Synthesis of chiral 2-(2′-pyrrolidinyl)pyridines from (S)- and (R)-proline:: potential ligands of the neuronal nicotinic acetylcholine receptors

A new strategy for a straightforward synthesis of novel optically active nicotine analogues starting from (S)- and (R)-proline is reported utilizing as the key steps the inverse electron demand Diels-Alder reaction of, hitherto unknown, chiral 5-(2'-pyrrolidinyl)-1,2,4-triazines (S)- and (R)-16. These serve as appropriate precursors for the preparation of different, highly enantiomerically enriched 2-(2'-pyrrolidinyl)pyridines, modifications of natural (-)-nornicotine and (-)-nicotine and potential ligands of the neuronal nicotinic acetylcholine receptors. The multistep syntheses proceed under mild conditions, with good overall yields and with stereochemical integrity of the original stereogenic centers. (C) 1999 Elsevier Science Ltd. All rights reserved.