Total synthesis of (+)-milbemycin (β3)

Abstract

The total synthesis of (+)-milbemycin β₃, has been achieved in two ways beginning from the appropriate spiroacetal moiety. In the first, coupling of a vinyl-lithium derivative (18) with the spiroacetal aldehyde (19), available from Swern oxidation of the corresponding alcohol generated the C(11)–C(25) segment of milbemycin β₃. Removal of the allylic hydroxy group was achieved by tributyltin hydride reduction of the dithiocarbonate although a mixture of two double-bond isomers was obtained. In an alternative and superior approach the C(14)–C(15) trisubstituted double-bond of milbemycin β₃, was established by reaction of a Wittig reagent with the spiroacetal aldehyde (19). The product of this reaction, after conversion into the iodide and enantiospecific alkylation to generate the 12-methyl group, was further elaborated to the same C(11)–C(25) segment prepared previously. The aromatic portion of milbemycin was incorporated by the Lythgoe-Kocienski modification of the Julia reaction involving reaction of a sulphone anion and an α,β-unsaturated aldehyde followed by reductive elimination to generate the C(8)–C(10) diene system. Final macrocyclisation followed essentially established procedures.