Ergot Alkaloid Syntheses

(a.k.a., crappy hippy)

2 November 2005
Ergot Alkaloids
Isolated from the dry sclerotium of the fungus Claviceps purpurea (ergot), a
parasite that grows on grains.
Modern sources include isolation from field-cultivated ergot, semisynthesis,
and fermentation of the fungus Secale cornutum.
Most biologically-active agents are amides or peptides of lysergic acid.
Methylation of the indole nitrogen increases serotonin-antagonistic effect of
the drug.

O Me O
H OH H
Me Me O Me O HO Me
HO N HO N N H N N
H H H
H N Me H
O N N
H
H O H

N N N
H H N H
Lysergic Acid Elymoclavine Ergotamine Ergonovine
H
(Gynergen) Uterine Contractions
Treatment of Migraines
 History & Ergot Alkaloids

Many ailments have been linked to ergot alkaloids.

St. Anthonys Fire (a.k.a., Devils curse, gangrenous ergotism)
Convulsive ergotism (delirium, epileptic-type seizures)
Historically, ergot was thought to be a normal part of rye.
Wet, rainy weather is particularly conducive to ergot growth.
Rye was mostly consumed by poor. (ergo, )
True cause of ergotism not discovered until 19th century.
Ergot attributed to witch trials (yes, Salem circa 1691).
In the middle ages, some instances of the black plague may have actually
been ergotism.
Last great epidemic occurred in 1926-1927, in certain areas of southern
Russia.
 O O
H
Me
N N N
The LSD Story N
H

Coramine
LSD N
Discovered by Albert Hofmann (Sandoz Co., Basel, CH). H
Worked under Arthur Stoll, who had interests in foxglove (Digitalis),
Mediterranean squill (Scilla maritima), and ergot of rye (Claviceps purpurea
or Secale cornutum).
LSD-25 (Lysergsure-dithylamid) was first synthesized in 1938.
I had planned the synthesis of this compound with the intention of obtaining
a circulatory and respiratory stimulant (an analeptic). Such stimulating
properties could be expected for lysergic acid diethylamide, because it
shows similarity in chemical structure to the analeptic already known at that
time, namely nicotinic acid diethylamide (Coramine). During the testing of
LSD-25 in the pharmacological department of Sandoz, whose director at the
time was Professor Ernst Rothlin, a strong effect on the uterus was
established. It amounted to some 70 percent of the activity of ergobasine.
The research report also noted, in passing, that the experimental animals
became restless during the narcosis. The new substance, however,
aroused no special interest in our pharmacologists and physicians; testing
was therefore discontinued.

See LSD: My Problem Child, by A. Hofmann

(http://nepenthes.lycaeum.org/Drugs/LSD/ProbChild/)
The LSD Story, continued
LSD-25 synthesized again in 1943.
In the process of recrystallizing the product: Last Friday, April 16,1943, I
was forced to interrupt my work in the laboratory in the middle of the
afternoon and proceed home, being affected by a remarkable restlessness,
combined with a slight dizziness. At home I lay down and sank into a not
unpleasant intoxicated-like condition, characterized by an extremely
stimulated imagination. In a dreamlike state, with eyes closed (I found the
daylight to be unpleasantly glaring), I perceived an uninterrupted stream of
fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of
colors. After some two hours this condition faded away.
Then decided to experimenttook 0.25 mg of the tartrate in 10 mL of water.
After 40 min., difficulty in concentration, visual disturbances, marked by
desire to laugh great difficulty in speaking coherently, my field of vision
swayed before me I had the impression of being unable to move from the
spot all objects appeared in unpleasant, constantly changing colors, the
predominant shades being sickly green and blue a remarkable feature
was the manner in which all accoustic perceptions were transformed into
optical effects
And the rest (Timothy Leary, Beatles, etc.) is history
 Ergot Alkaloid Biosynthetic Precursors

HO2C
OH
O O
via O P O P O
OH
O O
R-mevalonic acid farnesyl pyrophosphate
O
H Me
Me HO N NH2
HO N H
H Me
S CO2H
H methionine

N N H NH2
H H
Lysergic Acid Elymoclavine CO2H

N
H
L-tryptophan

Tetrahedron 1976, 32, 873-912

Lysergic Acid Total Syntheses (a lot)

J. Am. Chem. Soc. 1954, 76, 5256; J. Am. Chem. Soc. 1956, 78, 3087
(Woodward).
Tetrahedron Lett. 1969, 1569 (Julia).
Tetrahedron Lett. 1976, 4311; Tetrahedron Lett. 1981, 157 (Armstrong).
Helv. Chim. Acta 1981, 64, 478 (Oppolzer).
Heterocycles 1982, 19, 2279 (Kiguchi).
Tetrahedron Lett. 1983, 24, 859; J. Am. Chem. Soc. 1984, 106, 1813
(Rebek).
Chem. Pharm. Bull. 1986, 34, 442 (Kurihara).
Tetrahedron Lett. 1988, 29, 3117 (Ortar).
Synlett 1994, 487 (Vollhardt).
Org. Lett. 2004, 6, 3 (Hendrickson).
J. Org. Chem. 2004, 69, 5993 (Szntay)essentially the same as
Woodwards.
Also approaches to the skeleton by Padwa (J. Org. Chem. 1995, 60, 2704),
Martin (RCM: Tetrahedron Lett. 2001, 1635; VMR: Acc. Chem. Res. 2002,
35, 895), Mann (Synlett 1995, 27), many others.
Primer on Indole Syntheses
There are many ways to generate indoles. But among my
favorites (and most famous) is:
Fisher Indole Synthesis (Borsche-Drechsel Cyclization):

+ Me H ZnCl2
NH2 N
N O
H H
 O
H
Me
HO N
H

Woodward Synthesis of Lysergic Acid

N
H

HO O
CO2Et Br
O
O
1. SOCl2
Et2O Br2 or Py*HBr
2. AlCl3
N N CS2 N
N
H Bz Bz
O O Bz
NHMe
MeNH2
O
O
Me NHMe
N
MeHN
O

N
N
Bz
Bz
 O
H
Me
HO N
H

Woodward
N
H

O
O O

HCl/H2O Pd/C
p-cymene
N
N N
H
Bz H

HO

Pd/C
p-cymene N
Bz
 O
H
Me
HO N
H

Woodward
N
H

NH2
O O
1. pTsONH2
2. KOEt
3. H+ / H2O
N N
Neber rearrangement Bz
Bz
O

EtO H
NaOMe O
HO
HN H CN
O O O

HN3, TFA, H2SO4

Schmidt reaction
N N N
Bz Bz Bz
MINOR MAJOR
(desired)
 O
H
Me
HO N
H

Woodward
N
O O OMe O H
Me
N O O
H H O
H N
MeNH2 Me OMe
100 C

N N N
Bz
Bz Bz
RCO3H
O OMe O
Br
O O
1. NaOH/H2O
Br
1. MeO , Zn 2. (COCl)2, PhMe
2. HCO2H 3. CH2N2, CH2Cl2
N Reformatsky reaction N 4. HBr, H2O
N
Bz Bz Bz

O O NaBH4
HO Me
N O
OH
MeNH2 RCO3H

LOW YIELD

N N N
Bz Bz Bz
 O
H
Me
HO N
H

Woodward
N
H

H2N O
O OEt
HN
O O N
Cl O
EtO 1. NaOH/H2O H
2. PyHBr3
KOtBu
O
N Darzens condensation N
NH2
Bz Bz H2N N N
H Bz
O
OH

NC O

Me O
can't remove acetal because of O N 1. ethylene glycol
neighboring basic nitrogen
O pTsOH H
(generation of the stabilized cation
HO 2. PhCO3H
is hindered by the presence of
positive nitrogen atom) 3. MeNH2
4. acrylonitrile N
N
Bz Bz
" ... brutal means led only to deep-seated changes of no utility"
 O
H
Me
HO N
H

Woodward
N
H
O
O
O Me
O N
O O H OH
H HO N
Me HO
1. H2O2
2. NaBH4 low yield
N N
N
Bz Bz
Bz

NaIO4
H+

O
Br O
O Me
O O H N
N
Me O
NONPOLAR SOLVENT
N
Bz
N
Bz

11 steps from original ketone

 O
H
Me
HO N
H

Woodward Endgame
N
H

O O
O
Me Me O Me
N N HO Me
N N
O O
6 N HCl NaOMe 1. Ac2O
EtOH 2. NaBH4

N N N
N
Bz H H Ac
SOCl2
SO2 (l)

O O
NC Me Cl Me
Me Me N N
HO N HO N
Raney-Ni 1. H2SO4
MeOH NaCN
(heat deact.) HCN (l)
NaHAsO4 2. NaOH
H2O H2O
N N
N N
Ac Ac
H H
 O
H
Me
HO N
H

Oppolzer
N
H

HO 1. CBr4, PPh3 CO2Me 1. NaOH CO2Me

2. PBu3, PhH MeOH NO2
3. NaH, DMSO 2. nitroethene
then
N
Ts OHC
N N
CO2Me Ts H

1. NaOMe MeO2C OMe

CO2Me N
MeOH
N OMe 200 C
2. TiCl3
NH4OAc retro Diels-Alder
H2NOMe imino Diels-Alder
Nef reaction N
N
H
H O
Me
HO N
1. MeOSO2F
2. Al/Hg
3. KOH, EtOH

N
H
 O
H
Me
HO N
H

Padwa Approach
N
O O H

1. O3, NaBH4 OH 1. H2CrO4 MeN OMe

2. MnO2 2. (imid)2CO
O
3. Ph3PCH2 3. MeNH2
N N 4. O O
Bz Bz Cl OMe N
Bz
OMe O O
N2
O MeO NMe
O NMe O
MsN3 Rh2(pfb)4
Et3N H H
O

N
N Bz
Bz pfb = perfluorobutyrate
O O O O

MeO NMe S MeO NMe

HO 1.
BF3*OEt2 Cl OPh
H H
2. nBu3SnH/AIBN
Barton-McCombie
N N
Bz Bz