Total Synthesis of Manzamine A

Chris Wilhelmsen

Organic Synthesis Methodology

Dr. Totah CHE 686

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Background

• Natural product from sea sponges off the coast of Okinawa

• Higa and Bernardinelli isolated Manzamine A from Haliclona sp.1

• Noted for is antitumor properties

• Characterized via x-ray crystal, mass spec, UV spec, H1, and C13

• A 735g sample yielded 100mg of manzamine A hydrochloride

• Nakamura isolated the same compound from Pellina sp.2

• Noted for is antibacterial properties

• Reduces the risk of atherosclerosis and fat accumulation in the blood3

R. Sakai, T. Higa, C.W. Jefford, G. Bernardinelli, J. Am. Chem. Soc. 1986, 108, 64041

H. Nakamura, S. Deng, J. Kobayashi, Y. Ohizumi, Y. Tomotake, T. Matsuzaki, Y. Hirata, Tetrahedron Lett. 1987, 28, 6212

Keisuke Eguchi et al. Bioorganic and medicinal chemistry 21 (2013) 3831-38383

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Retro Biosynthetic Proposal

• Sir Jack Baldwin and coworker Roger Whitehead at the University of Oxford

• Framework for many manzamine alkaloids

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Retro Biosynthetic Pathway

J.E. Baldwin, R.C. Whitehead, Tetrahedron Lett. 1992, 33, 2059

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Retro Biosynthetic Pathway

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Winkler’s Synthetic approach to Manzamine A

• Useful help for construction would come from Kobayashi1

• Ircinal A (2) (an alkaloid) can be coverted to manzamine A

• Able to make keramaphidin B similar to the retro biosynthetic pathway proposed2

• Able to convert the bis-dihydropyridinium salt to the kermaphidin B using a diels alder reaction

M. Tsuda, J. Kobayashi, Heterocycles 1997, 28, 6211

J.E. Baldwin, R.C. Whitehead et al. Chem. Eur. J. 1999, 5, 311542 6

Winkler’s Retrosynthesis of Manzamine A

J.M. Axten and J.D. Winkler, J. Am. Chem. Soc. 1998, 120, 6425-64267

Winkler’s Retrosynthesis of Manzamine A

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Winkler’s Total Synthesis1

J.M. Axten and J.D. Winkler, J. Am. Chem. Soc. 1998, 120, 6425-642619

Winkler’s Total Synthesis

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Winkler’s Total Synthesis

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Winkler’s Total Synthesis

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Winkler’s Total Synthesis

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Winkler’s Total Synthesis

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Winkler’s Total Synthesis

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Winkler’s Total Synthesis

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Review of Winkler’s Synthesis

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Comments

• Total synthesis in 35 steps

• Longest linear sequence is 33 steps

• Overall percent yield of 2%

• Highlights• First synthesis of manzamine type alkaloids

• Selectively creates 3 stereo centers and 3 (6,6,5 membered) rings in one step

J.M. Axten and J.D. Winkler, J. Am. Chem. Soc. 1998, 120, 6425-6426

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Martin’s Retrosynthesis of Manzamine A

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Martin’s Retrosynthesis of Manzamine A

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Martin’s Total Synthesis1

S.F. Martin J. Am. Chem. Soc. 1999, 121, 866-8671

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Martin’s Total Synthesis

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Martin’s Total Synthesis

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Martin’s Total Synthesis

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Review of Martin’s Synthesis

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Comments

• Total synthesis done in 24 steps

• Longest linear sequence is 21 steps

• Overall yield of 0.32%

• Highlights• Constructs 2 6-membered ring with 3 stereo centers in one step

• One of the first examples of constructing 13 and 8 membered rings using ring closing metathesis in the presence of highly functionalized substrates

S.F. Martin J. Am. Chem. Soc. 1999, 121, 866-867

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References

• R. Sakai, T. Higa, C.W. Jefford, G. Bernardinelli, J. Am. Chem. Soc. 1986, 108, 6404

• H. Nakamura, S. Deng, J. Kobayashi, Y. Ohizumi, Y. Tomotake, T. Matsuzaki, Y. Hirata, Tetrahedron Lett. 1987, 28, 621

• Bioorganic and Medicinal Chemistry 21 (2013) 3831-3838 Keisuke Eguchi et al.

• J.E. Baldwin, R.C. Whitehead et al. Chem. Eur. J. 1999, 5, 31154

• J.M. Axten and J.D. Winkler, J. Am. Chem. Soc. 1998, 120, 6425-6426

• S.F. Martin J. Am. Chem. Soc. 1999, 121, 866-867

• K.C. Nicolaou; S.A. Snyder. Manzamine A: Classics in Total Synthesis II, VCH Weinheim: New York, 2003; pp 211-238

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