Bradley, Adrian; (1997) A novel approach to steganone analogues via metal-mediated cyclisations. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Transition metal mediated cyclisation reactions are utilised in the synthesis of analogues of the naturally-occurring antileukemic bisbenzocyclooctadiene lignan, steganone. The first approach involves the metal-mediated [2+2+2] cycloaddition of a rationally designed linear 1,9-diyne with a hindered alkyne. This diyne is formed via a convergent synthetic sequence starting from 3,4,5-trimethoxybenzaldehyde and paraconic acid. The cyclisation reaction proceeds diastereospecifically to give the atropisomer relevant to the natural product. The cycloadduct thus formed has been elaborated to give several novel analogues of steganone. The reaction of this diyne and a model diyne with a chromium carbenoid complex is investigated. This methodology is found to be unsuitable to the formation of this ring system. A family of macrocycles is postulated, in which one aryl ring present in steganone is replaced with an enediyne moiety. It is suggested these will furnish steganone analogues after Bergman cycloaromatisation. A number of approaches to this class of compound are described. Several advanced linear macrocycle precursors are synthesised, and their metal-mediated cyclisation reactions are investigated. The final approach to steganone analogues involves cascade carbopalladation of a linear bromoenyne. This bromoenyne is synthesised via a similar synthetic sequence to the diyne previously mentioned. The co-cyclisation of this bromoenyne with trimethylsilylethyne under conditions of palladium catalysis is investigated.

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