BIOGENETICALLY INSPIRED TOTAL SYNTHESIS OF LYCOPODIUM ALKALOIDS,(+)-FLABELLIDINE AND (–)-LYCODINE Masayuki Azuma, Tetsuya Yoshikawa, Noriyuki Kogure, Mariko Kitajima and Hiromitsu Takayama*
Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion
Introduction -Four major subclasses of the Lycopodium alkaloids bicyclo[3.3.1]nonane skeleton
Introduction -natural product (+)-Flabellidine Structure Property term Name (+)-Flabellidine Isolated from Lycopodium complanatum Isolated by Biological actitivity
Introduction -natural product (-)-Lycodine Structure Property term Name (-)-Lycodine Isolated from Lycopodium annotinum Isolated by Anet and Eves Biological actitivity
Introduction -Lycodine and structurally related Lycopodium alkaloids 形成dimer可作為抗神經衰退的藥物
Introduction -Total Synthesis of Lycopodium Alkaloids: (±)-Lycopodine, (±)-Lycodine, and (±)-Lycodoline Reference:Clayton H. Heathcock. J. Am. Chem. SOC. 1982, 104, 1054-1068.
Introduction -Concise Total Synthesis of (±)-Lycodine Reference:Chihiro Tsukano. Eur. J. Org. Chem. 2010, 4198–4200
Introduction -Development of an Enantioselective Route toward the Lycopodium Alkaloids: Total Synthesis of Lycopodine Reference: Rich G. Carter. J. Org. Chem. 2010, 75, 4929–4938
Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion
Proposed biosynthetic pathway by spender group 4-(2-Piperidyl) acetoacetic acid 5
Retrosynthesis of (+)-Flabellidine and (-)-Lycodine Diketone 9 Ene-iminium intermediate 10 Tetracyclic structure 12 Conjugated addtion Monoacetylation aromatization
Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion
Procedure of synthesis -Synthesis of Linear Substrate 21 Linear precursor 21 Chiral auxiliary 手性輔助 Hosomi-sakurai allylation Crotonamide 13 Ozonolysis Ozonide Terminal olefin 14
Procedure of synthesis -Total synthesis of (+)-Flabellidine and (-)-Lycodine Tetracyclic lycodine skeleton 23 Di-boc compound 26 Camphorsulfonic acid, sometimes abbreviated CSA or 10-CSA is an organosulfur compound .In organic synthesis, CSA and its derivatives can be used as resolving agents for chiral amines and other cations resolving agents 手性拆分劑 以boc作保護基以穩定iminium的形成 ,並且有助於cyclohexane的形成
Introduction Retrosynthesis of the nature product Procedure of synthesis conclusion
CONCLUSION the yield of the (+)-flabellidinen is 20.7% (11step) the yield of the (–)-lycodine is 14.6% (11step) The first asymmetric total synthesis of (+)-flabellidine tetracyclic lycodine skeleton which was inspired by the biosynthetic consideration
CONCLUSION Publish date author step yield production J. Am. Chem. Soc. XXXX, XXX, XXX−XXX Hiromitsu Takayama* 11 20.7% (+)-flabellidine 14.6% (–)-lycodine Tetrahedron Letters No. 43, pp 4125 - 4128 Clayton H. Heathcock 5 22% (±)-lycodine 20.5% (±)-lycopodine Eur. J. Org. Chem. 2010, 4198–4200 Chihiro Tsukano 15 2.8% (±)-Lycodine J. AM. CHEM. SOC. 2008, 13778–13789 Amos B. Smith III* 27 2.2% (+)-lyconadin A 28 (-)-lyconadin B J. AM. CHEM. SOC. 2008, 7222–7223 Richmond Sarpong* 18 10% (±)-Lyconadin A J. Am. Chem. Soc. 2013, 3243−3247 Tohru Fukuyama 13 0.71% 14 0.49% (±)-lyconadin B 5.13% (±)-lyconadin C
CONCLUSION Publish date author step yield production Angew. Chem. Int. Ed. 2014, 3922 –3925 Mingji Dai 8 5.87% lyconadins A 10 4.8% lyconadins C Angew. Chem. Int. Ed. 2012, 51, 491 –495 Xiaoguang Lei* 12 8% (+)-Fawcettimine 16% (+)-Fawcettidine (-)-8-Deoxyserratinine Angew. Chem. Int. Ed. 2011, 50, 8025 –8028 Hiromitsu Takayama* 19 16.4% Huperzine-Q Angew. Chem. Int. Ed. 2013, 52, 11373 –11376 Yong-Qiang Tu,* 5% (-)-Lycojaponicumin C, 2.0% 1.8% 1.6% J. AM. CHEM. SOC. 2010, 132, 14338–14339 Ju¨rgen Ramharter,* 15% (+)-Lycoflexine
REFERENCE J. AM. CHEM. SOC. 2008, 130, 13778–13789 Angew. Chem. Int. Ed. 2012, 51, 491 –495 Angew. Chem. Int. Ed. 2013, 52, 11373 –11376 Angew. Chem. Int. Ed. 2011, 50, 8025 –8028 J. Org. Chem. 2010, 75, 4929–4938 Angew. Chem. Int. Ed. 2014, 53, 3922 –3925 J. Am. Chem. SOC. 1982, 104, 1054-1068 Eur. J. Org. Chem. 2010, 4198–4200
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