Of manzamine

Biogenesis of manzamine alkaloids ((3-carboline marine alkaloids) 97H(46)765, 97YGK1114. 

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... 

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

Several examples reported in 2006 demonstrate that 2-substituted furans underwent spirocyclization at the 2-position. As illustrated in the scheme below, the reaction of a furan tethered at the 2-position to an iminium ion gave a spiro-2,5-dihydrofuran derivative as the sole diastereoisomer. This spirocyclization, which proceeded irrespective of the length of the carbon linker, was employed to construct the ABC tricyclic core of manzamine A <06OL27>. 

The first two reported syntheses of manzamine C utilized the two most common approaches to the /J-carboline ring system—the Pictet-Spengler reaction [13,14] and the Bischler-Napieralski reaction [15]. These two reactions are illustrated in Fig. 3. 

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. 

Ibrahim MA, Shilabin AG Prasanna S, Jacob M, Khan SI, Doerksen RJ, Hamann MT. (2008) 2-N-Methyl modifications and SAR studies of manzamine A. Bioorg Med Chem 16 6702-6706. 

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... 

The central five-membered ring of Manzamine A (315), a member of a family of antileukimic and antibacterial marine polycyclic alkaloids, has been constructed using intramolecular azomethine ylide technology (88). Model studies on the construction of the central ABC rings, by condensation of the aldehyde 316 prepared by standard chemistry with sarcosine ethyl ester, furnished the desired ABC ring system as a single diastereoisomer in 45% yield (Scheme 3.105). 

Langlois and co-workers have developed a Bradsher cycloaddition route, involving a [2,7]naphthyridinium salt toward the tricyclic core of manzamine A (Scheme 71) <1995TL9475, 1998TL837, 2000TL9251>. 

Microbial bioconversion studies of manzamine A and ent-8-hydroxymanzamine A have shown that they can be metabolized by several microbial species.76 Preparative-scale fermentation of manzamine A with Fusarium oxysporium f. gladioli ATCC 11137 resulted in the isolation of the known ircinal A (61) as a major metabolite. Preparative-scale fermentation of enf-8-hydroxymanzamine A with Nocardia sp. ATCC 11925 and Fusarium oxysporium ATCC 7601 resulted in the isolation of the new major metabolite 12,34-oxamanzamine F (62). The latter metabolite showed no cytotoxicity against different cell lines (>10 pg/ml). 

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.

Ethoxycarbonyl-l,3-dithiane (183), easily accessible from ethyl glyoxylate diethyl acetal, can be lithiated-alkylated to afford, after deprotection, a-ketoesters as exemplifies the product 184 (Scheme 53)237. This methodology has been used in the preparation of 3-deoxy-D-manno-2-octulosonic acid (KDO) derivatives238 and of the ABC ring system of manzamine A239. 

Ring-closing metathesis is now applied as the key step in many natural product syntheses. Prominent examples are the syntheses of manzamine A [15,17] and epothilone A [18] (Scheme 8). 

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. 

Oxamanzamine E [44], 6-hydroxy-12,34-oxamanzamine E and 12,28-oxamanzamine E [48] were isolated from a re-collection of the sponge Acanthostrongylophora sp. from Manado, Indonesia. In addition, 32,33-dihydro-31-hydroxymanzamine A, 32,33-dihydro-6,31-dihydroxymanzamine A, and 32,33-dihydro-6-hydroxymanza-mine A-35-one have been reported from another collection of the same Indonesian sponge [49]. Compounds 27 and 28 are likely the reduced derivatives of manzamines E and F. Alkaloid 29 is unique in that it possesses a ketone moiety at C-35, instead of a typical C-31 ketone as seen in manzamines E and F. 

Manzamine C (40) is characterized by a 2-ethyl-N-azacycloundec-6-ene connected to C-1 of a p-carboline. To date, only two analogs of this type of manzamine have been reported. Manzamine C was obtained from the same species Haliclona sp. that yields manzamine A [37a[. Keramamine C (41) was isolated from an Okinawan marine sponge Amphimedon sp. [18[. 

Source and Large-scale Preparation of Manzamine Alkaloids... 

---