Synthesis of Spirocyclohexene-pyrrolidone alkaloids

Abstract

In this thesis, synthetic studies of biologically active spirocyclic alkaloids are discussed. The selected targets contain common structural feature, namely spiro[cyclohexane-pyrrolidine]. The selected targets are immunosuppressive FR901483, homolog of cytotoxic cephalotaxine, and aryl analog of lepadiformine C, a potential cardiovascular drug. The common structural feature can be synthesized in diastereoselective fashion using chiral pool starting material L-asparagine which was converted to N-alkylsuccinimide. Grignard addition to the succinimide with in situ generated pentenylmagnesium bromide gave the corresponding g-pentenyl-g-hydroxylactam. This intermediate underwent acid-promoted spirocyclization to give spiro[cyclohexane-pyrrolidone] in highly diastereoselective fashion. The cyclized product could be used as synthetic precursor for construction of the polycyclic core of the target molecules with formation of additional ring between the cyclohexene and the N-alkyl group.

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