| Summary: | 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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