Total Synthesis of Spinosyn A. 1. Enantioselective Construction of a Key Tricyclic Intermediate by a Multiple Configurational Inversion Scheme

Abstract

The condensation of (+)-7,7-dimethoxynorbornen-2-one with the cerium reagent derived from enantiopure bromide (+)- 11 gives rise to an exo carbinol, which readily undergoes highly stereocontrolled anionic oxy-Cope rearrangement. Conversion of the resulting ketone into 20 proceeds with clean epimerization at C-11 (spinosyn numbering) to properly set the absolute configuration at that site. Reduction of 20 with lithium in liquid ammonia serves to introduce two additional stereogenic centers of the perhydro- as -indacene core. In addition, the protocol makes possible the convenient incorporation of a functionalized two-carbon appendage at C-3 and ultimate generation of a cyclohexene double bond after stereochemical inversion at C-7. This scheme leads to 34, a tricyclic compound subsequently shown to be an advanced precursor to the powerful insecticide spinosyn A.