Preparation of Intact Hexahydrobenzofuran Subunits of Ivermectin by Selective Ozonolysis of the Δ3,4‐Intermediate Secoester

Abstract

AbstractAvermectins, and especially their semi‐synthetic partial hydrogenation adduct Ivermectin, constitute a potent endectocide family of worldwide veterinary use that has been known for more than twenty years and has also demonstrated a great efficacy in the treatment of various human filariasis diseases. In a program to design new access to cost‐effective analogues with a new or optimised medical profile, we decided to develop a practical synthetic strategy starting from southern subunits cut from commercial Ivermectin, which is now easily available at a reasonable price. We describe here the first process for preparing intact hexahydrobenzofuran subunits by controlled degradation of Ivermectin in a basically three‐step process that totally preserves the integrity of the Δ3 unsaturated pattern of the unit, which is a requisite feature for the biological activity of this family of molecules. The two crucial steps of the sequence, developed here on a gram scale, involve a transesterification reaction in the presence of titanium(IV) alkoxide that allows the macrolactone opening without isomerisation in 55–70 % yields, followed by the selective ozonolysis of the C10–C11 double bond in the presence of different reducting agents to afford the expected southern unit in reasonable yields. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)