Total Synthesis of Manzamine

DIBAL-H xi, Dess-Martin periodinane xii, HC(OMe)3, MeOH, HCI xiii, CH2=CHCH2 CH2LI xiv, KOH, MeOH xv, DIBAL-H xvi, Dess-Martin periodinane xvii, tryptamine, TEA xviii, DDQ, TEA. 

The fourth approach to the synthesis of manzamine C involved a Ramberg-Backlund rearrangement in the key step for the preparation of the azacycloundecene ring [81[. Synthesis ofthis ring began with thecondensationof5-amino-l-pentanol 156 

DCM viii, KOtBu, DMSO ix, OSO4, NMO, THF-tBuOH-HjO x, (a) KOtBu, THF, 

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Approaches to the total synthesis of complex natural products using RCM have been investigated. Martin et al. succeeded in the construction of the core 13-membered ring from 37 and 8-membered ring from diene 39 using RCM in manzamine synthesis, and they then achieved the total synthesis of manzamine... 

Further investigation of the Okinawan sponge Haliclona sp. resulted in the isolation of manzamines B-F (182-186), which show cytotoxic activity (152-154). The structures of manzamines B (182) and C (183) were based on X-ray analysis. Manzamine F (186) was found to be identical with keramamine B, the structure of which with a 1,2,3-triazacyclohexane moiety (181) was revised to structure 186 containing a hexahydro-5(2//)-azocinone ring. Total synthesis of manzamine C (183) was achieved by the... 

For manzamine A, Martin et al. developed a strategy for the construction of the eight-membered ring E [15], Pandit et al. succeeded in the formation of the 13-membered ring D [18]. The efforts culminated recently in the total synthesis of manzamine A and related manzamine alkaloids, employing the ring-closing metathesis reaction as a key step [16]. Thus, 49 is converted into 50 with a yield of 67 % (Scheme 8). 

The unique structure and extraordinary bioactivity of manzamine alkaloids have attracted great interest from synthetic chemists as one of the most challenging natural product targets for total synthesis. Great efforts have been made to achieve total synthesis of manzamine A and related alkaloids. Methodological studies towards the synthesis of manzamine structural units have also been reported [31-33]. 

There are to date only two reports on total synthesis of manzamine A. The first total synthesis of manzamine A was reported in 1998 by Winkler et al., along with those of manzamine D, ircinal A, and ircinol A [63]. The second total synthesis was reported a year later by Martin et al. [64] using a different approach from Winkler s. 

With the completion of the total synthesis of manzamine C by Nakagawa et al. in 1991 [73], the synthesis and biological evaluation of manzamine C analogs were subsequently reported by the same group [136]. In this study, the azacyclic ring was modified from 11-membered to 5-, 6-, 7-, and 8-membered rings (Scheme 8.19). 

The Martin group was one of the first to use RCM in complex molecule synthesis, and have recently used two RCM reactions in the total synthesis of Manzamine A (Eq. 6.13) [34]... 

New approaches to total synthesis of manzamine A, ircinal A, and related alkaloids 99YGK1004. 

These novel structures, together with their biological aspects, make this family of alkaloids a highly attractive target for total chemical synthesis. Several approaches for the total synthesis of manzamine A have been published, although its synthesis has not yet been achieved. Likewise, in recent years other compounds such as papuamine, haliclonadiamine, saraine or cyclostellamine C have been candidates for total synthesis. 

A different approach for the synthesis of this compound was used by Pandit and coworkers. The strategically functionalized ABC core was stereoselectively synthesized from Z,-(+)-serine in 13 steps (11.8% overall yield) as an intermediate for the total synthesis of manzamine A (1). The final steps included the formation of an intramolecular Diels-Alder adduct, and a final conversion into a tricyclic ketone that was subsequently ketalized (see Scheme 19). This ketal showed a highly crystalline structure that, on the basis of spectral data and X-ray analysis, allowed corroboration of all structural assignments [80]. 

Towards the Total Synthesis of Manzamines. Rapid and Efficient Assembly of a Middle Core Model. Mark6, 1. E. Southern, J. M. and Adams, H. Tetrahedron Lett. 1992, 33, 4657. 

The first total synthesis of manzamine A was reported by Winkler and Axten in 1998 [18,19]. In their synthesis, a unique [2 + 2] photocycloaddition followed by retro Mannich/Mannich rearrangement furnished a 6/6/S/8 ring system in a highly stereospecific manner. The 13-membered ring was prepared by standard cyclization. 

In 1999, Martin et al. reported a second total synthesis of manzamine A [26,27]. The stereoselective synthesis of a fully functionalized central core by an intramolecular Diels-Alder reaction is a highlight of their synthesis. Use of the RCM methodology for the synthesis of eight- and 13-membered rings with (Z)-olefin was established by Pandit [77-79] and Martin. 

In the total synthesis of manzamine A (15, Scheme 24.5), which is a potent antitumor alkaloid isolated from marine sponges of the genera Halicha and Peliina, the challenging formations of the 13- and 8-membered rings were carried out using [Ru]-Ia by Martin et al. Thus, the RCM... 

Marko, l.E. and Chesney, A. (1992) Towards the total synthesis of manzamines preparation and reactions of 2-methoxycarbonyl-l,3-butadienes and P-amino aldehydes, Synlett, 275-278. 

Nakagawa, M., Torisawa, Y Uchida, H, and Nishida, A, (1999) New approaches to total synthesis of manzamine A, ircinal A and related compounds. J. Synth. Org. Chem. Japan, 57,1004-1015,... 

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