Manzamine total synthesis

Scheme 25 Sequential formation of 13- and 8-membered azacycles in Martin s total synthesis of ircinal A (129) and related manzamine alkaloids [78]...

For a total synthesis of ircinal A and related manzamine alkaloids via RCM, see Scheme 25... 

Marine sponges are a source of an array of polycyclic diamine alkaloids of common biogenetic origin. This class of secondary metabolites has been the subject of four previous reviews [4-7]. Therefore, the present review will include literature reports previously not discussed, dealing with the isolation, structure determination, biological activities, and total synthesis of polycycUc diamine alkaloids isolated from marine sponges. This review will not include guanidine alkaloids [8,9] or the manzamine alkaloids [10,11], since these compounds have been recently reviewed elsewhere. Only polycycUc... 

The polycyclic structure of manzamine A 74, an alkaloid with promising antitumor activity, constitutes an ideal testing ground for probing the effciency of RCM. Although no total synthesis of 74 has yet been reported, various approaches to this complex target rely on RCM-based strategies. 

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 intramolecular Pauson-Khand reaction has been extensively used as a key step in total synthesis of fairly complex polycyclic natural products. The [2 + 2 + IJcycloaddition was, for example, used in recent syntheses of magellanine (Scheme 269), tecomanine, toward palau amines and styloguanidines (Scheme 270), Sa-hydroxystreptazolone (Scheme 271), ceratopicanol (Scheme 272), 13-deoxyserratine (Scheme 273), ABC-rings of nakadomarin and manzamine (Scheme 274), cedrone (Scheme 275), (-)-dendrobine (Scheme 276), " toward kalmanol (Scheme 277), and (+)-epoxydictymene (Scheme 278). 

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]... 

The Ramberg-Backlund rearrangement was the key step in the total synthesis of the marine alkaloid manzamine C by D.l. MaGee and E.J. Beck. The azacycloundecene ring was stereoselectively formed by exposing the a-chloro sulfone to a strong base. The use of weaker bases either resulted in no reaction or gave rise to mixtures of ( )- and (Z)-alkenes. 

The enantioselective total synthesis of the manzamine alkaloid ircinal A was completed in the laboratory of S.F. Martin utilizing a novel strategy. A domino Stille/Diels-Alder reaction was used to assemble the ABC ring core of the natural product. The vinyl bromide intermediate reacted with vinyl tributylstannane in the presence of Pd to afford the 1,3-diene moiety, which cyclized via an intramolecular Diels-Alder reaction to give the ABC core. 

Enantioselective total synthesis of marine alkaloids, manzamine A, and related compounds 00JHC567. 

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. 

Martin SF, Humphrey JM, Ali A, Hillier MC (1999) Enantioselective total synthesis of ireinal A and related manzamine alkaloids. J Am Chem Soc 121 866-867... 

The asyrrunetric total synthesis of nakadomarin A, a marine manzamine alkaloid 05Y200. 

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