Synthesis of constrained prolines by Diels–Alder reaction using a chiral unsaturated oxazolone derived from (R)-glyceraldehyde as starting material

This report describes a new route for the asymmetric synthesis of enantiomerically pure 2-substituted 7-azabicyclo[2.2.1]heptane-1-carboxylic acids, which are new conformationally constrained β-functionalised proline analogues. Our strategy is based on the preparation of a valuable azabicyclic intermediate by a key step that involves the intramolecular cyclisation of a derivative obtained from the transformation of the adducts provided by the asymmetric Diels–Alder reaction of a chiral oxazolone derived from (R)-glyceraldehyde with Danishefskyʹs diene. The application of this procedure to the synthesis of (1S,2R,4R)-7-azabicyclo[2.2.1]heptane-1,2-dicarboxylic acid and (1S,2R,4R)-2-propyl-7-azabicyclo[2.2.1]heptane-1-carboxylic acid hydrochlorides, which can be also considered as l-aspartic acid and l-norleucine analogues respectively, is useful to illustrate the versatility of our methodology.