Madangamine alkaloids synthesis

Amat, M., Perez, M., Proto, S., Gatti, T., and Bosch, (. (2010) First enantioselertive synthesis of the diazatricyclic core of madangamine alkaloids. Chem. Eur.., 16,9438-9441. 

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. 

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. 

Taking into account that the specific rotation of synthetic (+)-madang-amine D, which has an unambiguous 2S, 5S, 9R, 12R absolute configuration, has the same sign as in the closely related madangamines A-C (see Table 1), the above synthesis confirmed the absolute configuration of these alkaloids. 

These alkaloids have received scarce attention from the synthetic standpoint, and only one total (enantioselective) synthesis of a member of this group, madangamine D, has been reported to date. This synthesis has provided, for the first time, a pure sample of the alkaloid, permitting the evaluation of its cytotoxic activity. Additionally, the dextrorotatory character of... 

Yamazaki, N., Kusanagi, T., and Kibayashi, C. (2004) Synthesis of the diazatricydic core of the marine alkaloids madangamines. Tetrahedron Lett., 45, 6509-6512. 

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