Synthetic Studies Towards the Stemona and Ergot Alkaloids
N O H H Me O O N O O H H N H
N H
Anthony Cuzzupe University of Pittsburgh Wipf Research Group November 12, 2005
Anthony Cuzzupe @ Wipf Group 1 11/12/2005 Presentation Outline
PART 1: Stemona Alkaloids - Stemona plants & historical uses - Stemona alkaloids: isolation, classification, biological properties, etc - Selected previous total syntheses and Wipf group work - Current approaches
PART 2: Ergot Alkaloids - Ergot & history of ergotism - Ergot alkaloids: isolation, classification, biological properties, etc - Current approaches
Anthony Cuzzupe @ Wipf Group 2 11/12/2005 PART 1: Stemona Alkaloids
Anthony Cuzzupe @ Wipf Group 3 11/12/2005 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 Nat. Prod. Rep. 2000, 17, 117
Stemona plants occur as subshrubs or twining herbs, mostly with perennial tuberous roots
Stemona Tuberosa Stemona Sessifolia
Stemona Sessifolia www.bihrmann.com www.bihrmann.com www.bihrmann.com
Anthony Cuzzupe @ Wipf Group 4 11/12/2005 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:
- Respiratory diseases such as tuberculosis and bronchitis - Antihelmintics in humans and cattle
- Insecticides J. Agric. Food. Chem. 2002, 50, 6383
www.clgc.rdi.ku.ac.th/research/stemona/stemona www.bihrmann.com
Anthony Cuzzupe @ Wipf Group 5 11/12/2005 Stemona Alkaloids: Isolation & Structural Elucidation
Phytochemical studies have been limited to only eight species, mostly from Stemona
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 O alkaloid to be isolated in 1934 by Suzuki H H O O O H N Structure of tuberostemonine was determined H by the combined efforts of a number of groups Tuberostemonine 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
Anthony Cuzzupe @ Wipf Group 6 11/12/2005 Structural Classification of Stemona Alkaloids
Large majority of the Stemona alkaloids are structurally characterized by the presence of a pyrrolo[1,2-a]azepine core 9 8 9a 1 7 2 N 3 6 5
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:
O Me Me O H H O O O OMe Me O N O O Me Me H H OH N H O Me O Me Et Stemoamide O H H N O O H N H Stemonamine O H H N O Stenine Tuberostemospironine Parvistemoline
A sixth miscellaneous group of compounds also exist where each member lacks the common azepine ring system Nat. Prod. Rep. 2000, 17, 117
Anthony Cuzzupe @ Wipf Group 7 11/12/2005 Structural Classification of Stemona Alkaloids
Stenine group Stenine Parvistemoline group Tuberostemonine Parvistemoline Tuberostemonine A Parvistemonine Tuberostemonol Didehydroparvistemonine Didehydrotuberostemonine Bisdehydroneotuberostemonine Neotuberostemonine
Stemoamide group Stemonamine group Stemoamide Stemonamine Stemonine Isostemonamine Neostemonine Stemonamide Bisdehydroneostemonine Isostemonamide Protostemonine Maistemonine Didehydroprotostemonin Oxymaistemonine e Isoprotostemonine Tuberostemoamide Tuberostemospironine group Miscellaneous group Stemoninine Tuberostemospironine Stemofoline Croomine Oxystemofoline Stemospironine Methoxystemofoline Stemotinine Parvistemoninine Isostemotinine Parvistemoninol Stemonidine Tuberostemonone Didehydrocroomine Tuberostemoninol Parvistemoamide
Anthony Cuzzupe @ Wipf Group 8 11/12/2005 Biological Studies on Stemona Alkaloids
Limited evidence that any pure Stemona alkaloid has therapeutic potential in humans
Tuberostemonine has antihelmintic activity
Tuberostemonine found to be a glutamate inhibitor (blocks neuromuscular transmission) in crayfish 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
Anthony Cuzzupe @ Wipf Group 9 11/12/2005 (+)-Croomine (Williams)
CO2Me 1. BnO(CH2)4MgBr, OH CuBr•DMS, 95% O 1. Swern CO2Me H O 2. DIBAL-H, 98% 2. Ph P=CHCO Me H MEMO 3 2 OBn 3. SAE, 83% MEMO 89% OBn MEMO
OBz 1. LiBH4, 81% 1. BF3•OEt2, 81% O 2. LiOH, 97% 2. Rh/Al2O3, H2, 62% O OBz N N3 3. BzCl, 97% 3 3. Swern, then 4. LiN , DMPU, 94% HO OBn 3 Ph3P MEMO OBn OBz 74%
1. aq. HBF , 72% 1. BCl3 then MeOH, 77% 4 H 2. LiOH, 86% 2. Swern, 92% CO Me CO Me N 2 A NH 2 3. Jone's Reagent O 3 3. PPh (Staudinger then O O 3 O B then CH N , 78% intramolec Wittig) 2 2 OBn then NaBH4, 90%
H I2, CH2Cl2/Et2O H N O O 26 Steps, ~0.5% Overall 25% O H O (+)-Croomine J. Am. Chem. Soc. 1989, 111, 1923
Anthony Cuzzupe @ Wipf Group 10 11/12/2005 (±)-Stenine (Hart & Chen)
H H OH IMDA 1. MsCl, NEt3 O O 67% NHCO Me 2. MeLi H 2 O O 94%
OAc
H H H 1. Jones reagent 2. Iodolactonization 1. NaBH N 4 N N O HO 3. DBU H CO Me 2. TBSCl H H 2 CO2Me CO2Me 76% O Confirmed by X-ray OTBS OH
O
Me N 2 H MeC(OMe)2NMe2
xylene, ! N H 93%, 3 steps CO2Me (Eschenmoser-Claisen) OTBS
J. Org. Chem. 1990, 55, 6236
J. Org. Chem. 1993, 58, 3840
Anthony Cuzzupe @ Wipf Group 11 11/12/2005 (±)-Stenine (Hart & Chen)
O O O Me2N 1. I , THF/H O H 2 2 H O O H 2. SnBu3 N N N H AIBN, Tol, H CO2Me CO Me H CO Me 62% 2 2 OTBS OH EtO2C
O O
H H O 1. OsO , NaIO O 1. TMS-I 4 4 S 2. Tol, SH S N N 2. HS 85% O R
R = O Confirmed by X-ray Lawesson's Reagent R = S 84% (3 steps) O
O H W-2 Raney Ni
75% N J. Org. Chem. 1990, 55, 6236 )-Stenine (± J. Org. Chem. 1993, 58, 3840
25 Steps, 5% Overall
Anthony Cuzzupe @ Wipf Group 12 11/12/2005 (-)-Stemoamide (Jacobi)
1. NaH OEt 1. Swern O HO O MeO O N O N Cl N 2. (MeO)2P(O)CHN2 MeO H O MeO O O THF, tBuOK N 65% N N 2. TsOH, MeOH 56% (2 steps)
O O O LDA, MeI N Diethylbenzene N ! N MeO 32% O ! RDA MeO O MeO O N N
O O + H workup N NaBH4, NiCl2 N 10 7 Steps, 4.5% Overall 53% (with C10 epimerization) O O O O H 73% H (-)-Stemoamide
J. Am. Chem. Soc. 2000, 122, 4295
Anthony Cuzzupe @ Wipf Group 13 11/12/2005 Wipf Group Research
Efficient stereoselective preparation of the hydroindole ring system of the Stemona alkaloids by oxidative cyclization of tyrosine:
O H N OH R PhI(OAc)2 NaHCO3 CO2Me CO2H HO MeOH, rt O MeOH, rt O N H 68% 75% R R = Boc or Cbz R NH O
PhI(OAc)2
MeOH, NaHCO3, rt 54% ** Reaction has been sclaed to > 100 g Tetrahedron Lett. 1992, 33, 5477
Selectivity attributed to A1,3 - strain:
O O O O H E R OH HO R N N H H E H 1,3 A - Strain J. Am. Chem. Soc. 1995, 117, 11106
Anthony Cuzzupe @ Wipf Group 14 11/12/2005 Wipf Group Research
Oxidation of tyrosine - used for the synthesis of a variety of targets:
O O O H O O N O O
N OH H (-)-Stenine Functionalized aranorosin core O J. Am. Chem. Soc. 1995, 117, 11106 OH J. Org. Chem. 1993, 58, 1649
CO2Me O O N H Cbz Cbz N O H HO
O N H N H O O H NH O O NH HN OH N H O O OH NH2 Aeruginosin 298-A (-)-Tuberostemonine
HO Org. Lett. 2000, 2, 4213 J. Am. Chem. Soc. 2002, 124, 14848 J. Am. Chem. Soc. 2005, 127, 225
Anthony Cuzzupe @ Wipf Group 15 11/12/2005 Total Synthesis of (-)-Stenine (Wipf)
OH OBz H 1. Bz2O, NEt3 Pd2(dba)3•CHCl3 CO2Me CO2Me CO2Me 2. Luche reduction Bu P, HCO H/NEt O N HO N 3 2 3 HO N H H H Cbz 89% Cbz 68% Cbz
O
H Me N 2 H 1. TPAP, NMO 1. Luche reduction CO2Me N CO Me O 2. CH C(OMe) NMe 2 2. KHMDS H Cbz 3 2 2 N H HC=CH(CH2)3OTf (Eschenmoser-Claisen) Cbz 46% 77%
O O
Me2N H H 1. I2 O
2. SnBu3 N N AIBN H H Cbz Cbz 77% OTIPS OTIPS
J. Am. Chem. Soc. 1995, 117, 11106
Anthony Cuzzupe @ Wipf Group 16 11/12/2005 Total Synthesis of (-)-Stenine (Wipf)
O O O
H H O O H O 1. Pd(OH)2, H2 N N N H H 2. C6F5P(O)Ph2 Cbz Cbz O 71% OTIPS CO2H
O
H 1. Lawesson's reagent O 25 Steps, 2% Overall 2. Raney-Ni N 73%
(-)-Stenine
J. Am. Chem. Soc. 1995, 117, 11106
Anthony Cuzzupe @ Wipf Group 17 11/12/2005 Total Synthesis of (-)-Tuberostemonine (Wipf)
H H H Et3SiH, Pd(OAc)2 CO2Me CO Me CO2Me 2 N RO N NEt3 N O H TBSO H Cbz 90% H H TBSCl R = OH 97% R = TBS Ph
H H 1. Luche reduction, 71% 1. Ph-SH, NEt3 Ru Metathesis 2. TBSCl, 79% CO2Me 2. H2, (PPh3)3RhCl CO2Me N 92% O N 3. DBU O 3. (Me)(OMe)NH•HCl 81% Me2AlCl 94%
O H Me H N OMe Li O O TBSO N O TBSO N O O O 95% O
J. Am. Chem. Soc. 2002, 124, 14848 J. Am. Chem. Soc. 2005, 127, 225
Anthony Cuzzupe @ Wipf Group 18 11/12/2005 Total Synthesis of (-)-Tuberostemonine (Wipf)
H H CH C(OMe) NMe H 3 2 2 1. L-Selectride, 80% (Eschenmoser-Claisen) TBSO N O O O O HO N H O O 2. TsOH, MeOH, 70% 78%
O 1. PhSeCl, ACN/H2O, 67% O Me2N H SnPh3 H H 2. AIBN O H 70% N O H O 3. LDA, MeI, 76% N H O O
O 1. Ru alkene isomerization H 2. Ru Metathesis, ethylene O H 24 Steps, 1.4% Overall 3. H2, Pd/C N H O O 67% overall
(-)-Tuberostemonine
J. Am. Chem. Soc. 2002, 124, 14848 J. Am. Chem. Soc. 2005, 127, 225
Anthony Cuzzupe @ Wipf Group 19 11/12/2005 PART 2: Ergot Alkaloids
Anthony Cuzzupe @ Wipf Group 20 11/12/2005 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)
Ergot fungal growth is suited to cool, damp climates - common in Europe, especially France and Germany
www.botany.hawaii.edu
Anthony Cuzzupe @ Wipf Group 21 11/12/2005 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)
NOTE: Ergotism was also known as “Holy fire” or “St. Anthony’s fire”
abdellab.sunderland.ac.uk grandfinale.at.infoseek.co.jp
Anthony Cuzzupe @ Wipf Group 22 11/12/2005 Ergotism/History
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
Ergotism and witchcraft? Salem witchcraft trials of 1692 in North America may have been due to ergotism
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
Anthony Cuzzupe @ Wipf Group 23 11/12/2005 Ergot Alkaloids
The first ergot alkaloid to be isolated from sclerotia of the ergot fungus was ergotamine in
1918 by Stoll Stoll, A.: Swiss patent 79879 (1918); German patent 357272 (1922)
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
CO2H CO2H H N H N N N H H Me Me Chem. Rev. 1950, 47. 197 Lysergic acid 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
2. Water-soluble lysergic acid type: Are often amide derivatives of lysergic and isolysergic acids
3. Water-insoluble lysergic acid type: Are mainly peptide derivatives of lysergic and isolysergic acids The Lancet Neurology, 2003, 2, 429
Anthony Cuzzupe @ Wipf Group 24 11/12/2005 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
They may act as agonists, antagonists or play a dual role as partial-agonist and antagonist
COR
OH OH
N NH2 NH2 NH2 CH3 OH HO HN OH OH NH Lysergic acid derivative Noradrenaline Dopamine Serotonin
Appl. Microbiol. Biotechnol. 2001, 57, 593
Anthony Cuzzupe @ Wipf Group 25 11/12/2005 Ergot alkaloids - examples and uses
HO HO O O N N OH N N O O HN HN O HN O Me Me Ph Me O N N O N H O H H
Br N N N Me H H Ergotamine 2-Bromo-!-ergokryptine Methysergide Migraine relief Semisynthetic Semisynthetic - anti-Parkinson's - Migraine relief - reduce lactation in women
OH HN N Me Me O N N H O H
N N H H Ergonovine Lysergic acid diethylamide (LSD) - Induces labour (oxytocic) Synthetic derivative of lysergic acid - Decrease excessive uterine - Powerful hallucinogen bleeding post-childbirth
Anthony Cuzzupe @ Wipf Group 26 11/12/2005 Acknowledgements
Prof. Peter Wipf Dr. David Mareska Dr. Steven Geib (X - Ray) Wipf Group Members (past & present)
Anthony Cuzzupe @ Wipf Group 27 11/12/2005