Marius Mewald, Jonathan William Medley, and Mohammad Movassaghi* COCISE AND ENANTIOSELECTIVE TOTAL SYNTHESIS OF (-)-MEHRANINE,(-)-,METHYLENEBISMEHRANINE,AND RELATED ASPIDOSPERMA ALKALOIDS Mohammad 穆罕默德 MEHRANINE 咩了米 Marius Mewald, Jonathan William Medley, and Mohammad Movassaghi*

Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

Introduction -natural product (-)-aspidospermidine Structure Property term Name (-)-aspidospermidi-ne Isolated from Isolated by Biological actitivity antitumor Pentacyclic skeletone 具有indole structure 所以屬於indole alkaloids 4 stereogenic center Biologeical actitivity is much, for example: as a antitumor agent 4 chiral center Unfunctional group 的aspidospermidine 為最間單的架構

Introduction -natural product (-)-mehranine Structure Property term Name (-)-mehranine Isolated from Tabernaemonta-na divaricata Isolated by Biological actitivity antitumor Difference: epoxide and methylation

Introduction -natural product (+)-(6S,7S)-dihydroxyl- N-Methylaspidosp-ermidine Structure Property term Name (+)-(6S,7S)-dihydroxyl-N- Methylaspidosp-ermidine Isolated from Tabernaemonta-na bovina Isolated by Biological actitivity antitumor

Introduction -natural product (-)-methylenebise- mehranine Structure Property term Name (-)-methylenebise-mehranine Isolated from Tabernaemonta-na bovina Isolated by Biological actitivity antitumor Methylenebismehranine is a dimer

Introduction -relative natural product 可分為上下兩邊看 上面為單體 下面為dimer Methyenebismehranine (4) 為 C15-CH2-C15’ Tabermaebovine(5) 為 C15-C2’

Introduction -Previous experiment 1 (Seiki Saito) J. Org. Chem. 2008, 73, 7498–7503 這一部份的合成是先合成CDF tricyclic ring 控制chiral center 在用indolization合成出產物 (Iain Coldham) Angew. Chem. Int. Ed. 2007, 46, 6159 –6162

Introduction -Previous experiment 2 (Jun-ichi Matsuo) Angew. Chem. Int. Ed. 2013, 52, 906 –910 這一類是由 indole structure 上的lone pair 作為driving force 的來源做連續合還反應 在2013年這篇經過2次的mannich reaction合成出CE ring 在1991年這篇經過michael addtion and mannich reaction to form CE ring Disadvantage: racimic production (Ernest Wenkert) J. Org. Chem. 1991, 56, 2915–2918

Introductin -Previous experiment 3 (Mario Rubiralta) J. Org. Chem. 1996, 61, 7882–7888 (Rodrigo B. Andrade) 這一類也是由indole structure derivative做為起始物，藉由接與indole structure的 R group作為drive force的來源進行合環，並且得以控制chiral center ，舉例來說，1996年這篇是由indole thioacetal做michael addition and alkylation on the indole structure, 而2013年這篇是藉由sulfoxide與ester控制在同向，進而得出具有特定立體位相的產物 J. Am. Chem Soc. 2013, 135, 13335–13337

Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

Retrosynthesis of Aspidoaperma Alkaloids 本篇的合成策略分為3個階段 1.Key intermediate 的合成 2.Key step的探討 3.Total syntheses of the nature product

Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

Procedure of synthesis -Synthesis of the key intermediate 13 氧陽離子:oxonium ion 1.Chiral axiliary 經由 hydrogent bonding 固定構型，故拔氫先拔嘎馬位置的氫，再經由beta上的phenyl控制位向，進而得 R form product 2.nBu4NOH相較於NaOH、KOH、LiOH較易溶於 orangic solution

Procedure of synthesis -Transannulaer cyclization to form asperdospermidine from the intermediate 13 ceric ammonium nitrate It is 3.22 埃 between C12 and C19 in the 27A 27B is more stable than 27A ,cis-28 is more than trans-28 27A 比 27B 反應性更快 在低溫下 所以在一個容易中大部分都是27B的comformation,然而反應大部分為27A轉為cis-28

Procedure of synthesis -Total synthesis of the nature product 作者做formylation 是因為 N 做methylation make N atom actitive ,and be oxidated. So use formylation to deactivate the N atom activity. 在dihydroxyl compound 3 epoxide的開環反應中，因C6比C7遮蔽更多，故選擇性的打在C7 position

Procedure of synthesis -Total synthesis of the nature product Scandium(III) triflate The mechanism is collect azaindane

Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion

CONCLUSION Sythesis concise and enantioselective (-)-aspidospermidine,(-)-mehranine,the (+)-(6S,7S)-dihydroxyl-N-Methylaspidospermidine The first total synthesis of (-)-methylenebisemhranine the yield of the (-)-aspidospermidine is 11% (10step) the yield of the (-)-mehranine is 8% (12step) the yield of the (+)-(6S,7S)-dihydroxyl-N-Methylaspidospermidine is 5% (13step) the yield of the (-)-methylenebisemhranine is 4% (14step)

CONCLUSION

REFERENCE J. Org. Chem. 2008, 73, 7498–7503 Angew. Chem. Int. Ed. 2007, 46, 6159 –6162 J. Org. Chem. 1991, 56, 2915–2918 J. Org. Chem. 1996, 61, 7882–7888 J. AM. CHEM. SOC. 2013, 135, 13335–13337 Angew. Chem. Int. Ed. 2013, 52, 4211 –4215

THE END

PROBLEM 命名發音比照學術發音 Reference 及title 第一字母大寫 其他小寫 2007 word 難改