1. BIOGENETICALLY INSPIRED TOTAL SYNTHESIS OF LYCOPODIUM ALKALOIDS,(+)-FLABELLIDINE AND (–)-LYCODINE
Masayuki Azuma, Tetsuya Yoshikawa, Noriyuki Kogure, Mariko Kitajima and Hiromitsu Takayama*

2. Introduction
Retrosynthesis of the nature product
Procedure of synthesis
conclusion

3. Introduction -Four major subclasses of the Lycopodium alkaloids
bicyclo[3.3.1]nonane skeleton

4. Introduction -natural product (+)-Flabellidine
Structure
Property
term
Name
(+)-Flabellidine
Isolated from
Lycopodium
complanatum
Isolated by
Biological actitivity

5. Introduction -natural product (-)-Lycodine
Structure
Property
term
Name
(-)-Lycodine
Isolated from
Lycopodium annotinum
Isolated by
Anet
and Eves
Biological actitivity

6. Introduction -Lycodine and structurally related Lycopodium alkaloids
形成dimer可作為抗神經衰退的藥物

7. Introduction -Total Synthesis of Lycopodium Alkaloids: (±)-Lycopodine, (±)-Lycodine, and (±)-Lycodoline
Reference:Clayton H. Heathcock. J. Am. Chem. SOC. 1982, 104,

8. Introduction -Concise Total Synthesis of (±)-Lycodine
Reference:Chihiro Tsukano. Eur. J. Org. Chem. 2010, 4198–4200

9. 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

10. Introduction
Retrosynthesis of the nature product
Procedure of synthesis
conclusion

11. Proposed biosynthetic pathway by spender group
4-(2-Piperidyl) acetoacetic acid 5

12. Retrosynthesis of (+)-Flabellidine and (-)-Lycodine
Diketone 9
Ene-iminium intermediate 10
Tetracyclic structure 12
Conjugated addtion
Monoacetylation
aromatization

13. Introduction
Retrosynthesis of the nature product
Procedure of synthesis
conclusion

14. 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

15. 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

16. Introduction
Retrosynthesis of the nature product
Procedure of synthesis
conclusion

17. 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

18. 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
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, –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

19. CONCLUSION Publish date author step yield production
Angew. Chem. Int. Ed. 2014, –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, –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

20. REFERENCE J. AM. CHEM. SOC. 2008, 130, 13778–13789
Angew. Chem. Int. Ed. 2012, 51, 491 –495
Angew. Chem. Int. Ed. 2013, 52, –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,
Eur. J. Org. Chem. 2010, 4198–4200

21. THE END

22. PROBLEM