Manzamines synthesis

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... 

A tandem Stille-Diels-Alder reaction to form tricycle 2.174 from vinyl bromide 2.173 was used in a manzamine synthesis (Scheme 2.60). Another aspect of this synthesis is discussed in Scheme 8.66. 

Mihara, Y, Matsumura, T., Terauchi, Y., Akiba, M., Arai, S., and Nishida, A. (2009) Asymmetric synthesis of hydroisoquinoline derivatives, a key intermediate for manzamine synthesis, by Diels-Alder reaction using 4-amino-2-siloxybutadiene. Bull. Chem. Soc. Japan, 82,1520-1527. 

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

Scheme 83 Synthesis of the manzamine AB ring segment 426 via enyne RCM [ 177]...

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

Another natural product synthesis using a metathesis as the key step has been reported to generate the ABCD ring system 133 of manzamine A. A multistep... 

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... 

Nishida A, Nagata T, Nakagawa M (2006) Strategies for the Synthesis of Manzamine Alkaloids. 5 255-280... 

A fourfold anionic domino process consistingofadominoMichael/aldol/Michael/ aldol process was used by Koo and coworkers for the synthesis of bicyclo[3.3.1]non-anes. They employed 2 equiv. of inexpensive ethyl acetoacetate and 1 equiv. of a simple a, 3-unsaturated aldehyde [290]. Differently substituted dihydroquinolines were assembled in a Michael/aldol/elimination/Friedel-Crafts-type alkylation protocol by the Wessel group [291]. An impressive approach in this field, namely the construction of the indole moiety 2-557, which represents the middle core of the man-zamines, has been published by Marko and coworkers [292]. Manzamine A (2-555) and B (2-556) are members of this unique family of indole alkaloids which were isolated from sponges of the genus Haliclona and Pelina (Scheme 2.126) [293]. 

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. 

We have been interested in the synthesis of nakadomarin A 1 [2], which belongs to manzamine alkaloids [3] by two different routes (Routes A and B). 

The basic alkaloid in Pilocarpus jaborandi (Rutaceae) is pilocarpine, a molecule of which contains an imidazole nucleus and is also used as a clinical drug. During alkaloid synthesis, L-histidine can produce the manzamine nucleus (Figure 27). These alkaloids are quite widespread, though they were first isolated in the late 1980s in marine sponges. They have an unusual polycyclic system and a very broad range of bioactivities. Common alkaloids with this nucleus include manzamine A, manzamine B, manzamine X, manzamine Y, sextomanzamine A and so on. 

Another case of long-range RCM is shown in equation 41. In 61 the C=C bonds are separated by 12 single bonds, four of which are restrained by ring systems. The product, 62, is an intermediate in the synthesis of manzamine A (a novel anti-tumour alkaloid)243 also see Martin244. 

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... 

In the synthesis of manzamine alkaloids, the AA of 8 proceeded with remarkable selectivity, given the fact that the double bond is electronically not differentiated [12]. The formation of 9 as the exclusive product can be understood by a transfer of the nitrogen group via the least hindered trajectory to the alkene, i.e. the less-substituted position of the double and equatorial approach. 

Scheme 5. Application of the AA toward the synthesis of manzamine alkaloids.

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). 

Scheme 8. Ring-closing metathesis as the key step in the synthesis of manzamine A and epothilone A.

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 several reviews referring to manzamine alkaloids [7,31-35]. In this chapter, we will review the structure and source of manzamine alkaloids including the large-scale preparation of manzamine alkaloids for preclinical evaluation. We also discuss the detailed synthesis and bioactivities of manzamine alkaloids. 

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