H N Synthetic Studies Towards the Stemona and Ergot Alkaloidsccc.chem.pitt.edu/wipf/Topics/Anthony.pdfOMe O Stemonamine O H Anthony Cuzzupe @ Wipf Group 7 11/12/2005. Structural Classiﬁcation

Synthetic Studies TowardsSynthetic Studies Towardsthe the Stemona Stemona and Ergot Alkaloidsand Ergot Alkaloids

NHO

O

H

O

O

H

HN

N

H

Me

H

N

O

Anthony CuzzupeUniversity of PittsburghWipf Research Group

November 12, 2005

Anthony Cuzzupe @ Wipf Group 1 11/12/2005

Presentation OutlinePresentation Outline

PART 1: Stemona Alkaloids

- Ergot & history of ergotism- Ergot alkaloids: isolation, classification, biological properties, etc- Current approaches

PART 2: Ergot Alkaloids

- Stemona plants & historical uses- Stemona alkaloids: isolation, classification, biological properties, etc- Selected previous total syntheses and Wipf group work- Current approaches


PART 1: Stemona Alkaloids


Family: Stemonaceae A monocotyledon family made up of three genera:

1. Stemona - About 25 species, occurring from southern Asia and Malaysia to northern Australia

2. Croomia - Three species from Atlantic North America and Japan

3. Stichoneuron - Two species from eastern Asia

Stemona plants occur as subshrubs or twining herbs, mostly with perennial tuberous roots

Nat. Prod. Rep. 2000, 17, 117

Stemona Sessifolia

Stemona SessifoliaStemona Tuberosa

www.bihrmann.com www.bihrmann.com

www.bihrmann.com


Stemonaceae: Historical Uses

Extracts from plants of the Stemonaceae family (Stemona and Croomia genera) have been used for centuries in Eastern folk medicines

Example: Extracts from the tuberous roots of Stemona Tuberosa, Stemona Japonica and Stemona Sessifolia have been used by the Chinese and Japanese for:

J. Agric. Food. Chem. 2002, 50, 6383

- Respiratory diseases such as tuberculosis and bronchitis

- Insecticides

- Antihelmintics in humans and cattle

www.clgc.rdi.ku.ac.th/research/stemona/stemona www.bihrmann.com


Stemona Alkaloids: Isolation & Structural Elucidation

Progress hampered by use of incorrectly identified plant material - caused by popular use of tuberous roots from different species sold on the market under the same names, eg. “Bai Bu” in China and “Bach Bo” in Vietnam

Tuberostemonine was the first Stemona alkaloid to be isolated in 1934 by Suzuki

NHO

O

H

O

O

H

H

TuberostemonineStructure of tuberostemonine was determined by the combined efforts of a number of groups in the 1960’s using various methods: NMR, MS, X-ray and chemical analysis

Since then more than 42 Stemona alkaloids have been isolated, mostly by Ren-sheng Xu and coworkers in the 80’s. The various structures were determined by X-ray analysis, spectroscopic methods and/or chemical studies

Phytochemical studies have been limited to only eight species, mostly from Stemona


Structural Classification of Stemona Alkaloids

Each member of the Stemona alkaloid family can be classified into five main groups according to their structural features - the name of each group being the name of the simplest member:

Large majority of the Stemona alkaloids are structurally characterized by the presence of a pyrrolo[1,2-a]azepine core

1

2

356

7

89

9a

N

A sixth miscellaneous group of compounds also exist where each member lacks the common azepine ring system

Nat. Prod. Rep. 2000, 17, 117

NO O

O

Me

H H

H

Stemoamide

N

H H

O

OOH H

HMe

Me

Parvistemoline

N

Et

O

O

Me

H

Stenine

N OH

O

OH

Me

O

Tuberostemospironine

N

Me

OO

Me

OMe

O

StemonamineO

H


Structural Classification of Stemona Alkaloids

Tuberostemospironine groupTuberostemospironine

CroomineStemospironine

StemotinineIsostemotinineStemonidine

Didehydrocroomine

Stemonamine groupStemonamine

IsostemonamineStemonamide

IsostemonamideMaistemonine

Oxymaistemonine

Parvistemoline groupParvistemolineParvistemonine

Didehydroparvistemonine

Stenine groupStenine

TuberostemonineTuberostemonine A

TuberostemonolDidehydrotuberostemonine

BisdehydroneotuberostemonineNeotuberostemonine

Stemoamide groupStemoamideStemonine

NeostemonineBisdehydroneostemonine

ProtostemonineDidehydroprotostemonin

eIsoprotostemonineTuberostemoamide

StemoninineMiscellaneous group

StemofolineOxystemofoline

MethoxystemofolineParvistemoninineParvistemoninol

TuberostemononeTuberostemoninolParvistemoamide


Tuberostemonine found to be a glutamate inhibitor (blocks neuromuscular transmission) in crayfish

Biological Studies on Stemona Alkaloids

Limited evidence that any pure Stemona alkaloid has therapeutic potential in humans

Tuberostemonine has antihelmintic activity

Brain Res. 1985, 334, 33

Tuberostemonine has potent antifeeding activity J. Agric. Food. Chem. 2002, 50,6383

Stemonine, stemospironine and stemofoline have some insecticidal activity, eg. active against Bombyx mori (silkworm larvae) Agric. Biol. Chem. 1978, 42, 457


(+)-Croomine (Williams)

MEMO

CO2Me

1. BnO(CH2)4MgBr, CuBr•DMS, 95%

2. DIBAL-H, 98%

3. SAE, 83% MEMO

OH

OH

OBn

1. Swern

2. Ph3P=CHCO2Me

89%

MEMO

OH

OBn

CO2Me

1. LiBH4, 81%

2. Rh/Al2O3, H2, 62%

3. BzCl, 97%

4. LiN3, DMPU, 94%MEMO

HO

N3

OBn

OBz 1. BF3•OEt2, 81%

2. LiOH, 97%

3. Swern, then

Ph3POBz

74%

N3O

O

OBn

OBz

1. aq. HBF4, 72%

2. LiOH, 86%

3. Jone's Reagent then CH2N2, 78%

N3

OBn

CO2Me

OO

1. BCl3 then MeOH, 77%

2. Swern, 92%

3. PPh3 (Staudinger then intramolec Wittig)

then NaBH4, 90%

CO2Me

OO

NH

H

A

B

I2, CH2Cl2/Et2O

25%O

ON

H

OH

H

O

(+)-CroomineJ. Am. Chem. Soc. 1989, 111, 1923

26 Steps, ~0.5% Overall


(±)-Stenine (Hart & Chen)

O

OIMDA

67%

O

H

ONHCO2Me

OHH

H

OAc

H

H

OH

1. MsCl, NEt3

2. MeLi

94%

N

CO2Me

1. Jones reagent

2. Iodolactonization

3. DBU

76%

H

HN

CO2MeO

O Confirmed by X-ray

1. NaBH4

2. TBSCl

H

HN

CO2MeHO

OTBS

MeC(OMe)2NMe2

xylene, !

(Eschenmoser-Claisen)

93%, 3 steps

H

HN

CO2Me

OTBS

Me2N

O

J. Org. Chem. 1990, 55, 6236

J. Org. Chem. 1993, 58, 3840


(±)-Stenine (Hart & Chen)

H

HN

CO2Me

OTBS

Me2N

O

1. I2, THF/H2O

2. SnBu3

AIBN, Tol, !

62%

H

HN

CO2Me

OH

O

O

H

HN

CO2Me

O

O

EtO2C

1. TMS-I

2. Tol, !

85%

H

N

O

O

O

Confirmed by X-ray

H

N

O

O

(±)-Stenine

25 Steps, 5% Overall

J. Org. Chem. 1990, 55, 6236

J. Org. Chem. 1993, 58, 3840

H

N

O

O

R

1. OsO4, NaIO4

2. HSSH

S

S

R = O

R = S

Lawesson'sReagent

84% (3 steps)

W-2 Raney Ni

75%


(-)-Stemoamide (Jacobi)

NH

OO

OEt1. NaH

N

O

MeOCl

2. TsOH, MeOHN

OMeO

NOHO

56% (2 steps)

1. Swern

2. (MeO)2P(O)CHN2

THF, tBuOK

65% N

OMeO

NO

LDA, MeI

32%

N

OMeO

NO

Diethylbenzene

!O

N

MeO

N

O

N

O

OMeO

!

RDA

H+ workup N

O

OOH

NaBH4, NiCl2

(with C10 epimerization)

N

O

OOH

10

(-)-Stemoamide

73%

53%

J. Am. Chem. Soc. 2000, 122, 4295

7 Steps, 4.5% Overall


Wipf Group ResearchEfficient stereoselective preparation of the hydroindole ring system of the Stemona alkaloids by oxidative cyclization of tyrosine:

PhI(OAc)2

MeOH, rt

NaHCO3

MeOH, rt N

R

CO2Me

OH

HOHO

HN

CO2HO

O

O

NH

R

R68% 75%

R = Boc or Cbz

PhI(OAc)2

MeOH, NaHCO3, rt

54%

** Reaction has been sclaed to > 100 g

Selectivity attributed to A1,3 - strain:

O

N

O

H

OHH

E

R

O

N

O

H

HOE

H

R

A1,3 - Strain

Tetrahedron Lett. 1992, 33, 5477

J. Am. Chem. Soc. 1995, 117, 11106


N

Cbz

CO2Me

OH

HOO

O

O

NH

Cbz

O

OH

O

NH

OO

O

Functionalized aranorosin core

N

HO

ONHO

OH

HO

O

HN

OH HNNH

NH2

Aeruginosin 298-A

H

N

O

O

(-)-Stenine

OH ON

HO

O

H

(-)-Tuberostemonine

J. Org. Chem. 1993, 58, 1649

Org. Lett. 2000, 2, 4213

J. Am. Chem. Soc. 1995, 117, 11106

J. Am. Chem. Soc. 2002, 124, 14848

J. Am. Chem. Soc. 2005, 127, 225

Wipf Group ResearchOxidation of tyrosine - used for the synthesis of a variety of targets:


Total Synthesis of (-)-Stenine (Wipf)

J. Am. Chem. Soc. 1995, 117, 11106

N

Cbz

CO2Me

OH

HO

1. Bz2O, NEt3

2. Luche reduction

89%

N

Cbz

CO2Me

OBz

HHO

Pd2(dba)3•CHCl3

Bu3P, HCO2H/NEt3 N

Cbz

CO2Me

HHO

H

68%

1. TPAP, NMO

2. KHMDS

HC=CH(CH2)3OTf

46%

N

Cbz

CO2Me

HO

H

1. Luche reduction

2. CH3C(OMe)2NMe2

77%


N

Cbz

CO2Me

H

H

O

Me2N

N

CbzH

H

O

Me2N

OTIPS

1. I2

2. SnBu3

AIBN

77%

N

CbzH

H

OTIPS

O

O


Total Synthesis of (-)-Stenine (Wipf)

J. Am. Chem. Soc. 1995, 117, 11106

N

CbzH

H

OTIPS

O

O

N

CbzH

H

CO2H

O

O

1. Pd(OH)2, H2

2. C6F5P(O)Ph2N

HO

O

O

1. Lawesson's reagent

2. Raney-Ni

73%

71%

N

HO

O

(-)-Stenine

25 Steps, 2% Overall


Total Synthesis of (-)-Tuberostemonine (Wipf)

N

Cbz

CO2Me

HRO

H

R = OH

R = TBSTBSCl

97%

Et3SiH, Pd(OAc)2

NEt3

90%

N

H

CO2Me

HTBSO

H

NCO2Me

HO

H

Ph

Ru Metathesis

92%N

CO2Me

O

H1. Ph-SH, NEt32. H2, (PPh3)3RhCl

3. DBU81%

NCO2Me

O

H 1. Luche reduction, 71%

2. TBSCl, 79%

3. (Me)(OMe)NH•HCl

Me2AlCl 94%

NTBSO

H

O

N

Me

OMeO

O

O

Li

95%

NTBSO

H

O OO

O

J. Am. Chem. Soc. 2002, 124, 14848

J. Am. Chem. Soc. 2005, 127, 225


Total Synthesis of (-)-Tuberostemonine (Wipf)

J. Am. Chem. Soc. 2002, 124, 14848

J. Am. Chem. Soc. 2005, 127, 225


2. SnPh3 AIBN

1. L-Selectride, 80%

2. TsOH, MeOH, 70%NHO

H

O

H

H O

NTBSO

H

O OO

O

CH3C(OMe)2NMe2

78%

N

H

O

H

H O

Me2N

O1. PhSeCl, ACN/H2O, 67%

70%

3. LDA, MeI, 76% N

H

O

H

H O

O

O

1. Ru alkene isomerization

2. Ru Metathesis, ethylene

3. H2, Pd/C

67% overall

N

H

O

H

H O

O

O

(-)-Tuberostemonine

24 Steps, 1.4% Overall


PART 2: Ergot Alkaloids


Ergot: Claviceps purpurea

Ergot: Originates from an old French word “argot”, meaning “spur”

Ergot is a fungal disease of rye and other cereal crops - invades grain and replaces them with hard fungal bodies called sclerotia (resting body of a fungus)

www.botany.hawaii.edu

Ergot fungal growth is suited to cool, damp climates - common in Europe, especially France and Germany


Ergotism/History

Ergotism is a disease which occurred frequently in the Middle Ages - caused by the ingestion of food made with grains infected with ergot, eg. bread

Two types of ergotism:

1. “Gangrenous” form: Intense burning pain in limbs and gangrene due to vasoconstrictive properties of ergot. In severe cases, limbs would become black and dry (mummify)

abdellab.sunderland.ac.uk

NOTE: Ergotism was also known as “Holy fire” or “St. Anthony’s fire”

grandfinale.at.infoseek.co.jp


Ergotism/History

Ergotism and witchcraft? Salem witchcraft trials of 1692 in North America may have been due to ergotism

2. “Convulsive” form: Sufferers could become delirious, lethargic, manic and have hallucinations with double vision due to neurotoxic properties of ergot. In extreme cases, epileptic-type seizures leading to death

www.uh.edu/ engines/epi1037.htm

The last reported European outbreak of ergotism occurred in 1951 in a French village - caused more than 200 cases and 4 deaths Modern drug discovery, 1999, 2, 20-21, 23-24, 28, 31


Ergot Alkaloids

The first ergot alkaloid to be isolated from sclerotia of the ergot fungus was ergotamine in 1918 by Stoll

The natural ergot alkaloids (>40) contain either lysergic acid (pharmacologically active, name ends with -ine) or isolysergic acid (pharmacologically inactive, name ends with -inine) as the parent structure

N

N

H

CO2H

Me

H

Lysergic acid

N

N

H

CO2H

Me

H

Isolysergic acid

The ergot alkaloids are classified into three main groups:

1. Clavine type - Simplest members considered as precursors to the other groups of ergot alkaloids in the biogenetic pathway

Stoll, A.: Swiss patent 79879 (1918); German patent 357272 (1922)

3. Water-insoluble lysergic acid type: Are mainly peptide derivatives of lysergic and isolysergic acids

Chem. Rev. 1950, 47. 197

2. Water-soluble lysergic acid type: Are often amide derivatives of lysergic and isolysergic acids

The Lancet Neurology, 2003, 2, 429


Biological activity The ergot alkaloids possess a wide spectrum of biological activity - act on the CNS

Derivatives of lysergic acid have affinities for the receptors of the neurotransmitters noradrenaline, dopamine and seratonin - possibly due to structural analogy between the ergoline ring system and these neurotransmitters

Appl. Microbiol. Biotechnol. 2001, 57, 593

They may act as agonists, antagonists or play a dual role as partial-agonist and antagonist

OH

OH

NH2

Noradrenaline

OH

NH2

Dopamine

NH

NH2

OH

Serotonin

HN

N

COR

CH3

Lysergic acid derivative

HO

OH


Ergot alkaloids - examples and uses

N

N

H

Me

HErgotamine

HN

O

O

N

N

OO

Ph

HO

N

N

H

Me

H

HN

O

OH

Ergonovine

N

N

H

Me

H

N

O

Lysergic acid diethylamide (LSD)

N

N

H

Me

H

HN

O

O

N

N

OO

HO

Br

2-Bromo-!-ergokryptine

N

N

H

Me

Me

HN

O

OH

Methysergide

Migraine relief Semisynthetic

- reduce lactation in women

- anti-Parkinson's

Semisynthetic

- Migraine relief

- Induces labour (oxytocic)

- Decrease excessive uterine bleeding post-childbirth

Synthetic derivative of lysergic acid

- Powerful hallucinogen


Acknowledgements

Prof. Peter WipfDr. David Mareska

Dr. Steven Geib (X - Ray)Wipf Group Members (past & present)


Documents

H N Synthetic Studies Towards the Stemona and Ergot Alkaloidsccc.chem.pitt.edu/wipf/Topics/Anthony.pdfOMe O Stemonamine O H Anthony Cuzzupe @ Wipf Group 7 11/12/2005. Structural Classiﬁcation