Madangamine

Scheme 5 Biogenetic pathway proposed by Andersen et al. [33,34] for the formation of the madangamine skeleton...

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. ... 

Hydroxy, Dihydro and Tetrahydro Manzamine A Derivatives Madangamines A to E... 

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. 

Special mention must be made of the isolation of madangamine (104). This compound is of interest because of its unique structure and the fact that it shows significant in vitro cytotoxic activity against a number of tumor cell lines, including human lung A549, brain U373, and breast MCF-7 [112],... 

In view of this interest, studies have been initiated directed toward a total synthesis of 104 [113]. As shown in Scheme 33, the key intermediate iV-SES-protected 2,6-dihydro-l//-pyridin-3-one underwent a [4+2] high pressure Diels-Alder condensation with butadiene to give a ketoazadecaline derivative, which was further manipulated to give the madangamine tricyclic core via application of the palladium-promoted aza-Claisen methodology. 

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. 

Madangamine A (13) (Fig. 3), which was isolated from Xestospongia ingens by Andersen et al. in 1994, has a 2,6-diazatricyclo[6.2.2.0 ]dodecane skeleton [41,42]. Weinreb prepared this skeleton from a cis-fused hydroisoquinoline derivative (33) by amino-merculation [43]. Diels-Alder reaction [43],... 

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). 

Murahashi s protocol d of the palladium-mediated aza-Claisen rearrangement in the course of the synthesis of madangamine A. d ... 

Stereoselective allylation can be accomplished using in situ aza-Cope rearrangement. The bicyclic compound 35, which is a precursor of Madangamine A, was treated with... 

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. 

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