Synthesis of (−)-malyngolide using reactions of alkylidenecarbenes

Abstract

An alkylidenecarbene has been generated by the reaction of dimethyl (diazomethyl)phosphonate (DAMP), Bu^tOK and methyl ketone 6, which itself has been derived from D-mannitol in high yield. The carbene undergoes an intramolecular 1,5 C–H insertion reaction to give the chiral cyclopentane derivative 3 in good yield. It has been found that the same conversion can be conveniently carried out on a large scale with lithiotrimethylsilyldiazomethane. The double bond of 3 has been cleaved to give the keto aldehyde 2, which has been subjected to a double C₁ elongation reaction via alkylidenecarbenes using DAMP and K₂CO₃. The resulting alkyne has been alkylated to give an intermediate 11 which has the carbon skeleton of malyngolide. Deprotection of 11, followed by elaboration of the functional groups completes the chiral synthesis of (–)-malyngolide 1.