Total synthesis of milbemycin E: development of a procedure for the introduction of the 3,4-double bond and synthesis of the C(1)–C(10) fragment

Abstract

Dehydration of the 5-hydroxycyclohexanecarboxylate 13 gives the exocyclic alkene 14 rather than its endocyclic isomer. However, the 3,4-double bond can be introduced into precursors of milbemycin E 1 using oxidative elimination of phenylselanyl ketones. The hydroxycyclohexanones 6 and 31 have been converted into the phenylselanyl ketones 19 and 37, which on oxidative elimination followed by stereoselective reduction give the 3-methylcyclohex-2-enecarboxylates 23 and 40 together with only 10–15% of the exocyclic alkenes 24 and 42. Interestingly, if the oxidative elimination is carried out on the alcohol 25, the 5-methylenecyclohexanecarboxylate 24 is the major product. Conversion of 40 into its benzoate, and oxidation of the furan ring using singlet oxygen, gives the hydroxybutenolide 43 ready for incorporation into a milbemycin synthesis. To test the compatibilty of the cyclohexene double bond with the proposed Wittig reaction, the alcohol 40 has been converted into the tert-butyldimethylsilyl ether 44 and the furan oxidised to give the hydroxybutenolide 45. Condensation with an excess of (2-methylpropylidene)triphenylphosphorane gives the Wittig product which has been isolated as its methyl ester and isomerised using a trace of iodine into the (Z,E)-diene 47.