A STEREOCONTROLLED ALKYLATION OF CHIRAL PYRIDINIUM SALTS WITH GRIGNARD-REAGENTS - SYNTHESIS OF (+)-NORMETAZOCINE AND (+)-NORDEXTRORPHAN

The synthesis of chiral pyridinium salts 3, bearing lipophilic counteranions, is described. These salts, soluble in THF or toluene, undergo nucleophilic alkylation with benzylic Grignard reagents to give, after reduction of the unstable dihydropyridine intermediates, adducts 4 with regio- and stereoselective attack at position 2, the observed stereoselectivity ranging from 8:1 to 12.5:1. These results allowed an asymmetric synthesis, following Grewe's route, of (+)-normetazocine and (+)-nordextrorphan, key precursors of various benzomorphan or morphinan drugs.