Synthetic Studies Towards the Stemona and Ergot Alkaloids
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1 Synthetic Studies Towards the Stemona and Ergot Alkaloids Anthony Cuzzupe University of Pittsburgh Wipf Research Group ovember 12, 2005 Anthony Wipf Group 1 11/12/2005
2 Presentation utline 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 Wipf Group 2 11/12/2005
3 PART 1: Stemona Alkaloids Anthony Wipf Group 3 11/12/2005
4 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 orth America and Japan 3. Stichoneuron - Two species from eastern Asia at. Prod. Rep. 2000, 17, 117 Stemona plants occur as subshrubs or twining herbs, mostly with perennial tuberous roots Stemona Tuberosa Stemona Sessifolia Stemona Sessifolia Anthony Wipf Group 4 11/12/2005
5 Stemonaceae: istorical 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, Anthony Wipf Group 5 11/12/2005
6 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 alkaloid to be isolated in 1934 by Suzuki Structure of tuberostemonine was determined by the combined efforts of a number of groups in the 1960 s using various methods: MR, MS, X-ray and chemical analysis Tuberostemonine 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 Wipf Group 6 11/12/2005
7 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 a 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: Et Stemoamide Stemonamine Stenine Tuberostemospironine Parvistemoline A sixth miscellaneous group of compounds also exist where each member lacks the common azepine ring system at. Prod. Rep. 2000, 17, 117 Anthony Wipf Group 7 11/12/2005
8 Structural Classification of Stemona Alkaloids Stenine group Stenine Tuberostemonine Tuberostemonine A Tuberostemonol Didehydrotuberostemonine Bisdehydroneotuberostemonine eotuberostemonine Parvistemoline group Parvistemoline Parvistemonine Didehydroparvistemonine Stemoamide group Stemoamide Stemonine eostemonine Bisdehydroneostemonine Protostemonine Didehydroprotostemonin e Isoprotostemonine Tuberostemoamide Stemoninine Tuberostemospironine group Tuberostemospironine Croomine Stemospironine Stemotinine Isostemotinine Stemonidine Didehydrocroomine Stemonamine group Stemonamine Isostemonamine Stemonamide Isostemonamide Maistemonine xymaistemonine Miscellaneous group Stemofoline xystemofoline thoxystemofoline Parvistemoninine Parvistemoninol Tuberostemonone Tuberostemoninol Parvistemoamide Anthony Wipf Group 8 11/12/2005
9 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 Wipf Group 9 11/12/2005
10 (+)-Croomine (Williams) MEM C 2 1. Bn(C 2 ) 4 MgBr, CuBr DMS, 95% 2. DIBAL-, 98% 3. SAE, 83% MEM 1. Swern 2. Ph 3 P=CC 2 Bn 89% MEM C 2 Bn 1. LiB 4, 81% 2. Rh/Al 2 3, 2, 62% 3. BzCl, 97% 4. Li 3, DMPU, 94% MEM 3 Bz 1. BF 3 Et 2, 81% Bn 2. Li, 97% 3. Swern, then Ph 3 P 74% Bz 3 Bn Bz 1. aq. BF 4, 72% 2. Li, 86% 3. Jone's Reagent then C 2 2, 78% 3 Bn C 2 1. BCl 3 then, 77% 2. Swern, 92% 3. PPh 3 (Staudinger then intramolec Wittig) then ab 4, 90% A B C 2 I 2, C 2 Cl 2 /Et 2 25% (+)-Croomine 26 Steps, ~0.5% verall J. Am. Chem. Soc. 1989, 111, 1923 Anthony Wipf Group 10 11/12/2005
11 (±)-Stenine (art & Chen) IMDA 67% C 2 1. MsCl, Et 3 2. Li 94% Ac C 2 1. Jones reagent 2. Iodolactonization 3. DBU 76% C 2 Confirmed by X-ray 1. ab 4 2. TBSCl TBS C 2 C() xylene,! 93%, 3 steps (Eschenmoser-Claisen) TBS C 2 J. rg. Chem. 1990, 55, 6236 J. rg. Chem. 1993, 58, 3840 Anthony Wipf Group 11 11/12/2005
12 (±)-Stenine (art & Chen) 2 TBS C 2 1. I 2, TF/ 2 2. SnBu 3 AIB, Tol,! 62% C 2 Et 2 C C 2 1. TMS-I 1. s 4, ai 4 S 2. Tol,! 85% 2. S S S R Confirmed by X-ray Lawesson's Reagent 84% (3 steps) R = R = S W-2 Raney i 75% (±)-Stenine J. rg. Chem. 1990, 55, 6236 J. rg. Chem. 1993, 58, Steps, 5% verall Anthony Wipf Group 12 11/12/2005
13 (-)-Stemoamide (Jacobi) Et 1. a Cl 2. Ts, 1. Swern 2. () 2 P()C 2 TF, t BuK 65% 56% (2 steps) LDA, I 32% Diethylbenzene!! RDA + workup ab 4, icl 2 53% (with C10 epimerization) 73% 10 7 Steps, 4.5% verall (-)-Stemoamide J. Am. Chem. Soc. 2000, 122, 4295 Anthony Wipf Group 13 11/12/2005
14 Wipf Group Research Efficient stereoselective preparation of the hydroindole ring system of the Stemona alkaloids by oxidative cyclization of tyrosine: R = Boc or Cbz R C 2 PhI(Ac) 2, rt ac 3, rt 68% 75% R R C 2 PhI(Ac) 2 ** Reaction has been sclaed to > 100 g, ac 3, rt 54% Tetrahedron Lett. 1992, 33, 5477 Selectivity attributed to A 1,3 - strain: R E E R A 1,3 - Strain J. Am. Chem. Soc. 1995, 117, Anthony Wipf Group 14 11/12/2005
15 Wipf Group Research xidation of tyrosine - used for the synthesis of a variety of targets: Functionalized aranorosin core J. rg. Chem. 1993, 58, 1649 (-)-Stenine J. Am. Chem. Soc. 1995, 117, Cbz C 2 Cbz Aeruginosin 298-A 2 (-)-Tuberostemonine rg. Lett. 2000, 2, 4213 J. Am. Chem. Soc. 2002, 124, J. Am. Chem. Soc. 2005, 127, 225 Anthony Wipf Group 15 11/12/2005
16 Total Synthesis of (-)-Stenine (Wipf) C 2 Cbz 1. Bz 2, Et 3 2. Luche reduction 89% Bz C 2 Cbz Pd 2 (dba) 3 CCl 3 Bu 3 P, C 2 /Et 3 68% C 2 Cbz 1. TPAP, M 2. KMDS C=C(C 2 ) 3 Tf 46% C 2 Cbz 1. Luche reduction 2. C 3 C() 2 2 (Eschenmoser-Claisen) 77% 2 C 2 Cbz 2 1. I 2 Cbz TIPS 2. AIB 77% SnBu 3 Cbz TIPS J. Am. Chem. Soc. 1995, 117, Anthony Wipf Group 16 11/12/2005
17 Total Synthesis of (-)-Stenine (Wipf) 1. Pd() 2, 2 Cbz TIPS C 2 Cbz 2. C 6 F 5 P()Ph 2 71% 1. Lawesson's reagent 2. Raney-i 73% 25 Steps, 2% verall (-)-Stenine J. Am. Chem. Soc. 1995, 117, Anthony Wipf Group 17 11/12/2005
18 Total Synthesis of (-)-Tuberostemonine (Wipf) R TBSCl 97% C 2 Cbz R = R = TBS Et 3 Si, Pd(Ac) 2 Et 3 90% TBS C 2 Ph C 2 Ru tathesis 92% C 2 1. Ph-S, Et , (PPh 3 ) 3 RhCl 3. DBU 81% 1. Luche reduction, 71% C 2 2. TBSCl, 79% 3. ()() Cl 2 AlCl 94% TBS Li 95% TBS J. Am. Chem. Soc. 2002, 124, J. Am. Chem. Soc. 2005, 127, 225 Anthony Wipf Group 18 11/12/2005
19 Total Synthesis of (-)-Tuberostemonine (Wipf) TBS 1. L-Selectride, 80% 2. Ts,, 70% C 3 C() 2 2 (Eschenmoser-Claisen) 78% 2 1. PhSeCl, AC/ 2, 67% 2. SnPh 3 AIB 70% 3. LDA, I, 76% 1. Ru alkene isomerization 2. Ru tathesis, ethylene 3. 2, Pd/C 67% overall 24 Steps, 1.4% verall (-)-Tuberostemonine J. Am. Chem. Soc. 2002, 124, J. Am. Chem. Soc. 2005, 127, 225 Anthony Wipf Group 19 11/12/2005
20 PART 2: Ergot Alkaloids Anthony Wipf Group 20 11/12/2005
21 Ergot: Claviceps purpurea Ergot: riginates 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 Anthony Wipf Group 21 11/12/2005
22 Ergotism/istory 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) TE: Ergotism was also known as oly fire or St. Anthony s fire abdellab.sunderland.ac.uk grandfinale.at.infoseek.co.jp Anthony Wipf Group 22 11/12/2005
23 Ergotism/istory 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 orth America may have been due to ergotism 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 Wipf Group 23 11/12/2005
24 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 (1918); German patent (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 Lysergic acid C 2 Isolysergic acid C 2 Chem. Rev. 1950, 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 eurology, 2003, 2, 429 Anthony Wipf Group 24 11/12/2005
25 Biological activity The ergot alkaloids possess a wide spectrum of biological activity - act on the CS 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 CR C Lysergic acid derivative oradrenaline Dopamine Serotonin Appl. Microbiol. Biotechnol. 2001, 57, 593 Anthony Wipf Group 25 11/12/2005
26 Ergot alkaloids - examples and uses Ph Ergotamine Migraine relief Br 2-Bromo-!-ergokryptine Semisynthetic - anti-parkinson's - reduce lactation in women thysergide Semisynthetic - Migraine relief Ergonovine - Induces labour (oxytocic) - Decrease excessive uterine bleeding post-childbirth Lysergic acid diethylamide (LSD) Synthetic derivative of lysergic acid - Powerful hallucinogen Anthony Wipf Group 26 11/12/2005
27 Acknowledgements Prof. Peter Wipf Dr. David Mareska Dr. Steven Geib (X - Ray) Wipf Group mbers (past & present) Anthony Wipf Group 27 11/12/2005
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