NEW APPROACH TO ENANTIOPURE OXYGEN HETEROCYCLES

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A wide variety of heterocyclic compounds, including compounds such as morpholines, dihydropyrans, and dihydrofurans have been shown to have important biological activities. This proposal describes a new approach to the synthesis of enantiopure heterocycles which contain an oxygen in the heterocyclic ring. This new synthetic approach is based on a method for the catalytic asymmetric addition of alkyltitanium reagents to achiral acetals. The addition to providing a new route to chiral secondary and tertiary alcohols, this method provides a new route to enantiopure heterocycles if cyclic acetals are used as substrates; the alcohol products resulting from the addition to the acetal may be further transformed to heterocycles. This proposal details the development of the asymmetric addition methodology with respect to substrate scope, catalyst development, and optimization of the reaction conditions. General strategies which could be used to transform the addition products into heterocycles are described. These strategies are then applied to the synthesis of the biologically active heterocycles SR 144190 (a NK-1 inhibitor), Mangone- A (a PAF antagonist), and Sesaminone (an antibiotic).