Stereodivergent Approach to the Avermectins Based on “Super Silyl” Directed Aldol Reactions

ABSTRACT: A stereodivergent approach to the spiroketal fragment of the avermectins is described. The strategy utilizes a sequence of three aldol reactions directed by the tris(trimethylsilyl)silyl “super silyl ” group. Central to this strategy is that each aldol reaction can be controlled to allow access to either diastereomer in high stereo-selectivity, thereby affording 16 stereoisomers along the same linear skeleton. The aldol products can be transformed into spiroketals, including an advanced intermediate in the total synthesis of avermectin A1a. Since their discovery in 1978, the avermectins have held aprominent place in natural products chemistry, as they have become some of the most widely used polyketide-derived therapeutics to date.1−3 Over the past 20 years, avermectin-based anthelmintics donated by Merck have been used to treat over 80 million cases of onchocerciasis in the developing world.4 In addition, the avermectins have found widespread use in veterinary medicine and as anti-insecticides in crop protection.