Synthesis of a model of the spiroketal portion of avermectin B Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/9p290c81m

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  • Avermectin Bia is a member of a class of medicinally important natural products known for its potent antiparasitic activity and interesting structural features. In this thesis, synthesis of a model for the spiroketal portion of the avermectins is presented. Oxidation of (S)-2-methylbutanol, followed by a stereoselective chromium mediated reaction with crotyl bromide, gave (3S,4R15S)-3,5- dimethy1-1-hepten-4-ol as the major isomer. After investigating a variety of protecting groups, the alcohol was masked as a t- butyldimethylsilyl ether and subsequent ozonolytic cleavage of the vinyl group afforded the corresponding aldehyde. Reaction of this aldehyde with carbon tetrabromide and triphenylphosphine resulted in its homologation to a dibromoolefin, which underwent elimination with butyllithium to yield (3S,4R15S)-4-t-butyldimethylsiloxy-3 5-dimethy1-1- heptyne. Selective protection of the primary alcohol of R-(-)-1,3- butanediol as its 214,6-triisopropylbenzenesulfonate, followed by the acetylation of the secondary alcohol, provided (2R)-4-(2,416- triisopropylbenzenesulfonyloxy)-2-acetoxybutane. The latter was converted to the corresponding iodide which, when treated with lithium diisopropylamide, cyclized to (R)-S-caprolactone. Alkylation of the S-lactone with either the dibromoolefin or the alkyne after treatment with butyllithium, followed by reaction with methanol on Amberlite ion exchange resin, gave (2RS16R)-2- [(3S,4R15S)-4-t-butyldimethylsiloxy-3,5-dimethyl-l-heptynyl]-2-methoxy -6-methyltetrahydropyran. Deprotection, and then Lindlar hydrogenation of this compound with an acidic workup led to the formation of the target compound (2R13S16R18R)-318-dimethy1-2f(1S)-1-methylpropy11- 1,7-dioxaspiro[5.5]undec-4-ene.
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