TOTAL SYNTHESIS OF MILBEMYCIN-E - SYNTHESIS OF THE C(11)-C(25) FRAGMENT

Treatment of 2-methylpropanal with the (E)-but-2-enyl(diisopinocamphey l)borane 9 prepared from (+)-alpha-pinene gives the anti- and syn-prod ucts 10 and 11, ratio 88:12, from which the major anti-isomer 10 is se parated by preparative GLC. Hydroboration-oxidation of its tert-butyld imethylsilyl ether 14 gives the primary alcohol 15 which has been conv erted into the bromide 16 and iodide 17. The propenyl(diisopinocamphey l)borane 23 prepared from (-)-alpha-pinene reacts with the aldehyde 22 prepared from (S)-malic acid to give the anti- and syn-1,3-diol deriv atives 24 and 25, ratio 86:14, and the anti-product 24 has been taken through to the epoxide 31. Sequential alkylation of 1,3-dithiane with the iodide 17 and the epoxide 31 gives the 2,2-dialkyl-1,3-dithiane 33 which is converted into the spiroacetal 4 by treatment with dilute aq ueous hydrogen fluoride. After protection, ozonolysis gives the aldehy de 43 which has been condensed with the ylide 34 to give the alpha,bet a-unsaturated ester 44. This has been reduced and converted into the i odide 46 which has been used to alkylate the chiral oxazolidinone 39 t o give the required C(11)-C(25) fragment 48 of milbemycin E 1 after re ductive removal of the chiral auxiliary. This has been converted into the phosphonium salt 2 ready for Wittig coupling with the hydroxybuten olide 3 for the assembly of the milbemycin nucleus.