PRPG

Photolabile Protecting Groups (PLPG): Synthetic and Biological Applications
Carmin Burrell October 15, 2008
First Examples: Cbz-glycine

O OH
O O
H N
H2, Pd/C or Li, NH3 or HBr
O H2N OH
O O
H N
O OH
h! (254 nm) Med. P Hg lamp 30 min, H2O 75%

H2N
O OH
Zweifel, G. S.; Nantz, M. H.; Modern Organic Synthesis: An Introduction; University Freeman: New York, 2007, 60. Barltrop, J. A.; Schoeld, P.; Tetrahedron Lett., 1962, 16, 697-699.
First Examples: o-Nitrobenzylesters

NO2
acetone h! (>280nm)
NO OH O NO2
O NO2 O2N H O
H Med. P Hg Lamp Pyrex Filter
h!
H O
O2N H O O H
(>280nm)
NO2 H O HO
NO H OH
NO OH O
Leighton, P. A.; Lucy, F. A., J. Chem. Phys., 1934, 2, 756-759. Barltrop, J.A.; Plant, P. J.; Schoeld, P.; Chem Comm, 1966, 22, 822-823.
First Examples: o-Nitrobenzylesters

NO2 H O R O
CCl4 h! (>280nm)
R'
O R'
O R
Med. P Hg lamp HO Pyrex Filter

R H Ph R' Ph Ph Time(hr) Yield 2.5 2.5 3.0 4.0 17 90 95 87
Ph C15H31 Ph CH2Ph
Barltrop, J.A.; Plant, P. J.; Schoeld, P.; Chem Comm, 1966, 22, 822-823.
Mechanism of Deprotection
O N O O O O N OH R O O R' O N O H O R O O N R' C R OH O O N O R HO R' O O
R' h!
R'
H R
H transfer
Barton, D. H. R.; Chow, Y. L.; Cox, A.; Kirby, G. W.; Tetrahedron Lett., 1962, 23, 1055-1057.
Excitation - Jablonski Diagram

S2 Internal conversion Vibrational relaxation S1 Excitation femto (10-15s) S0 Fluorescence nano (10-9s) pico 10-12s
Intersystem crossing T1 Phosphorescence !micro (10-6s)
Excitation promotes a HOMO electron to the LUMO Rearrangement occurs to cleave the PLPG
Laimgruber, S.; Schreier, W. J.; Schrader, T.; Koller, F.; Zinth, W.; Gilch, P.; Angew. Chem. Int. Ed. 2005, 44, 7901-7904.
Applications of PLPGs - Synthesis of (-)Diazonamide A

Me Me HO Me H N O HN O O O Cl O NH NH Me N N Cl
(-)-Diazonamide A
Snider, B. B.; Busuyek, M.V.; Tetrahedron, 2001, 57, 3301-3307. Li, J.; Jeong, S.; Esser, L.; Harran, P. G.; Angew. Chem. Int. Ed. 2001, 40, 4765-4769.

Me Me Me HO Me H N HN N N Cl O O O O Cl O NH NH
(-)-Diazonamide A
Me HN CbzHN O
Me N O CN
Na HN
Me N O O CN
o-NO2C6H4CH2Br K2CO3, NaI, DMF 52% Br
CbzHN
Br O O Ph OH NO2
OH O Ph OH
Li, J.; Jeong, S.; Esser, L.; Harran, P. G.; Angew. Chem. Int. Ed. 2001, 40, 4765-4769.

(-)-Diazonamide A
Me HN CbzHN O
Me N O CN CbzHN
Me HN O
Me N O O O
Cl3CCO2H
Br O O Ph OH NO2 Ph O O NO2 Br

(-)-Diazonamide A
Me HN CbzHN O
Me N O O O N H
NHAlMe2 Me HN CbzHN O O Me N HN O
NH
O O Ph
1.3 eq, toluene/CH2Cl2 0C!RT Br 83% (2 steps)

NO2
Br O O Ph OH NO2

(-)-Diazonamide A
NH Me HN CbzHN O O Me N HN O Me HN Me N O O HN O
NH
5 mol% nPr4NRuO4 1.5 eq NMO 4 MS, CH2Cl2 78%
CbzHN
Br O O Ph OH NO2
Br O O Ph O NO2

(-)-Diazonamide A
NH Me HN CbzHN O O Me N HN O Me Me N O O HN O
NH
350nm, 3x10-2M degassed dioxane excess Ac2O, py, DMAP, CH2Cl2, 85%
Br CbzHN
HN
Br O OAc O
O O Ph O NO2 Ph
Requirements for PLPGs
A Functionalized Aromatic System Substituents can allow for use of a specic

wavelength radiation
Fast Rate of Cleavage Reduce the time needed for deprotection High quantum yields
Stabilize the radicals or ions created after excitation
Photolabile Protecting Groups (PLPGs)

OR MeO O OMe
Pirrung, M.C.; Bradley, J. C., J. Org. Chem., 1995, 60, 1116-1117.
OMe O MeO O R O R' Ph Ph O
S O
O O
OR
Wang, P.; Wang,Y.; Hu, H.; Spencer, C.; Liang, X.; Pan, L. J. Org. Chem. 2008, 73, 6152-6157.
Kitani. S.; Sugawara, K.; Tsutsumi, K.; Morimoto, T.; Kakiuchi, K.; ChemComm. 2008, 2103-2105.
OR MeO MeO OR NO2 MeO O O
Furuta, T.; Wang, S. S.; Dantzker, J. L.; Dore, T. M.; Bybee, W. J.; Callaway, E. M.; Denk, W.; Tsien, R. Y.; Proc. Natl. Acad. Sci. 1999, 96, 1193-1200.
OMe
NO2
!"!# $max (nm) 184 n"!* $max (nm)
217 269
251 299
252 330
Lambert, J. B.; Shurvell, H. F.; Lightner, D. A.; Cooks, R. G.; Organic Structural Spectroscopy, Prentice-Hall: New Jersey,1998, 289.
A Functionalized Aromatic System Substituents can allow for use of a specic

wavelength radiation
Fast Rate of Cleavage Reduce the time needed for deprotection High quantum yields

Quantum Yield = ! = Number of molecules that undergo cleavage Total number of photons absorbed 0<!<1
OMe OMe Ph Ph O H O Ph
Chlorophyll = 0.25 Rhodopsin = 0.66
MeO O H O Ph
MeO
2 ! = 0.03
3 ! = 0.17
Wang, P.; Wang, J.; Hu, H.; Spencer, C.; Liang, X.; Pan, L. J. Org. Chem. 2008, 73, 6152-6157. Anslyn, E. V.; Dougherty, D. A.; Modern Physical Organic Chemistry; University Science Books: Sausalito, California, 2006, 971.
Dimethoxybenzoin Carbonates
X R4 R3 R2 R1 O
benzene h! (>280nm) Med. P Hg lamp Pyrex Filter

R2 R1 O R3
R4
R1 R2 R3 H H H H H H OMe H OMe
OAc
R4 X Time (hr) Yield H OAc 17 15 H Cl 18 1 H OAc 17 46
MeO O OMe
MeCN h! (360nm) Rayonet reactor pyrex filters 7min, N2

= 0.64
MeO
HOAc
O OMe
99%
Sheenan, J.C.; Wilson, R. M., J. Am. Chem. Soc., 1964, 86, 5277-5281. Sheenan, J. C.; Wilson, R. M.; Oxford, A. W, J. Am. Chem. Soc., 1971, 93, 7222-7228
X MeO O OMe
benzene h! (350nm) Rayonet reactor 1h, Ar
MeO
HX
O OMe
OH
SH MeO
OH OH
88%
95%
90%
94%
Pirrung, M.C.; Bradley, J. C., J. Org. Chem., 1995, 60, 1116-1117.
OAc MeO O OMe OAc MeO O OMe MeO O OMe MeO OMe OAc
h!
MeO O
HOAc
H OMe O
Boudebous, H.; Ko!mrlj, B.; "ket, B.; Wirz, J., J. Phys. Chem. A., 2007, 111, 2811-2813.
New PLPGs - Thiochromone S,S Dioxide

O
h! (" >280nm) ultra-high P Hg lamp pyrex filter

O O OEt
CD3OD (2.0X10-2M) 0.5h
S >99%
O O
OEt
O O
OR
O O
OR
Kitani, S.; Sugawara, K.; Tsutsumi, K.; Morimoto, T.; Kakiuchi, K. Chem. Comm. 2008, 18, 2103-2105.

O O O OEt
S O
CD3OD (2.0X10-2M) 0.5h
EtOH >99%

O O
h! (" >280nm)
S O O H O O O O XR
CD3OD
O
S O
O O
XR
CO2
S O O
O
HXR
O O
XR S O O
O
O O
OR
O O
OR

O

O O O O
-2 R CD3OD (2.0X10 M)
ROH
S O O
S O
Alcohol Irradiation Time(h) Yield(%) EtOH C8H17OH

OH OH
Alcohol
Irradiation Time(h) Yield(%) 1.0 >99 (98)
0.5 0.5 0.5 1.0 1.0
>99 >99 >99

Me
OH MeO
1.0
H OMe OAc
>99 (99)
97 98
H HO HO AcO OAc O
OH
0.5
>99 (99)

O R' N O

-2M) CD OD (2.0X10 3 R
O R H N R' O
S O O
S O
Amine C4H9NH2 Et2NH

NH2 CO2Bn
Irradiation Time/h 1.0 1.0 1.0
Yield(%) 97 98 97

O

O O O R
CD3OD (2.0X10-2M)
RCOOH
S O O
S O
RCOOH C11H23COOH C17H35COOH
Irradiation Time/h 1.0 1.0 1.0

COOH
Yield(%) >99 >99 >99
COOH
1.0
>99
New PLPGs - Ketones and Aldehydes Generation 1

OMe OMe
!MeO O H O H
!-
!-
O O H H Mulliken Charges
O H
O H
S1 -0.193
S0 -0.143
S1 -0.181
S0 -0.159
S1 -0.168
S0 -0.172
Ortho - meta effects on the excited state facilitate

heterolytic cleavage
Zimmerman, H. E.; J. Am. Chem. Soc., 1995, 117, 8988-8991 Wang, P.; Hu, H.; Wang,Y.; Org. Lett., 2007, 9, 2831-2833.
Gaussian 03, Revision C.02 CIS/3-21G for excited states HF/3-21G for geometry optimization
Excited State - Ortho - Meta Effect

MO 7 MO 6
MO 5 MO 4
MO 3 MO 2
MO 1
Zimmerman, H. E., J. Am. Chem. Soc.,1995, 117, 8988-8991.

OMe OMe
!MeO O H O H
!-
!OMe
O O H H Mulliken Charges
O H
O H
MeO
S1 -0.193
S0 -0.143
S1 -0.181
S0 -0.159
S1 -0.168
S0 -0.172
O R1
CH2 O R2
Ortho - meta effects on the excited state facilitate

heterolytic cleavage
Zimmerman, H. E.; J. Am. Chem. Soc., 1995, 117, 8988-8991 Wang, P.; Hu, H.; Wang,Y.; Org. Lett., 2007, 9, 2831-2833.
Gaussian 03, Revision C.02 CIS/3-21G for excited states HF/3-21G for geometry optimization

OMe MeO O H OMe O
h! (>280nm) Med P Hg lamp pyrex sleeve CD3CN/D2O (9:1) 1hr Ph

H
O Ph
50%
h! (>280nm) Med P Hg lamp pyrex sleeve

O H O
O H Ph
CD3CN/D2O (9:1) 1hr Ph h! (>280nm) Med P Hg lamp pyrex sleeve
8%
Ph O O CD3CN/D2O (9:1) H 1hr H Ph Wang, P.; Hu, H.; Wang,Y.; Org. Lett., 2007, 9, 2831-2833.

OMe O R1 R2 10 mol%, p-TsOH MeO OH OH OMe
h! (>280nm) Med. P Hg lamp pyrex filter MeCN/H2O (4:1)

CHO
MeO O R1 O R2
O O
Ph
CHO OPh MeO
16
Protection Yield: Deprotection Yield: Time (h):
92 81 4.0
99 79 0.5
93 86 3.0
91 93 3.5
Wang, P.; Hu, H.; Wang,Y.; Org. Lett., 2007, 9, 2831-2833.

O
OMe Ph O R1 O R2
OMe Ph
OMe Ph O R1 O R2
R1 R2 10 mol%, p-TsOH Ph
Ph
Ph
OH
OH
h! (>280nm) Med. P Hg lamp pyrex filter MeCN

CHO
O Ph CHO
8
OMe
MeO
Protection Yield: Deprotection Yield: Time (min):
99 90 60
99 89 60
91 86 60
93 84 80
Wang, P.; Hu, H.; Wang,Y.; Org. Lett., 2007, 9, 1533-1535.
New PLPGs - Ketones and Aldehydes Optimized System

OMe OMe Ph Ph OH 1 OH OH OH OMe Ph Ph OH OH
MeO
MeO
PPG 1 2 3
! 0.03 0.11 0.17
protection yield (%) deprotection yield (%) time (min) 92 99 99 81 90 92 240 60 30
Wang, P.; Wang, J.; Hu, H.; Spencer, C.; Liang, X.; Pan, L. J. Org. Chem. 2008, 73, 6152-6157.

O OMe Ph MeO OH R1 R2 10 mol%, p-TsOH Ph OMe Ph O R1 O R2 O O OPh MeO
16
OH
h! (>280nm) Med. P Hg lamp MeO pyrex filter MeCN/H2O 10%(v/v)

CHO
Ph
Ph
CHO
Protection Yield: Deprotection Yield: Time (h):
99 92 30
93 82 44
99 88 25
99 91 25

OMe Ph Ph O R2 OMe OMe Ph MeO O R1 O R2 R1 OMe Ph O R2
MeO O R1
h!
H2O
MeO O Ph Ph
h! -H2O
MeO OH
Ph Ph OH

Reagent PhLi LiAlH4 Solvent THF THF THF THF MeCN MeCN MeCN MeCN MeCN MeCN MeCN Conditions -78 to 23C, 6h 23C, 24h 23C, 24h 23C, 18h 23C, 24h 80C, 2h 23C, 24h 80C, 2h 23C, 24h 80C, 2h 23C, 24h 80C, 2h 23C, 24h 80C, 2h 23C, 24h 80C, 2h 23C, 24h 80C, 2h %Recovery 100 100 100 100 100 100 100 94 0 0 100 100 100 91 100 65 47 0 NaBH4 H2, Pd/C
OMe Ph Ph O H O Ph
t-BuOK DDQ CAN AcOH TFA HCl (37%) pTsOH
MeO
New PLPGs - Ketones and Aldehydes Amino Acetal

R1
h# (>280nm)
R2 O H O
O H Ph
Med. P Hg lamp pyrex filter Ph Yield 99 92 Time 16 30
R1 N(Me)2 OMe
R2 H OMe
! 0.13 0.17
"max 327 297
Orthogonality Using PLPGs
OMe Ph Ph O H O Ph
N Ph Ph O H O Ph
OMe
MeO
h! MeCN/ MeO H2O (1:1)
O Ph Ph O H O Ph H Ph
350nm, 20min: 98% sunlight, 3h : 98%
>89% >96%

O O S O O O O O O O O O O O O S O
h! (" >280nm) CD3OD, 0.5h 99%
OH O
CO2
S O

O O
mCPBA 85%
S O O O OH O S O O O O O OH
h! (" >280nm) CD3OD, 0.5h 99%
HO
OH S O O 85%
CO2
>99%

OMe O2N MeO O O O
n
OMe OMe
O O
n 254 nm 420 nm (%) (%) 0 420 nm 1 2 OMe 3 4 5

O O O
254 nm
h!, then CH2N2
O2N MeO O
n
OMe OMe
86 94 94 96 78 92
n
67 83 85 85 87 70
OMe O
O O
MeO
Blanc, A.; Bochet, C. G., J. Org. Chem., 2002, 67, 5567-5577.
o-Nitrobenzyl is most widely used and has been

applied to total syntheses
NO2 H O R O R'
Summary of Uses of PLPGs in Synthesis
Thiochromone systems could be an alternative

although optimization required
O S O O O O O R
Acetal protection system for aldehydes and ketones

is groundbreaking
OMe MeO O R1
Proof of orthogonality makes PLPG more practical
Ph Ph O R2
Caged Biomolecules
PLPG inactivates the biomolecule until irradiated Biomolecules that have been caged include: neurotransmitters, ATP, P , Glutamate An effective method to elucidate cellular functions of
i
biomolecules
Release occurs on a biologically relevant time scale as

compared to diffusion (temporal resolution) resolution)
Release can be controlled to a specic area (spacial

Furuta, T.; Wang, S. S.; Dantzker, J. L.; Dore, T. M.; Bybee, W. J.; Callaway, E. M.; Denk, W.; Tsien, R.Y.; Proc. Natl. Acad. Sci. 1999, 96, 1193-1200.
Caged Biomolecules - C. Elegans
Li, H.; Avery, L.; Denk, W.; Hess, G. P., Proc. Natl. Acad. Sci. USA, 1997, 94, 5912-5916.
Caged Biomolecules - C. Elegans

NO2 O COO-O NH3+ COO-
h!
NO O COOHO O
NH3+ COO-
Li, H.; Avery, L.; Denk, W.; Hess, G. P., Proc. Natl. Acad. Sci. USA, 1997, 94, 5912-5916.
Light Triggered Molecule-Scale Dosing

OCH3 O OCH3 O O O O O O O O OCH3 O O OCH3 O OCH3 OCH3
Acetylsalicylic acid
Ibuprofen
Ketoprofen
McCoy, C. P.; Rooney, C.; Edwards, C. R.; Jones, D. S.; Gorman, S. P.; J. Am. Chem. Soc. 2007, 129, 9572-9573.
Light Triggered Molecule-Scale Dosing

90 Yield of Ibuprofen (%) 60 Off 30 Off 0 0 Off On 10
OCH3 O OCH3 O O
Off Off On On
Off On On
On
20 Time (min)
30
O OCH3 O OCH3 HO
40
h! (365 nm) Hg lamp quartz cuvette
Ibuprofen
McCoy, C. P.; Rooney, C.; Edwards, C. R.; Jones, D. S.; Gorman, S. P.; J. Am. Chem. Soc. 2007, 129, 9572-9573.
Taxol Prodrug
O O OH O O O O HO O H O O O N H O OH HO O O H O O O O
O O H2N O
O O OH
Taxol 2.5 x 10-4 mg/mL Isotaxel 0.45 mg/mL
Skwarczynski, M.; Sohma, Y.; Noguchi, M.; Kimura, M.; Hayashi,Y.; Hamada,Y.; Kiso,Y.; Kimura, T.; J. Med. Chem. 2005, 48, 2655-2666.
Taxol Prodrug
N HCl O O
O O NH O O O
O O OH O O
O O OH
430 nm diode laser

H2N O O O HO O H O O O
HO O
H O
O O
Phototaxel < 2.5 x 10-4 mg/mL
Isotaxel 0.45 mg/mL
Skwarczynski, M.; Noguchi, M.; Hirota, S.; Sohma, Y.; Kimura, T.; Hayashi,Y.; Kiso,Y.; Bioorg. Med. Chem. Lett. 2006, 16, 4492-4496.
Taxol Prodrug
100
N HCl
80
2
O O NH O O O O
O O OH
60
(%)
O HO O H O O O
40
20
0 0 5 10 15 Time (min) 20 25 30
1
O O N H O OH
O O OH
OH
=1 =2 =5
O HO O H O O O
Skwarczynski, M.; Noguchi, M.; Hirota, S.; Sohma, Y.; Kimura, T.; Hayashi,Y.; Kiso,Y.; Bioorg. Med. Chem. Lett. 2006, 16, 4492-4496.
Taxol Prodrug
O
3 HCl
O
N NH
N H
N O O O O OH
O N O NH O O O
O O OH
O O
365 nm
H O O UV lamp O O
H2N O
O O
O HO O H O O O
HO O
Phototaxel 2 > 100mg/mL
Isotaxel 0.45 mg/mL
Skwarczynski, M.; Noguchi, M.; Hirota, S.; Sohma, Y.; Kimura, T.; Hayashi,Y.; Kiso,Y.; Bioorg. Med. Chem. 2008, 16, 5389-5397.
O O N H O O OH HO O O
O O OH
Taxol Prodrug
100
O H O O
(%)
80
Taxol
O
60
40
3 HCl
O
N NH
N H
N O O
20
O N O NH O O O
O O OH
0 0 10 20 30 Time (min) 40 50 60
O HO O H O O O
= Taxol = Phototaxel
Phototaxel
Skwarczynski, M.; Noguchi, M.; Hirota, S.; Sohma, Y.; Kimura, T.; Hayashi,Y.; Kiso,Y.; Bioorg. Med. Chem. 2008, 16, 5389-5397.
UV Damage
100 150 200 250 300 350 Wavelength 400 (nm)
X-Rays
Ultraviolet radiation UVC UVB UVA
Visible light
Preceding PLPGs required 280 - 365nm radiation for

cleavage
Matsumura, Y.; Ananthaswamy, H. N.; Toxicol. Appl. Pharmacol. 2004, 195, 298-308.
UV Damage
Sunburn, Suntan, Epidermal Hyperplasia DNA damage
Acute UV
Cell cycle control Apoptosis
DNA Repair
p53 induction
Maintenance of genomic stability DNA replication and repair Immune Suppression Angiogenesis inhibition
Skin aging (Photoaging)
Chronic UV
DNA damage accumulation
Genetic mutations
Immune suppression
Skin carcinogenesis
Matsumura, Y.; Ananthaswamy, H. N.; Toxicol. Appl. Pharmacol. 2004, 195, 298-308.
Two Photon Excitation
Maria Gppert-Mayer rst described non-linear

optics - 1931
Theodore Maiman developed the ruby laser -1960 W. Kaiser and C. B. G. Garrett observed two photon
excited uorescence in CaF2:Eu2+ crystals- 1961 microscopy - 1980s
Janis Valdemanis and R. L. Fork described multiphoton D. E. Spence, P. N. Kean and W. Sibbert developed Tisapphire femtosecond laser - 1990
Masters, B.R.; So, P. T. C., Microscopy Research and Technique, 2004, 63, 3-11.

S2 IC S1
Fluorescence
S2 IC ISC T1
Phosphorescence
Fluorescence
S1
ISC T1 Excitation Virtual State

Phosphorescence
S0
Excitation
S0
UV One Photon Excitation
IR Two Photon Excitation
Oheim, M.; Michael, D. J.; Geisbauer, M.; Madsen, D.; Chow, R. H.; Adv. Drug Deliv. Rev., 2006, 58, 788808
Utilizes IR radiation instead of UV Requires concentrated photons and provides increased

spacial and temporal control of excitation
Not sensitive to scattering No out-of-focus absorption Photobleaching and photodamage is limited to the
location of excitation
Increases Depth Penetration

Piston, D. W.; Adv. Drug Deliv. Rev., 2006, 58, 770-772.
One Photon UV
Two Photon IR
Caged Biomolecule
Released Biomolecule
PLPG
Furuta, T.; Wang, S. S.; Dantzker, J. L.; Dore, T. M.; Bybee, W. J.; Callaway, E. M.; Denk, W.; Tsien, R. Y.; Proc. Natl. Acad. Sci. 1999, 96, 1193-1200.
Oheim, M.; Michael, D. J.; Geisbauer, M.; Madsen, D.; Chow, R. H.; Adv. Drug Deliv. Rev., 2006, 58, 788808.
Oheim, M.; Michael, D. J.; Geisbauer, M.; Madsen, D.; Chow, R. H.; Adv. Drug Deliv. Rev., 2006, 58, 788808.



One Photon UV Two Photon IR
Denk, W.; Helmchen, F.; Nature Methods, 2005, 12, 932-940.


Confocal microscopy depth in

brain tissue: 50 - 100!m the brain tissue
Used for imaging of slices of Two Photon Excitation depth in

brain tissue: up to 1mm deeper in a tumor
Could lead to excitation

Denk, W.; Helmchen, F.; Nature Methods, 2005, 12, 932-940.
Coumarin Derivatives
O CH2OP(OC2H5)2 CH2Nu
h! (360nm)
H3CO O O
Nu
H3CO
Nu = CH3OH, piperidine, cysteine, tyrosine, "-chymotrypsin NH2

N O P O O O O N O N N NH2 N O P O O O HO N O N N
Dioxane/Water (1:1) h! (340nm) Xe lamp 1h, Ar, 90%
H3CO
cAMP
Givens, R. S.; Matuszewski, B., J. Am. Chem. Soc., 1984, 106, 6860-6861. Furuta, T.; Toriagai, H.; Sugimoto, M.; Iwamura, M., J. Org. Chem., 1995, 60, 3953-3956.
O MeO MeO O NO2 NH3 CO2 HO O O OAc Cl O O O OAc
1 !-DMNB-glu Cmpd 1 2 3 "(365nm) 0.006 0.025 0.01
2 !u(740nm (GM))
3 !u(800nm (GM))
1.07 0.05 1.07 0.07
0.13 0.001 0.34 0.02
Cross Sectional Area of Uncaging ("u)
Measures the efciency of the chromophore to

absorb two photons
Dependent on: Cross-sectional area of the chromophore

1"u = 10-50 cm4s/photon = 1GM
Albota, M., et. al.; Science, 1998, 281, 1653-1656.
O MeO MeO O NO2 NH3 CO2 HO O O OAc Cl O O O OAc
1 !-DMNB-glu Cmpd 1 2 3 "(365nm) 0.006 0.025 0.01
2 !u(740nm (GM))
3 !u(800nm (GM))
1.07 0.05 1.07 0.07
0.13 0.001 0.34 0.02
OAc Br O O O Br O Br 5 O OAc Br O
NH3 CO2 Br O
O Br O O O O 6
O O O
H N CO2
CO2
O 7 Bhc-glu
Cmpd 4 5 6 7
!(365nm) 0.037 0.065 0.019 0.019
!u(740nm (GM)) 1.99 0.09 0.96 0.05 0.89 0.24 0.95 0.21
!u(800nm (GM)) 0.42 0.01 3.1 0.2 0.42 0.11 0.37 0.06
100 80
60
(%)
40
!= 1 "!7
20
0 0 10 20 30 Time (min) 40 50 60
O MeO MeO O NO2 NH3 CO2 Br O O
O O O
H N CO2
CO2
1 !-DMNB-glu 7 Bhc-glu Furuta, T.; Wang, S. S.; Dantzker, J. L.; Dore, T. M.; Bybee, W. J.; Callaway, E. M.; Denk, W.; Tsien, R.Y.; Proc. Natl. Acad. Sci. 1999, 96, 1193-1200.
Coumarin Derivatives - Mechanism of Cleavage

OR H C H OR
333nm
H3CO CH2 O O H3CO O O
SET
CH2OH
OR
H3CO O O
H2O
H3CO O O
HOR
Schmidt, R.; Geisser, D.; Hagen,V.; Bendig, J., J. Phys. Chem. A., 2007, 111, 5768-5774.
Conclusions
Usage is an attractive alternative to classical protecting

groups
Technique is still in its infancy and further optimization

is required before wide spread usage systems tumors
Has the potential to revolutionize drug delivery Combined application with ber optics to target
Acknowledgements
Dr. Babak Borhan Dr. Ned Jackson Dr. Petr Klan Toyin, Aman, Arvind, Camille, Dan, Calvin, Xiaoyong, All of you for your attention
Mercy, Roozbeh, Atefeh, Sarah, Sing, Wenjing, Xiaofei, Chryssoula

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Photolabile Protecting Groups (PLPG): Synthetic and Biological Applications

Carmin Burrell October 15, 2008

First Examples: Cbz-glycine

H2, Pd/C or Li, NH3 or HBr

h! (254 nm) Med. P Hg lamp 30 min, H2O 75%

First Examples: o-Nitrobenzylesters

H Med. P Hg Lamp Pyrex Filter

First Examples: o-Nitrobenzylesters

Med. P Hg lamp HO Pyrex Filter

Excitation - Jablonski Diagram

Intersystem crossing T1 Phosphorescence !micro (10-6s)

Applications of PLPGs - Synthesis of (-)Diazonamide A

Applications of PLPGs - Synthesis of (-)Diazonamide A

o-NO2C6H4CH2Br K2CO3, NaI, DMF 52% Br

Applications of PLPGs - Synthesis of (-)Diazonamide A

Applications of PLPGs - Synthesis of (-)Diazonamide A

1.3 eq, toluene/CH2Cl2 0C!RT Br 83% (2 steps)

Applications of PLPGs - Synthesis of (-)Diazonamide A

5 mol% nPr4NRuO4 1.5 eq NMO 4 MS, CH2Cl2 78%

Applications of PLPGs - Synthesis of (-)Diazonamide A

Requirements for PLPGs

A Functionalized Aromatic System Substituents can allow for use of a specic

Stabilize the radicals or ions created after excitation

Photolabile Protecting Groups (PLPGs)

OMe O MeO O R O R' Ph Ph O

OR MeO MeO OR NO2 MeO O O

Requirements for PLPGs

!"!# $max (nm) 184 n"!* $max (nm)

Requirements for PLPGs

A Functionalized Aromatic System Substituents can allow for use of a specic

Requirements for PLPGs

Chlorophyll = 0.25 Rhodopsin = 0.66

benzene h! (>280nm) Med. P Hg lamp Pyrex Filter

R4 X Time (hr) Yield H OAc 17 15 H Cl 18 1 H OAc 17 46

MeCN h! (360nm) Rayonet reactor pyrex filters 7min, N2

benzene h! (350nm) Rayonet reactor 1h, Ar

Pirrung, M.C.; Bradley, J. C., J. Org. Chem., 1995, 60, 1116-1117.

New PLPGs - Thiochromone S,S Dioxide

h! (" >280nm) ultra-high P Hg lamp pyrex filter

CD3OD (2.0X10-2M) 0.5h

New PLPGs - Thiochromone S,S Dioxide

h! (" >280nm) ultra-high P Hg lamp pyrex filter

CD3OD (2.0X10-2M) 0.5h

New PLPGs - Thiochromone S,S Dioxide

New PLPGs - Thiochromone S,S Dioxide

h! (" >280nm) ultra-high P Hg lamp pyrex filter

Alcohol Irradiation Time(h) Yield(%) EtOH C8H17OH

Irradiation Time(h) Yield(%) 1.0 >99 (98)

0.5 0.5 0.5 1.0 1.0

>99 >99 >99

New PLPGs - Thiochromone S,S Dioxide

h! (" >280nm) ultra-high P Hg lamp pyrex filter

Amine C4H9NH2 Et2NH

Irradiation Time/h 1.0 1.0 1.0

New PLPGs - Thiochromone S,S Dioxide

h! (" >280nm) ultra-high P Hg lamp pyrex filter

RCOOH C11H23COOH C17H35COOH

Irradiation Time/h 1.0 1.0 1.0

Yield(%) >99 >99 >99

New PLPGs - Ketones and Aldehydes Generation 1

Ortho - meta effects on the excited state facilitate

Excited State - Ortho - Meta Effect

Zimmerman, H. E., J. Am. Chem. Soc.,1995, 117, 8988-8991.

New PLPGs - Ketones and Aldehydes Generation 1