm vng thnh phn ca dn xut colensan hoc conformations -thuyn hoc na gh. Cu trc ca cc diterpen c bit c xc nhn bi s tng hp mt phn[2b] t lmethoxycarbonylco-lensan-2-.Khi cy c cha c hai homo-A-v 1 loi khng phi diterpen, s rt th v suy on v ngun gc ca nguyn t carbon ca homo-diterpen(1)

Mt nghin cu k lng v Dacrydiurn kirkii cho thy[3] tm g c cha isopimaradiene, sclarene, cis-v trans-biformene, manoyl oxit, 14,15-bisnorlabda8 (1 7)-en-13, labda-8(17),13-dien-15-ol, manool, isopimara- dienol, torolusol, sandaracopimaradiene-3, 19diol, v isopimaric acid, cng vi hai hp cht mi, 7-hydroxymanool (3), v 2, 3-dihydroxymanoyl oxit (4). Cu trc ca chng, v c bit l v tr ca cc nhm hydroxy l du hiu v chng t n.m.r.

159

13-Epimanool c pht hin trong cc cht chit xut trung lp ca Larix europaea[4] trong v cy ca Sitka pruce [5] . Cupressus c kim tra bi g.l.c[6] v xc nh trong tt c axit imbricatolic (5) nhng semperuirens Cupressus. Axit ny ng xy ra vi axit cis-v trans-Communic v vi sandaracopimaric axit. 13 (16)-giao tip c phn lp[7] "nh methyl ester t Callitris columelfaris. Trong cng vic ny nhit isomerisation ca diene lin hp axit Communic c ghi nhn. Cu trc v lp th ca mt s 8-oxo-14norlabdanes c ngun gc t ozonolysis communate methyl c lm r[8]. 'Copaifera multijuga cha[9] axit copaiferolic v mt labdane i acid mi, 11hydroxylabda - 8(17), 13dien-15-oic axit. Du l ca Charnaecyparis nootkatensis cha hai oxit mi manoyl. Chng c ch nh[10] cc cu trc 8-epimanoyl oxit (6) v oxit 8,13 epimanoyl (7). Lp th C-13 c da trn mt s ng vng c li v c kh nng xc tc bng nha Amberlyst XN 1005. Cc oxit isopimara8,15-diene v pimara-8,15-diene tng ng, trong lp th C-13 c gi li

160

S hnh thnh ca mt trihydrochloride manool ph bin t manool, sclareol, manoyl oxit, 13-epimanoyl oxit, biformene, v abienol ng vai tr mt phn quan trng trong mi tng quan cu trc gia cc diterpenes. Trc ngi ngi ta ngh [11] "mt nguyn t clo 8-xch o, nhng trong trang ny [12] lm r im khc nhau 8,13,15-chloro-labdanes, monohydrochloride tng t t tetrahydroa- bienol c giao lp th 8-trc ha hc lp th (8). S kh hidro clo ng phn ny to ra ba olefin, trong khi epimer xch o c kh nng ch c (7) v 8 (l 7) olefin.

Gi thuyt ca Ruzikca cho rng pimaradienes c ngun gc t s ng vng ca labdane hoc tin thn manool c y mnh nghin cu trong s ng vng vitro acid-catalysed ca cc hp cht. Manool, 13-epimanool, v cc cis v trans-labda-8 (1 7),13-dien-15-ols cho cng mt hn hp cc sn phm, tc l khng i xng trong chui b ph hy trc khi ng vng. iu ch bng hn hp axid sulfuric- acid acetic trong 3 gi[13] tiu tn 13 epimeric C-13 hn hp ca pimaradienes (9). Sau 150 gi isopimara-8,15-diene chuyn i thnh mt hn hp cc sn phm, 50% trong s l rosadiene (10). iu ny cho thy s ng vng c m rng n vic tng hp ca rosenonolactone t methyl cupressate (ref. 159). S dng axit formic nh l tc nhn ng vng[14] , ba vng pimaradiene, sanda- racopimaradiene, v rosadiene c hnh thnh, cng vi mt 14-hydroxy-beyerane (11). Cc th nghim vi C-14 ca cc labdane gc 161

khng nh [15- 17] rng sn phm tetracyclic c hnh thnh thng mt cht 8 vng trung gian (13) ch khng phi bng cch ca s ng vng pimaradiene ( n 1). iu ch rosadiene (10) vi clorua hydro sn lng axit acetic rimuene (12). Mc d marrubiin c nghin cu t 1842 v lp th ca n v cu trc by gi cng c xc nh [18] l mt phn pht sinh cng t Spiro (14) premarrubiin - trong s tch n t Marrubiurn vulgare [19]. Tng t Spiro-ete c bo co t Solidago canadensi [23] v Leonotis leonorus [22] . Cng ngy cng c thm bng chng lin quan n lp th ca marrubiin ti v tr C-8 v C-9 cng xut hin [20]. Vng lacton lm bin dng vng B theo hnh thc thuyn i. Leonotin, mt furanoid diterpene c tch ra [21] t Leonotis nepetaefolia v L. Dysophylla [21] l 8-hydroxymarrubiin (15).

162

163

Khi c s hi lu ca triclorua photpho trong pyridin, n c chuyn i thnh epoxide vi s gim lithium nhm hydride to marrubenol. v 13 8, Trans-diaxial iol cng c bo v bi tnh tr ca n i vi ha hc. Qu trnh oxy ha vi crm trioxide dnh 139;196--dilactone 19 6--dilactone. Cc loi c lin quan, L. leonarus,ng thi cha [22b] lacton-spiro-ether (16) gi nh ca premarrubin. Solidagenone (17) v 9-13 ete lin quan c tch[23a] t Solidago canadensis. Cc cu trc c c trn c s d liu quang ph v ph hy nhm hydroxy- (17) hnh thnh, ty thuc vo thuc th, hoc l hay -khng bo ha ketone. Mi quan h ca nhmhydroxy, vng furan, v cu xeton-khng bo ha cho php mt s xc tc acid sp xp li . Solidagenone u tin[23b] cung cp cho mt dienone (18) ng vng vi (19), methoxy-ketone (20) l mt sn phm nh.

H Clerodane. Loi Solidago cng c cha mt lot cc clerodane diterpenes. Solidago elongata cha [24] kolavenol (21), kolavenic axit, 6-acetoxy v 6164

angeloyloxy-kolavenic axit, kolavelool (22), v 6-angeloyloxykolavelool, cng vi mt nhm cc butenolides -khng bo ha, A-E ko di (23) v (24), c xy dng gn nh hon ton trn cc bng chng quang ph. Solidagonic acid, b c lp t S. altissima, c xy dng nh 7-acetoxy kolavenic axit [25]. S xut hin rng ri ca cu trc clerodane c chng minh [26] bi s cch ly hardwickiic acid (25), cc ester C-15 monomethyl kolavenic furanoid, agbaninol (26, R = H) v agbanindiol B acid, v hai cht (26,R=OH) t Gossweilerod-

endron balsarniferurn (Caesalpiniaceae). Agbanindiol A c cu trc ny(27). Nhng hp cht ny c tng quan vi kolavenic axit v cc axit hardwickiic.

165

Chettaphanin-1 (28), t Adenochlaena siamensis (Euphorbiaceae) [27], li trnh by mt giai on trung gian th v trong s hnh thnh ca cu trc clerodane trong C-10 m khng phi C-4 methyl di c to thnh. Cu trc diterpene ny c da trn kh tng ng tetra-ol thnh 1,2,5 -trimethylnaphthalene v s hnh thnh ca mt trienone (29) qua qu trnh mt nc v kh. Cistodiol (30, R = CH2OH) v axit cistodioic (30, R = CO2H) l [28] cc thnh phn ca thuyt pht sinh sinh vt lot hp nht cis clerodane th v, nh tri ngc cho cc dng chy bnh thng xuyn lin quan n kolavenol. Cistus monspeliensis, ni m chng xy ra, v k l cng cha 8, 15-labdanediol. Fibleucin (31), cng c tch [29] t Fibraurea chloroleuca (Menispermaceae) l 7(8) dehydrocolumbin. 166

167

Chasmanthin, fibraurin, v 6-hydroxy-fibraurin xy ra theo cng hng [30]. Vi mt mc cao ca oxy ha, cc cu trc ca cc hp cht c bt ngun t n.m.r. ca chng quang ph. Fibraurin, 2,3-epoxide ca fibleucin tng quan vi 7 (8)-dihydro-phi sinh, palmarin.

3. Tricyclic Diterpenoids Pimaraaes. Sandaracopimaradien-19-01 c tm thy [31] trong Dacrydium colensoi.G ca D. biforme cha [32] isopimara-7,15-diene v 18-norisopimara4 (19),7,15-triene, c tng hp bng cch oxy ha tc nhm cacboxyl ca axit isopimaric vi ch tetra-acetate trong pyridin. Aralia racemosa cha [33] (-)pimara 8 (14),15-diene, kaurene, v pimara 8 (14),15-dien-19-OIC axit. Tng ng 7-hydroxypimara-8 (14) ,15-dien-19-oic axit v 7-keto-acid c tm thy [34] trong Aralia cordata. Cu trc ca chng c chng minh bi qu trnh oxy ha ca cc este methyl ca pimara-8 (14) ,15-dien-19-oic axit vi selen dioxide, cho 9- hydroxy v 7-hydroxy-acid. Mt tetra-ol c lin quan n darutigenol c c tch [35] t Siegesbuckia pubescens v th hin c 68,15,16,18-tetrahydroxy pimar-8 (14)-ene (32). S hin din ca nhm 18hydroxy lp th trong c lin kt vi v tr-6 bi s hnh thnh ca mt ether 6 18, to mt s th v thc t l 16,17-dihydroxy-l6(-)-kauran-19-oic acid xy ra theo cng 1 hng. Hai nm isopimaradienes, virescenol A (33, R = OH) v virescenol B (33, R = H), c tch [36] nh ca h -D-altropyranosides, t 168

Oospora virescens. Quang ph d liu v s tng quan vi sandaracopimara-8 (9) ,15-dien-3P-ol phc v thit lp cu trc ca chng. ng c gn vo ru chnh.

Abietanes.

Abieta-8,11,13-triene, c tch t dehydroabietic acid, c

phn lp t Thujopsis dolabrata v Podocarpus ferrugineu [37]. S oxi ha [4] ca phn cacbonyl trung tnh thu c t Larix europaea dn ti s c lp ca abietic, neoabietic, dehydroabietic, pimaric, v isopimaric axit, ng s hin din ca thnh phn cc aldehyde trong trch xut. 4-Epiabietic acid v 4-epipalustric acid c c tch [38] t Juniperus phoenicea. Callitrisic axid (4-epidehydro-abietic acid) [39] c lin quan n axit podocarpic thng qua mt dn xut phenolic chung [40]. N trc c to thnh [41] t agathate dimethyl. Nhiu hydrocacbon diterpene c tinh ch bng sc k trn bc nitrat trn silica gel. Tuy nhin, h thng ny c kh nng nitrat ha phenolic diterpene [42]. Ferruginol v axit podocarpic kh nng to 7-12% ca h dn xut 11-nitro trong iu kin tiu biu sc k . R kh ca Saluia miltiorrhiza c trong cc loi thuc Trung Quc tan-shen, c tch t mt s furanonaphthoquinonestanshinones, isotanshinones, v cryptotanshinones [43]. R cng cha mt onaphthoquinone, miltirone, c cu trc (34) c pht hin [44] trn c s quang 169

ph ca n, s hnh thnh ca mt triacetate thy phn v oxy ha a ra mt hydroxy-l,4-naphthoquinone. bao gm cc tumourinhibitory Mt nhm th v ca hot tnh sinh hc diterpenes, c tnh cht c ch tng trng, c phn lp t cy l kim. Chng quinone methides, taxodione (35, R = 0) v

taxodone (35,

), t Taxodium distichum (Cupressales) [45].

Cu trc gi nh fuerstione (36), [46] da trn U.V. ca chng v n.m.r. quang ph v chuyn i thnh11,12-dimethoxyabieta 8,11,13-triene cng thu c t sugiol. Cc podolactones A v B (37, R = H v OH) tch [47] t Podocarpus nariifolius (Podocarpales), l cht c ch mnh m t bo thc vt m rng v phn chia, c th so snh trong hot ng vi axit abscisic. Cc cu trc tip theo t n, m.r. quang ph ca chng, trong tt c cc proton c th c phn bit. Vic xc nhn n t vic chuyn i podolactone B thnh mt sn 170

phm qu trnh oxy ha (38) inumakilactone 3 acetate [48]. Mi lin quan nagilactone C [49] cho thy mt hot ng tng t. Cu trc v lp th ca nagilactones C v D (39) v (40) tng ng, c lm sng t bi chi tit nghin cu n.m.r vi vic s dng dung mi thay i, cc hng s khp ni, v cc hiu ng Overhauser ht nhn.

Cassanes.

-C-Caesalpin (41), t Caesalpinia pulcherrim[50], s hu

b xng cassane, v cc nguyn tc quan trng lin quan c c lp t ht Caesalpinia bonducella. Cassminic acid l mt thnh phn nh ca v Erythrophleurn guineense. Cc php o quang ph v mi tng quan mt vi axit cassane-16,19-dioic thit lp [51a] n nh l 6-oxo-7-hydroxycass-13ene-16, 19-dioic axit. S o lng n.m.r. v nghin cu brom ha v dehydrobrom ha ph hp [51b] vi trc 14 cu hnh c chp nhn cho cassamic axit diterpenes. 171

Cleistanthol (42), c chit xut t loi Cleistanthus schlechteri,[52] l mt ditecpen t gi tr. Ngc vi ditecpen cassane, cu trc ca n l kt qu s chuyn nhm C-13 etyl ca gc pimaradien. Khung cacbon ny c xc nh t s kh phenanthrol, n gn vi phenanthrol thu c t metyl vinhaticoat, iu chng t rng chng ch khc nhau bi s thay th gia nhm metyl v etyl. V tr nhm C-13 hydroxy phenolic c to bi qu trinh oxy ha 7-xeton ca dihydro- triaxetat sau l thy phn bng kim. Quang ph U.V ca sn phm l xeton p-hydroxylphenyl. V tr gia nhm diol ca vng A sau tch loi dimesylat to enol-mesylat v sn phm ng vng cha mt phn cu trc (43).

Tnh cht ha hc ca vng A. Hai cch c dng xc nh tnh cht ca olefin vng A. Deamin ca axit nitro 18-norabieta-8,l 1,13-trien-4-amin ho c [51] nhm amin tng t trong chui 12-methoxypodocarpa-8,1 1,13-trien [53b] to ra 3- v 4-olefin, v mt dn xut 4-axetat t C-4 cacboni ion. Mt hn hp tng t cng thu c t ch tetra-axetat decacbonxyl, dehydro axit abietic[54]v 12-methoxypodocarpic axit[55]. Trong trng hp hai c mt lng nh sn phm lactonic c sinh ra t qu trnh oxy ha 6 olefin [56]. Khng thu c lacton t phn ng gia ch tetra axetat v 7-xeton. Kh ha dn xut hn hp olefin t dehydro axit abietic to ra[54]ru bc mt (45)v 3 -alcol (46) vi mt lng nh 7-xeton khng r gc. Epoxi chn lc hn hp olefin t -podocarpic monoperphthalic axit [57]to mt hn hp tch ring 3,4- v 4,5-epoxi vi exocyclic 4 -olefin. 172

3,4-epoxi (47) phn ng vi liti alumin hydryt to 3-alcol, sau b oxi ha to 3-xeton. Epoxi (47) orm the 3a-alcohol, and the latter was oxidised to a 3ketone. The epoxide (47) sp xp to vng A-khng cha andehit c x l bng bo triflo. Mt khc, s sp xp 4,5-epoxi to ra mt hn hp A- khng cha 5-axetyl (50), mt 5-metyl bisnorpodoca-patrien (51), v mt dien (52).

Qu trnh epoxi chn lc cho php tch exocyclic olefin. Ozon ha to hp cht 4 oxo[54]t dn xut 3-oxo. Do , ngng t benzadehit, kh xeton, dehydrat v phn ct benzydien vi osmium tetroxit v natri periodat s cho 12rnethoxy-3-oxo-l8,19-bisnor- podocarpa-4,8,11,13-tetraen. Trnh t ny cng c dng chun b xc nh lin kt abietatetraen. Mt s dn xut th N ca dehydro abietylamin c chun b bng cch tng hp ton b [59]hoc mt 173

phn [60]v kim tra hot tnh khng khun.

174

Tnh cht ha hc ca vng B - 19-6

lacton (44, R = H) ca chui 12-

methoxy- podocarpa-8,11,13-trien thu c [61]bi qu trnh dehydrat 7 v 7 hydroxy-lacton vi toluen-p-sulphonic axit trong axetic anhydrit v s kh 6 enol-lacton trong than ci palladium. Kim tra rng cng hng ca C-6 proton dn n nhng kin cho rng vng B c cu trc dng thuyn. Cu trc tng t c xut trong chui marrubiin v tetracyclic kauren-olide lacton. S kh hydrit 7-xeton to7 -alcol. X l 7-keto-lacton vi natri hydroxit trong methanol to diosphenol. 6,7-diosphenol ny khng tham gia ng vng benzilic acit, nhng ng phn trong alkal to dng A/B-cis-6,7-dixeton. Hin nay ang c nhiu tranh ci v cu to lp th brom ha metyl 12-methoxy-7-oxopodocarpat. Tuy nhin phn tch cu trc bng tia X ch ra rng[62] nguyn t 6-brom chim mt cu hnh dng thuyn vi vng B. The 6 -brom-7-zeton (53) trong chui totarol, khi x l vi natri hydro cacbonat trong dimetyl sulphoxit,[63] xy ra phn ng phn tch l dn n s to thnh vng (54). Dn xut 5,6- mono-epoxit sp xp li to naphthalen thay th (55) vi sulphuric axit.

Quan tm n mi quan h cu trc hot ng ca gibberellin dn n s tng hp mt phn ca bn lp th v v tr 5 v 6 ca hexa-hydrofluoren (57). Anhydrit axit cha bo ha (56) c to bi s co vng axit benzilic of the 6,7-dixeton 175

thu c t qu trnh oxy ha desisopropyl dehydroabietic axit [64] v chuyn i[65] thnh axit bo ha bi s kh v epime ha xc tc baz.

176

Tnh cht ha hc ca vng C. Cu trc v lp th ca cc axit dihydroabietic khc nhau c xc nh.[66,67]. Kh trc tip axit abietic (58) bi cc cht xc tc c th gia tng sn phm 1,2- hoc 1,4-(59-64) v bin i cu trc lp th C-8 and C-13. Trong iu kin c bn hoc trung tnh, khi cc ng phn lin kt i khng ging nhau, xc tc phn ng kh axit abietic khng ch to ra cc axit t s tn cng mt (60 v 64) m c axit (e.g. 62). Phn ng liti-ammonia, u tin cho proton axia to ra axit (59), (60), (62), v(63), vi 59 l sn phm chnh. Lin kt i trong nhng axit ny c nh v bi qu trinh ozon ha xeto-aldehyt, n c xc nh bi ph cng hng t ht nhn[66]Cu hnh C-13 c thit lp bng cch chuyn i gia -lacton v -lacton (65 v 66) v tr cn bng v so snh s phn b gia cc ng phn. Cc dihydro-acit khc nhau c lin quan ba trong bn s axit tetra-hydroabietic . Mt trong s axit chuyn thnh khong fichtelite (18- norabietan) bi phn ng thoi bin Hofmann sau kh bng xc tc kt qu to olefin.[68]Trong mt s trng hp cc quy tc tn cng da trn s tng t steroit khng p dng cho vng C ca ditecpen ba vng. Do vy s osmyl ha lin kt i [63,64]to ra -glygol cn nu khng vn to ra -glycol.[69] Ph cng hng t dihydrochloride v dihydrobromide ca metyl abietat h tr[70]cho cu trc (67) hn l dn xut 8,13- pht sinh trc . Tch loi mt mol hydro chloride t dihydro- chloride s to ra 7,8 olefin. X l dihydrobromide vi natri othoxit s cho mt dien (68). Nghin cu trc y trn darutigenol ch ra rng lieen kt i bin i ng phn thnh 8,9-hn l s kh ha. Tuy nhin 177

di iu kin phn ng khc nghit hydro s th [71]

Dn xut 8(14) -epoxit

(69)[72] t 16-norpimaran d dng m vng , vi s hnh thnh -lacton (70). Mt khc, -epoxit, khi tip xc vi mt axit Lewis to ra sn phm (71) sp xp li cu trc. Cc dn xut ca C-8 carbonium ion bi dehydrat [73] sandaracopimar- 15-en8 -ol ch to mt sn phm ba vng nh sandaracopimaradien v isopimaradien, cng vi sn phm sp xp li khung (72).

178

Tiu Lun Hp Cht Thin Nhin

Khng c sn phm tetracyclic c phn lp. S quan trng ca cu trc lp th nhm vinyl trong qu trnh cyclic c ch ra bi s oxy ha thy ngn 179

Tiu Lun Hp Cht Thin Nhin

v s tch thy ngn ca nhm methyl v methyl sandaracopimarat. Dng ban u to ra 8-15 trong khi dng th hai to ra 15-alcohol. C u truc cua nhom isoropyl axit dehydroabietic a c xac inh bi qua trinh cyclic hoa cua nhom C12 hnh thnh mt -lacton (73) bng cch s dng ch tetra-acetate l cht oxy ha. Nhit hoa 12 - diazomethyl xeton cng dn n qua trinh cyclic hoa . Thay th trc tip ca isopropyl bi nhm nitro[76]trong qu trnh nitrat ha ca methyl 12-acetylabieta-8, 11,13 - trien-18-oate. H p ch t 13-nitro- (74) c chuyn i thng qua cc amin n phenol, v nhm acetyl c chuyn i bi qu trnh oxy ha thnh axit v decacboxyl xc tc ng . N to ra metyl 13hydroxylpodocarpa-8,11,13-trien-18oate 26% cn li l metyl abieta-8,11,13-trien18-oate.

Oxy hoa [77]metyl abiet-8(9)-en-18-oate vi t -butyl crom ta o m t hn h p 7v 11-,-xeton , 7,11-enedion , 11-hydroxyl 8,9) 7-xeton, v 8(9)-epoxyxeton. Kh metyl 11-oxo-13-abiet-8(9)-en-18-oate vi liti trong amoniac long to ra B/C-cis- t bn chuyn sang hp cht 8,9-cis . Kh 7-oxo-13-abiet-8(9)en-18-oate ta o ra 8,9-cis. Hydro abieta -7,9(11)-dien ta o c u hinh vong cis Hidro n i i 9(11) c mt , ca phn t , vng cacbon xut hin vi s lng khc nhau ph thuc vo cu trc vong B v C . Thng thng ngoa i suy t c u 12-oxopodocarp-13-en-19180 trc cui chui steroit ,vng D hn ch m vng . Dehidrobrom metyl 11-brom12-oxopodocarpan-19-oate co kha nng ta o ra metyl . Lin k t trc ti p 7,11-dixeton ta o dong phn B /C-trans vi c u hinh 8,9 .

Tiu Lun Hp Cht Thin Nhin

oate hn ng phn

9(11)

. C rt nhiu nghin cu v oxy ha vng C vi s

chu bi ch t n n tng h p ditecpen phc ta p . S chuan bi axit xeto (75) v t axit levopimaric (76) v t xeton cha no t metyl neoabietat c miu t tch ra v cu trc ha hc lp th c xc nh bi phng php ph vng C ca podolacton. . Qu trnh ozon ha axit podocarpic c lm v d .[81] Hydroperoxit (78) c cng hng t ha t nhn . trong cac san ph m kh co lacton cha no (79), vi c u truc

Tnh cht quang ha ca abietadien c ch

. Trong dung dich metanol , (82)[83]. Cn nu

metyl abietat ta o ra phc (80) v (81).[82]Trong etanol ta o 8,13-cyclopropan. Tuy nhin metyl neoabietat qua qua trinh quang hoa dehydro ta o ra dng axit resin trong dung dch axeton th to ra 18-norabieta-8,11,13-trien .

181

Tiu Lun Hp Cht Thin Nhin

Nghin cu phan ng Diels -Alder ca phc axit levopimaric tip tc ly v d v c u truc va hoa l p th cua phc vi cyclopenten va cyclopen -1-en-3,5-dion. Sn phm chnh vi cyclopenten l phc endo ,cis (83). enedion ta o hn h p vi phc enolic endo ,cis, c u truc cua no c xac inh bi quang ph a ra h p ch t (84). i chiu cng tng ng vi phc benzoquinon ,nh s co vong loa i favorskii cua epoxy ta o ra (86). N i i 13,(14) ca nhng phc ny b cn tr trong qua tri nh oxy hoa , ngoi tr phc vi axit acetylendicacboxylic .Ngng tu 12-hydroxymetylabiet -7(8)-en-18-oic axit vi formandehit ta o ra ete cyclic (87).

4. Tetracyclic Diterpenoids 182

Tiu Lun Hp Cht Thin Nhin

Cc hp cht Kaurane Phyllocladane. a c nhi u s phn loa i nh vao thanh ph n hoa ho c trong mt s nghin cu v s phn b ca hydrocarbon diterpene gia cc Podocar paceae, Sciadopityaceae, v Taxodiaceae. Mt cu c nghin cu chi tit hn vi tm mi bn mu vt ca cc Cryptomeria japonica cho thy mt bin th c u trc c s ca qu trnh hnh thnh hydrocarbon. V vy, mc d 66 cy cho kaurene, chn cy cho phyllocladene thu c dy ha hc lp th i lp . Tht vy thm ch cy t cng mt ngun ging cng khng gi ng nhau trong vi c hinh thanh hydrocarbon ca chng. Bi vit ny cng ghi li mt ghi chu v s ng phn hoa d dng ca kaurene v phyllocladene vo h ng phn ca chng. Tip tc kim tra Xylopia aethiopica[89], chnh t axit xylopic [15-acetoxyKaur-16-en-19-oic axit] c phn lp[90], dn n s c lp ca axit Kaur-L6-en-19-oic, axit 15-hydroxy- and 15-oxo, cng vi kauran-l6-ol, v kauran-l6,19-diol. Enhydra fluctans,thu c nhom Compositae, cng cha kauran16-ol v kaur-16-en-19-oic axit. Espeletia schultzii, mt thnh vin khc ca Compositae, cha kauran-l6a-ol v kaura-9(11), 16-dien-19-oic axit. B khung carbon ca axit ny c thnh lp bi s kh hidro t pimanthrene v s chuyn i ca cc dn xu t -tetrahydro thnh mt dihydrokaurene, v tr ca nhm carboxy C-19 c xac inh t gi tr pK v quang ph n.m.r ca ru tng ng. S xu t hi n ca n i i duy nht (11) c hnh thnh bi ozonolysis v s loi sn phm ru to 1,6-dimethylnaph-thalene trong phan ng kh hidro , c l l mt trong cc nhm methyl i n la k t qua t m t ph n con la i ca vng D.Axit 15-Acetoxy Kaur-16-en-19-oic (axit grandifloric, trc y c c l p c a ra t E.Grandijlora[93a]) cng c ta o thanh . 2-O-Methyl-atractyligenin ng thi vi atractyligenin[93b] trong Atractylis gummifera. X ly 2183

Tiu Lun Hp Cht Thin Nhin

hydroxybeyeran-15,16-epoxide,vi ch acetate-tetra cho ta t

2 n 20 dung

mi.[94] S hin din ca 15,16-epoxide a cho php ng phn ho a cc hp cht dng kaurene. Cc 2,3 Diol cung c p 3-mono-toluene-p-sulphonate qua qu trnh loi b to thnh 2-xeton. Axit 7-Hydroxy Kaur-16-en-19-oic v 6,7dihydroxy Kaur-16-en-19-oic c chu n bi [95,96] iu tra vo qu trnh sinh tng hp axit gibberellic, trc y la phan ng Meerwein Ponndorf, phn ng kh ca xeton-7 v sau ny l phn ng osmylation ca mt olefin 6,7. Isodon japonicus tip tc l mt ngun diterpenoids tetracyclic mi, v mt m hnh v thuy t phat sinh sinh v t th v ca cc hp cht ang ni ln. Sodoponin (88)vn gi li b khung kauranoid [97], cu trc ca n ph thuc vo acid xc tc sp xp li cc vng D t mt xeton-15 dn n l s phn ct ca vng B vi ion periodate cung cp cho phn ng dihydroepinodosin. t Epinodosinol cng c phn lp t ngun ny. Oridonin (89), cng c tm thy trong loi Isodon khc ,[98b] v shikokianin (90) c tch ring Isodon shikokianus[98a]. T quang ph hc v phn ng acetylation a thit lp c s hin din ca ba nhm hydroxy, mt Hemi-acetal, v mt xeton cha no trong oridonin.[98b] B khung carbon ca n c xc nh bi qu trnh oxy ha periodate to thnh mt dn xut ca isodocarpin, mt diterpenoid enmein. Bi n th ny c quy t inh bi s hin din ca glycol vng B v mt ru C-1. S xu t hi n ca nhm 14-hydroxy la do thng qua mt phn ng retro Claisen lin quan n s phn hch ca lin k t 8-15 hnh thnh mt nhm 15carboxy, do to thnh 1514--lacton. S thy phn shikokianin v qu trnh oxy ha vi periodate to mt lin kt vi nodosin, mt diterpenoid enmein.

184

Tiu Lun Hp Cht Thin Nhin

Phn tch tia X ca mt dn xut enmein (91) c ghi la i[99] vng A l dnh mt chic gh mo. Vng c cng c dng gh b bp mo khng ging nh mt s diterpenes tetracyclic khc, v d nh methyl gibberellate c dng thuyn. Vng D gi ng vi dng mt na chic gh hn so vi dng mt phong b. Nh trong lot abietane ba vng, phn tch hnh th ca diterpenes tetracyclic l phc tp hn so vi steroid. Enmein c chuy n i t axit cacboxylic (95) phc v nh mt ch t trung gian trong qu trnh tng hp kaurene, atisine, garryine, v veatchine. Giai on quan trng trong qu trnh ny l ngng t acyloin ca hp cht (92) vi mt hn hp ca 620,720 Hemi-ketals v ru, v d: (93) v (94). S kh lin tip sau o bi qu trnh oxy ha mt C-20 to axit cacboxylic (95). Trichokaurin (96) c chuyn i thnh mt dn xut enmein. (97) Vng A nhm hydroxy b l y i v vng D nhm acetoxy b hidro phn vi canxi trong amoniac lng cung cp cho hp cht (98) N gim theo cc iu kin Wolff-Kishner v sau b oxy ha cung c p(99), do cung cp bng chng v cu trc v cu hnh tuyt i ca trichokaurin.

185

Tiu Lun Hp Cht Thin Nhin

S chuyn i ( thayi) ca cc loi ( hpcht) khng sinh vn tip tc thu ht c nhiu s quan tm. Lp m (xctc) axeton ca toluen_p_sufonat ca exo v endo - 17-norkauran-16-ols v 17-norphyllocladan-16-ols c trnh by [102] cho ta mt hn hp ca axetas v axit olefil, s phn ng ca n c th hin hnh 2, gia cc phn ng oxi ha cacbon l mt chui cc phn ng hydrat. Trong cc phyllocladene mt s thay i ca nhm OH c th to ra 15 hp cht khc nhau cha oxi. ng lc ca qu trnh l s thay i gc lin kt gia cc nhm metyl, thc t bn cht ca qu trnh ny l s sp xp li v tr nhm epoxide v tri 15 v 16 trongvng beyer, hay theo thuyt beyer n nh 186

Tiu Lun Hp Cht Thin Nhin

l mt phng php hnh thnh cc hp cht trung gian. Ngc li, s sp xp li nhm epoxide ca xterol to ra hp cht 17-hydroxy-beyerane tng t nh isoxterol v n c s dng trong qu trnh tng hp erythroxydiol A.[103]

S i ch ca cc phn t toluene-p-sunfonat (hnh 99) [104a] vi mt axetol (hnh 100), Chng to iu kin ph hp hn cho vic sp xp li mt nhm hydroxybeyerane v tr C12 (111). Hin ti h p ch t neopentyl(C7H18) 187

Tiu Lun Hp Cht Thin Nhin

trong erythroxylol B [104b] l mtcht xc tc cho qu trnh thy phn . Qu trnh thy phn ca toluene-p-sunfonat dn n qu trnh m vng v hnh thnh cc cu axetat (hnh 103 v 104).

Cc Grayanotoxins. Mc d Grayanotoxins c bit n t rt nhiu nm nhng cu trc ca n ch c lm r trong thp k qua. Trn c s O.r.d xc nh t l ca A/B cho ta thu c cu trc dng cis. Tuy nhin, trong 2 nghin cu nycng chng minh c cu trc dng trans ca phn t cng ging nh cc bng chng trc y c 2 chng minh trn u da trn c s ca trans vng ete. Khi grayanotoxin-II (hnh 105) thc hin thy phn[105] vi thy ngn axetat ta c hp cht 5-9 dung mi ete, Nhng khc bit hnh thnh khi ta thay i c u trc phn t v tr C 6 .Nhm OH l mt nhm th beta v nhm ny c xem nh dng sis vinhm OH C5. Cn khi n tn ti dng 5-9 ete th n c cu trc khng gian v nm trn mt beta ca phn t.Th 2 khi tetra-acetylgrayanotoxin-II tc dng vi N-bromosuccinimide [106] cho ta mt ete brom cha cu ni oxi 5-10 ete.

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Trong cc hp cht trn th nhm OH v tr C3 v C5 cng tham gia lin kt trong qu trnh hnh thnh axetal . Nhng ete ny c c u to mch nhnh dng trans. Khi n c cu trc dng sis -5-6-glycol th grayanotoxins c tch ra cng tetra-axetat v n th hin t ( lin kt ) 14 n 6 hemi-acetal[107], Tuy nhin trong grayanotoxin -II hang loa t cc hp cht hemi -acetal b ngng t [108] cho ta mt cp C-1 epimeric ca spiro -axetol (hnh 107). Qu trnh ny thun li hn v mt nhit ng cho qu trnh hnh thnh lin kt gia nhm OH ca C3 v nhm OH ca C6 ch tn ti mt trong 2 cu trc ca spiro-xeton c cu trc dng cu axetal. Bc tip theo l qu trnh hydrat ha ca 20-norgrayanotoxin-II [107] dn n s hnh thnh homoannulardienone ph hp vi cu trc vng 7 cnh ca grayanotoxins.

Cc c t ca Pieris japonica c bt u nghin cu t nm 1982.Hai trong s cc c t asebotoxins I va II [109] 14-propionates nm v tr III. M grayanotoxins-III and -II. Cu trc ca n th hin hnh 108, n c hnh thnh bng s kt hp ca rhodojaponin I,IIv III viasebotoxin rhodojaponin I,IIv III c hnh thnh t Rhododendron japonicurn cn 189

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asebotoxin III c hnh thnh t Pierisjaponica v c nghin cu bi m .n.r [110]. Nhng hp cht ny c miu t bng s c mt ca vng epoxide Lyoniatoxin [111] ho c ((lyoniol A [112]) ci ma c phn bit t .

Lyoniaoualifolia vic thay th nhm OH C14 ca rhodo japonins bng nhm OH v tr 7 ca hp ch t ny . y c xem nh l c mt qu trnh c gng lm vic ca m.n.r v cc thnh vin trong nhm.

Cc Gibberellin. Trong phn ny chng ti thc hi n vi c anh

s li

gibberellane. Quan tm c bi t n h thng ang c s dng. Trong h thng gibberellane (109) v tr 2 - v 3- c o ngc so vi s anh s gibbane c. Gibberellins c oxy chc nng c hai trung tm c bit. S r i loa n cng c th pht sinh do 7-deoxygibbanes v to thnh mt nhm c hot ng sinh hc th v. Trn h thng gibberelane mi, v tr 7 - l nhm carboxy quan tro ng v m t sinh hc.Tt c cc gibberellins c bit n u thu c dn xu t cua b khung ent (10-me), mt im phi c ghi nh khi ti n hanh oxy ha C-18 v C-19.

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Mt s nh gi v s hu ch ca cu trc v qu trnh trao i cht ca bibberellins xut hin. Nh vi cc diterpenoids khc, cng vic t ng h p sinh hc v trao i cht trn gibberellins l c trnh by trong chng 6 ca bo co ny. Bo co r hn v gibberellins A21 v A22 (canavalia gibberellins 1 v 2) xut hin. Gibberellin A25, hay 3-deoxygibberellin A13, tr thanh chu cho mt s h thng sinh hc th nghim. Cc kt qu thu c kha r t th v t nhng c i m sinh ho c c trong gibberellin A25 l t hot ng hn so vi gc aldehyde tng ng, gibberellins A24. S c lp ca gibberellins A26 v A27 cng nh 2 glucosides ca chng t ht ging non ca cy Pharbitis nill [116] a c thc hi n . Gibberellin A26 t khi c mt nhm vng cacbonyl. 2-O--Dglucosylgibberellin A29 cng c thc hi n t Pharbitis nill[117]. Gibberellin A29 thiu 1 nhm 3-hydroxy. Cu trc ca n c xy dng t mi quan h lin 191

Tiu Lun Hp Cht Thin Nhin

h vi gibberellin A5. Cc pht hin ngy cng c ph bin rng ri ca gibberellins hay glucopyranosides ca n l v d in hnh [118] cho s c lp ca gibberellins A8 O-2-D-glucopyranoside (trc y c m t nh l Phaseolus ) t Phaseolus coccineus. ng ngc nhin (trong thc v t ) l s tp trung ca acid gibberellic c ghi nhn[119] trong cc b phn ca hoa ca Cassia fistula, trong khi cc tc gi ny cng tuyn b[120] c lp acid tetrahydrogibberellic t Sonneratia apetala. V tr thnh mu ca h , tuy nhin,nhi t nng chy 150oC a c ghi nhn, v hn na, n c kh nng hp th trong u.v. Tn gibberellins A25 a c nhng tc gi trc s dng[115] m t gibberellin khc, v chng ti ngh rng n s b thu hi. i u ch y l th tc t tn gibberellins mi,[121] c xut m t cch c th trnh nhm ln nh vy. H thng vng A ca acid gibberellic tng t nh cc sn phm c mong i t oxy ha trong anh sang ca mt -gibberellin chng hn nh gibberellins A5.[122] C gng oxy b ng anh sang vng A hoc vng D lin kt i ca gibberellin A5 hoc axit gibberellic hng. Du cho axit allogibberic to cn nguyn thuy , epiallogibberic axit khng phn ng, tc l phn ng dng nh b nh hng bi lin k t gia vng B / C. Cch s l cc este methyl ca sn phm oxy ha bng axit gibberate hydroxymethyl v mt sn phm do s sp xp li allylic. S ao ng c vong D ca axit gibberic c th c mang li[123] bi s kh nhom NH 2 ca mt amin C-16.

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Cc Diterpene alkaloid. Cu trc tinh th ca mt s diterpene alkaloid phc tp c bo co. Denudatine. Khi ln u tin c a ra c mt cu trc ha hc cha ro rang . Hai phn tch tia X [124, 126] cho thy rng n c cu trc v do n chim mt v tr quan trng nh mt trung gian c th c trong s phat sinh sinh v t ca b xng aconitine t b xng atisine. Kobusine ( 120,R=H ) v pseudokobusine ( 120,R=OH ) c cu trc lin quan n bo mn . Mt phn tch tia X chnh xc [127] trc l c cu kobusine c thc hin trn c s nghin cu ha hc. Miyaconitine v miyaconitinone l alkaloid chnh ca Aconitum miyabei. [ 128] S oxy ha c ban lm xut hin gi v mt dng c th hnh thnh (122) ca cy cu carbon 13-20, ca hetisine hay tri ng c vi atisine alkaloids. C u truc ca miyaconitine c xc nh bi s kt hp ha hc v vi c s du ng tia X. Cng h vi cc alkaloid l hetidine (123). Cc cu trc tinh th hydroiodide ca n c xc nh bng phn tich tia X.[130] Delnudine a c t ng h p [131] t nhng ht ging ca cy Delphinium denudatum v ph phn tch X-quang c cu trc (124).[132] S phat sinh sinh v t cua vng b t thng -h thng c 193 th d kin v kh nng sp xp li ca dn xut hetisine(125).

Tiu Lun Hp Cht Thin Nhin

6. Diterpenoids co s vong ln va s ta o vong cua chung Phorbol va h p ch t cua no . Euphorbiaceae c cha rt nhiu Diterpenoids . Casbene hydrocarbon (126), ch t co lin quan n diterpene macrocyclic cembrene, c phn lp t Ricinus communis [133]. N cng c th lin quan n ngu n g c hydrocarbon ca nhm phorbol trong diterpenoids. K t khi cng b nhng phn tch tia X ca phorbol, thnh phn gy ung th Croton tiglium, xut hin y u m t v tinh ch t hoa ho c ca n.[137] Mt tnh nng c o ca phorbol (l27) l s hin din ca acyclopropanol v mt h thng cyclopropylcarbinol. Phn ng ca phorbol vi axit sulfuric 0.02N dn n 194

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vic to ra mt ion carbonium C-12 c th a c sp xp li hoc vi s phn ct ca vng cyclopropyl v s hnh thnh crotophorbolone (128) vi s hnh thnh ca mt cyclobutanone, crotophorbolone K (phorbo butanone ) (129, R = H). [137,138] Mt s sn phm acyloin c thu c khi x ly ca xeton-12 vi natri methoxide.[139] sn phm chnh l hydroxyphorbobutanone (129, R = OH) v mt sn phm nh Hemi-acetal (130). Cc qu trnh oxy ha ca phorbol penta-acetate vi osmium tetroxide a cho [140] mt s 6,7 Diol khc cng vi mt 7-acetate trong mt s chuyn i acyl v tr C-4 xy ra.

Cc dn xu t cua phorbol(131) c phn lp t Croton rharnnifolius.[141] Mt nhm este thc y ca khi u, thnh phn chnh l 12-desoxyphorbol, c phn lp t Euphorbia coopetri[142] v cu trc E. triangularis.[143] ca chng c tm tt trong (132). Hoa Spurge tr ng, Euphorbia lathyris, c cha 195

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mt nhm ba vng ca h p ch t

phorbol, Iathyrol v epoxylathyrol

(euphorbiasteroid) (133). M rng nghin cu ha hc [144] v mt nghin cu tia X[145] dn n s trao i ca cc cu trc cc hp cht ny. Xc tc axit trong nhm ny khng ch lm thay i vng cyclopropane, m cng c cung cp t phn ng cyclisation transannular, v d, (134).

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Cc c u ta o c trng cc k c hi ca Daphne mezereum cng c a ra lot bi ny. Phn tch X ca bromoacetate v m t [146] daphnetoxin c cha cc cu trc orthobenzoate bt thng (135).

Taxane Diterpenes. B khung taxane i din cho mt thay th ong vong ca hydrocarbon diterpene macrocyclic. By dn xut taxane mi c phn lp [147a] t Taxus baccata v c trng trn c s d liu quang ph v cc d li u khac . Cu trc ca n c tm tt trong cc cng thc sau y (1 36ag).Ngoi ra, cu trc ca baccatin-III (137), mt nhm este phc tp c phn lp t cng mt ngun, c hon thnh [147b] Vic p dng cc quy tc bt t t lin kt i taxane 11(12) dn n cu hnh tuyt i 148 ca cc diterpenes.

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7. Tng hp ca Diterpenoids Tng hp ca cc hp cht ba vng da trn cc s ng vng ca methyl geranyl geranoate c m t mi tm nm trc y. Tuy nhin, vic pht hin ra expoxy squalene l cht trung gian trong sinh tng hp steroid, v cc th nghim ng vng tng t trong ng nghim , li nh thc s quan tm n lnh vc tng hp diterpen. Cc nghin cu v cu trc v lp th ca s ng vng ca epoxy-olefin-trans (138) trong ng nghim c nghin cu. 149. Hai hp lp. nht ba Cc vng levanteno A / B-trans- cc hp cht (139) v (140) c phn

lides (142)(143) thu c t hai h gn nhau. Trc tin, butenolide (141), dn xut t bromide monocyclofarnesyl , 150, cho ra - v -levantenolides (142) v (143) ng vng. 198 bng vic ng vng vi clorua stannic. Sau c ,151, butenolide mch h tng ng dn xut t bromide farnesyl

Tiu Lun Hp Cht Thin Nhin

Tng hp lp th ca axit nha cy C-4 epimeric diterpenoid thu ht s ch ng k. S methyl ha ca cc keto-nitrile (144) to ra (152) mt sn phm c mt nhm methyl bao quanh, tri ngc v s metyl ha ca cc vng A bo ha -keto-este-ankyl ha vt tri hoc thm ch l vic alkyl ha dc trc c quan st thy. Mt l do s c a ra gii thch cho vic ny. S lin quan ca mt enolate kim loi c th thc y mt trng thi chuyn tip trong s ng phng ca nhm cacbonyl v ester l quan trng. Vi mt enolate i nhn, ( lin kt mi mt khong cch ln hn) nhng tng tc 1,3-steric nn c gim bt. Cui cng, tng tc vi cc vng quanh C-6 tn ti trong cc este, nhng khng c trong cc nitrile. Qu trnh tng hp ca mt s cht 3 vng thm 20 c -norditerpenoids m t (153). Axit cn thit (146) c to ra bi vic ng

vng ca (145). Rt nhiu lp th A / B c c to ra theo cch ny bng kim loi xc tc hoc kim loi nng chy, gim axit cha bo ha hoc y-lacton (hnh 3). Trc cng vic cho thy rng qu trnh oxy trong oxy ha khi ha chn 199 crom trioxide ca cis A/B podocarpatrienes cho mt diketone, trans A/Bch cho mt monoketone. Tuy nhin,qu trnh

Tiu Lun Hp Cht Thin Nhin

on ny khng xut hin din ra trong lot 20-nor. Ton b s tng hp ca tanshinone-I (147), tanshinone-II, Alder ca3-methylbenzofuran-4,7-quinone v 6,6-dimethyl-

cryptotan

shinone c m t. Phng php s dng c da trn phn ng Dielsl-vinylcyclo hexene. Axit lacton 5-Hydroxy-8-oxodecahydronaphthoic c to ra (155) nh mt trng thi trung gian c th cho s tng hp ca mt s diterpenoid lactone.

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Qu trnh tng hp ca hai phn lp th ca axit (+)-9-desoxocassamic c cng b. H thng ba vng c xy dng bng cch ngng t ca 2 methyl-3-methoxyphenylacetylene vi ethyl 1,3-dirnethylcyclohexan-2-one 1 carboxylate. Sn phm b gim i v ng vng to ra axit 14-methyl-13methoxypodocarpic . Vic gim xc tc ca phenol tng ng v b sung t bn cnh s dng ethoxyacetylene dn n s tng hp cc epimers ti C-8 v C14 ca axit 9-desoxocassamic. S tng hp ca axit sandaracopimaric t khung androstane c m t. Trong vic ny c mt s tng phn th v gia vic ankyl ha cc ketoester bo ha (148) to ra sn phm theo hng dc trc, v ester khng bo ha (149) to ra sn phm l mt nhm metyl v tr xch o. S thay th ca cp lin kt 14,15 trong androstane cho php cu hnh ca C-13 methyl: mu vinyl th.

Methyl isocupressate (150) hnh thnh cc vt liu khi u cho vic tng hp rosenonolactone (156) v desoxyrosenonolactone (hnh 4) da trn nhng nghin cu v vic ng vng m t trn. Vic to vng ca methyl isocupressate trong axit sulfuric acid acetic cp cho C-13 epimeric hp cht ca pimaradienes (151). B khung rosane (152) c to ra t iu ny bng cch sp xp li vi axit fomic Lacton ha ca 5(10) lin kt i cho cu hnh cis A / B vng gip nhau (153) v sp xp li to thnh vng abietane. 201

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Cc vng ni nhau ng (155) c to ra bng cch m nhm 5(10)-epoxide (154). Nhm vinyl c bo v v C-5 ca nhm hydroxy b b i bng s hidrat ha v hydro ha cho ra desoxyrosenonolactone, v trong mt vi giai on l rosenonolactone (156). Ton b tng hp steviol c cng b. Cc h ba vng trung gian (157) ca qu trnh tng hp axit kaurenoic c chuyn i thnh cc 202

Tiu Lun Hp Cht Thin Nhin

ketol tetracyclic t to dixeton tng ng (158). Cc bc quan trong tng hp l vic gim Clemmensen ca dixetone ny

trng xetol

cho mt

(159) v C / D ng phn ca n. Qu trnh phn r ca cyclopropyl glycol trung gian trong s gim to ra cu c trng ca nhm hydroxy steviol. Mt cch tng t c s dng ti to li h thng vng C/ D ca axit epiallogibberic.

Khng cn nghi ng g na nhng thnh tu tng hp ln ca nm l trong lnh vc tng hp gibberellin. Chi tit y ca s tng hp phn chnh. Th nht, tng hp cc axit gibberic racemic (161, R = H) v axit epigibberic . Th hai, vng A ca axit gibberic c kch hot bi nitrat ha (161, R = NOz) v nitro nhm chuyn i thng qua cc amin to phenol (161, R = OH) S gim ca phenol ny sau to racemic diketo-ester (162), c sn nh l mt chuyn tip. T giai on th ba l s brom ha v hydro brom ha 203 ca gibberellin A, xut hin. Cng vic ny, tri qua hn mi nm, bao gm nm

Tiu Lun Hp Cht Thin Nhin

to dienone .Trong giai on th t, vng A c hinhg thnh li. S to thnh ketal chn lc ngn cn vng D v sau vng A c carboxymethylate ha, suy gim v vng lacton hnh thnh. S epime ha ca vng A nhm hydroxy to mt sn phm suy thoi (164) ca gibberellin A1. Cui cng, t s o ngc ca vng D c cp n vic ny dn ti s tng hp ca gibberellin A4. C20 ca gibberellin, gebberellin A15 (172) c tng hp. S tng hp ny bt u t (166), mt trung gian trong ton b qu trnh tng hp ca cc alkaloids diterpene. S gim ca acetate enol ca n t mt lin kt i trong vng B.

Qu trnh ozon v xc tc c bn cho mt B-nor-aldehyde (167)

ln

lt chuyn i thnh cc xeton cha bo ha tng ng (167a). Qu trnh hydrocyan sau to cho nitrile gc cnh, cchuyn i thng qua dn xut 204

Tiu Lun Hp Cht Thin Nhin

formyl aldehyde khng bo ha (168) v t hnh thnh diacetoxy toluene-psulphonate (169). Ozon ha chn lc to ra mt aldehyde theo s to vng nht nh. X l vi bazo to ra theo 2 giai on (170-171), mt giai on trung gian to ra khung 4 vng. Cu amin sau c chuyn qua azomethine ri thnh gibberellin A15 (172).

Tng hp ring phn ca gibberellin A15 nor-xeton t 7-hydroxy kaurenolide c m t. Giai on chnh trong qu trnh tng hp ny l s hot ha ca nhm methyl C-20 bng quang phn ca mt amid C-19 (173). 205

Tiu Lun Hp Cht Thin Nhin

Mt phng php n gin to khung cacbon 4 vng ca cc gibberellin c li cho vic to c nhm hydroxy u v methylen cui ca h octan 2 vng [3,2,1] c m t. N bao gm x l bromo- olefin (174) vi Liti ng Butyl c mt dn xut hu c ca kim loi cng vo nhm cacbonyl cho sn phm (175). S tng hp ca mt on (176) ca cc diterrpen ankaloids cng c m t di y.

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KT LUN
Sau m t thi gian tim hi u va tham khao cac tai li u , cng vi s gip nhit tnh ca c gio v bn b gip chng em hon thnh bi tiu lun ny . Da trn vic tm hiu v dch ti liu tham kho, bi tiu lun cho chng ta mt cch nhn tng quan v cch phn loi, c im cu trc, tnh cht ha hc v s ph bin cng nh nhng ng dng ca cc diterpenoid. M c du co nhi u c g ng song ch c ch n bai ti u lu n cua chung em vn con nhi u thiu sot v hn ch , v vy chng em rt mong nhn c s ng gp kin nhi t tinh cua cc Thy , C va cng nh cac ba n chung em kip thi sa cha va b sung thm ki n thc .. M t l n na , chng em xin chn thnh cm n hon thnh tt bi tiu lun ny . Nhm sinh vin thc hin 207 c gio a giup chung em

Tiu Lun Hp Cht Thin Nhin

TI LIU THAM KHAO

1. J. W. Rowe, Forest Products Laboratory, U.S. Dept. of Agriculture, Madison, Wisconsin.

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Tiu Lun Hp Cht Thin Nhin

2. * P. K. Grant and M. J. A. McGrath, Tetrahedron, 1970, 26, 1619; P. K. Grant, L. N. Nixon, and J. M. Robertson, ibid., p. 1631. 3. R. C. Cambie, P. K. Grant, C. Huntrakul, and R. J. Weston, Austral. J. Chem., 1969, 22, 1691. 4. K. Bruns, Tetrahedron, 1969, 25, 1771. 5. I. H. Rogers and L. R. Rozon, Canad. J. Chem., 1970,48, 1021. 6.L. J. Gough and J. S. Mills, Phytochemistry, 1970, 9, 1093. 7. ' P. W. Atkinson and W. D. Crow, Tetrahedron, 1970,26, 1935. 8. R. M. Carman, D. E. Cowley, and R. A. Marty, Austral. J. Chem., 1969, 22, 1681. 9. F. Delle Monache, T. Leoncio d'Albuquerque, G. Delle Monache, and G. B. Marini Bettolo, Ann. Chim. (Italy), 1970, 60, 233. 10. Y. S. Cheng and E. von Rudloff, Tetrahedron Letters, 1970, 1131. 11. R. M. Carman and N. Dennis, Austral. J. Chem., 1967,20, 163. 12. R. M. Carman and H. C. Deeth, Austral. J. Chem., 1969,22,2161. 13. T. McCreadie and K. H. Overton, Chem. Comm., 1968, 288. 14. E. Wenkert and Z. Kumazawa, Chem. Comm., 1968, 140. 15. J. L. Fourrey, J. Polonsky, and E. Wenkert, Chem. Comm., 1969, 714. 16. 0. E. Edwards and R. S. Rosich, Canad. J. Chem., 1968,46,1113 ; 0. E. Edwards and B. S. Mootoo, ibid., 1969,47, 1189. 17. S. F. Hall and A. C. Oehlschlager, Chem. Comm., 1969, 1157. 18. L. Mangoni, M. Adinolfi, G. Laonigro, and E. Doria, Tetrahedron Letters, 1968,4167; D. M. S. Wheeler, M. M. Wheeler, M. Fetizon, and W. H. Castine, Tetrahedron, 1967, 23, 3909; R. A. Appleton, J. W. B. Fulke, M. S. Henderson, and R. McCrindle, J. Chem. SOC. (C), 1967, 1943. 19. M. S. Henderson and R. McCrindle, J. Chern. SOC. (0, 1969,2014. 20. L. J. Stephens and D. M. S. Wheeler, Tetrahedron, 1970, 26, 1561. 209

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21. J. D. White, P. S. Manchard, and W. B. Whalley, Chern. Comm., 1969, 1315. 22. E. R. Kaplan, K. Naidu, and D. E. A. Rivett, J. Chem. SOC. (C), 1970, 1656; E. R. Kaplan and D. E. A. Rivett, J. Chem. SOC. (C), 1968, 262. 23. T. Anthonsen, P. H. McCabe, R. McCrindle, and R. D. H. Murray, Tetrahedron, 1969, 25,2233; bT. Anthonsen, P. H. McCabe, R. McCrindle, R. D. H. Murray, and G. A. R. Young, Tetrahedron, 1970, 26, 3091. 24. T. Anthonsen and R. McCrindle, Acta Chem. Scand., 1969,23, 1068 25. S. Kusumoto, T. Okazaki, A. Ohsuka, and M. Kotaki, Bull. Chern. SOC. Japan, 1969, 42, 812. 26. E. U. Ekongand J. I. Okogun, J. Chem. SOC. , 1969,2153. 27. A. Sato, M. Kurabayashi, H. Nagahori, A. Ogiso, and H. Mishima, Tetrahedron Letters, 1970, 1095. 28. G. Berti, 0. Livi, and D. Segnini, Tetrahedron Letters, 1970, 1401. 29. K. Ito and H. Furukawa, Chem. Comm., 1969,653. 30. T. Hori, A. K. Kiang, K. Nakanishi, S. Sasaki, and M. C. Woods, Tetrahedron, 1967, 23, 2649. 31. P. K. Grant, C. Huntrakul, and J. M. Robertson, Austral. J. Chem., 1969, 22, 1265. 32. R. A. Appleton and J. Roeraade, Chem. Comm., 1969, 1407. 33. J. R. Hanson and A. F. White, Phytochemistry, 1970,9, 1359. 34. S. Mihashi, I. Yanagisawa, 0. Tanaka, and S. Shibata, Tetrahedron Letters, 1969, 1683. 35. L. Canonica, B. Rindone, C. Scolastico, K. D. Han, and J. H. Kim, Tetrahedron Letters, 1969, 4801. 36. J. Polonsky, Z. Baskerevitch, N. Cagnoli-Bellavita, and P. Ceccherelli, Bull. SOC. chim. France, 1970, 1912. 210

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37. M. Kitadani, A. Yoshikoshi, Y. Kitahara, J. de P. Campello, J. D. McChesney, D. J. Watts, and E. Wenkert, Chem. and Pharm. Bull. (Japan), 1970, 18,402. 38. C. Tabacik and C. Poisson, Bull. SOC. chim. France, 1969, 3264. 39. R. M. Carman and H. C. Deeth, Austral. J. Chem., 1967, 20, 2789; L. J. Gough, Tetrahedron Letters, 1968, 295. 40. Y. S. Chuah and A. D. Ward, Austral. J. Chem., 1969,22, 1333. 41. R. M. Carman, H. C. Deeth, R. A. Marty, K. Mori, and M. Matsui, Tetrahedron Letters, 1968, 3359. 42. E. Wenkert, D. J. Watts, and L. L. Davis, Chem. Comm., 1969, 1293. 43. H. Kakisawa, T. Hayashi, and T. Yamazaki, Tetrahedron Letters, 1969, 301 ; A. C. Baillie and R. H. Thomson, J. Chem. Soc. (C), 1968,48 44. T. Hayashi, H. Kakisawa, H. Y. Hsu, and Y. P. Chen, Chem. Comm., 1970,299. 45. S. Morris Kupchan, A. Karim, and C. Marcks, J. Org. Chem., 1969,34, 3912. 46. D. Karanatsios, J. S. Scarpa, and C. H. Eugster, Helo. Chim. Ada, 1966, 49, 11 5 1. 47. M. N. Galbraith, D. H. S. Horn, J. M. Sasse, and D. Adamson, Chem. Comm., 1970, 170. 48. S. Ito, M. Kodoma, M. Sunagawa, T. Takahashi, H. Imamura, and 0. Honda, Tetra- hedron Letters, 1968, 2065; Y. Hayashi, s. Takahashi, H. Ono, and T. Sakan, Tetra- hedron Letters, 1968,207 1. 49 S. Ito, M. Kodoma, M. Sunagawa, H. Honma, Y. Hayashi, S. Takahashi, H. Ona, T. Sakan, and T. Takahashi, Tetrahedron Letters, 1969, 2951. 50. P. Sengupta, S. Roy, and K. G. Das, Chem. andlnd., 1970, 534.

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51. B. Blessington, D. W. Mathieson, and A. Karim, J. Chem. SOC. (C), 1970,1703; D. W. 52. E. J. McGarry, K. H. Pegel, L. Phillips, and E. S. Waight, Chem. Comm., 1969, 1074 53 a R. N. Seelye and W. B. Watkins, Tetrahedron, 1969, 25, 447; C. R. Bennett, R. C. Cambie, and T. J. Fullerton, Austral. J. Chem., 1968, 21, 2473. 54 J. W. Huffman, J. Org. Chem., 1970, 35, 478. 55 C. R. Bennett and R. C. Cambie, Tetrahedron, 1967, 23, 927. 56 C. R. Bennett, R. C. Cambie, and W. A. Denney, Austral. J. Chem., 1969,22, 1069. 57 R. C. Cambie and W. A. Denny, Austral. J. Chem., 1969,22, 1699. 58 R. C. Cambie, C. R. Bennett, R. A. Franich, and T. J. Fullerton, Austral. J. Chem., 1969, 22, 171 I. 59 R. Albrecht, H. Heidepriem, and E. Schroder, Annalen, 1969, 725, 154. 60 R. Albrecht, C. Rufer, and E. Schroder, Annalen, 1969, 728, 184. 61 R. C. Cambie and W. A. Denny, Austral. J. Chem., 1969,22, 1989. 62 G. R. Clark and T. N. Waters, J. Chem. Sac. (0, 1970,887. 63 R. C. Cambie, D. R. Crump, and R. N. Duve, Austral. J. Chem., 1969,22, 1975. 64 J. F. Grove and B. J. Riley, J. Chem. SOC., 1961, 1105; A. Tahara, 0. Hoshino, and 65 A. Tahara and Y. Ohtsuka, Chem. and Pharm. Bull. (Japan), 1970, 18, 859. 66 A. W. Burgstahler, J. N. Marx, and D. F. Zinkel, J. Org. Chem., 1969,34, 1550. 67. J. W. Huffman, J. A. Alford, and R. R. Sobti, J. Org. Chern., 1970,35,473. T. Ohsawa, Chem. and Pharm. Bull. (Japan), 1969,17,54,64,78. 212

Tiu Lun Hp Cht Thin Nhin

68 A. W. Burgstahler and J. N. Marx, J. Org. Chem., 1969, 34, 1562. 69 B. E. Cross and P. L. Myers, J. Chem. SOC. (0, 1969,711. 70 R. H. B. Galt and A. K. Saksena, J. Chem. SOC. (C), 1969, 1033. 71. Gh. Angles dAuriac, F. Derguini, and A. Diara, Bull. SOC. chim. France, 1970, 1846. 72. J. W. ApSimon and H. Krehm, Canad. J. Chem., 1969,47, 2859. 73. W. J. Chin, R. E. Corbett, D. R. Lauren, and R. A. J. Smith, Austral. J. Chem., 1969, 22, 2033. 74 J. W. ApSimon and H. Krehm, Canad. J. Chem., 1969,47, 2865. 75 R. C. Cambie and R. A. Franich, Chem. Comm., 1969, 725. 76 R. C. Cambie and R. A. Franich, Chem. Comm., 1970, 845. 77 Werner Herz and J. J. Schmid, J. Org. Chem., 1969,34, 3464. 78. Werner Herz and J. J. Schmid, J. Org. Chem., 1969,34, 3473. 79. R. A. Bell and M. B. Gravestock, Canad. J. Chem., 1969,47, 3661. 80. S. W. Pelletier, C. W. J. Chang, and K. N. Iyer, J. Org. Chem., 1969, 34, 3477. 81. R. A. Bell and M. B. Gravestock, Canad. J. Chern., 1970,48, 1105. 82 J. C. Sircar and G. S. Fisher, J. Org. Chem., 1969,34, 404. 83 J. C. Sircar and G. S. Fisher, Chem. and Ind., 1970, 26. 84 R. C. A. Rottlander, Tetrahedron Letters, 1969,4127. 85 Werner Herz and M. G. Nair, J. Org. Chem., 1969, 34,4016. 86 Werner Herz and R. C. Blackstone, J. Org. Chem., 1969,34, 1257. 87. D. W. Black and G. W. Hedrick, J. Org. Chem., 1969,34, 1940. 88 R. A. Appleton, R. McCrindle. and K. H. Overton, Phytochernistry, 1970,9, 581. 89 D. E. U. Ekong, E. 0. Olagbemi, and F. A. Odutola, Phytochemistry, 1969, 8, 1053. 213

Tiu Lun Hp Cht Thin Nhin

90. D. E. U. Ekong and A. U. Ogan, J. Chem. SOC. (C), 1968, 31 1. 91 S. C. Pakrashi, P. P. Ghosh Dastidar, and S. K. Gupta, Phytochernistry, 1970,9, 459. 92 C. H. Brieskorn and E. H. Pohlmann, Chem. Ber., 1969, 102, 2621. 93 F. Piozzi, V. Spiro, S. Passannanti, and R. Mondelli, Gazzetta, 1968,98, 907; L. F. Piozzi, G. Savonna, and R. Mondelli, ibid., 1969, 99, 373. 94. J. R. Hanson, Tetrahedron, 1970, 26, 271 1. 95. J. R. Hanson and A. F. White, Tetrahedron, 1969, 25, 2743. 96. B. E. Cross, J. C. Stewart, and B. L. Stoddart, Phytochernistry, 1970, 9, 1065; J. R. Hanson and J. Hawker, unpublished results. 97. E. Fujita, T. Fujita, M. Taoka, H. Katayama, and M. Shibuya, Tetrahedron Letters, 1970,421. 98. a T. Kubota and I. Kubo, Bull. Chem. SOC. Japan, 1969,42, 1778; E. Fujita, T. Fujita, H. Katayama, M. Shibuya, and T. Shingu, J. Chem. SOC. (C), 1970, 1674. 99 P. Coggen and G. A. Sim, J. Chem. SOC. (B), 1969,413. 100 E. Fujita, T. Fujit3, and H. Katayama, Tetrahedron, 1970, 26, 1009. 101 E. Fujita, T. Fujita, M. Shibuya, and T. Shingu, Tetrahedron, 1969, 25, 2517. 102 R. A. Appleton, P. A. Gunn, and R. McCrindle, J. Chem. SOC. (C), 1970, 1148. 103 K. Mori and M. Matsui, Tetrahedron Letters, 1970, 3287. 104 a R. M. Coates and E. F. Bertram, Chem. Comm., 1969, 797; *J. C. Fairlie, R. McCrindle, and R. D. H. Murray, J. Chem. SOC. (0, 1969,2115. 105 J. Iwasa and Y. Nakamura, Tetrahedron Letters, 1969, 3973. 106 Z. Kumazawa and R. Iriye, Tetrahedron Letters, 1970, 927.

214

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107 M. Yanai, H. Mishima, T. Kozima, H. Kakisawa, and K. Nakanishi, Chem. and Pharm. Buff. (Japan), 1969, 17, 2036. 108 Z. Kumazawa and R. Iriye, Tetrahedron Letters, 1970, 93 1. 109 H. Hikino, K. Ito, and T. Takemoto, Chern. and Pharm. Buff. (Japan), 1969, 17, 854. 110 H. Hikino, K. Ito, T. Ohta, and T. Takemoto, Chem. and Pharm. Bull. (Japan), 1969, 17, 1078. 111. H. Hikino, Y. Hikino, T. Takemoto, and S. Takahashi, Chem. andPharm. BUN. (Japan), 1970, 18, 852. 112. M. Yasue, T. Kato, and J. Sakibara, Chem. and Pharm. Bull. (Japan), 1970,18, 854. 113 A. Lang, Ann. Rev. Plant Physiot., 1970, 21, 537. 114 N. Murofushi, N. Takahashi, T. Yokota, and S. Tamura, Agric. and Biol. Chem.(Japan), 1969,33, 598. 115 G. V. Hoad, Planta, 1969,87, 164. 116 T. Yokota, N. Takahashi, N. Murofushi, and S. Tamura, Planta, 1969, 87, 180. 117 T. Yokota, N. Murofushi, and N. Takahashi, Tetrahedron Letters, 1970, 1489. 118 K. Schreiber, J. Weiland, and G. Sembdner, Phytochemistry, 1970, 9, 189. 119 P. K. Sircar, B. Dey, T. Sanyal, S. N. Ganguly, and S. M. Sircar, Phytochemistry, 1970, 9, 735. 120 S. N. Ganguly, T. Sanyal, P. K. Sircar, and S. M. Sircar, Chem. and Ind., 1970, 832. 121 J. MacMillan and N. Takahashi, Nature, 1968,217, 170.

215

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122 M. F. Barnes, R. C. Durley, and J. MacMillan, J. Chem. SOC. (0, 1970, 1341. 123 J. C. Brown and B. E. Cross, J. Chem SOC. (0, 1970,71. 124 F. Brisse, Tetrahedron Letters, 1969, 4373. 125 M. Gotz and K. Wiesner, Tetrahedron Letters, 1969, 4369. 126 L. H. Wright, M. G. Newton, S. W. Pelletier, and N. Singh, Chem. Comm., 1970, 359. 127 S. W. Pelletier, L. H. Wright, M. G. Newton, and H. Wright, Chern. Comm., 1970, 98. 128 Y. Ichinohe, M. Yamaguchi, N. Katsui, and S. Kakimoto, Tetrahedron Letters, 1970, 2323. 129 H. Shimanouchi, Y. Sasada, and T. Takeda, Tetrahedron Letters, 1970, 2327. 130 S. W. Pelletier, K. N. Iyer, V. K. Bhalla, M. G. Newton, and R. Aneja, Chem. Comm., 1970, 393. 131 M. Gotz and K. Wiesner, Tetrahedron Letters, 1969, 5335. 132 K. B. Birnbaum, Tetrahedron Letters, 1969, 5245. 133 D. R. Robinson and C. A. West, Biochemistry, 1969, 9, 70. 134 R. C. Pettersen, G. Ferguson, L. Crombie, M. L. Games, and D. J. Pointer, Chem. 135 W. Hoppe, F. Brandl, I. Strell, M. Rohrl, I. Gassman, E. Hecker, H. Bartsch, G. Kreibich, and Ch. von Szczepanski, Angew. Chem. Internat. Edn., 1967,6, 809. 136 E. Hecker, H. Barisch, G. Kreibich, and Ch. von Szczepanski, Annafen, 1969, 725, 130. 137 L. Crombie, M. L. Games, and D. J. Pointer, J. Chem. SOC. (C), 1968, 1347. 216

Tiu Lun Hp Cht Thin Nhin

138 H. W. Thielmann and E. Hecker, Annalen, 1969,728, 158. 139 H. Barisch and E. Hecker, Annafen, 1969, 725, 142. 140 H. W. Thielmann and E. Hecker, Annalen, 1970,735, 113. 141 K. L. Stuart and L. M. Barrett, Tetrahedron Letters, 1969,2399. Comm., 1967, 716. 142 M. Gschwendt and E. Hecker, Tetrahedron Letters, 1970, 567. 143 M. Gschwendt and E. Hecker, Tetrahedron Letters, 1969, 3509. 144 W. Adolf, E. Hecker, A. Balmain, M. F. Lhomme, Y. Nakatani, G. Ourisson, G.Ponsinet, R. J. Pryce, T. S. Santhanakrishnan, L. G. Matyukhina, and I. A. Saltikova,Tetrahedron Letters, 1970, 2241. 145 K. Zechmeister, M. Rohrl, F. Brandl, S. Hechfischer, W. Hoppe, E. Hecker, W. Adolf,and H. Kubinyi, Tetrahedron Letters, 1970, 3071. 146 G. H. Stout, W. G. Balkenhol, M. Poling, and G. L. Hickernell, J. Amer. Chem. SOC., 1970,92, 1070. 147 D. P. Della Casa de Marcano, T. G. Halsall, and G. M. Hornby, Chem. Comm., 1970,216. 148 D. P. Della Casa de Marcano, T. G. Halsall, A. I. Scott, and A. D. Wrixon, Chem. Comm., 1970, 582. 149 D. J. Goldsmith and C. F. Phillips, J. Amer. Chem. Soc., 1969, 91, 5862. 150 T. Kato, M. Tanemura, T. Suzuki, and Y. Kitahara, Chem. Comm., 1970,28. 151 M. Tanemura, T. Suzuki, T. Kato, and Y. Kitahara, Tetrahedron Letters, 1970, 1468. 152 M. E. Kuehne and J. A. Nelson, J. Org. Chem., 1970,35, 161. 153 U. R. Ghatak, N. R. Chatterjee, A. K. Banerjee, J. Chakravarty, and R. E. Moore, J. Org. Chem., 1969, 34, 3739. 154 Y. Inouye and H. Kakisawa, Bull. Chem. SOC. Japan, 1969,42,3318. 217

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155 T. L. Eggerichs, A. C. Ghosh, R. C. Matejka, and D. M. S. Wheeler, J. Chern. SOC. , 1969, 1632. 156 F. Fringuelli, V. Mancini, and A. Taticchi, Tetrahedron, 1969, 25, 4249. 157 A. Taticchi, F. Fringuelli, and V. Mancini, Tetrahedron, 1969, 25, 5341. 158 A. Afonso, J. Org. Chem., 1970, 35, 1949. 159 T. McCreadie, K. H. Overton, and A. J. Allison, Chem. Comm., 1969, 959. 160 K. Mori, Y. Nakahara, and M. Matsui, Tetrahedron Letters, 1970,241 I. 161 K. Mori, M. Matsui, and Y. Sumiki, Tetrahedron Letters, 1970, 429. 162 K. Mori, M. Shiozaki, N. Itaya, M. Matsui, and Y. Sumiki, Tetrahedron, 1969, 25, 1293. 163 W. Nagata, T. Wakabayashi, Y. Hayase, M. Nansada, and S. Kamata, J. Amer. Chem. SOC., J 970, 92, 3202. 164 B. E. Cross and I. L. Gatfield, Chem. Comm., 1970,33. 165 E. J. Corey, M. Narisada, T. Hiraoka, and R. A. Ellison, J. Amer. Chem. Soc., 1970, 92, 396. 166. K. Wiesner, A. Deljac, T. V. R. Tsai, and M. Przybylska, Tetrahedron Letters, 1970, 1145.

MC LC

218

Tiu Lun Hp Cht Thin Nhin

Phn I: M U .................................................................................220 Phn II: NI DUNG. ...........................................................................221 Chng 4. Tritecpenoids ......................................................................221 1. ....................................................................................................................... Squalen 221 2. .................................................................................. Nhm Fusidane-Lanostane 224 3. ...............................................................................Nhm Dammarane-Euphane 233 4. .......................................................................................................... Nhm Lupane 248 5. ..................................................................................................... Nhm Oleanane. 251 6. ........................................................................................................... Nhm Ursane 258 7. .......................................................................................................... Nhm Hopane 260 8. ..................................................................................................... Nhm Serratane. 262 TI LIU THAM KHO ....................................................................265 Phn III: KT LUN...........................................................................272

219

Tiu Lun Hp Cht Thin Nhin

Phn I: M U
Thnh phn chnh ca mt s loi tinh du thm cy l nhn l cc hp cht c cu to mch thng v vng m c th coi nh l nhng dime, trime v polime ca izopren.

l cc hp cht tecpen cha : 10 nguyn t cacbon dime ca izopren. 15 nguyn t cacbon trime ca izopren hay Setquitecpen. 20 nguyn t cacbon tetrame ca izopren hay ditecpen. 25 nguyn t cacbon Sestertecpen. 30 nguyn t cacbon tritecpen. 40 nguyn t cacbon tetratecpen. . 220

Tiu Lun Hp Cht Thin Nhin

n v nh nht ca tecpen l C5H8 hay cng thc tecpen l (C5H8)n.Trong n ln hn hoc bng 2. Trong chng ny chng ta tm hiu v mt loi tecpen c ngha ln, l Tritecpen.

Phn II: NI DUNG.

Chng 4. Tritecpenoids
1. Squalen Biellmann v Ducep [1] c mt tng hp vi nng sut cao v hydrocacbon squalen vi s kt hp ui ui. Phng php ny lin quan n ankyl ha cc trans, trans-fanesyl bromide ca cacbanion (1) c ngun gc tng ng t trans, transfanesyl thioether bng cch x l vi n-butyl-diazabicyclooctane-lithium tetrahydrofuran.Lu hunh trong sn phm sunfua hu c (2) c loi b bng Li trong etylamin.u im ca phng php ny l khng c s ng phn ha. Mt cch tng hp squalen [2] khc c s dng l sp xp li trong phn t ca cc ylide thu c t farnesyl nerolidyl sunfua bng cch x l vi benzyne. 2,3 ;22,23221

Tiu Lun Hp Cht Thin Nhin

diepoxide squalen b ng vng t cc m cy mm xi trng trong ng nghim, to thnh 24,25-epoxycycloartenol(4)[3].

Mt phng php rt ngn gn phn bit gia 4

v 4 -metyl ca tritecpen

tr nn hu dng vi s pht hin ca Moss and Nicolaidis[4] rng s sp xp li Beckman mt cch by thng ca tritecpen 3-ketoximes phn ln c s b tr c nh trong khng gian.

V th, s sp xp li ca oxim (5) vi toluene-p-sulphonyl clorid trong pyridin to ra nitril khng bo ha (6), trong quang ph n.r.m khng c tn hiu ca proton vinyl. Phn ng ny c th tin hnh thng qua cc tosyloxy-imine (7; mi tn) bng cch sp xp li mt cch c ch nh trong phn t. Chi nhm 4 -metyl mi c th gi thit hnh dng bn ngoi cho trans-elimination. Cc tc gi s dng s sp xp 222

Tiu Lun Hp Cht Thin Nhin

Beckman bt thng chng minh r rng [5] rng nhm 4 -metyl ca lanosterol c ngun gc t C-2 ca axit mevalonic.

C Halsal [6] and Moss [5] u a ra mt kin th v rng trong khi 3 hydroxy tritecpen c to ra bi s ng vng nhanh ca (3S)-2,3-oxidosqualen dng gh-gh-gh (8), tng ng vi 3 -hydroxy epimers c th to ra t cht i hnh (3R)-2,3-oxidosqualen vi dng thuyn-gh-gh (9). Quan im trc kia cho rng, nhm 4 -metyl l dn xut C-2 ca axit mevalonic, trong khi , sau ny li cho rng n li l nhm 4 -metyl. S ng vng ca squalen to ra 2,3-epoxid (10), trong sn phm phm cng to 3 vng, ru bicylic (11) c l c to ra t ion bicyclic carbonium (12) bi mt chui cc hydride v metyl di c. Sharpless v van Tamelen a ra kin [7] rng mt trong s cc chc nng ca cyclase enzyme l ngn chn s di c kiu ny i vi bc ca ru bicylic. S hnh thnh v ng vng ca squanlen c tho lun chi tit trong phn II, chng 8. 223

Tiu Lun Hp Cht Thin Nhin

2. Nhm Fusidane-Lanostane Cu trc ca axit helvolic c sa i [8] thnh (13). Vng nhm B axetoxy l C-6 ch khng phi C-7 nh xut trc kia. Kt qu l, phi c mt s thay i cho cc cu trc ca axit helvolinic,axit 7-deacetoxyhelvolic, v axit 7-oxofusidic. Hai ng phn lin kt i (14), (15) c phn lp [9], cng vi axit helvolic, t Cephalosporiurn caerulens. T khi cc hp cht ny c cn nhc l nguyn mu ca cc sterol tn protostane c xut cho cc hydrocacbon c bn (16). Khi [2-C] mevalonate c vi cht chit xut t t bo t do Emericellopsis sp. v cc cht chuyn ha c kim tra bng cch pha long, 3 -hydroxyprotosta-17(20),24-diene (14) c tm thy hot ng (0.27% kt hp)[10]. Cht khng hot ng c pht hin trong cc ng phn lin kt i (15). Sau c chuyn i [9] bi axit vo dihydrolanosterol bi Arigoni and Godtfredsen. Thm vo , bng chng cho cu trc ca protosterol trc ca Corey v ng nghip, t 20,2l-dehydro-2,3oxidosqualen bng cch ng vng vi 2,3-oxidosqualene sterol cyclase c cng thc (17) c dng thng dng nh bn di [11]. Protosterol, c gn vi ng v 224

Tiu Lun Hp Cht Thin Nhin

nng ca hydro C-16, c hydro ha hn cht xc tc rhodiumcharcoal, v axetate tng ng trn ln vi dihydrolanosteryl acetate. Mt lng kt tinh cung cp cho dihydrolanosteryl acetate khng hot ng. Phn ng ca sn phm hydro ha vi axit theo cc iu kin c s dng bi Arigoni sp xp li (15) sinh ra bi s acetyl ha v ph gia vi dihydrolanosteryl acetate. iu ny cho thy rng protosterol c th c xy dng c th hn nh (18) v cung cp h tr cho cc lp th fusidane ca nhn.

Mt s halothurinogenin c bo co. Djerassi v ng nghip phn lp[12] ternaygenin (1 9), koellikerigenin (20), and seychellogenin (21) bng axit. Hydrolysis ca hn hp glycoside thu c t da chut bin. Bohadschia 225

Tiu Lun Hp Cht Thin Nhin

Koellikeri cung cp bng chng u tin r rng v cu trc ca nhm ny bi s tng quan ca seychellogenin vi lanosterol.

Seychellogenin c chuyn i bi mt chui cc phn ng tiu chun vo triol (22), cht m cng c chun b t 11 -hydroxylanostanyl acetate theo cch sau. Qu trnh oxy ha 11 -hydroxylanostanyl acetate vi ch tetra-iodine-acetate di nh sng cho ra[13] cc iodoether (23). Khi qu trnh oxy ha c thc hin trong axit axetic v ngay lp tc trong lithium aluminium hydride gim ete (24) v (25) c phn lp[13] . 11,18 ete (24) c oxy ha thnh -lactone cho, gim lithium aluminium hydride, triol mong mun (22). S tng quan ny vn cn nghi ng cu hnh ti C-20 trong cc holothurinogenin. Praslinogen [14], mt thnh phn nh ca hn hp aglycone l 17 -hydroxy-derivative (26). Nhm 17 -hydroxy-derivative c kh nng chng mt nc, x l bng phosphorus oxychloride trong pyridine, mt methanol thay v nc cung cp cho (27). Holothurinogenin (28) v tng ng vi 25-methoxy- v 17deoxy-25methoxyderivatives (26) v (19) thu c [15] bng cch thy phn cc c t ca Holothuria polii. Cc dienes khng lin hp stichopogenins A2 (31) v A4 (32) c tm thy[16] hi sm, da chut bin.

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N cng c cho rng 25-methoxylated holothurinogenins cp trn l mt artefact trong qu trnh thy phn cc glycosides do tnh axit ca methanol. Chanley v Roosi[17,18] khng nh iu ny qua bng cch kim tra axit nh v thy phn enzyme holothurin A, glycoside chnh ca Actinopyga

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Agassizi v ch ra rng h thng diene tm thy trong holothurinogenins cng l mt artifact. Thy phn trong mi trng axit yu neoholothurinogenin, v d 12 cc glycoside to ra cc - methoxy 7 , 8 dihydro 24 , 25 -

dehydroholothurinogen (33) v tng ng hp cht 12 ,25-dimethoxy (34), n c chuyn i vo holothurinogenins trong iu kin axit mnh hn.

Xem xt s thay i dung mi ( CdCl3 pyridine) ca nhm C-21 trong mt lot 17a-hydroxy v 17-desoxy-neoholothurinogenin v holothurinogenins khin cc tc gi gn cu hnh C-20 nh hnh v (ging nh lanosterol). Enzyn thy phn [18] ca desulphated holothurin A a ra, lin quan n mt s hp cht 12amethoxylated. iu ny cho thy cc cu hnh ca oxy thay th C-12 trong glycoside l .

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Dn xut mi lanostane c cng b: 3 -hydroxylanosta-7,9 (11), axit 24trien-2l-oic (35) t Poria cocos[19] , t Fumes senex [20] ,v axit 6ahydroxypolyporenic (37) t Trarnetes feei[21]. Cycloneolitsin (38), mt cyclopropanoid tritecpenoid ete, c tm thy[22] trong Neolitsea dealbata. Cu trc ca n c xc nh bi s chuyn i ca cycloneolitsin v cycloartenol. Cu trc ca axit mangiferonic (40) t acuminata c xc nh [23] ch yu bng cch so snh cc nhm metyl ca n thay i ha hc vi nhng cycloarotenone. Cu trc lp th ca chui pha trong cimigenol (41) c lm sng t[24] bng k thut n.r.m v o.r.d. Kt lun tng t c a ra[24] sau khi xc nh cu hnh tuyt i bng phng php Horeau, C-24 ca sn phm sau khi loi b km (42) ca cc xeton C-15 c ngun gc t cimigenol. Bi bo y v s ng gp ca 1 tc gi ngi cho cu trc ca actein (43) c ng ti [25]. Sn phm ca phn ng quang ha ca 11-oxolanostanol c thay i [26] cng thc thnh (44). T n c chuyn i thnh cc dixeton cyclopropyl. Bi bo y v s tng hp ca cycloartanol t lanosterol bng con ng lin quan n s quang phn nitrit vi s c mt ca iot c cng b[28]. Mt bo co trc y v tng hp cycloartanol bng con ng tng t c rt li[29].

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Tiu Lun Hp Cht Thin Nhin

Vic ozon ha 9 ,19-cyclolanostane c bo co[30] cho hiu sut tt, tng ng 7-xeton. Qu trnh oxy ha ny i hi s c mt ca vng cyclopropane t lanostanyl acetate khng b nh hng bi cc iu kin tng t. Vic oxy ha ca Jone ca cycloartanyl acetate cho hiu qu thp c 2 hp cht 7-oxo- v 11-oxo-. Mt mi tng quan gia lanostane v cucurbitane c bo co [31,32] bi Barton v ng nghip. Cucurbitacin A (46) c chuyn i[32] vo trong cc dn xut cyclopropane (47) bng tc dng ca tosylate (48) vi natri borohydride. Vng cyclopropane ca hp cht tetrahydro (49) c m ra bi qu trnh anion c lin quan n s proton ha ca cht khi mo 19-methyl carbanion bi nhm hng tm 2 -hydroxy (49), to ra tretra xeton (50) sau qu trnh oxy ha[31] ca axit eburicoic(51). D hexanorcucurbitacin (52) thu c t c Begonia[33]. N lun c sn bi qu trnh oxy ha metaperiodate natri diacetate cucurbitacin D (53).

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Tiu Lun Hp Cht Thin Nhin

Tng hp k hiu lanosterol, cycloatenol v cc dn xut parkeol s dng trong cc nghin cu sinh tng hp c nghin cu[34] v m t. Cc phng php loi b 1 hoc 2 nhm metyl t 4,4-dimetylsteroids c cng b[35]. Lanosterol b suy bin[36] thnh trimetyl pregnenolone (54).

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3. Nhm Dammarane-Euphane Vic phn tch ln u tin hp cht dammarane t mt loi a y c bo co[37]. Diacetylpyxinol (55) c thu thp t loi a y Pyxine endochrysma v cu trc c thit lp bng cch phn tch X-quang[38]. N l 3-epimer triterpene C, trc y c tch ra[39] t Betula platyphylla. iu th v so snh cu to ca vng tetrahydrofuran trong pyxinol [24-(R)] v bromoderivative (56) [24-(S)] c to ra bi qu trnh oxy ha N-bromosuccinimide ca betulafoliene triol (57). phn trc, tetrahydrofuran nm trong cng mt mt phng nh phn cn li ca phn t, trong khi cu trc tinh th cc cht sau[40] c nh hng gn nh vung gc vi mt phng ca phn tetracyclic. Axit dryobalanonolic (58) xy ra[23] trong Dryobalanops arornatica vi dipterocarpol (59) v dryobalanone (60). Cu trc ca n c quy nh trn c s so snh s thay i ha hc ca methyl gia (59) v (60).

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Bn axit mi, axit masticadienolic (61) v 3-epimer (62) v axit isomasticadienolic (63) v 3-epimer (64), c phn lp[41] t nha ca Pistacia terebinthus. S nhm ln m bao quanh cc axit elemi c gii thch[42] bi Halsall v cc cng s ca ng. mt nghin cu t m cc axit t nha elemi, h xc nh c axits 3-oxotirucalla-8,24-dien-2-1oic (65), tng ng dn xut 3hydroxy- v 3-hydroxy (66) v (67), v axit 3 hydroxytirucalla-7,24-dien-21-oic (68). H cho rng 'mt axit elemolic' ca ngi lm trc y l mt hn hp ca cc axit3-hydroxy-7-v-8-, rt kh phn tch.

Sapelin A (69) v sapelin B (70) thu c[43] t Entandrophragrna cylindricurn (Meliaceae) l nhng v d thm ca nhm euphane tirucallane v dn xut cng xy ra vi nhau, l tin cht c tim nng,

tetranortriterpenoids (xem sau). Sapelin A lin quan ti bourjotinolone A (71)[44] Sapelin B phn ng vi natri periodate cho dialdehyde (72) c bin i thnh cng hn hp natri v trioxidecrom vo -lacton (73) trc y thu c t sapelin A v bourjotinolone A. Triterpenoid Penta-ol (74), lin quan cht ch n odoratol (75), c phn lp[45] t Cedrela glaziovii. Bi bo y v aphnamixin (76) c a ra[46]. Cc kin[47] cho rng aphnamixin c th l 3-epiturreanthin b bc b.

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Cc dn xut trung gian apo-euphol tirucallol trong biogenesis ca tetranortriterpenoids nhn c s h tr mnh m vi vic c lp[48] cc grandifoliolenone (77), mt tin cht gedunin tim tng, t Khaya grandifoliola vo 235

Tiu Lun Hp Cht Thin Nhin

nm 1967. Cyclopentenone tng ng (78) cng xy ra K.grandilfoliola[49]. Mt s cc hp cht thuc loi ny c cng b. Lavie v Levy tm thy[50] cc lacton (79), r rng c lin quan n melianone (80)[51], trong tri cy ca Melia azedarach. Adesogan v Taylor thu c[52] tin cht khivorin (81)Khaya iuorensis. Ngoi ra, nhm Jamaica Chan v Taylor phn lp[53] mt s hp cht apo-, bao gm c cc triol (82) lin quan ti grandifoliolenone, t sapele (Entandrophragm cylindricurn).

Tetranortriterpenoids. Khi tip xc vi nh sng mt tri trong s hin din ca oxy gedunin c chuyn i, hiu sut 35%, vo photogedunin (83, trng vi mt hp cht tm thy trong chit xut Cedrela odorata[54]. 6-Hydroxygedunin (84) c tng hp[55] mt cch r rng t 6,7 236

Tiu Lun Hp Cht Thin Nhin

anhydrogedunin qua 6,7- epoxide. K t khi cc tnh cht vt l (84) khc nhau t nhng hp cht t Carapa guianensis, trc y cng thc[56] nh l 6-hydroxygedunin, n c l l ng phn 6- hydroxy-. Trong mt cuc tm hiu boron cc trifluoride xc tc cho vic sp xp li 14,15 epoxy--lactones trong dy ny Ekong v Selema ch ra rng[57] cc sn phm ph thuc vo lp th ca nhm hydroxy ti C-7.

S sp xp li 7-hydroxyderivatives (85) c lin quan n 7-deacetylkhivorin v 7-deacetylgedunin mang li -keto-lacton (86) v diene (87). S tham gia ca 7hydroxygroup m epoxide c chng minh bi thc t rng 1,2-epoxide 1,2-epoxy-7-deacetylgedunin nh khng thay i trong qu trnh phn ng. Tng t x l tng ng vi dn xut 7-hydroxych yu sn phm sp xp li l 7-xeton (88).

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C mt ngoi l cn hn ch cho n nay vn cng nhc ca vng b phn ct tetranortriterpenoidscho cc thnh phn ca Rutaceae xut hin,[52] vi s phn lp methylivorensate (89) t Khaya ivorensis (Meliaceae). Methyl ivorensate c to ra hiu sut thp bi qu trnh oxy ha acid perbenzoic ca methyl angolensate. Zapoterin rt c th l 11-hydroxyobacunone (90)v n cho thy mt ht nhn Overhauser hiu lc gia cc proton C-1 olefinic v proton carbinol ti C-11[58]. Cu trc (90) trong ph hp vi xut[59] trc , nhng mu thun vi s thay i c thc hin bi Dreyer[60].

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Ton b t liu trn andirobin (9) a ra[61]. Tng ng 1,2- dihydro- derivative, aphnamixinin (92), c phn lp[46] t Aphnarnixis polystacha. C41H52O17, mt limonoid phc tp t

Bicyclononanolides.

Utilin,

Entandrophragrna utile [62], c chng minh bng cch phn tch X-quang[63] c cu trc (93) vi cc tnh nng cha tng c hnh thnh lin kt gia mt trong nhng nhm C-4 methyl (C-29) v C-1 cng nh s hin din ca mt orthoacetate. Utilin c l pht sinh bng s thay i tip theo ca tin thn vi bicyclononane bnh thng vng h thng tm thy trong cc cht ca nhm ny. Ngun gc ca lin kt mi C-C lm tng kh nng hp dn c th . Hai sn phm methanolysis ca utilin[62] by gi c th c xc nh l cu trc (94) v (95).

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Mt s th v l 8,30-epoxide, xylocarpin (96), thu c[64] t Xylocarpus granatum bi Okorie v Taylor. Trn vic x l vi chromous clorua n cho deoxy-derivative tng ng (97) cng c tm thy trong dch chit xut. Xylocarpin sp xp li trong axit ti diene (98) v c s -lactone v mt bis-lactone c xc nh l cc cu trc (99) v (100) tng ng. Vic tm hiu[65] v Cedrela augustifolia bi Lavie, Zelnik v cc cng s i ti s phn lp ca fissinolide (101), augustadienolide (102), 2-hydroxyaugustadienolide (103). Cc tc gi chorng thay i ha hc v H-17 cung cp mt tin on cho v tr cn li ca lin kt i trong dy cht ny, v trn c s sa i cu trc v fissinolide (104) vi cc lin kt kp trong v tr 8,9. Taylor, tuynhin, xut bn nhng th nghim[66] cng hng t i v bng chng[67] khc c nhng h tr mnh m cho cu trc ban u (101) cho fissinolide. 2Hydroxyfissinolide (105) v dihydro-derivative tng ng (106) c phn lp t Khaya ivorensis [52]v K.madagascariensis [66] tng ng. Hp cht dihydro(106), x l vi base, tri qua mt chuyn hydride intramolecular t C-3 ti C-1 cung cp, sau khi acetylation, acetate ketol ng phn (107). S hin din ca nhm hydroxy-cp ba ti C-2 ngn cn qu trnh retro-nghch o-realdolisation m thng xy ra trong dy cht ny. Dihydrokhayasin (108) thu c[68] t K. anthotheca. Cu trc ca n c xc nhn bi mi lin kt vi carapin (109).

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Trong s cc hp cht mi lin quan n 6-hydroxycarapin (110) t Cedrela glaziovii[45], the 3-acetate (111) t K. Nyasica[69]v lacton (112) c ngun gc t mexicanolide, t K. ivorensis[52].Nhng ti liu y xu thin trn nyasin t K. nyasica[69], khayanthone t K. anthotheca[68], v 11-acetoxykhivorin t K. madagascariensis[66]. N c th l nimbolin A (113), nimbidinin (114), v nimbolin B (115)i din cho ba giai trn con ng n vng c-ct tetranortriterpenoids. Nimbolins A v B c ly[70] t Melia azedarach v Azadirachta indica v nimbidinin t s thy phn ca M. indica[71].

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Fraxinellone (116) cng c tm thy trong M.azedarach chit xut[70] v hin c phn lp t cy thuc c hai h Meliaceae v Rutaceae. x l ca fraxinellone vi N-bromosuccinimide mang li bromo-derivative (117), c cu hnh tuyt i c xc nh l (117)] bi phn tch X-quang[72]. Kt qu ny nhn mnh mi quan h gia fraxinellone v tetranortriterpenoids thm ch mc d con ng s thoi ha vn m h. Tng t nh limonoid phn mnh, pyroangolensolide (118), c to ra[73] bi s nhit phn ca methyl angolensate.

S sch ghi nhn cc qu trnh invitro m phng cc bc khc nhau trong chng trnh biogenetic c xut cho s hnh thnh ca triterpenoids tetranor t tin thn euphol hoc tirucallol. Halsall v cc ng nghip ca ng, trong bi bo y [74] trn s hnh thnh ca cc cht dn xut apotirucallol sp xp li tirucallol 7,8 epoxit [v d nh (119) + (120)] cho rng s thay i nhm methyl C14 v s mt mt ca proton C-15 xy ra bi mt qu trnh phi 243

Tiu Lun Hp Cht Thin Nhin

hp lin quan n vic loi b intramolecular H 15 ca chc C-7 oxy. iu ny c l l do cc loi 1,3-diaxial ca mi quan h gia C-15 to ra hydro v oxy li ca epoxide. Cc tc gi ny cng iu tra sp xp li[74] tng ng 8,9-epoxit.

Cc 8,9 epoxide cho 7,9 (11) diene nh bo co trc y trong khi cc 8, 9-epoxide (121) sp xp li bng cch di c diene methylcis lin hp khng (122) .Mt s mi tng quan t c bng cch s dng oxidations Baeyer-Villiger .Lavie v Levy chuyn i[75] epoxyazadiradione (123) vo gedunin (124) nng sut 90% vi acid perbenzoic. X l lu hn 1,2-dihydro epoxy azadiradione mang li[75] mt hn hp ca 1,2-dihydrogeduninand acetate 1,2-dihydr0-7a-obacunyl (125).

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Tng t nh vy, khayanthone (126) c chuyn i [76]thnh khivorin (127) hydrogen peroxide kim trong t-butanol.Tetranortriterpenoid n gin (128), trc y tng hp t trreanthin[77], c chuyn i[76] vo azadirone (129) bng phn ng vi brom ng tip theo l dehydrobromination.

Cc cu hnh ca oxy ether C-1 trong methyl angolensate (130) c th hin r rng c tng hp[78] mt phn 7 t7-deacetyl-7 oxokhivorin thng qua cc hp cht deoxy-(131).Loi th hai l qu trnh oxy ha axit convertedby peracetic 245

Tiu Lun Hp Cht Thin Nhin

& lacton(132) v iu ny c m ra bi acid -sulphonic toluene trong benzen cung cp cho diene-lacton (133).Thy phn kim nh cc nhm acetate tip theo l qu trnh axit ha dn n Michael b sung ca nhm-1-hydroxy ,-lacton khng bo ha. qu trnh oxy ha nh hon thnh vic chuyn i methyl angolensate (130) . Cc -diketone (134), mt tin cht quy nh i vi nhm bicyclononanolide, cng c chun b[79] t 7-deacetyl-7oxokhivorin mt l trnh tng t. X l (134) vi mt baz rt yu d c [79]phn ng Michael ti C-2 h thng diene-lactone hnh thc mexicanolide (135).

Quassinoids-Simarolide (136) trc y ch c cung cp mt lin kt cu trc gia limonoids v quassinoids.Apicrasin lin quan (137) c phn lp[80] t Picrasmaquussioides (P. ailan-thoides) c i km trong trch xut cc picrasin B (138)[81] c chuyn i sang quassin (139) bi qu trnh oxy ha v methyl ha oxit bismuth . Mt lot cc dn xut quassin lin quan cht ch, nigakilactones A (140), B (141), C(142), E (143), v F (144) xy ra vi quassin P. aiIanthoides[82,83]. Cu trc ca amarolide c sa i [84] thnh (145).

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Quan st ca mt khp ni ln gia H9 v H11 trong NMR ph lm cho 11chuyn nhng trc, 12-ol khng ng vng.Cc cu trc (146), trc y ngh [85] cho bisnorquassin, c xc nhn c th bng cch phn tch X quang cng tit l cc stereochemistry[86].

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Mt bi bo y v eurycomalactone (147) t Eurycomalongifolia, xut hin[87] hin nay l Eurycomalactone l v d duy nht ca loi hp cht ca C.

4. Nhm Lupane Hui v Fung phn lp[88] glochidonol (148)t Glochidion wrightii. N tri qua tnh trng mt nc sn sng glochidone, v lithium hydride nhm gim mang li mt hn hp ca glochidiol v 1b tng ng vi 3b-diol.Th hai cng c tm thy cc loi Glochidion[89].Lupeol c chuyn i[90] thnh glochidone bng cch ca xeton-dibromo (149). Mt thnh vin th hai ca A(1), 28 bisnorlupaneseries , deoxyemmolactone (150), c tm thy[91] trong v Alangium villosum.V tr ca cc lin kt tng gp i trisubstituted vn cn nghi ng. Jingullic acid, t Emmenospermum alphitonioides , c ch nh [92] cu trc(151). l tng quan vi sn phm qu trnh oxy ha thy ngn acetate (152) ca axit dihydroceanothic (153).

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Cc nghin cu Degradative ch ra [93] rng qu trnh oxy ha acetate thy ngn acetyl-betulinic axit (154) v axitdihydroceanothic (153) kt qu trong s hnh thnh ca C-28 +C-19 lactones (155) v (152).Cc cu hnh ca hydro C-18 trong nhng hp cht ny l .Trong iu kin tng t betulin (156) c chuyn i [94] thnh ether (157). Cc sn phm ca qu trnh oxy ha acetate thy [95] v ngn ca acetate phi l khng

lupenyl (158)3b-acetoxylupa-18, 20 (29)-diene (159)

13(18), 20(29) dieneas trc ngh x l vng seconitrile (160),xut pht t lanostenone, vi acetate thy ngn dn n cc dn xut thm (161) [96].

Halasall v cc cng s ca ng lm sng t[97] cu trc cc sn phm ph ca s phn gii ozon ca metyl axetyl betulinate(162).Ngoi c nhng k vng v norxeton, h thu c 2 hp cht trisnor (163) v sn phm Baeyer-Villiger, v bisnor axit(166).Nhng kt qu ny l hp l trong gii hn ca 3 c ch phn hy khc nhau ca ozonit(167).

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Trong nhng nghin cu[98] tng t ca s phn gii ozon ca betulin iaxetat, Vystrcil, v Budesinsky thu c cc cht inter alia (168),(169), v (170).Tip tc nhng nghin cu v s epime ha C-19 trong chui lupine, cc tc gi tuyn b s hnh thnh ca lacton vi s cn bng acid ca acid bisnor (172) [99]. S oxi ha axit performic (HCOOH)[100] ca nhm iso-propenyl c m t trong mt s dn xut ca lupine. Hu ht cc sn phm c hp l ha vi vic gi thit v s sp xp li ca mt epoxit hnh thnh ban u.

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5. Nhm Oleanane. Ba hp cht mi,l cc axit platycogenic A,B v C thu c t platycodon grandiflorum[101] bi Kubota v cc cng s ca ng .Axit Platicogenic A c phn lp ging nh -lacton (174) , cht m nu nh x l vi boro-hydride s c platicodigenin(175), v d u tin ca 4,4-dihydroxylmetyl-triterpenoid. Platicogenic B v C theo th t c gn cho cc cu trc(176) v (177). Acerotin(178) v acerocin(179) l 2 triterpenoid aglycon mi xut pht t cc saponin gip c ch cc khi u ca Acer negundo[102]. Thy phn kim c (178) v (179) sinh ra axit acerogenic (180),c metyl ete c kh bi lithi hydrua(LiH) n 16deoxybarringtogenol C(181). Ngoi ra, acerotin lm quay quang trans, trans-dienoic axit trong khi acerocin lm quay quang cis,trans-dienoic axit(183).

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Kupchan v cc cng s ca ng y cho rng nhm ete cha no trong acerotin v acerocin c th c 1 chc nng quan trng trong hot ng c ch cc khi u ca cc saponin. Castanogenol(184), t v ca cy Castanospermum australe [103] c iu ch bng cch kh bayogenin metyl ete vi lithihyrua (185).

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Cu trc ca entagenic axit(186) c sa li [104].H thng ln cn glycol c ngun gc ban u t 21,22.Rubusic axit (3,7-dihydroxyolean-12-en-28-oic axit) c phn lp t Rubus moluccanus [105]. S thay i trong cc chuyn v ha hc ca nhm tertiary metyl dn n s thay i vi cc m hnh thay th, c m t[106-108].Cc d liu c sn c dng gn cu trc cho cyclo miretin E(187), t Cyclamen europa[106], v 2,3dihydroxyolean-12-en-28-oic axit, t Shorea acuminata[107].Cht sau l ng nht vi 1 trong 2 cht ca cis-2,3-diols thu c bng cch oxi ha osimi(Os) tertroxit ca olean-2,12-dien-28-oic axit. Cc cu trc trc c gn vo 2 cht ca cis-2,3diols l li v phi c thay i[107].-Peltoboykinolic axit c chng minh l C-27 cacboxylic axit bi mi tng quan vi cincholic axit(189) [109].[cf. peltoboykinolic (xem sau)]. Serratagenic axit, t Clerodendron serratum [110] , c xc nh l 3-hydroxyolean-12-en-28,29-dioic axit (190). Ti liu y v jegosapogenol (barringtogenol C,aescinidin) v cu hnh C-21 v C-22 trong barringtogenol D, aescigenin, protoaescigenin, and isoaescigenin, c xut hin[111].

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Aleuritolic axit (191) t Aleuritus mnontana, d dng c chuyn i[112] bi axit thnh axit acetyloleanolic. Este tng ng s cho myricadiol (192) bng cch kh vi lithihyrua (LiH). Bryonolic axit (193), t r ca Bryonia dioica[113], c bin i thnh isomultiflorenol (l94). N c to thnh t cc -lacton (195) bng cch x l axit v -xeton cha no (196) vi axit percloric v anhydrit axetic.

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S tch lp quang ha ca friedelin c din ra[114] cung cp nor-secoacid (197) cho seco-acid thng dng. Putranjivic axit (198), mt seco-acid cha no, c tuyn b t Putranjiua roxburghii[115]. Cc nhm cacbonyl trong friedelan-x-one (199) c thay th[116] ti C-21 trn c s ca s phn tch quang. S chia tch em li axetalehit v dien khng lin hp (200).

255

Tiu Lun Hp Cht Thin Nhin

Hai ti liu[117,118] xut hin m t mt s phng php tng hp ca alnusenone (201). Cc bc bao gm s chun b ca epimeric octahydropicenes (202) v (203).

Cis,syn-isomer (202) c bin i thnh brom-xeton (204), c ha hc lp th c xc nh bng cch phn tch tia X. Trans,anti-isomer (203) c chuyn thnh xeton (205) vi yu cu ha hc lp th cho mt tin thn ca alnusenone. Tuy nhin, hiu sut thp cn tr vic tip tc ca phng php ny.

256

Tiu Lun Hp Cht Thin Nhin

-Amyrin c bin i thnh axit oleanolic[119]. Cc bc quan trng bao gm functionalisation ca nhm methyl ti C-28 bi s quang phn ca nitrite-13nitrite.T khi -amyrin c tng hp, qu trnh ny c cho l mt cch tng hp chnh thc ca oleanolic axit. Axit ursolic thu c t -amyrin vi mt cc bc tng t[119] . S oxy ha bng nh sng ca axit spergulaginic (206) ,tip theo l phn ng vi tetra-axetate dn n s hnh thnh ca cc eupteleogenin, nortriterpenoid (207) [120]. Cc qu trnh oxy ha cc olefin triterpenoid ti xeton vi N-bromosuccinimide trong dung dch ioxan c tuyn b[121] thu c nng sut cao, hn hp phn ng phi c chiu x vi nh sng nhn thy. Cc o.r.d. v c.d. b cong ca mt lng ln 12 axit triterpenoid c tranh lun[122]v kt qu c xem l tng t vi cc axit no v cc hyrocacbon no . Oleanolic v cc loi axit ursolic xut hin tn ti trong dung dch vi mt cu trc c u tin hn c nhm carboxy syn-phng vi lin kt (C-16)-(C-17).

S hydroxyl ha vi sinh vt ca liquiritic (208) v axit 18-quiritic (209) c nghin cu [123] xut pht t 7, 15, hoc c hai.

257

Tiu Lun Hp Cht Thin Nhin

6. Nhm Ursane Mt imetyl ete -lactone mi t nha Dammar c chng minh l c cu trc (210) bng cch phn tch tia X[124].1 biogenesis rt c th xy ra t Asiatic axit [(211) - (212) - (210)] c xut.

258

Tiu Lun Hp Cht Thin Nhin

Madasiatic axit (213), c cc lin h gn vi axit asiatic v madecassic axit, c phn lp t Centella asiatica[125]. Vic bo v h thng diol ln cn, bng qu trnh oxy ha cc xeton-6 v s kh Wolff-Kishner thu 2, 3-dihydroxyurs-12-en28-oiac axit.

Rubitic axit, t Rubus fruticosus[126], l 6 hoc 7-hydroxyursolic axit (214).

Peltoboykinolic axit t thn r ca Peltoboykinia tellimoides [109] l urs-12-en-3-ol27-oic axit (215). y l v d u tin ca mt dn xut -amyrin vi mt nhm 259

Tiu Lun Hp Cht Thin Nhin

carboxy duy nht C-27. -peltoboykinolic axit, dn xut tng ng vi -amyrin, cng c m t (xem trn).

7. Nhm Hopane Phlebic axit A, cht cng xut hin[127] trong a y Peltigera aphthosa cng nh 15-acetoxy 22-hydroxyhopane (dustanin monoaxetate) l 28-acetoxy-22hydroxyhopan-23-oic axit (216). Mollugogenol B v C, cc saponin mi t Moflugohirta[128,129], c cu trc theo th t l (217) v (218).

260

Tiu Lun Hp Cht Thin Nhin

Cc ti liu y v mollugogenol A (219) [130] v 3, 4-epoxyfilicane (220)[131] c xut hin. Clorua Pyridinium c s dng cho vic chuyn i ca mt s tetrasubstituted epoxit trong lot cht ny vo cc ien cha c sp xp li[132].

261

Tiu Lun Hp Cht Thin Nhin

8. Nhm Serratane. Ru Nht Bn, Lycopodium clavatum, l mt ngun phong ph ca cc dn xut serratane.T chng Tsuda v cng s phn lp c 21-episerratriol (221)[133] (serrat-14-en-3, 21 ,24-triol), 16-oxolycoclavanol (222)[134], lycoclavanin (223)[135], v ba iol 16-oxo (224), (225), v (226)[136] .16-Oxoserratriol (227) thu c t L. Serratum [134].Cu trc ca cc hp cht ny c c xc nhn trn c s ca quang ph n.m.r. v mi quan h tng ng vi cc hp cht c bit n. c bit, qu trnh oxy ha ca metylen allylic ti C-16 vi t-butyl cromat cung cp mt hng d dng to cc chui 16-oxo.

262

Tiu Lun Hp Cht Thin Nhin

Cc ti liu y v tohogenol v tohogeninol t L. Serratum [137] v cc dn xut serratene ca v cyPicea sitchensis (Sitka Spruce)[138] xut hin. Mt s hp cht mi lin quan n serratenediol c tm thy trong v ca P.sitchensis[139]. Chng bao gm 3, 21-dimethoxy v 3-methoxy-21-keto . Phlegmanol A t L. phlegmaria c ch r[140] l 3-dihydrocaffeic axit ,este ca serratenediol. Khi lng mnh v quang ph ca 14 serratene v cc dn xut ca n c pht hin[141].Vng by cnh xut hin kim ch s tch lp v qu trnh retro-Diels-Alder in hnh c tm thy trong 14-taraxerene lin quan n triterpenoids pentacyclic th t quan trng hn nhiu. Ngoi ra cc phn ng (Epoxidation, hydroboronation, osmylation) to 14 lin kt i ca serratenes xy ra ch yu l t mt , mc d hydro cung cp gn nh cc lng bng nhau 14 v 14 serratanes[142].S sp xp li xc tc axit ca 14, 15-epoxyserratane dn [142] n alehit (228),cht m vi s kh Wolff-Kishner to neoserratane (229).

263

Tiu Lun Hp Cht Thin Nhin

264

Tiu Lun Hp Cht Thin Nhin

TI LIU THAM KHO

[1] : J. F. Biellmann and J. B. Ducep, Tetrahedron Letters, 1969, 3707. [2] : G. M. Blackburn, W. D. Ollis, C. Smith, and I. 0. Sutherland, Chem. Comm, 1969, 99. [3] : R. Heintz, P. C. Schaefer, and P. Benveniste, Chem. Comm., 1970, 946. [4] : G. P. Moss and S. A. Nicolaidis, Chem. Comm., 1969, 1077. [5] : G. P. Moss and S. A. Nicolaidis, Chem. Comm., 1969, 1072. [6] : G. P. Cotterrell, T. G. Halsall, and M. J. Wriglesworth, J. Chem. Soc. (0, 1970, 739. [7] : K. B. Sharpless and E. E. van Tamelen, J. Amer. Chem. Soc, 1969,91, 1848 [8]: S. Iwasaki, M. I: Sair, H. Igarashi, and S. Okuda, Chem. Comm., 1970, 1119. [9]: T. Hattori, H. Igarashi, S. Iwasaki, and S. Okuda, Tetrahedron Letters, 1969, 1023 [10]: A. Kawaguchi and S. Okuda, Chem. Comm., 1970, 1012. [11]: I E. J. Corey and H. Yamamoto, Tetrahedron Letters, 1970, 2385. [12]: P. Roller, C. Djerassi, R. Cloetens, and B. Tursch, J. Amer. Chem. Soc., 1969, 91,4918. [13]: P. Roller and C. Djerassi, J. Chem. Soc. (C) ,1970, 1089. [l4]: B. Tursch, R. Cloetens, and C. Djerassi, Tetrahedron Letters, 1970, 467. [l5]: G. Habermehl and G. Volkwein, Annalen, 1970, 731, 53. [l6]: G.B.Elyakov, T.A.Kuznetsova,A.K.Dzizenko, and Y.N.Elkin, Tetrahedron Letters, 1969, 1151. [17]: J. D. Chanley and C. Rossi, Tetrahedron, 1969, 25, 1897. [18]: J. D. Chanley and C. Rossi, Terrahedron, 1969, 25, 1911. 265

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[55]: [56]:

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Phn III: KT LUN.

Triterpen c cha trong tinh du, nha ca thc vt bc cao.Triterpen c trong nm, tam tht, nhn sm, sm Ngc Linh, c tc dng tng cng chuyn ha v

272

Tiu Lun Hp Cht Thin Nhin

tng sc khng cho c th, l thnh phn gip phng mt s bnh nh ung th, tiu ng, tng m mu,tng huyt p, gim sc khng Triterpen thng gp trong thc vt di dng tit, gucozit hoc trng thi t do. Tiu biu cho triterpen l Squalen c trong cht bo ca gan c mp cng nh cc c khc. Mt triterpen khc c bit n l axit masticadienic. Axit ny c dung lm sn bng.

TRNG I HC BCH KHOA H NI 273

Tiu Lun Hp Cht Thin Nhin

VIN CNG NGH HA HC B MN HA DC V HA CHT BVTV

TIU LUN
HA HC CC HP CHT THIN NHIN TI: CAROTENOID V POLITERPENOID

GV HNG DN : PGS.TS TRN THU HNG SV THC HIN : V L TIN NGUYN MNH THNG NGUYN DANH THANH NGUYN TH THY MSV: 20082670 MSV: 20083504 MSV: 20082343 MSSV:20072812

H NI 11/2011

274

Tiu Lun Hp Cht Thin Nhin

MC LC
Mc lc 2 M u3 1. Gii thiu4 2. Phng php vt l...5 3. Cc carotenoid t nhin mi.9 Carotenoid khng tun hon10 Cc carotenoid n vng.13 Cc carotenoid 2 vng..14 Cc carotenoid vng pentanoid v vng thm......17 Alenic v Carotenoid Acetylenic18 Glycose v Isoprenylated Carotenoid.21 4. Ha hc carotenoid.24 5. Cc carotenoid suy thoi27 6. Polytecpenoids35 Kt lun...36

275

Tiu Lun Hp Cht Thin Nhin

M U
Ha hccc hp cht thin nhin lun l mt b phn quan trng ca ha hc hu c, thm ch cho n cui th k th 19 hai khi nin ny vn c coi l mt.Nh nhng tin b to ln trong cc lnh vc l thuyt v thc hnh ha hc cng nh nh kt qu ca cc chng trnh sng lc c h thng m cc hng nghin cu ny t c nhng trnh han thin cao v s hiu bit ca chng ta v cc hp cht thin nhin c ht sc m rng. Ta c th k n mt s cht cht c phn lp t thc vt v ng vt nh sau : axit tactaric (1769), axit lactic (1782), mocphin (1805), quinin (1820), nicotin (1828),hematin (1826), carotene (1831). V c bit s pht trin ca ha hc hu c ni chung v ca thuyt cu to ni ring to c s cho vic nghin cu h thng cc lp cht nh Carotenoid v Polyterpenoid. Trong giai on hin nay lnh vc ha hc cc hp cht thin nhin ngy cng c y mnh nghin cu. Do nhm 5 chng em c giao nhim v dch, tm hiu cc hot tnh, cc tnh cht Carotenoid v Polyterpenoid di s hng dn ca PGS.TS ging vin Trn Thu Hng. Bi dch chc chn cn nhiu thiu xt mong cc thy c v cc bn gp nhm chng em han thin thm. Chng em xin chn thnh cm n!

276

Tiu Lun Hp Cht Thin Nhin

CHNG 5 CAROTENOID V POLITERPENOID

1. Gii thiu : Nhng nm gn y, vic p dng mt lot cc k thut vt l hin i dn n s tin b nhanh chng trong ha hc cc nhm cht carotenoid. Nhng nghin cu ny lm sng t cc cu trc ca nhiu carotenoid, bao gm c cu hnh tuyt i ca chng. Nhng nh gi gn y r rng phn nh nhiu s quan tm trong lnh vc ny. Cc cuc hp thng xuyn v caroten ca IUPAC tho lun cc nghin cu v phng php vt l [1], trc khi ph [2], tng hp [3], v cu trc [4] ca chng. Phng php quang ph c tng quan [5] ging nh allenic v acetylenic carotenoid [6]. Ngoi ra qu trnh trao i cht ca carotenoid a ra mt s terpenoid quan trng. Vitamin A (retinol) [7] c to ra bng cch chia tch cc lin kt i trung ng. Cu trc, v tng hp sinh hc, c lin quan l hoormon thc vt abscisic axit [8]. Mc d polyterpene c bit n nhiu nht l cao su, nghin cu gn y chng gii thch mt lot cc polyprenols v cc hp cht lin quan nh vitamin E v K [9].

[1]U. Schwieter, C. Englert, N. Rigassi, and W. Vetter, Pure Appl. Chem., 1969, 20, 365. [2]C. R. Enzell, Pure Appl. Chem., 1969, 20, 497. [3]B. C. L. Weedon, Pure Appl. Chem., 1969,20, 531 ; 1967,14,265. [4]S. Liaaen-Jensen, Pure Appl. Chem., 1969,20,421; 1967,14,227. [5]B. C. L. Weedon, Fortschr. Chem. org. Naturstofe, 1969,27, 81. [6]B. C. L. Weedon, Rev. Pure Appl. Chem., 1970. 20, 51. [7]0. Isler, Experienria, 1970, 26, 225.

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[8]P. F. Wareing and G. Ryback, Endeavour, 1970,27, 84. [9]F. W. Hemming, Biochem. Soc. Symp., 1969,29, 105.

2. Phng php vt l : Mt kh khn trong thc nghim l carotenoid him khi tn ti vi s lng ln v rt khng n nh . Chu n bi t .1.c. c tc dng ln phn lp chng. S dng magie cacbonate l yu cu [9a] to iu kin thun li cho vic tch ng phn cis t cc dng trans. C ti 95% thu c mc 1-2 g sau khi t.1.c trn sucrose [9b]. Phng php quang ph xc nh cu trc ph bin nht c l l quang ph U.V. T nghin cu [10] v hiu ng dung mi trn quang ph U.V ca astaxanthin (1) kt lun rng ch s khc x ca dung mi tng quan cht ch vi nhng thay i hn l hng s in mi hoc cc hiu ng solvat. Tuy nhin, sau khi nghin cu -carotene (2) v cc h thng lien quan xc nh [11] thuyt solvate d dng gii thch cc bin i. U.V nhit thp 770K lm tng cu trc mn v mt t thay i bc sng cc i. Mt lot carotenoid [12] v retinal [13]cng c nghin cu nhit ny. Ho hc lp th tuyt i ca carotenoid ch yu da vo s tng quan [14] ca h ng c tuyn o.r.d. Cho n nay, tt c cc mu carotenoid chng minh c cng s bt i xng. Hn na, nhm 3-hydroxy trong tt c cc trng hp dng nh c cng mt dng ho hc lp th tuyt i (xem di y). Nguyn tc cng tnh cho php d on s hon v ca cc nhm kt thc bt i xng. Rt t cc php o ng c tuyn o.r.d c cng b. Bn -caroten (3) tng quan vi -caroten (4) qua cc nghin cu c.d. [15]. 278

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Proton n.m.r c ng dng ph bin. S ra i ca ph k 220 MHz cho php phn tch chi tit hn cc carotenoid. C hai hiu ng nhit v dung mi c kim tra [16]. Khi kt hp vi thun t s gy ra s thay i cng v mt vng quay c suy din cho cc nguyn t cacbon ca vng mc Schiff cn c bi methyl amine [17]. ng phn cis v trans ca theaspiron (8) v (9) c phn bit bng cch s dng cc ht nhn hiu ng Overhauser [18]. Khi nhm 5-methyl c chiu x tn hiu n.m.r. cho cc proton 4 v 9 c gia tng cng . Nghin cu u tin s dng C n.m.r cho thy rng k thut ny t ra l mt phng php rt mnh. Tt c 20 loi nguyn t cacbon ca -carotene (2) v cc h lin quan c phn bit [19].

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Ph khi lng l k thut gn y nht c p dng rng ri nghin cu cu trc carotenoid. Enzellet al ghi li rt nhiu ph [20]. Nhng tin b gn y cng nhn s thiu m.u 106 v 92 (nh xylen v toluene) l c trng ca chui polyene [21]. Cc on cn li trn mi cnh ca plyene c th on nhn bi s phn hch bisallylic [22]. Carotene xeton cho thy s phn on in hnh [23]. MacMilan v Gaskin [24] pht hin 0.3g axit abscisic hoc axit phaseic s dng g.l.c.-m.s. Quang ph laser tng cng cng hng Raman rt nhy cm trong vic pht hin ca carotenoid [25]. K thut ny c dung pht hin -carotene (2) v lycopene (16) trong m sng [26]. ng dng ca php kho st tinh th bng tia X tng i kh khn. Canthaxanthin (5) v 15,15 '-dehydro canthaxanthin c kim tra [27] v cho thy c mt lin kt S-cis [28] gia vng xyclohexene v chui polyene, mc d chui cong v hi b gp [29]. Cu hnh lp th ca xeton trit quang (10) c tng hp ho hc [30], v cht ng phn quang ha c dn xut ra c xc nh, v khun ging nh sn phm c gim hot tnh quang hc t fucoxanthin [32]. Ngoi ra, ho hc lp th tuyt i ca mu cui c th hin nh cng thc (10). Kt qu quan trng ny xc nhn ho hc lp th tuyt i ti C-3 ca hng lot cc carotenoid cng h vi zeaxanthin.

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Cc kt qu tng hp sinh hc ca Goodwin v ng nghip [33] s dng [2C,3R,5R-H]-mevaloic axit cho thy hydroxyl ho ti C-3 dn n s bin mt ca tritium khi zeaxanthin hoc -cryptoxanthin c hnh thnh. T khi ho hc lp th tuyt i ca nguyn t tritium C-3 c bit n, trc khi hydroxyl ho kt qu ny xc nhn c s lu gi cu hnh. Vic gi thit s duy tr hydroxyl ho dn n lutein mt tritium t c 2 v tr khi tng hp sinh hc ch ra ho hc lp th tuyt i [32] C-3 v C-3.

[9a] H. Nitsche and K. Egger, Phytochem., 1969,8, 1577. [9b] W. Jeffrey, Biochim. Biophys. Acta, 1968, 162, 271. [10] M. Buchwald and W. P. Jencks, Biochem., 1968,7, 834. [11] F. Feichtmayr, E. Heilbronner, A. Nurrenbach, H. Pommer, and J. Schlag, Tetrahedron, 1969,25, 5383. [12] B. Ke, F. Imsgard, H. Kjesen, and S. Liaaen-Jensen, Biochirn. Biophys. Acta, 1970,210, 139 [13] W. Sperling and C. N. Rafferty, Narure, 1969, 224, 591. [14] L. Bartlett, K. Klyne, W. P. Mose, P. M. Scopes, G. Galasko, A. K. Mallams, B. C. L.Weedon, J. Szabolcs, and G. Tbth, J. Chem. SOC. (0, 1969, 2527. [15] R. Buchecker, H. Yokoyama, and C. H. Eugster, Helv. Chim. Acta, 1970, 53, 1210. [16] D. J. Patel, Nature, 1969, 221, 825. [17] D. J. Patel and R. G. Shulman, Proc. Nut. Acad. Sci., U.S.A., 1970,65,31. [18] Y. Nakatani, T. Yamanishi, and N. Esumi, Agric. and Biof. Chem. (Japan), 1970, 34,152.

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[19] M. Jautelat, J. B. Grutzner, and J. D. Roberts, Proc. Nut. Acad. Sci., U.S.A., 1970, 65, 288. [20] C. R. Enzell, G. W. Francis, and S. Liaaen-Jensen, Acta Chem. Scand., 1969, 23, 727. [21] C. R. Enzell, G. W. Francis, and S. Liaaen-Jensen, Acta Chem. Scand., 1968, 22, 1054. [22] B. H. Davies, E. A. Holmes, D. E. Loeber, T. P. Toube, and B. C. L. Weedon, J. Chem.SOC. (C), 1969, 1266. [23] J. Baldas, Q. N. Porter, A. P. Leftwick, R. Holzel, B. C. L. Weedon, and J. Szabolcs, Chem. Comm., 1969,415; G. W. Francis, Acta Chem. Scand., 1969,23,2916. [24] P. Gaskin and J. MacMillan, Phytochem., 1968, 7, 1699. [25] L. Rimai, R. G. Kilponen, and D. Gill, J. Amer. Chem. SOC., 1970, 92, 3824. [26] D. Gill, R. G. Kilponen, and L. Rimai, Nature, 1970, 227, 743. [27] J. C. J . Bart and C. H. MacGillavry, Acra Cryst. 1968, B24, 1569, 1587 [28] B. Pullman, J. Langlet, and H. Berthod, J. Theor. Biol., 1969, 23, 492. [29] H. A. Nash, J. Theor. Biol., 1969, 22, 314. [30] T. E. DeVille, M. B. Hursthouse, S. W. Russell, and B. C. L. Weedon, Chem. Comm.,1969, 754 [31] T. E. DeVille, J. Hora, M. B. Hursthouse, T. P. Toube, and B. C. L. Weedon, Chem. Comm., 1970, 1231. [32] T. E. DeVille, M. B. Hursthouse, S. W. Russell, and B. C. L. Weedon, Chem. Comm.,1969, 1311. [33] T. J. Walton, G. Britton, and T. W. Goodwin, Biochem. J., 1969, 112, 383.

3. Cc carotenoid t nhin mi : Carotenoids khng tun hon: Diphenylamine-th ng Rhodospirillum rubrum sn xut ra mt lot hp cht hydrocacbon v dn xut ca spheroidene [37]. ng ch nht l 7,8,11,12-tetrahydrolycopen(11) [38]; 3,4,11',12'tetrahydrospheroidene (12); v 11',12'-dihydrospheroidene (13) [39]. Cu trc ca chng c chng minh bi php o ph khi lng v ch ra rng vic hydro ha khng cn thc hin cc bn ca lin kt i trung tm nh gi s trc . 282

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Nhng Carotenoid khc c tch t dy ny bao gm : spheroidene; hydroxyspheroidene [40]; l-hydroxy-l,2dihydrophytoene (14); v 1 -hydroxy-l,2dihydrophytofluen [41].

Hai nhm khng tun mi cui cng c tm thy. Phytoene-l,2-oxide (15) c chit tch t qu c chua [42].Trong vi khun Rhodopseudornonas viridis [43] ngi ta thy rng mc d neurosporene v lycopene c xut hin, hu ht cc carotenoid trc o ngh l hai hp cht ny, nhng thc t ln lt l dn xut ca 1,2-dihydro-derivatives(17). Thm vo 1,2-dihydro-3,4dehydrolycopene cng c mt(18). Mt cuc nghin cu li v lycoxanthin (19) v lycophyll (20) ch ra rng [44] nhm allynic hydroxy c trong nguyn t C cui cng. Kt qu ny c khng nh bi vic oxi ha c mt nickel peroxide ti aldehydes tng ng. 283

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Hai carotenoid ch yu trong Shepherdia canadensis l [45] lycopene (16) v methyl apo-6-lycopenoate (21). Cht sau c tng hp t apo-8lycopenal(22) bi ngng t Wittig. Vic tng hp metyl bixin vi lin kt cis t nhin c ngun gc t lactol c phc ha trong Scheme l [46]

Diapo-carotenoid carotenoid v oxit axit c tch t Jacquinia augustifolia[47]. 284

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[37] B. H. Davies, Pure Appl. Chem., 1969, 20, 545. [38] B. H. Davies, Biochem. J., 1970, 116, 93. [39] B. H. Davies, Biochem. J., 1970, 116, 101. [40] H. C. Malhotra, G. Britton, and T. W. Goodwin, Phytochern., 1969, 8, 1047. [41] H. C. Malhotra, G. Britton, and T. W. Goodwin, FEBS Letters, 1970, 6, 334. [42] G. Britton and T. W. Goodwin, Phytochem., 1969,8,2257 [43] H. C. Malhotra, G. Britton, and T. W. Goodwin, Chem. Comm., 1970, 127. [44] L. Cholnoky, J. Szabolcs, and E. S. Waight, Tetrahedron Letters, 1968, 1931; M. C.Markham and S. Liaaen-Jensen, Phytochem., 1968, 7, 839 [45] H. Kjersen and S. Liaaen-Jensen, Phytochem., 1969,8,483 [46] G. Pattenden, J. E. Way, and B. C. L. Weedon, J. Chem. SOC. (0, 1970,235. [47] C. H. Eugster, H. Hurlimann, and H. J. Leuenberger, Helu. Chim. Acra, 1969,52, 806.

Cc Carotenoid n vng : Gazaniaanthin v Rubixanthin (26): c cu trc tng t nhng tnh cht vt l khc nhau, th hin qua ng phn cis-trans lin kt i 5 [48,49]. Mt s s khc bit v tnh cht vt l cng c gii quyt. Cc 0.r.d. ng cong v c bn ging nhau, vkhng nh lp th tuyt i l ging nh trong zeaxanthin ti C-3. S ph thuc dung mi ca ng cong th ng quan tm [49].

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Trong vi khun Stigrnatellu auruntiacu , y-carotene (27) xy ra vi 4-keto,1 ', 2'-dihydro-l'-hydroxy-, v 4-keto-1 ', 2'-dihydro-l'-hydroxy-y-carotene. Ngoi ra sn phm dehydrohalogen ha 4-keto-1 ', 2'-dihydro-1'-hydroxy-torulene(cf. 28) c thc hin[50]. Hai trung gian (29) v (30) gia torulene (28)v torularhodin (3 1) c phn lp t mt nm men [51].

Cc este methyl ca neurosporaxathin c phn lp t Nectria cinnaborina[52].

[48] B. 0. Brown and B. C. L. Weedon, Chem. Comm., 1968, 382. [49] N. Arpin and S. Liaaen-Jensen, Phytochem., 1969,8, 185. [50] H. Kleinig and H. Reichenbach, Arch. Mikrobiol., 1969, 68, 210. [51] R. Bonaly and J. P. Malenge, Biochim. Biophys. Acta, 1968, 164, 306. [52] J. L. Fiasson and M. P. Bonchez, Phyrochem., 1970,9, 1133.

Cc crotenoid 2 vng : Cc lp th tuyt i ca -caroten(4) xc nh bi Eugster v cng s [53] do s lin quan dn xut -iononeca manool v ambrein. Trong t nhin (+)--carotene (4) c tng hp t (+)--ionone v s lin quan ca 0.r.d. mt vi carotenoid khc vi trung tm bt i, v d mt cryptoxanthin-(zeinoxanthin) (32) [54]. Ch rng trong t nhin (+)--carotene l R ang c s dng theo quy nh 1966 [55]. Tuy nhin nhng quy tc trc s c chnh sa li. 286

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Yokoyama v cng s c lp mt lot cc seco-carotenoids t Rutaceae.Sime-carotenone (3) [56] ch ra bi cc nghin cu c.d thy c cu trc lp th tuyt i ging vi -carotene. Cc v d khc c tch ra l carotenone (33), -carotenone (34) [57] v triphasiaxanthin (35) [58].

Diphenylamine b c ch bi nigrum Epicoccum to ra 3,4-dehydro-carotene (36) v 3,4,3,4-bisdehydro--caroten (37) [59]. Mt s to carotenoid hydroxy ha nhm methyl trong chui. Loroxanthin (38) c ch ra bng ph khi thy nhm hydroxymethyl ti C-9 [60]. Siphonaxanthin(39) tm s lin quan n ha hc vi loroxanthin bng cch chuyn i nhm 8-oxo-sang lin kt i 7,8 bng phn ng kh v tch loi [61]. Pyrenoxanthin l mt ng phn ca loroxanthin hydroxymethyl ti C-13, C-13 ' [62].

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Trong thin nhin thng xuyn este ha carotenoids. Siphonein l este ha chnh nhm hydroxy ca siphonaxanthin [61]. Nhiu 3-hydroxy-carotenoids thng c este ha. Trn T.L.C ln n tm thnh phn khc nhau ca chng trong acid bo c chng minh cho mt lot cc xanthophylls [63].Cc lin kt trong carotenoproteins hin nay l cha bit. Trng lng phn t khong hn mt triu [64]. Tuy nhin, trong crustacyanins cc dng v khong na triu v -crustacyanin khong 48.000.Do trng lng phn t khong 25.000 per carotenoid (astaxanthin, 1) [65].
[53] C. H. Eugster, R. Buchecker, Ch. Tscharner, G. Uhde, and G. Ohloff, Helu. Chim Actu, 1969, 52, 1729. [54] J. Szabolcs and A. Rbnai, Acta Chim. Acad. Sci., Hung., 1969, 61, 309. [55] R. S. Cahn, Sir Christopher Ingold, and V. Prelog, Angew. Chem,, Internat. Edn., 1966, 5, 385. [56] H. Yokoyama and H. C. Guerrero, Phytochem, 1970,9, 231. [57] H. Yokoyama and M. J. White, Phytochem., 1968,7, 1031. [58] H. Yokoyama, H. C. Guerrero, and H. Boettger, J. Org. Chem., 1970, 35, 2080. [59] F. H. Foppen and 0. Gribanovski-Sassu, Biochim. Biophys. Acta, 1969, 176, 357. [60] K. Aitzetmiiller, H. H. Strain, W. A. Svec, M. Grandolfo, and J. J. Katz, Phytochem.,1969, 8, 1761. [61] H. Kleinig, H. Nitsche, and K. Egger, Tetrahedron Letters, 1969, 5139.

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[62] H. Y. Yamamoto, H. Yokoyama, and H. Boettger, J. Org. Chem., 1969,34, 4207. [63] H. Kleinig and H. Nietsche, Phytochem., 1968, 7, 1171. [64] P. F. Zagalsky, H. J. Ceccaldi, and R. Daumas, Cornp. Biochem. Physiol., 1970,34,579. [65] M. Buchwald and W. P. Jencks, Biochern., 1968,7, 844.

Cc carotenoid vng pentanoid v vng thm : Iolerythrin (40) l carotenoid c mu xanh c hnh thnh do thy phn v oxy ha nh ca c chn ngng bin diesteractinioerythrin (41) [66] . Cc xut sinh tng hp lin quan n sp xp li benzilic ca trione-2,3,4 t qu trnh oxy ha ca astaxanthin (1) c tng hp violerythrin t astacene diosphenol (42) ca qu trnh oxy ha vi mangan dioxide [67] .

[66] S. Hertzberg and S. Liaaen-Jensen, Acta Chem. Scand., 1968, 22, 1714; S. Hertzberg, S. Liaaen-Jensen, C. R. Enzell, and G. W. Francis, Acta Chem. Scand., 1969, 23, 3290. [67] R. Holzel, A. P. Leftwick, and B. C. L. Weedon, Chem. Comm., 1969,128. [68] F. Arcamone, B. Camerino, E. Cotta, G. Franceschi, A. Grein, S. Penco, and C. Spalla, Experientia, 1969, 25, 241 ; F. Arcamone, B. Camerino, G. Franceschi, and S. Penco, Gazzetta, 1970, 100, 581.

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Mt s vi khun c th sp xp li carbon bnh thng cung cp cho cc carotenoid thm .V d Phenolic c phn lp t Streptomyces mediolani. Cng nh cc isorenieratene hydrocarbon (43), 3-hydroxy-(44),v 3,3 'dihydroxyisorenieratene (45) c cu trc vng chc nh tng hp [68]. Trong Thiothece gelatinosa cc carotenoid chnh l okenone(46), nhng cc ng phn (47) v desmethyl derivative (48) cng c mt. Cc cu trc ca cc hp cht th hai c xc nhn bi vic tng hp [69].
[69] N. Pfennig, M. C. Markham, and S. Liaaen-Jensen, Arch. Mikrobiol., 1968, 62, 178.

Allenic v Carotenoid Acetylenic : Trc y alloxanthin (49) c cng nhn nh l mt hp cht acetylenic, thuc chc carotenoids. Kh khn ca vic 290

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pht hin do cc lin kt ba yu pht tn hiu v hiu ng nh trn quang ph U.V. c th c khc phc trong tng lai bng cch ph 13C NMR. Lp th tuyt i ca alloxanthin c xc nh lin quan ti zeaxanthin (6) bi perhydrogenation. Cc thnh phn chnh ca axit asterinic t nhng con sao bin l dehydroastaxanthin (50) [70] .Trong mt s sinh vt n bo v to, diatoxanthin (51) 7 'v diadinoxanthin (52) [71,72] c tm thy nhiu hn zeaxanthin (6) hoc antheraxanthin .Mt axetylen to khc l heteroxanthin (53) [73] .Mt cng thc khc c thy l nhm enol ca fucoxanthin v tr cui cng [74] . Tuy nhin, mt ph n.m.r. khng tng thch vi nhm ny cui v tuyn b phn ng gim hydride khng quan st vi fucoxanthin. Cc carotenoid t nhin phong ph nht l fucoxanthin (54). Mt bo co xc nh cu trc ca n bi Weedon v cng s [76]. Phn ng suy thoi chnh vi permanganat km. Tia X-quang xc nh cu trc lp th tuyt i ca allenic. T fucoxanthin c chuyn i thnh zeaxanthin(6), nu epoxit c dng trans vi nhm hydroxy l cu trc hon chnh c bit n.Trong nhm bin, Paracentrotus licidus, tng ng trio1 fucoxanthin, fucoxanthinol c mt cng vi paracentrone (55) v c th iso-fucoxanthinol (56). Qun trnh oxy ha tip theo l thy phn fucoxanthin paracentrone cho nng sut 9% [77].

[70] N. A. Sewensen, S. Liaaen-Jensen, B. Barrdalen, A. Hang, C. R. Enzell, and G. W Francis, Acta Chem. Scand., 1968, 22, 344. [71] K. Egger, H. Nitsche, and H. Kleinig, Phyfochem., 1969, 8, 1583. [72] K. Aitzetmuller, W. A. Svec, J. J. Katz, and H. H. Strain, Chem. Comm., 1968, 32. [73] H. H. Strain, K. Aitzetmuller, W. A. Svec, and J. J. Katz, Chem. Comm., 1970, 876. [74] H. Nitsche, Tetrahedron Letters, 1970, 3345.

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Neoxanthin (foliaxanthin) (57) c trong l xanh. ng phn 9-cis b c lp, trong khi tt c cc ng phn trans neoxanthin-X c th sn xut t nhin [78]. Hai hp cht ny khc nhau ng k vng 0.r.d. Gim mui nhm Lithiumneochrome (58) bng cch cho zeaxan mng (6) [78,79]. Neochrome c hnh thnh bng cch x l acid nh ca neoxanthin. Di iu kin cho d thdiadinochrome (59) c hnh thnh [80]. "Trollixanthin c biu din cng ging nh neoxanthin [81]. De-epoxineoxanthin (60) c phn lp t guttatus Mimulus, v n c a ra gi thuyt l trollein [82]. Cc to carotenoid vaucheriaxanthin l hydroxy neoxanthin ha.Mt nhm 9'-hydroxymethyl c gi thuyt bi Nitsche v Egger [83]. 292

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[75] R. Bonnett, A. K. Mallams, A. A. Spark, J. L. Tee, B. C. L. Weedon, and A. McCormick, J. Chem. SOC. (0, 1969, 429. [76] G. Galasko, J. Hora, T. P. Toube, B. C. L. Weedon, D. Andre, M. Barbier, E. Lederer, and V. R. Villanueva, J. Chem. Soc. (0, 1969, 1264. [77] J. Hora, T. P. Toube, and B. C. L. Weedon, J. Chem. SOC. (0, 1970, 241. [78] L. Cholnoky, K. Gyorgyfy, A. Ronai, J. Szabolcs, G. Toth, G. Galasko, A. K. Mallams, E. S. Waight, and B. C. L. Weedon, J. Chem. SOC. (C), 1969, 1256. [79] K. Tsukida and M. Yokota, Bitamin., 1969, 39, 125. [80] K. Egger, A. G. Dabbagh, and H. Nitsche, Tetrahedron Letters, 1969, 2995. [81] K. Egger and A. G. Dabbagh, Tetrahedron Letters, 1970, 1433. [82] H. Nitsche, K. Egger, and A. G. Dabbagh, Tetrahedron Letters, 1969,2999; H. Nitsche, Tetrahedron Letters, 1970, 3343. [83] H. Nitsche and K. Egger, Tetrahedron Letters, 1970, 1435.

Glycosides v Isoprenylated Carotenoids : Vi khun v to xanh lc c rt nhiu im tng ng, mt trong s chng c mt carotenoid glycosides. Cu trc ca myxoxanthophyll c sa i bi Jensen v ng nghip [84] ti dn xut rhamnosyl(61). H ch ra rng bis-P-L-rhamnosyl dn xut oscillaxanthin(61) cng c mt [85] . Trong mi lin h cht ch c 2 carotenoid ny u c mt tng ng l dn xut 0-methyl methylpentosyl, bn cnh c 4-keto-compound (63) c ng l methyl pentose,c th l rhamnose [86]. Trong vi khun Nocardia kirovani b phn glucose ca phlei xanthophyll(64) l monoesterifi [87]. Tng t, myxobacton ester (65) v myxobactin ester (66) c mt trong mt vi c th Myxobacteriales, l nhng mono este ca dn xut inositol [88]. Dn xut methyl apo-8'-lycopenoate(67) c mt cng vi dn xut tng ng ca apo8'-lycopenol trong mt vi loi vi khun [89].

293

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Mt vi loi vi khun sn xut ra C45 v C50 carotenoid cha mt hoc hai nhm isoprenyl. Mc d s tng hp cua chng vn cn ang nghin cu, nhng c mt gi thit cho rng n c thay th bng vng proton khi u im cui cng dy polyene, tn cng dimethyl ally1 pyrophosphate kt qu c cht i xng decaprenoxanthin (P439) (68) [90].

294

Tiu Lun Hp Cht Thin Nhin

Nhng carotenoid khc c mc trong Flauobacteriurn dehydrogenans bao gm hp cht monohydroxy (69), nonaprenoxanthin (70) v 1 1 ', 12'dehydronoaprenoxanthin [92]. Nonaprenoxanthin l mt v d khc ca vic de hydro ha mt bn ca lin kt i trung tm. Monoglucoside ca decaprenoxanthin xy ra Corynebacteriurn erythrogenes [93]. Loi ny cng cha C45 carotenoid khng tun hon (70), cht nh bacterioruberia, ch ra rng vic ng vng khng cn thit cho phn ng cng thm gc isoprenyl [94]. Sarcaxanthin l ng phn ca decaprenoxanthin vi mt nhm hydroxy gc isoprenyl v nhm hydroxymethyl tn cng vo C-5 hoc C-5 [95].

295

Tiu Lun Hp Cht Thin Nhin

[84] S. Hertzberg and S. Liaaen-Jensen, Phytochem., 1969, 8, 1259. [85] S. Hertzberg and S. Liaaen-Jensen, Phytochem., 1969, 8, 1281. [86] G. W. Francis, S. Hertzberg, K. Andersen, and S. Liaaen-Jensen, Phytochem., 1970, 9, 629. [87] M.-J. Vacheron, N. Arpin, and G. Michel, Compt. rend., 1970, 271 C, 881. [88] H. Kleinig and H. Reichenbach, Naturwiss., 1970, 57, 92. [89] A. J. Aasen, G. W. Francis, and S. Liaaen-Jensen, Acta Chem. Scand., 1969, 23, 2605. [90] S. Liaaen-Jensen, S. Hertzberg, 0. B. Weeks, and U. Schwieter, Acta Chem. Scand., 1968, 22, 1171 [91] U. Schwieter and S. Liaaen-Jensen, Acta Chem. Scand., 1969, 23, 1057. [92] 0. B. Weeks, A. G. Andrewes, B. 0. Brown, and B. C. L. Weedon, Nature, 1969,224,879. [93] 0. B. Weeks and A. G. Andrewes, Arch. Biochem. Biophys., 1970, 137, 284. [94] S. NorgArd and S. Liaaen-Jensen, Actu Chem. Scund., 1969, 23, 1463. [95] S. NorgArd, G. W. Francis, A. Jensen, and S. Liaaen-Jensen, Acta Chem. Scand., 1970, 24, 1460.

4. Ha hc carotenoid : 296

Tiu Lun Hp Cht Thin Nhin

S tng hp ca methyl bixin (24) v carotenoids thin nhin khc c cp trn. Mt tng hp v mt di truyn cm ng ca -carotene s dng cc titan tetraclorua phc ca lycopene (16). Dehydrolycopene cng c ring bit [96]. C nhiu hn hai s tng hp ca -carotene c c bo co s dng trung gian trong qu trnh tng hp vitamin A (xem phn 2). Mc d 11-cis--carotene c sn xut [97] n nhanh chng chuyn v dng ban u. H thng ni i lin hp c mang mu m trc cha bit [98]. Mt v d khc ca h thng ny, nhng vi mt ln thm 4 nhm oxo, c tng hp bi Surmatis et l [99] trong mt nghin cu v tng hp cc xeton carotenoids. H chun b echinenone(73) v hai hp cht bo v 3,3-dioxo--carotene l (74) v (75). Phn ng ca ketal vi axit sunfuric to sn phm ch yu l 3,3-dioxo--carotene (76) trong khi cho sn phm sau. Qu trnh oxi ha -carotene vi mangan dioxit-vanadi pentoxit cho khong 20% ca mng li [100]. S dng tng ng 5,6-oxit (78),

Scheme2 297

Tiu Lun Hp Cht Thin Nhin

qu trnh oxi ha vi tetraoxit hydro peoxit-osmium s cho mng v 5,6-oxit [101]. Trong s c mt ca oxi trong bng ti th -carotene b oxy ha thnh 5,6oxit (78), 5,6,5,6-dioxit, 5,8-oxit v 5,8,5,8-dioxit [96,102]. Tuy nhin, canthaxanthin cho tng ng 13,14-oxit [96]. Quang ha. oxy n l rt c hiu qu dp tt -carotene [103]. Nu h thng polyene c rt ngn li gy kch ng ba cng dp tt. Tuy nhin, thc t l phn m rng ca h thng c nh hng rt nh n mt qu trnh khuch tn [104]. Hin tng ny cho thy rng mt trong nhng chc nng ca carotenoids trong t nhin l bo v c th chng li qu trnh oxy ha quang ha. ng phn ca 15,15-cis--carotene v tt c cc dng ng phn c xc tc bi oxy n [105]. Di iu kin mnh hn 5,6-oxit, 5,8-oxit, hydroxy-xeton, allenes v acetylen tuyn b [106]. Hn na qu trnh oxy ha ph v mch cacbon cung cp cho -ionone, dihydroactinidiolide (99) v 2-hydroxy-2,6,6trimetylcyclohexan [107]. Violaxanthin tng t c ct cung cp cho loliolide v tng ng

298

Tiu Lun Hp Cht Thin Nhin

9-xeton v 11-aldehyt, xanthoxin (86). Qu trnh oxy ha ca xanthoxin cho axit (+)-trans-abscisic t nhin [108]. Qu trnh oxy ha quang ha c xut [109] nh l ngun gc sinh tng hp ca allenes v mt s carotenoids b suy thoi. Tuy nhin, lp th ca allene quang khng ng nht vi allene t nhin. Hp cht quang ca carotenoids b suy thoi pha di.
[96] C.Bodea, Pure Appl, Chem , 1969,20,517. [97] J.D.Surmatis and R.Thommen, J.Org.Chem , 1969,34,559. [98] J.D. Surmatis, J.Gibas, and R. Thommen, J.Org. Chem , 1969,34,3039. [99] J.D. Surmatis, A. Walser, J.Gibas, U.Schwieter, and R.Thommen, Helv.Chim.Acta , 1970,53,974.

[100] R. K. Barua and A. B. Barua, Indian J. Chem , 1969,7,528. [101] R.K. Barua and A.B. Barua, Indian J. Chem ,1969,7,1017. [102] A.H. El-Tinay and C.O. Chichester, J.Org.Chem ,1970,35,2290. [103] C.S. Foote and R.W. Denny, J.Amer. Chem. Soc ,1968,90,6233. [104] C.S. Foote, Y.C. Chang, and R. W.Denny, J.Amer. Chem.Soc ,1970,92,5216. [105] C.S. Foote, Y.C. Chang, and R. W.Denny, J.Amer. Chem.Soc ,1970,92,5218. [106] K.Tsukida, S,C, Ch, and M.Yokota, Chem. Pharm. Bull , 1969,17,1755. [107] S. Isoe, S.B.Hyeon, and T.Sakan, Tetrahedron Letters, 1969,279. [108] R. S. Burden and H. F. Taylor, Tetrahedron Letters, 1970, 4071; H. F.Taylor and R.S. Burden, Phytochem , 1970, 9 ,2217. [109] M. Mousseron-Canet, J, -P. Dalle, and J. -C. Mani, Tetrahedron Letters, 1968, 6037.

5 . Cc Carotenoid suy thoi

299

Tiu Lun Hp Cht Thin Nhin

Mt s terpenoit xut hin c bt ngun t carotenoids bi s phn ct ca chui polyene. Chng bao gm vng mc (C20), axit trisporic (C, 18), abscisic acid (C15),m tionone-(C13), v loliolide (CLL). Vng mc (81) to thnh mt c s Schiffs vi lysine -nhm amin ca protein opsin, khi cc sc t th gic c to ra [110].Mt s steric c xc nh bi s tng hp bng cch sa i cc vng mc. Cc b xng carbon c bn l cn thit nhng khng phi l lin kt i 5,6 hoc nhm 9 - hoc nhm 13-methyl [111]. 11,12-Dehydroretinal c tng hp bi Mousseron-Canet v ng nghip [112].nhm nghin cu cc quang ho ca vitamin A khi mt loi phn ng Diels-Alder hnh thnh lin kt gia C-11 v C-14 ca mt trong phn t v C-13 v C-14 ca nhau[113]. Chiu x ca vng mc cho ng phn 9 - v / hoc 11-sis[114]. Cc quang ph hp th ba-ba ca vng mc v retinol c ghi li[115].
[101] R. K. Barua and A. B. Barua, Indian J. Chem., 1969,7, 1017. [102] A. H. El-Tinay and C. 0. Chichester, J. Org. Chem.. 1970, 35, 2290. [103] C. S. Foote and R. W. Denny, J. Amer. Chem. Soc., 1968,90, 6233. [104] C. S. Foote, Y. C. Chang, and R. W. Denny, J. Amer. Chem. Sac., 1970,92,5216. [105] C. S. Foote, Y. C. Chang, and R. W. Denny, J. Amer. Chem. SOC., 1970,92, 5218. [106] K. Tsukida, S.-C. Ch8, and M. Yokota, Chem. Pharm. Bull., 1969,17, 1755. [107] S. Isoe, S. B. Hyeon, and T. Sakan, Tetrahedron Letters, 1969,279. [108] R. S. Burden and H. F. Taylor, Tetrahedron Letters, 1970, 4071; H. F. Taylor and R. S. Burden, Phytochem., 1970, 9, 2217. [109] M. Mousseron-Canet, J.-P. Dalle, and J.-C. Mani, Tetrahedron Letters, 1968, 6037. [110] M. Akhtar, P. T. Blosse, and P. B. Dewhurst, Biochem. J., 1968, 110, 693.

Cc kch thch t axit trisporic B v C c hin th c mt carotenoid gc[116]. Cc lp th tuyt i ca C acid trisporic (82) c thnh lp bi ozonolysis [116-118] v o [117] cd. Ngoi ra tt c cc ng phn trans, 9 cis axit trisporic cng xut hin.[118]

300

Tiu Lun Hp Cht Thin Nhin

Abscisic acid (83) c lp th tuyt i c trnh by [119], by gi nn c xc nh[55] "l enantiomer S.

[111] P. E. Blatz, M. Lin, P. Balasubramaniyan, V. Balasubramaniyan, and P. B. Dewhurst, J. Amer. Chem. SOC., 1969. 91, 5930. [112] J.-L. Olive, M. Mousseron-Canet, and J. Dornand, Bull. SOC. chim. France, 1969,3247. [113] M. Mousseron-Canet, D. Lerner, and J.-C. Mani, Bull. SOC. chim. France, 1968,4639. [114] M. Mousseron-Canet and J.-L. Olive, Bull. SOC. chim. France, 1969, 3242. [115] A. Sykes and T. G. Truscott, Chem. Comm., 1969,929. [116] D. J. Austin. J. D. Bu'Lock. and D. Drake, Experientia. 1970, 26, 348. [117] J. D. Bu'Lock, D. J. Austin, G. Snatzke, and L. Hruban, Chem. Comm., ' 1970, 255. [118] T. Reschke, Tetrahedron Letters, 1969, 3435. [119] J. W. Cornforth, W. Draber, M. V. Milborrow, and G. Ryback, Chem. Comm., 1967, 114

301

Tiu Lun Hp Cht Thin Nhin

S tng quan ca axit abscisic (83) vi violaxanthin (80) qua xanthoxin (85)[108] tng mt cu hi th v lin quan lp th ca phn ng oxy ha hoc ca cc terpenoit. Trong thin nhin,cc ng phn trans ca axit abscisic c chng minh trong hoa hng[120] v -D-glucopyranoside ca ng phn cis trong Lupinus Iuteus.[121] Axit Phaseic (86) c chun b t cht chuyn ha C (84)[122] sang th hin cu trc furanoid ca hp cht c hn l mt h thng vng nh[123] hn. Cu trc Xanthoxin trong t nhin mt s loi thc vt.[124] Cht chuyn ha C ln u tin c cng nhn bi cc nghin cu chuyn ha bng cch s dng [2-14C] abscisic acid tng hp theo cch thng thng t [2-14C] bromoacetic este[125]. Butyl cromat qu trnh oxy ha ca mt iononecung cp mt tng hp hiu qu ca acid abscisic ( n 3)[126]. Mt s lng ln cc hp cht lin quan n axit abscisic tng hp kim tra hot ng sinh hc ca h.[127] Nhn chung, thng thng phng php tng hp c s dng. Reformatsky phn ng c th c s dng nh mt thay th cho cc phn ng Wittig cho s tng hp cc a-ionylidene aceticester.[128] Mt phng php th v cho vic chun b ca allylic B-ionylidene tng ng acetonitrile v phn s ng dng vi mui isoamyl triphenylphosphonium nitrite v base.[129]

Scheme 3 Quang ha qu trnh oxy ha ca acid acetic B-ionylidene (87; R = CMe: CH-CO, Me) a ra mt hn hp ca ba sn phm (88), (89), v (90), sau khi kh ca nhm hydroperoxide[130]. 30 Dehydro-B-ionone dn xut (91)

302

Tiu Lun Hp Cht Thin Nhin

cho peroxit (88) hoc (92) khi R = CMe: CHCH: CH-CMe: CHCO2Me hoc R = CMe: CH-Ch CHCO2Me[131].
[120] B. V. Milborrow, J. Exptl. Bot., 1970, 21, 17. [121] K. Koshimizu, M. Inui, H. Fukui, and T. Mitsui, Agric. and Biol. Chem. (Japan), 1968, 32, 789. [122] B. V. Milborrow, Chem. Comm., 1969, 966. [123] J. MacMillan and R. J. Pryce, Tetrahedron, 1969, 25, 5893, 5903. [124] H. F. Taylor and R. S. Burden, Nature, 1970, 227, 302. [125] J. W. Cornforth, R. Mallaby, and G. Ryback, J. Chem. SOC. (C), 1968, 1565. [126] D. L. Roberts, R. A. Heckman, B. P. Hege, and S. A. Bellin, J. Org. Chem., 1968, 33, 3566. [127] S. Tamura and M. Nagao, Agric. and Biol. Chem. (Japan), 1969, 33, 1357; T. Oritani and K. Yamashita, Agric. and Biol. Chem. (Japan), 1970, 34, 108, 198, 830. [128] J. Kamamoto, 0. E. Smith, C. M. Asmundson, R. B. Ingersoll, and H. A. Sadri, J. Agric. Food Chem., 1970, 18, 531. [129] M. Matsui and G. Yabuta, Agric. and Biol. Chem. (Japan), 1968,32, 1044. [130] J.-P. Dean, M. Mousseron-Canet, and J.-C. Mani, Bull. SOC. chim. France, 1969, 232; M. Mousseron-Canet, J.-P. Dalle, and J.-C. Mani, Photochem. and Photobiol., 1969,9, 91. [131] J.-L. Olive and M. Mousseron-Canet, Bull. SOC. chim. France, 1969, 3252.

303

Tiu Lun Hp Cht Thin Nhin

Lp th ny c d on bi Mousseron-et Canet[109] cng nh bi Foote v cng s[132] nghin cu qu trnh oxy ha quang ha ca (87,R = CME: CH,). Latia luciferin (94) c phn lp t cc limpet[133] v cu trc c xc nh t tng hp. [134-135]
[132] C. S. Foote and M. Brenner, Tetrahedron Letters, 1968, 6041. [133] O. Shimomura and F. H. Johnson, Biochem., 1968, 7, 1734. [134] M. G. Frachebond. 0. Shimomura. R. K. Hill, and F. H. Johnson, Tetrahedron Letters. 1969, 3951. [135] F. Nakatsubo, Y. Kishi, and T. Goto, Tetrahedron Letters, 1970, 381.

Ha lp th ny ca lin kt i enol ester th hin c chuyn bi Baeyer-Villiger qu trnh oxy ha ca cis v trans aldehyt(93)[135]. Cc chui phn ng s c nu trong n 4. Cc bi tit phng th ca chu chu microptera Romalea cha allenic xeton Cu trc ny l r rng lin quan n neoxanthin(57). Racemic mu (10)[136] c tng hp[137-138] t 2 con ng( n 5) v,mc d c mt s khc bit gia hai sn phm, NMR ca h quang ph cho thy rng chng thuc v dng t nhin v r rng khc vi cc ng phn quang tng hp (3-OH, 90, R = Ac)[31]. Cc lp th ca ra tng hp racemate[137] ch ra [30] ca X-quang tinh th lography c ging nh mt mu hot ng quang hc bt ngun t s suy thoi ca fuoxanthin[32] lp th tuyt i ca cc mu sau ny c l cng p dng cho chnh cc xeton chu

304

Tiu Lun Hp Cht Thin Nhin

chu

Scheme 5
[136] J. Meinwald, K. Erickson, M. Hartshorn, Y. C. Meinwald, and T. Eisner, Tetrahedron Letters, 1968, 2959. [137] S. W. Russell and B. C. L. Weedon, Chem. Comm., 1969, 85. [138] J. Meinwald and L. Hendry, Tetrahedron Letters, 1969, 1657.

Mt trong nhng thnh phn ca hng thm ca tr, l theaspirone (96)[139140]. Khng t hn nm tng hp cc hp cht ny c cng b ( n 6)[141-143]. Mt trong nhng phn ng ng ch nht l kh chn lc ca mch h enone (95) ri khi cyclohexenone nguyn vn[143-144]. Cc ng phn 305

Tiu Lun Hp Cht Thin Nhin

cis v trans (8) v (9) ca sn phm racemic c tch ra v cu trc ca h c giao s dng hiu ng Overhauser ht nhn.[18] Vomifoliol (97) b c lp t RauwolJu uomitoriu dng nh l mt s sn phm suy thoi ca acid abscisic v c th l mt tin cht ca Theaspirone[144]. Damascenone, mt phn nh trong du hoa hng Bungari, c cho[145] l lin hp ng phn (98) ca dehydroionone. Mt tetrahydro-damascenone c chun b bng cch x l -ionone-7 ,8-oxit vi hydrazine[146].

n 6 Cc du vt cui cng ca chui polyene carotenoid cn li trong dihydroactinidiolide (99), mt hp cht hnh thnh trn oxy ha quang ha ca carotene[107], gn y c lp t thuc l[147] v tr aromas[140]. Mt s tng

306

Tiu Lun Hp Cht Thin Nhin

hp (99) c i din cng nh ca actinidiolide lin quan n cc sn phm t nhin (3,4-dehydro 99)[148,149] v loliolide[149].
[139] K. h a , Y. Sakato, and H. Fukami, Tetrahedron Letters, 1968,2777. [140] F. Miiggler-Chavan, R. Viani, J. Bricout, J. P. Marion, H. Mechtler, D. Reymond,and R. H. Egli, Helv. Chirn. Acta, 1969,52, 549. [141] A. Sato and H. Mishima, Tetrahedron Letters, 1969, 1803. [142] Y. Nakatani and T. Yamanishi. Tetrahedron Letters, 1969, 1995. [143] R. A. Heckman and D. L. Roberts, Tetrahedron Letters, 1969,2701. [144] J.-L. Pousset and J. Poisson, Tetrahedron Letters, 1969, 1173. [145] E. Demole, P. Enggist, U. Sauberle, M. Stoll, and Es. Kovats, Helv. Chim. Actu, 1970, 53, 541. [146] G. Ohloff and G. Uhde, Helv. Chim. Acta, 1970, 53, 531.

6.Polytecpenoids : Nhng tin b gn y trong ha hc polyterpenoid l mt h qu ca sinh tng hp nghin cu bng cch s dng [2 - "4C, 3R, 4R-3H] axit mevalonic v ng phn (4S) ca n(xem phn I, chng 6). C 2 phng php n.m.r v quang ph khi lng ch gii hn cho thy cu trc ca chng, v nh ni , n khng th xc nh v tr cc lin kt i.

307

Tiu Lun Hp Cht Thin Nhin

N cho thy rng 3 hoc 4 n v isoprenoid c cng kt thc l dng trans (bao gm c n v dimethyl allyl cui) v nhng n v isoprenoid cn li l dng sis. Mt v d tiu biu l ru cn C55 (101; n=3; m =7) t LactobacilIus plantareum, [150] quan trng trong s tng hp sinh hc thnh t bo. Dolichols, tn ti nhiu loi ng vt, thng este ho trong t nhin [151] v bao gm mt nhm cc hp cht vi lin kt i bo ho, in hnh l n v alcoholic isoprenoid (dihydro 101; n=3; m=3-18) [152]. Trong nm mc fumigatus, dn xut hexahydro c xc nhn c n v alcoholic isoprenoid v 2 n v kt thc l bo ho (hexahydro 101; n=4; m=14-20) [153]. Bombiprenone (102)l mt hp cht dng trans c c lp t cy du tm v tm [154]. V plymer dng sis (cao su) vi khi lng phn t khong 4000 c tm thy Satureia motana [155].

[150] D. P. Gough, A. L. Kirby, J. B. Richards, and F. W. Hemming, Biochem. J., 1970,118, 167 [151] P. H. W. Butterworth and F. W. Hemming, Arch. Biochem. Biophys., 1968, 128, 503. [152] D. P. Gough and F. W. Hemming, Biochem. J., 1970, 118, 163. [153] K. J. Stone and F. W. Hemming, Biochem. J., 1968, 109, 877. [154] M. Toyoda, H. Fukawa, and T. Shimizu, Tetrahedron Letters, 1968, 3837. [155] C. Tabacik and M. Hubert, Phyrochem., 1970, 9, 1129.

308

Tiu Lun Hp Cht Thin Nhin

309

Tiu Lun Hp Cht Thin Nhin

KT LUN

Vic tm hiu v nghin cu cu trc ha hc v tnh cht ca cc hp cht thin nhin c hot tnh sinh hc l mt giai on ca qu trnh tng hp ra cc hp cht c c tnh tng t nhng c nhiu u th trong vic s dng. Qua bi tiu lun ny, chng em c bit v hiu hn v nhm cht carotenoid v plyterpenoid ni ring v ha hc cc hp cht thin nhin ni chung, qua chng em nhn thy tm quan trng ca ha hc trong i sng hin nay.

310

Tiu Lun Hp Cht Thin Nhin

TRNG I HC BCH KHOA H NI VIN CNG NGH HA HC B MN HA DC V HA CHT BVTV

TIU LUN
HA HC CC HP CHT THIN NHIN TI: SINH TNG HP TERPENOIDS V STEROIDS

GV HNG DN : PGS.TS TRN THU HNG SV THC HIN : NGUYN MINH VN MSV: 20083114 XUN TRNG HONG VN TUN MSV: 20082824 MSV: 20082862

H NI 10/2011

311

Tiu Lun Hp Cht Thin Nhin

M U

Ha hccc hp cht thin nhin lun l mt b phn quan trng ca ha hc hu c, thm ch cho n cui th k th 19 hai khi nin ny vn c coi l mt.Nh nhng tin b to ln trong cc lnh vc l thuyt v thc hnh ha hc cng nh nh kt qu ca cc chng trnh sng lc c h thng m cc hng nghin cu ny t c nhng trnh han thin cao v s hiu bit ca chng ta v cc hp cht thin nhin c ht sc m rng. Ta c th k n mt s cht cht c phn lp t thc vt v ng vt nh sau : axit tactaric (1769), axit lactic (1782), mocphin (1805), quinin (1820), nicotin (1828),hematin (1826), carotene (1831). V c bit s pht trin ca ha hc hu c ni chung v ca thuyt cu to ni ring to c s cho vic nghin cu h thng cc lp cht nh Terpenoids v Streroids.Cc terpen khng ch bao gm cc hidrocacbon m bao gm c cc dn xut ca ancol, ete, adehitchng c chit xut trong cy c bit l trong hoa, qu v di dng tinh du thm. Cn cc steroids th bao gm cc sterol, cc amin mt, cc hoocmon gii tnh, cc coctiroit cng nh cc stero ancaloit, sapogenin.. Trong giai on hin nay lnh vc ha hc cc hp cht thin nhin ngy cng c y mnh nghin cu. c bit l cc hp cht c hot tnh sinh hc v c ng dng nhiu trong thc t nh Terpenoids v Steroids. Do nhm 6 chng em c giao nhim v dch, tm hiu cc hot tnh, cc tnh cht v qu trnh sinh tng hp Terpenoids v Steroids di s hng dn ca PGS.TS ging vin Trn Thu Hng. Bi dch chc chn cn nhiu thiu xt mong cc thy c v cc bn gp nhm chng em han thin thm. Em xin chn thnh cm n!

312

Tiu Lun Hp Cht Thin Nhin

MC LC

CHNG 6: TNG HP TERPENOIDS V STEROIDS

1.Gii thiu..................................................................................... 314 2.Tin thn ca hp cht mch thng.............................................. 314 3. Hemiterpenoids........................................................................... 318 4. Monotecpenoids ......................................................................... 323 5. Sesquiterpenoids . ................................................................. 329

7. Sesterterpenoid ........................................................................... 337 8. Steroid Trisnortriterpenoids ........................................................ 338 9. Cholesterol Metabolism .............................................................. 349 10. Tritecpen................................................................................... 356 11. Carotenoid ................................................................................ 358

CHNG 6 : TNG HP TERPENOIDS V STEROIDS

313

Tiu Lun Hp Cht Thin Nhin

1. Gii thiu
Nhn chung vi hu ht cc ti liu khoa hc khc, vic tm hiu qu trnh sinh tng hp terpene pht trin nhanh chng trong vi nm qua.ng Rittenberg1 cng b mt trong nhng ng dng ca vic xc nh ng v u tin trong mt nghin cu cc tin cht ca cholesterolterol vo nm 1937. Tuy nhin, cng xut hin thm 2 cht quan trng khc l axit mevalonic vo nm 1956 bi nhm Merck2, v s tng hp ca cc axit mevalonic c xc nh t nguyn t hydro prochiral bi Cornforth3 vo nm 1964. K t sau , nhng cht ny pht trin nhanh chng. Tng s cc bi vit lin quan n cc cht ny tng gp i nh gi nhng pht hin trong khong thi gian 1967-1970 a ra khong tng s cc ti liu c cng b. Mt vi cuc hi tho a ra cc c im sinh hc ca terpenoids nhng khng c cng b4. Mt quyn sch mi5 y trong chui Enzim hc gii quyt vn sinh tng hp v Enzim hc.

2.

Tin thn ca hp cht mch thng

Chi tit v qu trnh sinh tng hp loi hydrocarbon khng bo ha c gii thch bi Popjk v Cornforth6 vo nm 1966; nhng kt lun ca h c tm tt sau y v chng l tin c bn hiu bit nhng cng trnh nghin cu khc. 314

Tiu Lun Hp Cht Thin Nhin

Cc ngun ha sinh chnh ca mevalonate l acetyl coenzyme A. Lynen v ng nghip7 cho rng l hemithioacetak ca mevaidate v coenzyme A ( hay cn gi l enzim) bin i thnh axit mevalonic.

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Tiu Lun Hp Cht Thin Nhin

N lc thnh cng nht phn lp cc enzim tham gia vo qu trnh sinh tng hp c tin hnh t nhng giai on u. H thng nghin cu trong ng nghim th s s thng xuyn i8,9 ( 2-14C) axit mevalonic (1) thnh phtphat (2) v pyrophosphate (3), isopentenyl pyrophosphate (4), v dimethylallylpyrophosphate (5).Tuy nhin, du hiu duy nht nhn bit phng x c tm thy t cc cht prenol pyrophosphates (6). Cng nh axit phosphorylating mevalonic tng t nh enzim, hoc mt cht g lin quan, c th l phosphorylate geraniol 10 [ to(6; n=1)] hoc linalool. Trong cnh hoa hng tn ti cc cht c ngun gc t axit mevalonic l vng glucozit monoterpene khng tun hon. Liu rng cc cht ny c hnh thnh trc tip t pyrophosphate tng ng [ v d.( 6;n=1)] hay thng qua cc phn t ru t do cha c xc nh.

Vi enzim c trng giai on u qu trnh sinh tng hp ca terpene b phn lp. Mevalonic kinase * EC 2.7.1.36,, (1) (2)+ c tm thy t 316

Tiu Lun Hp Cht Thin Nhin

mt s ngun, v d nh Phaseolus vulgais 12 v gan ln13. C ch kim sot s phn hi c cho l14 c trong enzim ng vt. Kekwick14 xc nh d liu ng hc chi tit ca cht pyrophosphomevalonate decarboxylase *EC4.1.1.33, (3) (4)+ phn lp t Heuea brusiliensis. Cc nghin cu v ng lc15 v s c ch16 c bo co v cht isopentenyl pyrophosphate isomerase *EC 5.3.3.2, (4) (5)+ phn lp t gan ln v cht Cucurbita maxima tng ng. Cc bc tip theo lin quan n17 vic b sung isopentenyl bng enzim truyn prenyl *EC 2.5.1.1, (4) + (5) (6)+. Mt nghin cu chi tit bi Popjak v cc ng nghip18 v loi enzyme ny t gan ln cho rng hot tnh ny l mt ng vn trong protein khng cha cc cht bo c bit l nhm lin kt cc pyrophosphate. Loi enzyme ny cha t cht, cng nh to ra cc mono-, sesqui-, v dterpenoidi acyclicprecursors [(6; n = 1,2, v tng ng vi 3), n cng s c hot tnh vi cht nn t nhin. D liu hn ch cng c sn cho tng ng vi C. enzim maxima16,20.

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Tiu Lun Hp Cht Thin Nhin

Theo c ch farnesyl pyrophosphate (6;n=2) c chuyn i thnh loi hydrocarbon khng bo ha (7) xy ra nhiu phn ng ha hc v qu trnh sinh ha. C30 pyrophosphate (9) gip cn tr vic ln men xy ra qu trnh gia. Rilling v cc ng nghip21 xut cu to cyclopropanoid (9a) trong khi Popjk v cc cng s22 xut vng pyrophosphate diester (9b) . S tham gia cng mt lc k gia gy ra s kt hp phng x t diester (9), chun b cho vic ln men, thnh hydrocarbon khng bo ha , t gan ca mt con chut. Tuy nhin, c ch c xut cho s hnh thnh diester th kh chp nhn bng vic tm hiu nerolidyl pyrophosphate th khng c thch hp.
C th l chu k gia tng t lin quan n qu trnh sinh tng hp phytoene. Tuy nhin thay v loi b cht pyrophosphate, nh trong qu trnh sinh tng hp

hydrocarbon khng bo ha , bng cch loi

b lin kt i 15 (15) t c gc ban u. Woodwin v cc ng nghip24,25 ch ra rng c proton trong lin kt i ny c xc nh bi axit mevalonic [2-'4C, 3R, 5R-3H].* Porter v cc ng nghip nghin cu ng lc hc ca mt h thng enzyme t c chua cho vic chuyn i geranyl geranyl pyrophosphate (6; n = 3) thnh phytoene.

3. Hemiterpenoids
318

Tiu Lun Hp Cht Thin Nhin

Nhiu sn phm t nhin cha mt thnh phn isoprene c phn lp c ngun gc t axit mevalonic, do , nhng hp cht ny c th c xem nh cc cht dn xut hemiterpenoid. Trong hu ht cc trng hp tin thn trc tip c th l dimethyl ally1pyrophosphate (5). Vic thay th electrophilic nhm N-6 ca adenosine bng nhm ny th c tm quan trng c bn trong qu trnh sinh tng hp (STH) protein. Vic chuyn RNA ch xy ra phn ng khi xut hin cht nn c thay th. Hall v Peterkofsky v nhng ng nghip chng minh qu trnh sinh tng hp ca cc nucleoside ny t cc cht tin thn c d kin trong Lactobacillus sp.,27,28 men,28-30 m thuc l31 v gan chut29. Cc qu trnh chuyn hha tip theo cha thnh phn hemiterpenoid. Hamada v Chubachi32 nghin cu qu trnh sinh tng hp ca rotenone (l0). H nhn thy rng phng x t axit mevalonic [2-14C] th phn ln ngu nhin gia hai im cui ca nguyn t carbon [nhn hnh (l0), t l phn trm c xc nh bng s thoi bin]. Tuy nhin, nhng kt qu ny khng phn bit s ngu nhin gia thnh phn cn nguyn vn (nh c tm thy vi monoterpenes cyclopentanoid) v gim xung trc axetat. Qu trnh la chn th ba i vi loi thnh phn ph ny c xut bng cch nghin cu cc cht alkaloid lophocerin (11). C axit mevalonic v acid amino leucine l tin thn ca cht hemiterpenoid. Liu rng chng c cho cc quy trnh STH thay th hay cho d chng bin i thnh cc cht khc, khng c bit n. Grundon v cc ng nghip ch ra rng trong qu trnh sinh tng hp alkaloid ravenoline (13) mt loi phn ng Claisen khng bnh thng xy ra t ravenine (12).

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Tiu Lun Hp Cht Thin Nhin

Ergot Alkaloids.- Nh c d kin, thnh phn hemiterpenoid ca ergot alkaloids th th v ch, ch c mt nguyn t carbon duy nht c xc nh bi axit mevalonic [2-14C] [c nh du * trong cng thc (14) (17)] nhng ha hc lp th c s thay i trong nguyn t ny. Cc nghin cu chuyn su ca Floss v nhng ng nghip35,36 ch ra rng chanoclavine I (14) c chuyn i thnh elymoclavine (17) thng qua aldehyde (15) v c th i qua agroclavine (16) (tuy nhin, nhn vo phn tham kho 36a). Qu trnh ny lin quan n hai ng phn ha v lin kt i v b phn lp. Trong vic chuyn dimethyl ally pyrophosphate ( 5 ) c xc nh l axit mevalonic [2-14 C]. ng phn ha ny c gi thit gi li trong cht dn xut alkylated tryptophane ( ging nh hnh ca axit claviceptic ) m ng trc chanoclavine I(14).

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Tiu Lun Hp Cht Thin Nhin

Khi ng phn ha ny b o ngc nh cu trc hnh (14) 9-H, c xc nh l axit mevalonicacid [2-14 C, 3R, 4R-3H], c gi li. Tuy nhin, trong qu trnh o ngc th hai (15 )( 16) th nguyn t hydro b mt i nghim trng. Elemoclavine l mt trong nhng terpenoid m n c chng minh rng ch (3R) enantiomer ca axit mevalonic c chuyn ha (xem ch thch trang 224).

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Tiu Lun Hp Cht Thin Nhin

Furamumarin v cc cht dn xut Furanoquiaoline. Thm hai nguyn t cacbon ca vng cha furanoid c ngun gc t C-4, 5 ca axit mevalonic. C l qu trnh ny xy ra tng t c hai loi chuyn ha th cp. V d,38,39 psoralen (21; R = H) v bergapten (21, R = OH) c ngun gc umbelliferone (18) i qua uiamarmesin (19) v dn xut dihydro (20) ca chng.

Qu trnh tng t xy ra38 vi h thng vng isomeric ca angelicin (22) v cc dn xut c hydroxyl ha ca n.[4-14C]3-(Dimethylallyl)-2,4 dihydroxyquinoline (23) l mt tin thn ca furanoquinoline alkaloids, mui platydesmonium(24) v dictammine (25; R = H). Tng t nh vy, axit 322

Tiu Lun Hp Cht Thin Nhin

mevalonic [4-14C] v [5-14C] v ru dimethylallyl [L-14C] l tin thn xc nh ca skimmiamine (25; R = OH).

4.

Monoterpenoids

Nhng bc tin nhanh chng c thc hin trong nghin cu v cc cht monoterpenoids cyclopentanoid tng i him do s tham gia ca chng trong qu trnh sinh tng hp indole alkaloid. Foliamenthin bismonoterpenoid (26) c pht hin trong cc nghin cu ny. Arigoni v ng nghip42 chng t s kt hp hiu qu ca geraniol (27) vo c hai na ca mch (26). Battersby t c kt qu tng t vi 6,7dihydrofoliamenthin. Nh d kin, trong c hai trng hp, mt na mch khng tun hon th nhiu phng x hn.Tin thn mch h ca monoterpenoids thng c cho l geranyl pyrophosphate (6; n = 1) nhng, r rng, cht ny khng th trc tip tham gia vo cu trc ca foliamenthin. Hai tin cht thay th l44 linalool pyrophosphate (28,R =P2O63-)v nerolpyro phosphate (29;R=P2O63-).

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Tiu Lun Hp Cht Thin Nhin

Tht khng may, c ba cht ny khng c xem xt trong cng mt mch, nhng hoc l mt tin cht hiu qu hn geranyl pyrophosphate, tc l (28; R =P2O63-) trong Citrus sp45 v (29; R = P2O63-) trong Pinus radiata46. Trong trng hp tin thn mch h ca indole alkaloids l47 10-hydroxynerol (10-OH, 29; R = H). Tng SN2 thy phn ca nhm pyrophosphate cung cp geraniol c cho l khi Arigoni pht hin ra axit mevalonic [3R, 5R-3H] (1) v geraniol [1S-3H] (27) c xc nh l 1-H ca loganin (35; R = Me). Tuy nhin, tin thn mch h C10 u tin phi l geranyl pyrophosphate (6; n = 1) k t khi hai nguyn t tritium c kt hp bi isomer [2-14C, 3R, 4R-3H] v khng c cht no c to t (4S)-isoner. Theo c ch c xut bi Arigon47 i vi vng ny lin quan n vic trialdehyde (33). Potty v cc ng nghip52 phn lp mt loi enzyme t Citrus spp m lm xi ha geraniol (27) vi andehit tng ng. Thng thng n c cho rng trong sinh tng hp terpenoid th thnh phn mi isoprenoid s c ghi ha tr bng axit mevalonic [2-14C]. tuy nhin, Banthorpe53 pht hin ra rng trong qu trnh STH camphor (30), hu ht phng x im C-6. Gi v s cu to ca dimethyl ally pyrophosphate (5), kt qu l c th gip gii thch nhng kh khn v tnh cht ca monoterpenoids.

Mt vn khc c pht hin bi Banthorpe54 rng nhiu cht menthane v thujane terpenoid trong Tanacetum vulgare th c th thay i ln nhau. Tuy nhin, thi gian nghin cu phng x versus ch ra rng c mt s lng cht Methan terpenoid n nh trong cy bc h cay. Khi pulegone [14C] (31) c b 324

Tiu Lun Hp Cht Thin Nhin

sung56 vo h thng phn t t do, ch menthone v isomenthone l cc phng x. Vic mt mt ny ch xy ra vi s hin din ca NADPH. Hin tng dp da bi loi b cnh cng n t Ty Ban Nha, cantharidine (32), khng tun theo tun theo nh lut ca isoprene. Tuy nhin, s kt hp57 ca axit mevalonic [ 2-14C] ch ra ngun gc ca terpenoid.

Cyclopentanoid Monoterpenoids v indole alkaloid. Mt s ti liu nh gi nhng tin b trong qu trnh sinh tng hp indole alkaloid. Kt qu ca cng vic ny, qu trnh sinh tng hp loganin (35; R = Me) n nay c nghin cu nhiu nht trong s terpenoid, ngoi tr cholesterol.Kt qu t vic cung cp axit mevalonic [2-14C, 3R] (1) c c xc nh bi tritium (2R)-,51(2S)-,51(4R)-49-51, (4S)-49-51 v (5R)-48 vi v tr nh [2-14C ,6-3H2] geranio59 c tm tt di y. c bit qu trnh gia ca trialdehyde (33) c xut bi Arigoni gii thch vic ngu nhin quan st ha tr t axit mevalonic [2-14C] gia C-9 v C-10. ng ch l, ha hc lp th c thnh lp c ngha l mt dn xut nerol b oxy ha c tham gia47,60. Sau khi to vng, c du hiu chng t axit 5desoxyloganic (34;R=H) v 5-desoxyloganin (34, R = Me) nh chu k gia, nhng iridodial th khng tham gia. 325

Tiu Lun Hp Cht Thin Nhin

Battersby cng cng s64,65 ch ra rng secologanin (36) [cf. (26) c to ra t loganin trong cht Menymthes trifoliata v Vincu rosea . Khng c c ch tch vng. Sweroside kt hp66,67 indole alkaloid trong Vinca rosea cho thy hoc l ng thay th, hoc thc vt c kh nng chuyn ha mt tin cht khng t nhin (xem di y). Secologanin (36) c th chuyn i64,68 trc tip thnh vincoside (37 ) v isovincoside [C-5 epimer (37)]. Nhng chuyn i hn na ca 326

Tiu Lun Hp Cht Thin Nhin

alkaloids indole th nm ngoi phm vi quyn sch ny. Ngi c nn tham kho58 mt s bi vit gn y v cc n phm47,49,60,62,64-71. Garg v Gear70 a ra mt li tuyn b th v ch n glycine l mt tin cht c th hn acetate, khng c h tr71 bi cc nghin cu gn y bng cch s dng cc loi thc vt khc nhau. C s lin quan cht ch n secologanin l gentiopicrosid (39). Theo d kin, n ch kt hp vi mt nguyn t tritium t axit mevalonic [3R, 4R-3H], v khng c t ng phn (4S). Nghin cu lin quan n axit mevalonic [3R, 2R-3H] cho thy rng mt nguyn t tritium c th c tch hp nhng khng c kt hp vi ng phn (2S)-. iu ny ch ra rng nu secologanin (36) l mt tin cht th aldehyde proton nn c xc nh. Cc tin cht c chng minh hiu qu bao gm axit loganic50,51 (35; R = H), loganin61,72 (35, R = Me), v sweroside66 (38). Alkaloid gentianine lin quan cht ch n gentiopicroside. Thm vo axit mevalonic50,51,73 glycine cng l mt tin cht tt73.

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Tiu Lun Hp Cht Thin Nhin

Mc d trong qu trnh sinh tng hp indole alkaloid C-9 v C-10 ca loganin thng c xc nh nh nhau bi axit mevalonic [2-14C] , trng hp ny khng phi lun lun c74. Trong cy trng thnh loi c roi nga oflcinalis, verbenalin (40) ch yu c xc nh ti C-9, trong khi trong cc cy con khc u c xc nh ti C-9 v C-10. Inouye cng ng nghip61,75 chng minh trong cc loi thc vt khc nhau, nhiu chuyn i gia cc cyclopentanoid monoterpenoids. H ch ra axit 5-desoxyloganic (34, R = H) c chuyn i thnh verbenalin (40), v cho rng asperuloside ( 41) cng c hnh thnh t loganin (35; R = Me) thng qua geniposide (42). Hp cht ny (42) cng l tin thn ca scandoside (43) v aucubin (44), v cc hp cht lin quan gardenoside v catalposide. 328

Tiu Lun Hp Cht Thin Nhin

5.Sesquiterpenoids
Famesol (ru t 6; n = 2) l76 mt cht c kh nng l tin thn ca ipomeamarone (45). C l mt dn xut ng phn 2-cis ca farnesol l tin thn trc tip ca vng furan ca terpenoid ny, v s trao i cht dendrolasin nh hnh (46)77. Mt bi vit44 gn y tho lun v ng phn ca farnesyl pyrophosphate c th c to vng cung cp cho cc nhm sesquiterpenoids khc nhau.

Trong khi 2-cis-isomer cung cp cht bisabolene, curcumene, v cc cu trc lin quan. S h tr th nghim cho gi thuyt ny khng phi l c sn, mc d dihydrocostunolide (47) c kt hp78 thnh cht santonin (48). Terpenoid ca petasin (49 R = CO.CMe: CHMe) c chng minh79 trong bi nghin cu "Non-Isoprene Rule.

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Tm quan trng chnh ca -bisabolene nh mt tin cht ph bin ca sesquiterpenoids l t cu hi nghin cu gn y ca helicobasidin (50; R = OH), deoxyhelicobasidin (50; R = H) v phenol (51). Vi [2-14C, 3R, 4R-3H] mevalonic axit hai nguyn t triti c kt hp vo quinon (50) v ba vo cc phenol (51).

Tuy nhin, trong h thng c lin quan ca trichothecolone (52; R = O) v trichothecol (52; R = H2), [2-14C, 3R, 4R-3H] mevalonic axit labelled82 nh du v tr v [1-3, 2 -14C] farnesyl pyrophosphate kt hp mt nguyn t triti ti C-11, kt qu ny l tng thch vi mt ngun gc -bisabolene. v c bit quan trng v n gii thch c kt lun m trc y gp nhiu kh khn gii thch. N cng cn lu rng s kt hp ca (4R) - dn nhn mevalonic axit ng s hnh thnh ban u ca tt c cc xuyn farnesyl pyro-phosphate (6, n = 2). M hnh dn nhn [.. (53)] c tm thy t s kt hp ca 2-14C - mevalonic axit vo coriamyrtin84 (53; R = M) v tutin84,85 (53, R = OH) ph hp vi mt ngun gc 330

Tiu Lun Hp Cht Thin Nhin

curcumene. C hai th nghim cho thy cc nhm methyl v methylene c xc nh nh nhau, v Arigonis84 tm thy nhiu hn ng k phng x C-12 hn ti cc v tr khc. Kt qu ny cho thy pyrophosphate geranyl c nhiu thc vt. Ngun gc terpenoid ca furnagillin [55; R = CO. (CH: CH)4. CO2 H] c chng minh bi Birchetal86. H cho rng isoprenologue cha c -pinen (54) c phn tch nh c hin th.

Abscisic acid (56; R = H) trnh by mt vn cho d l mt carotenoid sesquiterpenoid hoc b suy thoi [cf: axit trisporic (115) l. Cc nghin cu ca nhm Shell87 khng gii quyt cu hi ny. Cc ng phn cis tng gp i c bt ngun bi isomerisation ca h thng trans k t khi [2-14C, 3R, 4R-3H] mevalonic axit kt hp hai nguyn t triti. Trong c chua, [2-14C abscisic acid l metaboliseds cung cp cho cc glucoside enantiomer khng t nhin v cht chuyn ha C (56; R = OH). Siccanochromenic acid (57) c th c ngun gc tng t nh axit abscisic, s kt hp hiu qu ca acid mevalonic c chng minh. 331

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6. Diterpenoids
Mt nh gi ca sinh tng hp diterpenoid c xut bn. 90 Kt qu s b c bo co91 v sinh tng hp cc acetate crassin (57a). Mt terpenoid cyclotetrade-ma, casbene c hnh thnh92 t geranylgeranyl pyrophosphate (6;n= 3) Ricinus communis. Cc enzym tham gia c c mt phn tch ri nhau. Mc d mt phm vi rng ca diterpenoids c hnh thnh t pyrophosphate copalyl (58), loi enzyme khc nhau c lin quan n s hnh thnh ca skeleton rosane93 (60) (59), b khung kaurane92,94,95 [(62) v (63)] ent-( 59), beyerene v tachylo bane92,95 t ent- (59), v sandaracopimaradiene92,95 t ent (59) vi cu hnh ngc li ti C-13. Coleone A c bit n96 nh mt dn xut 1, 10seco-abietane. Achilladelis v Hanson97 nghin cu s kt hp ca [2-14C ,2-3H2] - [2-14C, 3R, 4R-3H] - [2-14C ,5-3H2] axit mevaionic vo rosane terpenoid (60) Kt qu ca h, cng vi s kt hp ca pimaradiene93, khng bao gm bt k trung gian gia diene (59) v (60). K t khi labda 8 (17) ,13-diene-15 ,19-diol v acid isocupressic c lin kt lng lo so vi ngay c copalol (58, tng ng vi ru), n phi c kt lun rng lacton hnh thnh khng din ra cng mt lc nh sp xp li [xem (59)]

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Tiu Lun Hp Cht Thin Nhin

C th gii thch rng 10- hydroxyros-14-ene c hnh thnh thng qua cc via trans b sung v s chuyn ha SN217. Hn na s trao i cht97,98 ca desoxyrosenolactone (60) cung cp cho rosenololactone (60; 6 -OH) v rosenonolactone (60, 7-oxo).

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Kauranes v axit Gibberellic. Diterpene tetracyclic m c ngun gc t cc axit gibberellic l ent-kaurene (62). Mt s cng nhn c mt phn tinh ch cc enzym tham gia vo vic chuyn i cc axit mevalonic vo entkaurene. [ 14C,32P] Geranylgeranyl pyrophosphateg5 (6; n = 3) v ent-pyrophosphate copalyl [ent (58) l trung gian trong qu trnh ny. Cc kt qu t s kt hp ca [2-14C ,2-3H2], [214

C, 2R-3H, 3R] - 100 [2-14C, 3R, 4R-3H] -, v [ 2-14C, 3R, 5R-3H-mevalonic axit

ph hp vi cc m hnh ghi nhn tm tt trong cng thc (62). C ch c th lin quan n cyclisation ca bicyclic ent (58) thnh ion carbonium ba vng ent (59) v t tetracyclic ion '(61) sp xp li kaurene-ent (62). ent Pimaradiene khng tham gia trong qu trnh ny.

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Qu trnh chuyn ha kaurene-ent (62) l ph hp vi mt con ng duy nht, lin quan n qu trnh oxy ha bng cch s dng [18O2] kh oxy102 cung cp cho 19-hydroxy-ent-Kaur-16-ene102, v t thng qua cc aldehyde-19-ent Kaur-16en-19-oic axit102. y l axit hydroxy ha cung cp cho 7-hydroxy-ent-Kaur16-en-19-oic axit102,104 l im chi nhnh kaurenolides (63) v axit gibberellic (64) v (68). Hydroxyl ha104 v tr 6-cho kaurenolide (63; R = H) l tip tc hydroxy ha diol (63; R = OH). Trong nhng hydroxylations ti C-6 v C-7 c lu gi cu hnh100. Mc d 7-hydroxykaurenoic acid chuyn ha104 thnh axit gibberellic A3 (68; R = OH) v A12 (64) v aldehyde gibbane (64; aldehyde C-7), tt c cc dn xut kaurene khc c th nghim nh l tin thn cho vng tht bi. Chng bao gm 6, 7-103, cc dn xut 6, 7-103 v 6, 7-diols105,106, v 6-kaurene pht sinh103. C hai 6, 7-diol105 v 6-phi sinh103, tuy nhin, cho 335

Tiu Lun Hp Cht Thin Nhin

6,7-seco h thng ca fujenal. Vic kt hp [2-14C, 3R, 5R-3H] mevalonic axit cho thy rng100 trong s ng vng proton 6 ca o hm kaurene b mt. Tuy nhin, khng c g c bit n s phn ca 6-proton. Hnh thnh gibbane pht sinh u tin c l l gibbane aldehyde104,107 (64 aldehyde ti C-7). K t khi mt 6 , 7-dihydroxykaurene phi sinh c v nh khng xy ra giai on trung gian, s ng vng c th lin quan n oxy ha trc tip sp xp li ca 7 hydroxykaurenoic axit hoc isomerisation ca 7-oxokaurenoic acid.

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Tiu Lun Hp Cht Thin Nhin

Aldehyde Gibbane107 c chuyn thnh axit gibberellic hoc A12 (64) hoc A14(65). do hydroxyl ha C-3 phi t trc qu trnh oxy ha C-7 khi c hnh thnh A14. Axit A14 l ln lt chuyn i107 thnh hoc A4 (67; R = H), A13 (66). Ngi ta cho rng108 axit gibberellic [i.e, A3, (68; R = OH) c hnh thnh t A4, via hoc l A1, (67; R = OH) hoc A7 (68; R = H). Cc m hnh ghi nhn c tm thy axit gibberellic (68; R = OH) sau khi c phn ng feeding vi [2-14C, 2-3H2,]-94 [2-14C,2R-3H,3R]-100 [2-14C,3R,4R-3H]-94 v [2-14C,3R,5R-3H]100

axit mevalonic cho thy rng nhm 3-hydroxy c gii thiu vi gi cu

hnh, tri vi cc thng tin lin lc s b v lin kt i 2 lin quan n mt cisloi b.

7. Sesterterpenoid
Vic a109 tt c cc pyrophosphate xuyn geranylfarnesyl (6; n = 4) nhng khng phi l ru tng ng hoc pyrophosphate cis-geranylfarnesyl vo ophioBolin F (69) l mt v d th v ca cc c trng ca cc enzyme. Sesterterpenoid ny r rng l h thng u b oxy ha bin thnh ophiobolins C (69; 5,21-dioxo), B (69, 14-hydroxy-5 ,21-dioxo), v A (69 ;14, l7R-oxido-5,21-diox). Cc kt qu110 trc lo t s kt hp ca [2-3H2]-, [2-14C,2R-3H,3R]-, [2-14C,2S3

H,3R]-, [2-14C,3R,4R-3H]-, and [2-14C, 3R,4S-3H]- axit mevalonic c tm tt

trong cng thc (69). Glycine l mt tin thn tt hn so vi axit mevalonic, nhng khng c d liu suy thoi c bo co 111. Kt qu gn y112 trn fusicoccin (70) cho thy rng cc n v isopentenyl c tng hp vi tc khc nhau t h thng ba vng. Kt qu ny ng rng mc d fusicoccin c cu

337

Tiu Lun Hp Cht Thin Nhin

trc tng t nh cc ophiobolins, n c th i din cho mt lp mi ca diterpenoids.

8. Steroid Trisnortriterpenoids
Trong iu kin sinh tng hp, steroid l nhng sn phm trao i cht ca triterpenoids. Do tm quan trng quan trng ca cholesterol, sinh tng hp cc hp cht steroid ny lin quan c xem xt trong phn ny. Hn na s trao i cht ca cholesterol c xem xt trong mc 9, trong khi triterpenoids khng steroid c xem xt trong mc 10. Kh nng biosynthesise steroid v cc qu trnh trao i cht steroid ng vt chn t c xem xt trong mc 13. Nhng tin b gn y trong sinh ha steroid c bo co 113. Cyclisation ca squalene. ng vt v nm hnh thnh triterpenoid chu k u tin l lanosterol (73). Squalene tin thn mch h (7) l epoxidised cung cp cho (3S) -2,3-oxidosqualene (71) sau cyclised lanosterol. Bloch v cng nhn114 b c lp hai enzym tham gia t cc m gan v ch ra rng 338

Tiu Lun Hp Cht Thin Nhin

cyclaseoxidosqualene c trng lng phn t khong 90,000. Nghin cu su hn cc yu cu steric ca enzyme ny bi van Tamelen115 v Corey116 v cc ng nghip ca h cho thy enzyme tng i khng nhy cm vi tnh cht ca oxy v khng cn phi sp xp li tng ng sinh hc ca cc ion carbonium (72 ) sn xut mt terpenoid min ph. Tuy nhin, mi trng ca nhm epoxide l quan trng. Mc d hai enzyme c th c tinh ch v c c hai hot ng ring l, c kim tra kh nng ca mt phc hp enzyme lin kt cc bc khc nhau gia pyrophosphate farnesyl (6; n = 2) v lanosterol c kim tra117.

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Tiu Lun Hp Cht Thin Nhin

Trong s hin din ca [4S-3H] NADPH cc lanosterol cha 47,9% ca tritium ti 11 v 37,4% v tr-12. iu ny cho thy ch hi lin kt ca ba giai on, c th c kim sot bi s hnh thnh o ngc ca mt phc tp gia squalene v 1 lipoprotein.118 Stereospecificity ca cc kt qu cyclisation trong nhm trans-methyl c hai u ca squalene v epoxide ca n, v nhm 4-methyl lanosterol c dn nhn bi [2-14C] mevalonic axit119. Kt lun tng t t c120 t s kt hp ca squalene chun b t axit mevalonic trong s hin din ca deuterium oxide. Mt c gng121 xc nhn c 1,2-hydride ghi trong (72; mi tn) l mt phn thnh 340

Tiu Lun Hp Cht Thin Nhin

cng.Trong s kt hp ca [1,5,9,16,20,24 -

14

C6, 9,11,14,16,10, 15'-3H10,]

squalene vo lanosterol c l mt tn tht 13,3% ca tritium ( tc l t C-11 ca squalene trong vic hnh thnh cc tri phiu 8 kp). S xung cp ca cc lanosterol cho thy rng c mt s lng khng ng k ca tritium ti C-20 v ch c 11,6% C-17 (tng ng vi 10% ca tritium trong squalene). Trong trng hp khng c cc hiu ng ng v, gi tr ny nn c 13,3%, v i din cho C-14 ca squalene (tng ng vi C-11). R rng hai ca 1,2-hydride xy ra ch khng phi l mt s thay i 1,3-hydride.

Vic ghi nhn tritium m hnh lanosterol khng c nghin cu rt chi tit. Tuy nhin, n c th c rt ra n mt mc ln t kt qu vi cholesterol, 341

Tiu Lun Hp Cht Thin Nhin

c tha thun vi s kt hp ca [2-14C,3R, 4R-3H] -122 v [2-14C,3R, 5R-3H] 123

mevalonic axit vo lanosterol. Khng t hn bn nhm nghin cu thnh lp

cng ty [2-14C, 2R-3H, 3R] acid mevalonic v (2) - ng phn124-127 vo cholesterol. Ngoi ra, [2-14C, 3R, 4R-3H]128 v [2-14C, 3R-5R-3H] mevalonic axit123,124 c kt hp. Nhng kt qu ny c tm tt trong cng thc (73) v (74). Tt c cc kt qu trn tham kho chut h thng gan. C l, kt qu tng t cng p dng cho lanosterol (73)c chun b129 bng cch cho n nm men vi [2-14C, 2R-3H, 3R axit mevalonic hoc ng phn (2S). Tuy nhin, mc d steroid c phn phi rng ri trong t nhin (xem mc 13), triterpenoid u tin c hnh thnh trong cc nh my cao hn (vi ngoi l ca mt s Euphorbia sp. 130) Cycloartanol (75). Theo d kin, 2,3-oxidosqualene (71) incoi-porated131 v cc m hnh ghi nhn l c l ging nh lanosterol (73) [2-14C, 3R, 5R-3H] mevalonic axit123. [2-14C, 3R, 4R-3H mevalonic axit , su nguyn t triti c kt hp132-134 [xem (75)]. Cc nguyn t triti thm c tr nh d kin ti C-8132. Cycloartanol cng c hnh thnh thay v lanosterol trong cc Ochromonas mal-hamensis135 sinh vt n bo, to fucus spiralis,136 v polypodioides vulgare137,138 dng x. Trong hai trng hp cui cng, m hnh ghi nhn c hin th trong cng thc (75) c h tr. Chuyn ha hn na song song cycloartanol ca lanosterol vi thm mt bc khi vng cyclopropane c phn tch thnh nhng cung cp cho cc 8-ene. Phn ng ny dng nh c th xy ra bt k giai on no, nhng c l khng bnh thng khng lm nh vy trc s mt mt ca mt nhm C-4-methyl. mt lin kt i khng phi l hnh thnh v, tt nhin, cc nhm 14-methyl khng c th b mt cho n khi mt lin kt 8-tng gp i hin nay (xem bn di).

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Tiu Lun Hp Cht Thin Nhin

Mt 4,4 Dimethyl Groups.-Trnh t cc bc khc nhau gia lanosterol v cholesterol xy ra l khng chnh xc thnh lp. nhng mt lin kt i 8 l cn thit cho s mt mt ca cc nhm l4-methyl. l thun tin xem xt cc bc ny mt cch ring bit. Khi cycloartenol134,
137, 138

dn nhn [2-14C, 3R, 4R-3H] axit mevalonic c

chuyn i thnh 4-desmethylcycloartenol, c mt mt ca cc nguyn t 3-triti v nhm 4-methyl dn nhn.119, 120 Tng t nh vy, lanosterol dn nhn vi [2-14C, 3R ,5-3H2] mevalonic axit l [3H1,
14 14

C6], trong khi lophenol l [3H11,

C5],. N phi c kt lun rng, tri vi bo co trc , 4 nhm methyl l b l ng phn 4343

mt u tin. Kt qu ny c chng minh bi s kt hp 142 ca 4-hydroxymethyl-4-methylcholestan-3-ol nhng khng phi hydroxymethyl. Hn na, 4-methylcholestan-3-ol l phn ln chui cc s kin

Tiu Lun Hp Cht Thin Nhin

dng nh th l methyl 4 b oxy ha cho mt nhm carboxyl v 3-hydroxyl mt xeton-3. Decarboxylation ca axit 8-keto Tip theo l gim nhanh chng143, 144 sau 3-xeton 3-ru. Trong s hin din ca nc tritiated C-3 v C-4 tr thnh phng x145 .

Mt ca nhm 14a-Methyl. S mt mt ca nhm 14-methyl c th khng lin quan n mt axit -keto (2-4, k t khi tritium l c mt ti C-15 sau khi cho n 2-14C, 2R-3H, 3R] mevalonic acid126, hoc mt vinologous B-keto axit t tritium sng st ti C-11 t 2-14C, 3R, 5R-3H] axit mevalonic123,
124

. Do n

gin decarboxy-lation (76) phi xy ra sau khi qu trnh oxy ha ca methyl14614 . C bng chng cho s hnh thnh v a thm mt 8(14) c cha cht steroid146, 147 (77; R1= H). Isomerisation n nh hn 8(14) tr li lin kt tng gp i n 8(79) xy ra thng qua mt 8,14 diene- (78). Diene ny c hnh thnh thng qua cc allylic ru (77; R1 = OH), gi nh duy tr cu hnh qu trnh oxy ha, v mt 15-H124-127, 129, 148, 149.

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Tiu Lun Hp Cht Thin Nhin

Ngi ta khng bit cho d qu trnh oxy ha ny xy ra bnh thng trc khi150, hoc sau khi151 mt ca nhm 14-methyl. Mt s nhm ch ra rng mt 8,14-diene (78) c hnh thnh152 v a vo153 steroid khc. Trong gim ca lin kt 14 tng gp i 14-H c ngun gc t NADPH154 v 15- H t trung bnh145, 155. Isomerisation t lin kt i 8- 5 . giai on u tin trong vic chuyn giao ca B vng lin kt tng gp i vng l mt isomerisation t 8- 7 (80). Mc d c nhng bo co tri c v nh t nghi ng rng phn ng ny c th c o ngc. Cholest-7-en-3-ol trong s hin din ca microsomes gan chut v nc tritiated c tnh phng x trn reisolation, vi hu ht ca tritium ti C9156.

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Tiu Lun Hp Cht Thin Nhin

Tng t nh vy, cholest-8-en-3-ol c chuyn thnh[ 9-3H] cholest-7en-3-ol bi h thng ny157. Trong h thng gan chut proton 7 b mt158, v xc nhn bi vic lu gi tritium ti C-7 cholesterol dn nhn bi [2-14C, 2R-3H, 3R] mevalonic axit125-127 nhng khng phi do ( 2 S) ng phn124, 125, 127. Tuy nhin, trong Saccharornyces v Aspergillus l 7-proton b mt129, 149, 127. Ngc li, cc sinh vt n bo Ochromonas sau h thng ng vt c v148. Cc lin kt 5 steroid tng gp i c gii thiu bi kh 7-steroid (81) 5,7 diene (82). Mc d c nhng tuyn b cho hydroxyl lin-trung gian mt nghin cu chi tit cho thy rng cholest-7-ene 3 , 5-diol c chuyn i tr li cholest-7-en-3-ol trc khi c chuyn i thnh cholesterol. Enzyme kh l mt trong s t c bit n hai protein systems161. Trong tt c cc loi nghin cu 6-123, 124, 160, 162-164 v 5 proton136 b mt. Mt hiu ng ng v ng k c quan st163 vi [4 -14C, 5, 6-3H2] cholest-7-en-3-ol. Phn ng ngc li (83) xem xt trong phn 9. Trong bc cui cng, cc lin kt tng gp i 7-gim enzyrne hai protein165. Lp th (83) l mt ln na xuyn, vi proton-8 c nhn c t mi trng145,
166

(82) c

v 7-proton t NADPH166. Gim lin kt i A24- S gim ca lin kt i 24- mt ln na l mt qu

trnh xuyn. Caspi v cng s ch ra rng cholesterol (24R) - hydro c dn nhn [2 - 14C, 3R, 4R-3H] axit mevalonic, v trn lation-hydroxy (25R)-cholest-5ene-3, 26-diol nhm hydroxymethyl c dn nhn bi [2-14C mevalonic axit (74)]. Kt qu th hai l ngc li tm thy cho tigogenin (88) trong thc vt168 cao hn. NADPH cung cp169 hydro C-25 trong khi hydro C-24 c ngun gc t mi trng145, 169.

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Tiu Lun Hp Cht Thin Nhin

Chui Alky1ation pha-C-ankyl ha sinh hc c xem xt bi Lederer170. Nhm ca ergosterol 24-methyl (86; R1= Me) c ngun gc t 24-methylenesteroid (85; R1 = CH2)171 ln lt c hnh thnh t S-adenosylmethionine v 24-steroid.
172

Ankyl ha c th xy ra bt k lc no sau khi lanosterol nhng c

l tliuo xy ra ch yu giai on trung gian chng hn nh 24-methylenezymosterol171. Cc methylene 24-steroid l tt nht c cng nhn l mt trung gian bng cch kt hp ch c hai nguyn t deuterium t [CD3] methionine. Mt phm vi rng ca nm sn xut ergosterol v steroid c lin quan bi qu trnh 347

Tiu Lun Hp Cht Thin Nhin

ny170,

173

, tuy nhin, trong mt s trng hp thnh lp cng ty thp ca (86; R1 =

deuterium r rng l do mt phn ng o ngc (85; R 1= CH2) t (84) (85; R1 = CH2) (85; R1 = CHMe) (86; R1 = Et).

Me). Cc cht dn xut 24-Ethyl v ethylidene ni chung c ngun gc cc trnh

V d in hnh c tm thy trong thc vt bc cao 174, 175, to nu175 (fucus), v ng vt nguyn sinh (Qchromonas)176. Trong trng hp cui cng, n c tip tc th hin poriferasterol (86, R 1= Et) cha 1,3, hoc 4 nguyn t teri trong ch ra rng giai on (85, R1 = CH2) n (85; R1 = CHMe c kt hp) ba nguyn t deuterium. Mt processoccurs khc nhau trong nh my ofthe Myxomycetes nguyn thy (Dictyostelium, Physarum)170,
177

v Chlorophyceae

(Chlorellu)178 k t khi nhm 24-ethyl cha ti nm nguyn t deuterium177, 178 v ergost-7-en-3-ol c ba nguyn t teri178. Proton vinyl C-24 khng phi l b mt132, 133, 136, 137, 179 trn-ankyl ha nhng l xuyn ferred C-25136, 180. C th tt c cc steroid c hnh thnh thng qua mt enzyme gii hn ph bin trung gian ngoi quan ti C-25. ngh ny c h tr bi cc obvervation137 cyclolaudenol (87, R1= Me) gi li tt c cc nguyn t triti ba t [C3H3] methionine, v proton C-24 vinyl. Tng t nh vy, ny proton vinyl c gi li trong (24S)ethylcholesta 5 ,22,25-trien-3-ol133.

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Tiu Lun Hp Cht Thin Nhin

Lin kt i 22.bn kh chui c xem xt bi Lederer170. Khng ging s kh hydro ca ht nhn steroid, gii thiu lin kt 24 tng gp i xuyn ergosterol v steroid c lin quan khng yu cu s hin din ca mt lin kt i 24 - 24(28). Tuy nhin, s hnh thnh ngh182 ca ergosta-5, 7,22,24 (28) tetraen-3-ol l c h tr bi cc nghin cu thnh lp cng ty. Lp th ca qu trnh ny ph thuc vo loi. Trong ng vt nguyn sinh (Ochrornonas tetruhyrnenu) (22R)184v (23S) hydrogens cholesterol b mt, tc l hydrogens ti cc v tr ny c ngun gc t [2R-3H, 3R]148,
184, 185

v [3R, 5R-3H]164,

185

axit

mevalonic. Ngc li, trong nm (Aspergilus)149, v c l hu ht trong cc thc vt( Camellia)186, cao hn cp i din ca hydrogens b mt. Trong Nicotiana tobacum c bng chng187 cho vic gim ca lin kt 22-tng gp i. Tuy nhin, n khng phi l r rng nu iu ny l bnh thng trong qu trnh c th sng.

9. Cholesterol Metabolism
Tm quan trng quan trng ca cholesterol (74) trong cc h thng ng vt t lu c cng nhn.N tr nn r rng rng steroid ny c th ng mt vai tr quan trng khng km trong h thng thc vt mc d n him khi c th c c 349

Tiu Lun Hp Cht Thin Nhin

lp. S kt hp ca 8-sitosterol(86, R1= Et) vo progesterone cho thy rng nhm 24-alkyl khng ngn cn s phn ct ca , lin kt C-20, 22188 C th k cn trng chui pha,phn ng-ankyl ha c th c o ngc (xem Phn 13). Mt phn ng m c th c o ngc l gim lin kt 7-tng gp i. Tetrahyrnena pyriforrnis cholesterol c chuyn i thnh cholest-5,7,22-trien3-ol.189. Lin k 7 -tng gp i c hnh thnh bi s mt mt ca 7 - v 8hydrogens cholesterol184,185,190. S quan trng ca hormone ecdysterone cn trng (122) v ponasterone tin thn ca n A (123) cng xy ra mt s thc vt bc cao. Theo d kin, c hai mevalonicaxit v cholesterol c kt hp vo cc steroid191. Mt hydroxy-lin quan lated steroid, chiograsterol A (3, 16,23,24-tetrahydroxy-5-cholestan-6trn chuyn i thnh hoc B chiograsterol (tng ng 6-ol) hoc chiogralactone (tng ng tetranor-23, 15-olide).192

Spirostanols-Tigogenin193 (88) v diosgenin194 5 (88) c hnh thnh t cholesterol v nguyn t hydrogen C-25. T [2-14C, 3R, 4R-3H] axit mevalonic nhm 25-methyl c nh168 vo 14C v ch c hai nguyn t triti tn ti, 20-H ca cholesterol b mt i195. (25R)-Cholest-5-ene-3,26-diol196 350

Tiu Lun Hp Cht Thin Nhin

v glycoside bt ngun t (25R)-3,26-dihydroxycholest-5-en-22-one hemiacetal197 kt hp vi diosgenin. Lin kt i 5-cholesterol phi c loi b trc khi thy phn khi tigogenin c hnh thnh trong digitalis. Cc bc tin hnh thong qua cholest-5-4-en-3-one198,5-cholestan-3-one199,5cholestan-3-ol199 v 5-cholestan-3,16,26- triol200

Cardenolides v Bufatenolides:Nghin cu rng hn v digitoxigenin (89)gitoxigenin (89;16-OH) qu trnhsinh tng hp trong Digitalis sp tm ra c nhiu chi tit trong qu trnh. Giai on u tin t cholesterol hoc -sitosterol188 nh s phn tch ca qu trnh trn cung cp cho pregnenolone201. Cholest-5-en-3,20-diol khng tham gia vo dy truyn202. Lin kt i 5 ca pregnenolone gim i trong progesterone203(4-ene3-one) 5-regnan-3,20-dio v 5-pregnan-3-ol-20-one204. Hydroxyl ha cho 5pregnan-3,14-diol-20-one205 v 5-pregnan-3,14, 21-triol-20-one206. Cui cng vng butenolide c hnh thnh. Digitoxigenin (89) sau c th c hydroxy ha t gitoxigenin (89; 15-OH) hocdigoxigenin (89, 12351

Tiu Lun Hp Cht Thin Nhin

OH).204, 206 Tuy nhin,s hnh thnh sn phm digoxigenin 5-pregnan-3, 12diol-20-one.204 17- ch khng phi l cc nguyn t hydro 17digitoxigenin c k hiu bi [3R,4R-3H] mevalonic axit195. Trong Struphanthus Kornbe azarigenin (89; 5-H) c hnh thnh t 5pregnen-olone207. Mt s qu trnh tng ng vi cc dn xut pregnane c chng minh thc vt bc cao208. Cc bufatenolides (90) c qu trnh sinh tng hp thc vt tng t nh cardenolides. Pregnenolone c kt hp209 vi hellebrin [(90) (89;5-OH, 19-oxo)] v scilliroside210
211

[(90) (89, 4)] Tuy nhin, trong con cc(Bufu) dn xut ca acid cholanic l tin cht tt hn so vi cc cht l dn xut ca pregnane210, . iu ny cho thy rng tt c cc nguyn t cacbon ca vng enolester (90) c th c bt ngun t cholesterol trong con cc so vi ch c hai trong loi thc vt bc cao.Trong con cc, marinobufagin [(90) (89,5-OH, 14,15-oxide)] l tin ca telecinobufagin [(90) (89; 5-OH)].212 thn

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Tiu Lun Hp Cht Thin Nhin

Side Chain Cleavage. C hai phng php phn bit cho s gim ca phn ng ph. Trong cc h thng ng vt c v, -glycols c phn tch thnh cc xeton tng ng. C hai dn xut androstane v pregnane c th c hnh thnh trc tip213. Hydroxyl ha ca cholesterol (91, R1= R2 = R3 = H) din ra c hai C-20 v C-22 cung cp cho diols tng ng (91; R1R2 = H, OH,R3 = H) v trio1 (91, R1= R2 = OH, R3 = H) vi mt s thch hp214 cho cholest-5-ene-3, 22R-diol (91; R1= R3 = H, R2 = OH).Tuy nhin, qu trnh i hi215 cht 20hydroperoxide (91; R1= OOH, R2 = R3 = H) l tin thn.Cc enzyme cho qu trnh phn tch ca 20,22-diol ph thuc vo oxy v NADPH216. Pregnenolone (92; R = H) c k hiu217 l [18O2] nguyn t oxy c c l nh s hydro ha. Sn phm khc l 2.-methylheptan-6-one. Qu trnh c thng qua 7-hydroxyxeton-20 (92; R = OH) c phn tch thnh androstane (93, R = O). Qu trnh phn tch trc tip 17-20-diol (91; R1= R3 = OH, R2 = H) cng thu c sn phm l lacton (93, R = O) v axit isocaproic213.

353

Tiu Lun Hp Cht Thin Nhin

Qu trnh phn tch ca progesterone (92, R = H) i trc tip t Axetat (93; R =-OAc,-H) nh qu trnh sinh tng hp ca Baeyer-Villiger. Cc nguyn t 17-hydro c gi218 li trong qu trnh ny v oxy ete c k hiu l 18O2219. C ch ny cng c p dng cho cht trao i viridin (94) c ngun gc t mt triterpenoid steroid220.

Qu trnh trao i sterol ng vt: S gim ca lin kt i 5-cholesterol c nghin cu thc vt bc cao. Mt qu trnh tng t xy ra ng vt. Qu trnh oxy ha C-3 theo sau s ng phn ha cung cp cho cc h thng lin hp 4-en-3-one. Trong gan chut,quan st thy mt ng v khi nh s th t mt trong hai nguyn t 3hay 4-hydro . C hai nguyn t b mt trong cc phn ng, trong khi ch c mt lng nh 4-3H c chuyn n v tr 6-. Ngc li vi cc th nghim nhau thai ca con ngi, nguyn t 4- c gi li trn ng phn iso ca lin kt i222. Oxy ha to ra ru cn c NADPH cng vi tritium t [4S-3H] NADPH223. Qu trnh kh ca progesterone t pregn-4-en-20-ol-3-one cn NADPH v tritium c kt hp t [4R-3H] NADPH224. Qu trnh sinh tng hp ca con ln cn th v, nhng steroid 5-androst-16-en-3-one trong tinh hon khng cho bit lin kt i 16 to thnh nh th no. Chng cht no sau kt

354

Tiu Lun Hp Cht Thin Nhin

hp vi tin cht drostane. Mc d progesterone (92,R= H) l s dng cc hp cht 17-hydroxy (92, R = OH).225

Qu trnh oxy ha androst-4-en-3,17-dione (95; R = Me) c estrone (97). Kh androstadiendione (96; R = Me) xy ra s mt mt l-v 2-proton226. Hydroxyl ha C-19 c th xy ra trc hoc sau khi kh. Hu ht cc phng x [19R-3H] -androst-5-ene-3, 17,19-triol (95; R =
CH2OH,

3-OH) c thu hi

bng axit formic cng vi ng phn (19S) ca tritium trong nc. iu ny c ngha l ton b qu trnh oxy ha cc hp cht 19-oxo (95; R = CHO, 3-OH) l loi b bi axit formic.227

355

Tiu Lun Hp Cht Thin Nhin

10. Tritecpen
Ba phng php khc nhau chng minh cho s hi lu ca squalene. Mc d hu ht cc triterpenoids theo mt quy trnh tng t nh lanosterol [(7) (71) (72) (73)] 3-desoxytriterpenoids chng hn nh fernene (98) c hnh thnh t squalene (7) ch khng phi t 2,3-oxidosqualene (71)228. Mt proton bt u hi lu, tip theo l loi b mt nguyn t hydro, cng hoc khng c,s sp xp li ion carbonium. Khi [2-14C, 3R, 4R-3H] axit mevanolic c lm nguyn liu cho polypodioides vulgare bn triterpenoids c phn lp. Diploptene,fernene (98) v serratene cha tt c cc nguyn t su triti trong khi hopene-1, nh mong i, ch c nm. Trong serratene mt nguyn t triti c t ti C-13229.

Tetrahymanol (99) cho thy mt qu trnh bin th ca carbonium ion t proton ban u n squalene (7) b kh bi mi trng. Mt ln na 2,3oxidosqualene (7 1) khng c sp xp li230, 231. Trong s hin din ca doteri oxit, mt nguyn t doteri c kt hp C-3 trong khi [18O] nc k hiu l 21-hydroxy-group231,
232

. Su nguyn t triti c kt hp t

[2-14C, 3R, 4R-3H] axit mevalonic vo tetrahymanol (99)233 . 356

Tiu Lun Hp Cht Thin Nhin

Axit fusidic (100) v axit helvolic (101) l steroid ging nh triter-penoids c ngun gc t cc ion carbonium (72) m khng cn sp xp li v sau s tch i mt nhm 4-methyl. Khi c th thu c duy nht [2 - 14C, 3R, 4R-3H] axit mevalonic kt hp bn nguyn t triti [xem (100)]234.

2,3 Oxidosqualene (71) c kt hp235 v c th l ngun cung cp protosta17(20), 24 -dien-3-ol. Emericallopsis salmosynnemata [2-14C] axit mevalonic c kt hp vo triterpenoid ny cng nh vo lanosterol (73) nhng khng thnh protosta 13 (17),24-dien-3-ol236. Dn xut ca 4-hydroxymethyl l tin cht ca axit helvolic (101)237,v cc chc nng vng oxy B c th c gii thiu cui mi giai on238. Mi quan h gia Simaroubaceae v gc limonoid c xc nhn bng glaucarubolone (102) c ngun gc t triterpenoid239.

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-Amyrin (103) l mt triterpenoid pentacyclic in hnh m nh qu trnh sinh tng hp nghin cu c. Su nguyn t triti c kt hp t [2-14C, 3R, 4R-3H] - axit mevalonic179 v v tr c t240. iu ny khng nh c ch thng dng cho sinh tng hp ca h vng 2,3 oxit squalete241.

11. Carotenoid
Vi nt v qu trnh sinh tng hp carotenoid c xem xt.242 Nhiu trong cc tin thn ca phytoene (8) d dng kt hp thnh carotenoid.26, 243 Tuy nhin, phytoene dng nh l tin thn chnh v n thng gi li hu ht cc phng x. Mc d carotenoid thng c coi l ng phn ca thesised ch bi lin kt i, mt bo co gn y cho thy rng m tru, b c th tng hp Carotene t acetat244. Trong hu ht cc lin kt i, giai on u tin ca qu trnh sinh tng hp carotenoid lin quan n vic kh ca phytoene (8) lycopene (104)245. Cyclisntion lycopene c th to thnh -carotenen246 (105) hoc Carotene (106)246, 247. Hn na qu trnh oxy ha-carotene bi loi ng vt thn gip Salina Arternia cho248 echinenone (107) v canthaxanthin (108). Ru thng allylic th khng c pht hin. Qua thi gian nghin cu vi aureus 358

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Staphvloccus a ra gi thuyt -carotene (109) c th l mt tin thn ca Rubixanthin(110)249, mt enzyme cho qu trnh oxy ha ca -carotene (106) n vng mc (114; R = CHO) c phn lp t rut heo 250.

Mt trong nhng vn chnh ca qu trnh sinh tng hp terpenoid l khng bit n kh nng kt hp c th ca loi (v d nh mevalonic axit). Nguyn nhn chnh gy kh khn chc chn l compartmentalisation, theo xy ra s thay th 359

Tiu Lun Hp Cht Thin Nhin

n gin ca nhm th bn cnh khi hp cht 3-chloro-2 ,19-Oxido (51) c thay th bng kim loi km hoc natri axetat trong axit axetic 102.

-S tham gia ca oxy ete (52) dn n s tn cng vo v tr 2 v 3nucleophin, to thnh c 2 cht 3-acetoxy-2 ,19-Oxido (53) v 2-acetoxy-3 , 19-oxido (54).

S kt hp ca mt nguyn t triti trn mt phn t isoprenoid t [2-14C, 3R, 4R-3H] axit mevalonic cho thy c tin thn ca tt c cc cht tham gia, v d nh ubiquinone (116) (6, n = 8), -tocopherol (117) (6; n = 3)258. S gim ca lin 360

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kt i, v d nh mt - tocopherol (117), tritium c kt hp t [4R-3H] NADPH259

Tri ngc vi tt c cc terpenoid coi cao su l mt mch h cis-terpenoid. S khc bit ny c phn nh trong cc kt hp ca tritium t [2-14C, 3R, 4S3

H] mevalonic axit nhng khng phi t ng phn (4R)3. Polyprenols (118) cha

c hai lin kt cis-v trans-gp i. Bi v kch thc ca chng, cc qu trnh sinh tng hp c c bit quan trng xc nh s lng ca tng cht. Trong hu ht cc trng hp kim tra theo cch ny, ba lin kt i c mt ngun gc c th, 3 lin kt i cui c dng trans (118; n = 3) v phn cn li l cis.

Vic kt hp phng x t [14C] farnesyl pyrophosphate (6; n = 2) vo betulaprenols (118; n = 3, m = 3-6), c kin cho rng nhng polyprenols c tng hp bng cch cho pyrophosphate farnesyl tc dng ti v tr cis260. Phng thc tng hp ny c ph bin rng ri trong thin nhin, bao gm c cc lin kt i thc vt bc cao (v d betulaprenol), vi khun 261polyprenol-11 (118; n = 3, m = S) v h ng vt c v262 dolichol [(118; n =3, m = 14-16)]. Mt hp

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cht trong nm Aspergillus fumigatus c bo ha lin kt i. S gim t l ca polyprenol cho thy rng cc lin kt i b bo ha.263

13. Taxonomy
Cc kin thc v qu trnh sinh tng hp terpenoid khng cho thy c chi tit v tm quan trng trong s phn loi ca n. Tuy nhin, mt s khc bit cp phyla l r rng. Qua nhn xt trn cho thy s khc bit quan st thy s hnh thnh ca steroid 7 v 22 ti lin kt i, cc nhm 24- alkyl, v cho d lanosterol hoc cycloartenol c hnh thnh t squalene epoxide. Trong th gii thc vt (vi khun264, to, nm, pteridophyta, v cc thc vt bc cao), kh nng tng hp terpenoid l gn nh hon ton. Ngoi l duy nht c th l to mu xanh-mu xanh l cy (Cyanophyceae) cc kt qu tri ngc nhau nhng ch c th phn nh nhng kt thc nghim th hin qu trnh sinh tng hp terpenoid. Khng c kh nng s dng axit mevalonic, v kt hp nhng pyrophosphate 362

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farnesyl vo squalene Pseudoplexaura sp. (Zooxanthellae) c th gii thch ti sao n sng cng sinh ng vt khng xng sng bin266. Trong th gii ng vt, v tr phc tp hn nhiu. Tt c ng vt c xng sng u c th tng hp steroid t tin cht n gin. Tuy nhin, khng c bng chng tt v tng hp steroid trong ng vt chn t, mc d mt s cng nhn tuyn b khc. Qua trnh iu tra ch ra rng kt hp cc tin cht gn vo steroid c ch nh bi cc vi khun ng rut. V l do ny, sai lm l trong gii thch cc kt qu tch cc, trong khi kt qu tiu cc ch c th ch ra mt khng c kh nng chuyn ha thm cc tin cht, hoc cht khng t cc enzym cn thit. ng vt chn t xng sng. cc Protozoa c th tng hp terpenoid [v d nh. (99)]. Tuy nhin, khng c bng chng v sinh tng hp squalene hoc steroid trong Coelenterata,267
273

Echinodermata,268 Nematoda,269-271hay

Platyhelminthes272,

. Trong mt s trng hp, mt s h c th tng hp

steroid, v khng cn mt ngun c ngun nguyn liu u. Hymenolepis dimunuta c th tng hp farnesol t axit mevalonic273. Trong Annelida phylum th v tr t r rng hn. Trong khi mt s loi c th tng hp steroid cn nhng loi khc ch c th tng hp squalene274. C th l phn loi ny cho thy s khc bit gia hai lp Polychaeta v Oligochaeta. Tuyn trng c th chuyn ha steroid cung cp cho 5,7-dienes t cholesterol271 hoc p-sitosterol, v o ngc ankyl ca phn sau steroid (86, R1= Et)(84)(74)270. Mollusca l mt phylum taxonomically. T cc d liu c sn, cc Bivalva 268 v Cephalopoda275 khng th tng hp steroid hoc squalene. Tuy nhin, trong cc lp Gastropoda Stenoglossa khng th tng hp steroids 276. In Stylommatophora c mt kh nng ln277, v sinh tng hp steroid c mt trong Archaeogastropoda 278, Mesogastropoda,279 v Basommatophora.280 Arthropod Sinh tng hp steroid dng nh vng mt ti tt c cc phylum ny. V d v cc lp Arachnida, Diplopoda, 281 loi ng vt gip sc,281,282 v 363

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Insecta283 c kim tra. Qu trnh trao i cht steroid trong cc loi cn trng c kim chng284. Hy nh rng cn trng c th tng hp c mt s terpenoid [v d: (32) v (46)], nhng c mt yu cu ch n ung tuyt i cho cc steroid. Phytosterol nh hitosterol l chuyn i tr li vo cc cht dn xut cholesterol r rng bng cch o ngc-ankyl ha chui bn (86, R 1= Et) (85; R1 = CHMe) (85; R 1= CH2) (84 ) (74). Ngoi ra mt tri phiu tng gp i 7-intro-duced286.Parasites, v cc sinh vt t nhin khc, c th ng gp vo mt s nhng phn ng ny.287

Cc hoc mn cn trng quan trng ecdysone (1 21) v steroid c lin quan cng c mt trong cc nh my (Phn 9). Sinh tng hp cholesterol t ca h c th tin hnh thng qua cc 5-diene289 triolone (119)290. Cc chui bn sau c hydroxy ha hydroxy-(120)291`, mt ecdysone (121)292, v -ecdysone (122) 364

Tiu Lun Hp Cht Thin Nhin

(crustecdysone). Cui cng, s c ca -ecdysone cho axit 4-hydroxy-4methylpentanoic293. (xem thm phn 9)

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KT LUN

Ngy nay vic tm ra cc hp cht thin nhin c cu trc ha hc cng nh c hot tnh sinh hc l cc xut pht im cho cc chng trnh nghin cu phong ph khc, cc m tng hp thch hp vi nhiu trin vng thnh cng cho vic iu ch cc hp cht c cu trc tng t nhng c tnh cht u vit hn v thch hp mi trng hn cho vic s dng. trn ta nghin cu v mi lin quan cu trc tc dng, cu trc- th th v s chuyn ha cng nh v c ch tc dng phn t ca cc phn t terpenoids v steroids. Nhng iu trn y cho thy tm quan trng v ca cc terpenoids, steroids ni ring v ca cc hp cht thin nhin ni chung qua cho thy tm quan trng trong ngnh nghin cu lnh vc ha sinh hc Hu c hin nay.

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