New Approaches to the Synthesis of the Manzamine Alkaloids: Total Synthesis of (-)-Nakadomarin A
J. Stephen Clark
School of Chemistry University of Glasgow, UK
Time & Place
Wed, 23 Nov 2016 12:00:00 NZDT in Rutherford Room 531
All are welcome
Nakadomarin A was first isolated from a sponge of Amphimedon sp. by Kobayashi and co-workers in 1997 and was found to possess a unique hexacyclic structure. 1 This unusual alkaloid exhibits cytotoxicity against murine lymphoma L1210 cells, antimicrobial activity and inhibitory activity against cyclin-dependent kinase 4. The intriguing structure of nakadomarin A combined with its diverse and significant biological activities make it a very attractive synthetic target and several total syntheses have been reported. 2 Nakadomarin A is a member of the manzamine family of alkaloids but is architecturally distinct from the other manzamines because it possesses a contracted B-ring and an extraneous furan. Kobayashi and co-workers identified a direct biosynthetic route from ircinal A to nakadomarin A,1 which suggests that a common synthetic approach to both compounds and manzamine A might be possible.
Various synthetic approaches to the total synthesis of manzamine A and nakadomarin A will be presented. The short and efficient total synthesis of nakadomarin A will be presented in which a tetracyclic ketone intermediate is prepared using a strategy that involves a rearrangement reaction, an RCM reaction and an unusual amination reaction. 3 The tetracyclic ketone should also serve as an advanced intermediate for both ircinal A and manzamine A, and efforts to complete syntheses of these natural products will be discussed.
References 1. Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org. Chem. 1997, 62, 9236.
2. Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem. Int. Ed. 2004, 43, 2020. Young, I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465. Jakubec, P.; Cockfield, D. M.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 16632. Nilson, M. G.; Funk, R. L. Org. Lett. 2010, 12, 4912. Cheng, B.; Wu, F.; Yang, X.; Zhou, Y.; Wan, X.; Zhai, H. Chem.– Eur. J. 2011, 17, 12569. Bonazzi, S.; Cheng, B.; Wzorek, J. S.; Evans, D. A. J. Am. Chem. Soc. 2013, 135, 9338.
3. Clark, J. S.; Xu, C. L. Angew. Chem. Int. Ed. 2016, 55, 4332.