a novelsynthesisof (-)-huperzinea · a novelsynthesisof (-)-huperzinea f. giornal 14.11.2013 j. d....
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A Novel Synthesis of (-)-Huperzine A
F. Giornal 14.11.2013
J. D. White, Y. Li, J. Kim, M. Terinek Org. Lett. 2013, 15, 882-885.
Introduction
1(a) J.-S. Liu, Y.-L. Zhu, C.-M. Yu, Y.-Z. Zhou, Y.-Y. Han, F.-W. Wu, B.-F. Qi Can. J. Chem. 1986, 64, 837. (b) X. C. Tang, X. C. He, D. L. Bai Drugs Future 1999, 24, 647. (c) R. Wang, H. Yan, X.-C. Tang Acta Pharmacol. Sin. 2006, 27, 1.
(-)-Huperzine A
• Isolated from Huperzia serrata
• Used in chinese medicine: schizophrenia, blood disorder, loss of memory
• Potent and reversible acetylcholinesteras inhibitor
• Clinical studies for the treatment of Alzheimer’s disease
• High interest because of its biological activity
• Several previous total syntheses
Introduction
2(a) Y. Xia, A. P. Kozikowski JACS 1989, 4116. (b) L. Qian, R. Ji Tetrahedron Lett. 1989, 30, 2089. (c) P. Zhao, C. M. Beaudry Org. Lett. 2013, 15, 402-405.
• First total syntheses of (±)-Huperzine by Kozikowski and Ji in 1989
• Most efficient enantioselective total synthesis: 16 steps, 35-45% overall yield
(-)-Huperzine A
• 26-28 kcal/mol ring strain in cyclobutanes
• Use of the release of this ring strain
• Tandem of the fragmentation with Aza-Prins cyclisation, which will initiate the process
Synthetic strategy
3
Tandem Aza-Prins cyclization / cyclobutane fragmentation
Synthetic strategy
4
Retrosynthesis
H2N
HN
O
NH
H
OMe N OMe
O
H
H
OO
O
H
H
OTIPS
HN O
SePh
O
H
H
OO
OOH
HO
HO COOH
(-)-Huperzine A
OH
Synthesis of (-)-Huperzine A
5
Preparation of the cyclohexenone
(a) Danishefsky et al. JACS 1989, 3738. (b) B. M. Trost, A. G. Romero JACS 1986, 2332.
Synthesis of (-)-Huperzine A
6
Preparation of the tricyclic core
• Change the strategy
Synthesis of (-)-Huperzine A
7
Construction of the Fused Pyridone via [2+2] cycloaddition
(a) P. Magnus, P. Rigollier, J. Lacour, H. Tobler JACS 1993, 12629 (b) P. Magnus, J. Lacour JACS 1992, 767.
Synthesis of (-)-Huperzine A
8
Construction of the Fused Pyridone via [2+2] cycloaddition
DBU, TolReflux, 43%
O
H
H
O
HN
O
H
Synthesis of (-)-Huperzine A
9
Construction of the Fused Pyridone via [2+2] cycloaddition
Synthesis of (-)-Huperzine A
10
Opening of the ether and preparation of the last intermediate
N
OH
H
OMe
O
Ph3PCH3 Br
BuLi, THF-78 °C, 27%
NH
H
OMe
O
N
OTfH
H
OMe
O
Comins Reagent,KHMDSTHF74%
Pd(PPh3)4(SnMe3)276%
Synthesis of (-)-Huperzine A
11
Construction of the Fused Pyridone via [2+2] cycloaddition
Synthesis of (-)-Huperzine A
12
Tandem Aza-Prins / Cyclobutane fragmentation
13
Conclusion
• Novel strategy implying cyclobutane-strain release
• Use of [2+2] cycloadditions
• Low conversion for the key step
• Several changes of strategy: versatility of the synthetic path
Thanks for your attention