Synthesis of enantiopure analogues of 3-hydroxyproline and derivatives

All four enantiomerically pure 2-hydroxy-7-azabicyclo[2.2.1]heptane-l-carboxylic acids, novel restricted analogues of 3-hydroxyproline, are described. The synthesis starts with the Diels-Alder reaction between methyl 2-benzamidoacrylate and Danishefsky's diene and uses as key steps a base-promoted internal nucleophilic displacement of the methanesulfonate group in the cyclohexane ring, followed by a resolution method that involves formation of diastereomers and further separation by crystallization. This synthetic route allowed us to obtain both enantiomers of the N-Boc-7-azabicyclo[2.2.1]heptan-2-ones. valuable ketones used as precursors of (-)- and (+)-epibatidine and other more interesting analogues. (C) 2002 Published by Elsevier Science Ltd.