Synthetic studies towards the maytansinoids

Hodgson, David Michael (1989) Synthetic studies towards the maytansinoids. University of Southampton, Doctoral Thesis.

Abstract

A synthesis of the C-3 to C-10 eastern fragment of the maytansinoids has been developed. The correct relative stereochemistry at C-6 and C-7 was set via epoxide opening of 1,3-epoxycyclohexene using dimethylmagnesium. Ozonolytic cleavage of the resultant homoallylic alcohol gave a dialdehyde, which underwent a regioselective aldol reaction to provide a suitably functionalised cyclopentene for the key step. In the key step, ozonolytic cleavage of the cyclopentene, followed by in situ Wittig reaction, gave a ketoester in which the correct relative C-9 stereochemistry was subsequently introduced on carbinolamide ring formation. A novel route towards the aromatic portion of the maytansinoids, which uses dichlorocarbene insertion into a cyclopentene followed by ring expansion and aromatisation, has also been developed. Synthetic methodology has also been developed towards the C-11 to C-14 (E,E)-diene fragment of the maytansinoids. In a model study, (E)-3-methyl-4-phenyl-2-butenal was coupled in one pot with iodoform using chromium (II) chloride, followed by catalytic nickel (II) chloride and benzaldehyde (as a model for the eastern fragment) to give a diene with the required (E,E)-geometry. Finally, further synthetic studies on the utility of the eastern fragment in maytansinoid synthesis are discussed.(DX89579)

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