Total synthesis of milbemycin E: synthesis of the C(11)–C(25) fragment

Abstract

Treatment of 2-methylpropanal with the (E)-but-2-enyl(diisopinocampheyl)borane 9 prepared from (+)-α-pinene gives the anti- and syn-products 10 and 11, ratio 88∶12, from which the major anti-isomer 10 is separated by preparative GLC. Hydroboration–oxidation of its tert-butyldimethylsilyl ether 14 gives the primary alcohol 15 which has been converted into the bromide 16 and iodide 17. The propenyl(diisopinocampheyl)borane 23 prepared from (-)-α-pinene reacts with the aldehyde 22 prepared from (S)-malic acid to give the anti- and syn-1,3-diol derivatives 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 aqueous hydrogen fluoride. After protection, ozonolysis gives the aldehyde 43 which has been condensed with the ylide 34 to give the α,β-unsaturated ester 44. This has been reduced and converted into the iodide 46 which has been used to alkylate the chiral oxazolidinone 39 to give the required C(11)–C(25) fragment 48 of milbemycin E 1 after reductive removal of the chiral auxiliary. This has been converted into the phosphonium salt 2 ready for Wittig coupling with the hydroxybutenolide 3 for the assembly of the milbemycin nucleus.