Total synthesis of (+)-milbemycin (β3)

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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.