Milbemycin synthesis: synthesis of a macrocyclic analogue of non-aromatic β-milbemycins

Abstract

Stereoselective base-catalysed addition of the keto ester 15 and 3-methylbut-3-en-2-one gave the hydroxycyclohexanone 16. Reduction and methylation gave the monomethyl ether 23, which was regioselectively converted into the butenolide 25 by oxidation using bromine in methanol and hydrolysis of the mixture of intermediate dimethoxydihydrofurans 24. Bromination of the butenolide 25 followed by hydrolysis gave the hydroxybutenolide 40 which was condensed with the ylide generated from the phosphonium salt 62 to give the conjugated dienes 63 and 64. Treatment with a trace of iodine induced (Z)- to (E)-isomerisation of the 10,11-double bond, and ester exchange under basic conditions with 2-(trimethylsilyl) ethanol followed by esterification with diazomethane gave the diesters 67 and 70. Deprotection gave a mixture of the hydroxy acids 71 and 72, and the hydroxy acid 71 was cyclised to give the macrolide 73. Reduction of the methyl ester gave the alcohol 74, a macrocyclic analogue of non-aromatic β-milbemycins.