Yu, Man Tat; (1995) Studies towards the total synthesis of colchicine. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis is divided into three chapters. In the first chapter, brief accounts of the occurrence, isolation and structural determination, biological properties and biogenesis of colchicine are presented. Moreover, since one of the key structural features of colchicine is the tropolonyl ring C, significant preparative methods for tropones and tropolones are briefly reviewed. The general drawbacks of the previous syntheses of colchicine itself due to the tautomeric nature of the tropolonyl ring C are discussed and the key steps of each of the previous syntheses are also highlighted. In the second chapter, the general strategies of the total synthesis of (-)-colchicine employed in this project are discussed and two synthetic approaches are then described. The first approach, to which most of the work was directed, involves the cycloaromatisation of a 12-membered macrocycle containing an enediyne moiety via a Bergman cyclisation. The efforts made towards the synthesis of this macrocycle are divided into two areas, namely the investigations into the generation of the stereocentre and the construction of the macrocyclic framework. Although an advanced acyclic precursor for ring closure containing all of the requisite functionality was prepared, initial cyclisation studies were unsuccessful. The second approach involves a transition metal- mediated [2+2+2] cycloaddition of a tethered diyne and an appropriate cyclopropenone derivative. The synthesis of the diyne precursor and model studies of the [2+2+2] cycloaddition protocol are described. The third chapter provides a formal description of experimental results and procedures.

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