Tetrahydro-1,3-oxazin-6-ones as templates for the stereoselective synthesis of β-substituted L-aspartic acids

Abstract

Protected (4S)-4-carboxytetrahydro-1,3-oxazin-6-ones have been synthesised either by Baeyer–Villiger reaction on a 4-ketoproline derivative or, more directly, from an aspartate derivative. Two strategies have been used to develop these compounds as chiral templates in the synthesis of β-substituted aspartic acids. In the first, formation of an enaminone using Bredereck’s reagent, followed by reaction with a Grignard reagent gave a series of alkylidene derivatives which could be reduced from the less hindered side by heterogeneous catalytic hydrogenation to give cis-oxazinones in a completely stereoselective manner. Alternatively, an alkylation strategy, although trans-selective, gave mixtures of isomers. The oxazinones were converted to β-substituted aspartic acids and to regioselectively protected β-substituted aspartic acids without loss of stereochemistry at either centre.