Madangamine alkaloids madangamines

An example of intramolecular aminomercuration has been reported by Weimeb as part of the synthetic strategy to the tricyclic nucleus of madangamine A - an alkaloid that shows cytotoxicity toward a number of tumor cell lines (equation 15). Pearson has recently reported the first example of an azidomercuration involving aliphatic azides (see equation 16) according to a protocol that exhibits wider applicability and is, therefore, more convenient than the analogous acid-promoted Schmidt reaction. ... 

Rearrangement of the ingenamine-type intermediate 126, as shown in Figure 3.10, can lead to the madangamine skeleton [69], The madangamines are the only examples to date of 3-alkylpiperidine alkaloids with rearranged carbon skeletons. 

Madangamine A, a Novel Cytotoxic Alkaloid from the Marine Sponge Xestospongia ingens. Kong, F. Andersen, R. J. and Allen, T. J. Am. Chem. Soc. 1994, 116, 6607. 

The synthesis of the tricyclic core of the cytotoxic marine alkaloid Madangamine required an efficient method to generate the central quaternary carbon function. Weinreb employed an aza-Claisen rearrangement in the presence of a palladium catalyst [21c]. After treatment of ketone 116 subsequently with TOSMIC and DIBALH, the formed carbaldehyde 117 was reacted with diallylamine in the presence of Pd(OCOCFj)2/PPh,. Initially, the enamine 118 was formed, which underwent diastereoselective aza-Claisen rearrangement The unsaturated imine 119 was cleaved with aqueous HCl and the corresponding aldehyde 120 was isolated in 68% yield. Several further steps allowed one to complete the synthesis of the core fragment 121 of the natural product (Scheme 10.27). 

This chapter is focused on madangamines, a small group of complex diamine alkaloids Isolated from marine sponges of the order Haplosclerlda, and covers their Isolation, characterization, biogenesis, biological activity, and synthesis. Structurally, madangamines are pentacyclic alkaloids with an unprecedented skeletal type. 

Ptire madangamines A—C and F were isolated as optically active compounds (see Table 1 for the [a] values). Although the absolute configuration of the alkaloids has not been unambiguously established, it may be tentatively deduced by correlation with the putative precursor ingenamines (see Section 3). No X-ray crystallographic analysis of these alkaloids is available to date. 

The synthesis of alkaloids of the madangamine group has been Httle explored. The most logical approach to the pentacyclic skeleton of these alkaloids involves the initial construction of the bridged diazatricycHc ABC core common to all madangamines, with the appropriate substitution and functionality to allow the subsequent building of the peripheral macro-cyclic D and E rings. 

A new synthetic entry to the diazatricyclic core of madangamines was reported by Bonjoch in 2008. The synthesis starts from 4-(aminomethyl) anisole derivatives 40 (R = Me or Bn), which incorporate the carbocyclic C ring and the Cg—Ny atoms of the target alkaloids, and involve the successive construction of the piperidine B and A rings (Scheme 14). 

Due to the h h yields of the above synthetic transformations, compound 100 prepared by the route outlined in Scheme 22 was used to assemble the E ring of madangamine D and complete the synthesis of this alkaloid. 

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