Gibb, Peter Timothy; (1996) Synthetic approaches towards a total synthesis of colchicine. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis is divided into three chapters. The first chapter provides a review of the fascinating chemistry of the enediynes and related compounds. The triggering systems contained within the structures of the naturally occurring enediyne antibiotics are discussed, as are general methods for the formation of the enediyne moiety itself. Moreover, since one of the key aspects of our approach to colchicine is the formation of a highly unsaturated macrocycle, significant preparative methods for the macrocyclisation of enediynes are briefly reviewed. In the second chapter, a brief account of the occurrence, isolation, biological properties and previous syntheses of colchicine are presented, and then three synthetic approaches are described. The first approach involves the formation and subsequent Cope rearrangement of a functionalised dialkynylcyclopropane, for which preliminary studies on the formation of the cyclopropane via a Fischer carbene are presented. The second approach involves a novel [5+2] cycloaddition reaction for the formation of the tropolone C-ring. Although the synthesis of a suitably functionalised pentadiene model is described, attempts to construct a precursor containing all of the requisite functionality were unsuccessful. The third approach, to which most of the work was directed, involves the cycloaromatisation of a 12-membered macrocycle containing an enediyne ketone via a novel variant of the Bergman cyclisation. The synthesis of a 12-membered macrocycle via an intramolecular Noyori-type aldol reaction is described, but formation of the unsaturated macrocycle proved elusive. The third chapter provides a formal description of experimental results and procedures.

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