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.

N

N

H

MeHO

OH

H

Lysergic Acid

N

N

H

MeHO

H

H

Elymoclavine

N

N

H

MeNH

OH

HErgonovine

Uterine Contractions

Me

HO

H

Ergotamine(Gynergen)

Treatment of Migraines

N

O

NH

O

O

MeN

N

N

H

H

MeH

OH

O

History & Ergot Alkaloids

• Many ailments have been linked to ergot alkaloids.– St. Anthony’s Fire (a.k.a., “Devil’s 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.

The LSD Story

• Discovered by Albert Hofmann (Sandoz Co., Basel, CH).• Worked under Arthur Stoll, who had interests in foxglove (Digitalis),

Mediterranean squill (Scilla maritima), and ergot of rye (Claviceps purpureaor Secale cornutum).

• LSD-25 (Lysergsäure-diäthylamid) 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 stimulatingproperties could be expected for lysergic acid diethylamide, because itshows similarity in chemical structure to the analeptic already known at thattime, namely nicotinic acid diethylamide (Coramine). During the testing ofLSD-25 in the pharmacological department of Sandoz, whose director at thetime was Professor Ernst Rothlin, a strong effect on the uterus wasestablished. It amounted to some 70 percent of the activity of ergobasine.The research report also noted, in passing, that the experimental animalsbecame restless during the narcosis. The new substance, however,aroused no special interest in our pharmacologists and physicians; testingwas therefore discontinued.“

See “LSD: My Problem Child”, by A. Hofmann(http://nepenthes.lycaeum.org/Drugs/LSD/ProbChild/)

N

N

H

MeN

OH

H

LSD

N

N

O

Coramine

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 theafternoon and proceed home, being affected by a remarkable restlessness,combined with a slight dizziness. At home I lay down and sank into a notunpleasant intoxicated-like condition, characterized by an extremelystimulated imagination. In a dreamlike state, with eyes closed (I found thedaylight to be unpleasantly glaring), I perceived an uninterrupted stream offantastic pictures, extraordinary shapes with intense, kaleidoscopic play ofcolors. After some two hours this condition faded away.“

• Then decided to experiment…took 0.25 mg of the tartrate in 10 mL of water.After 40 min., “…difficulty in concentration, visual disturbances, marked bydesire to laugh … great difficulty in speaking coherently, my field of visionswayed before me … I had the impression of being unable to move from thespot … all objects appeared in unpleasant, constantly changing colors, thepredominant shades being sickly green and blue … a remarkable featurewas the manner in which all accoustic perceptions were transformed intooptical effects…”

• And the rest (Timothy Leary, Beatles, etc.) is history…

Ergot Alkaloid Biosynthetic Precursors

N

N

H

MeHO

OH

H

Lysergic Acid

N

N

H

MeHO

H

H

Elymoclavine

NH

NH2

CO2H

H

L-tryptophan

NH2

CO2HSMe

methionine

OHHO2C

OH

R-mevalonic acid

via O P

O

O

O P

O

O

O

farnesyl pyrophosphate

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 (Szántay)—essentially the same as

Woodward’s.• 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 myfavorites (and most famous) is:

• Fisher Indole Synthesis (Borsche-Drechsel Cyclization):

N

H

NH2

+ Me

O

H ZnCl2

N

H

Woodward Synthesis of Lysergic AcidN

N

H

MeHO

OH

H

NH

CO2Et

N

Bz

HO O

1. SOCl2 Et2O

2. AlCl3 CS2 N

Bz

O

Br2 or Py*HBr

N

Bz

O

Br

MeNH2

N

Bz

MeHN

NHMe

NHMeOO

N

Bz

O

NMe

O

O

WoodwardN

N

H

MeHO

OH

H

N

Bz

O

HCl/H2O

N

H

O

Pd/Cp-cymene

N

H

O

N

Bz

HO

Pd/Cp-cymene

WoodwardN

N

H

MeHO

OH

H

N

Bz

O

N

Bz

O

NH2

N

Bz

O

HO

N

Bz

O

HN H

O

N

Bz

O

CN

1. pTsONH2

2. KOEt

3. H+ / H2O

Neber rearrangement

EtO H

O

NaOMe

HN3, TFA, H2SO4

Schmidt reaction

MINOR MAJOR(desired)

WoodwardN

N

H

MeHO

OH

H

N

Bz

O

MeO

O

Br1. , Zn

2. HCO2H

Reformatsky reaction N

Bz

O OMe

1. NaOH/H2O

2. (COCl)2, PhMe

3. CH2N2, CH2Cl24. HBr, H2O

N

Bz

OBr

NaBH4

N

Bz

O

RCO3H

N

Bz

O

O

MeNH2

N

Bz

NOH

HO

LOW YIELD

Me

RCO3H

N

Bz

O OMe

O

MeNH2

100 °C

N

Bz

N

O

Me

H

NOMe

O

N

Bz

O

O

H

H

Me

Woodward

N

Bz

O

EtO

O

Cl

KOtBu

Darzens condensation N

Bz

O OEt

O 1. NaOH/H2O

2. PyHBr3O

NH

H2NNH2 N

Bz

NHN

H

H2N O

OH

O

O

N

Bz

O

H

1. ethylene glycol

pTsOH

2. PhCO3H

3. MeNH2

4. acrylonitrileN

Bz

O

O

NMe

NC

HO

can't remove acetal because of neighboring basic nitrogen (generation of the stabilized cation is hindered by the presence of positive nitrogen atom)

" ... brutal means led only to deep-seated changes of no utility"

N

N

H

MeHO

OH

H

Woodward

N

Bz

O

H1. H2O2

2. NaBH4

N

Bz

O

HOHN

Me

OO

low yield

N

Bz

OH

HO

NMe

O

O

NaIO4

H+

N

Bz

O

NMe

O

O

11 steps from original ketone

N

Bz

O

Br

H

NOO

NONPOLAR SOLVENT

Me

N

N

H

MeHO

OH

H

Woodward Endgame

N

Bz

O

NMe

O

O

N

H

O

NMe

O

6 N HCl

N

H

NMeO

1. Ac2O

2. NaBH4

N

Ac

NMeHO

SOCl2SO2 (l)

N

Ac

NMeCl

NaCNHCN (l)

N

Ac

NMeNC

1. H2SO4

MeOH

2. NaOH

H2O

N

H

NMe

HO

O

N

H

NMe

HO

O

Raney-Ni

(heat deact.)

NaHAsO4

H2O

NaOMeEtOH

N

N

H

MeHO

OH

H

Oppolzer

N

Ts

HO 1. CBr4, PPh3

2. PBu3, PhH

3. NaH, DMSO

then

CO2Me

OHCN

Ts

CO2Me 1. NaOH MeOH2. nitroethene

N

H

CO2MeNO2

1. NaOMe

MeOH

2. TiCl3 NH4OAc

H2NOMe

Nef reaction N

H

CO2MeN OMe 200 °C

retro Diels-Alderimino Diels-Alder

N

N

H

OMeMeO2C

1. MeOSO2F

2. Al/Hg

3. KOH, EtOH

N

N

H

MeHO

O

N

N

H

MeHO

OH

H

Padwa Approach

N

Bz

1. O3, NaBH4

2. MnO2

3. Ph3PCH2

N

Bz

OH 1. H2CrO4

2. (imid)2CO

3. MeNH2

4.

N

Bz

O

MeN

Cl

O

OMe

O

MsN3

Et3N

N

Bz

O

NMeO

OMe

ON2

Rh2(pfb)4

pfb = perfluorobutyrate

N

Bz

NMe

O

O

MeO

O

H H

BF3*OEt2

N

Bz

NMe

O

MeO

O

H

HO 1.

2. nBu3SnH/AIBN

Barton-McCombie

Cl OPh

S

N

Bz

NMe

O

MeO

O

H

O

OMe

O

N

N

H

MeHO

OH

H