Approach towards C12 oxo analogues of the side chain of pumiliotoxin B/allopumiliotoxin 339A and B

A route towards synthesis of analogues of the pumilotoxin/allopumilotoxin side-chain is described. The C15,C16 diol was introduced by asymmetric dihydroxylation using AD-mix β of C10,C17 eneyneone intermediate 14, or of C13,C17 precursor 17, or by using a chiron-based route from 24. The trisubstituted alkene functionality was established using thioaryl conjugate addition to yneones 16 and 27, followed by a copper-catalyzed stereoretentive reaction with methylmagnesium bromide. The approach enables access to C12 oxo systems and offers an approach towards new C14 analogues.