Synthesis of the C1-C28 portion of spongistatin 1 (altohyrtin A)

A synthetic approach was developed to the C1-C28 subunit of spongistatin 1 (altohyrtin A, 65). The key step was the coupling of the AB and CD spiroket al moieties via an anti-aldol reaction of aldehyde 62 and ethyl ketone 57. The development of a method for the construction of the AB spiroketal fragm ent is described and included the desymmetrization of Ct-symmetric diketone 10 and the differentiation of the two primary alcohols of 16. Further elab oration of this advanced intermediate to the desired aldehyde 62 included a n Evans' syn-aldol reaction and Tebbe olefination. The synthesis of the CD spiroketal fragment 56 involved the ketalization of a triol-dione, generate d in situ by deprotection of 45, to provide a favorable ratio (6-7:1) of sp iroketal isomers 46 and 47, respectively. The overall protecting group stra tegy, involving many selective manipulations of silyl protecting groups, wa s successfully developed to provide the desired C1-C28 subunit of spongista tin 1 (altohyrtin A) (65).