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UBC Theses and Dissertations

A synthetic approach to the variecolin class of sesterterpenoids : total syntheses of (+-)-5-deoxovariecolin, (+-)-5-deoxyvariecolol and (+-)-5-deoxyvariecolactone. A new cyclopheptenone annulation method employing the bifunctional reagent (Z)-5-iodo-1-tributylstannylpent-1-ene Walker, Shawn Duane

Abstract

The syntheses of three structurally related substances, (±)-5-deoxovariecolin (204), (±)-5-deoxyvariecolol (93) and (±)-5-deoxyvariecolactone (226) are described as part of a general synthetic strategy toward the variecolin class of sesterterpenoids (48-52). Thus, the known Grignard reagent 99 was combined with 3-methylcyclohex-2-en-l-one (95) in a two step cyclopentene annulation sequence to provide 98. Conjugate addition of cuprate 107 to the enone 98 followed by an epimerization step provided ketone 44 with the correct relative configuration set at three stereogenic centers. Application of a novel cycloheptenone annulation protocol employing the bifunctional reagent 53 furnished the tricyclic intermediate 59. A sequence consisting of dissolving metal reduction and a 1,2-carbonyl transposition provided the ketone 129. A regioselective ring expansion of 129 provided the cyclooctenone 60. The latter was converted to the tetracyclic ketone 61 through an efficient methylenecyclopentane annulation featuring reagent 190. Ketone 61 was further elaborated to the ester 94 through a series of reactions including a palladium-catalyzed methoxycarbonylation. A chemo- and stereoselective double bond hydrogenation and subsequent carbonyl group reduction transformed 94 to the alcohol 203. Oxidation of the alcohol function of 203 provided 204. A key remote functionalization step converted 203 to 93. Chemoselective allylic oxidation of 93 produced 226, a critical intermediate for future synthetic studies. In the second part of the thesis, the generality of the newly developed cycloheptenone annulation sequence was explored. Thus, alkylation of A^N-dimethylhydrazones of general structure 261 with the bifunctional reagent 53 followed by iododestannylation and hydrolysis of the hydrazone function provided keto alkenyl iodides 262. Butyllithium mediated cyclization of 262 and oxidative rearrangement of the resultant allylic alcohols 57 provided the cycloheptenones 58. The annulation method was also extended to cyclic P-keto ester substrates. The individual reactions involved are experimentally straightforward and the overall yields of the annulation processes are good to excellent.

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