Milbemycins spiroketal portion

A more recent example of a functionalized alkyne addition can be seen in Crimmin s synthesis of tala-romycin A (equation 42). ° This particular alkynide is an equivalent of the formyl acetone dianion and its use has been generalized as an entry into the spiroketal portion of the milbemycins (Scheme 20). This approach differs from the Hanessian strategy in that formation of the C(17> (21) pyran ring is constructed last, through use of the alkynic unit. 

The diene pcntions of avermectin and milbemycin have been synthesized by application of the Julia coupling. For the total synthesis of milbemycin 3s by Baker and coworkers, the aromatic ring was incorporated as the aldehyde (431) and the spiroketal portion added as the sulfone (430 equation 100). The overall yield was 70-80% of the ( , )-alkene (432), exclusively. The identical bond disconnection was studied by Kocienski, but with the aldehyde (433) and sulfone (434) components reversed (equation 101). The anion was formed with LDA and, following functionalization and reductive elimination, the alkene was isolated in 39% yield in a 5 1 ratio of the ( )- and (Z)-isomers (435). 

Cover picture The molecule depicted on the cover is (+)-milbemycin pa along with its electrostatic isopotential surface. Milbemycin was chosen because the spiroketal portion of the structure was synthesized from both malic and tartaric acids. 

The milbemycins are a family of 16 membered lactones produced by Streptomyces hygroscopicus. The structures are character zed By a b.b spiroketal unit, a side chain with eight carbon atoms, and a complex cyclohexene carboxylic acid. A synthetic route for the spiroketal and connecting chain, and an approach to a southern portion analog via Diels Alder Chemistry are described. 

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