Asymmetric syntheses of (R)-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines, important 5-HT2C agonist precursors

Abstract Asymmetric syntheses of N -protected ( R )-4-halo-6,6a,7,8,9,10-hexahydro-5 H -pyrazino[1,2- a ][1, n ]naphthyridines, advanced intermediates for the synthesis of highly potent and selective 5-HT 2C agonists, are described. The key transformation involves ring opening of N -protected bicyclic sulfamidate ( R )-hexahydro-3 H -pyrazino[1,2- c ][1,2,3]oxathiazine 1,1-dioxide with (4-halo-2-fluoropyridin-3-yl)lithiums or (3-bromo-5-fluoropyridin-4-yl)lithium. In situ hydrolyses of the resultant sulfamic acids and subsequent intramolecular nucleophilic aromatic substitutions (S N Ar) produce the enantiopure tricycles. The two step procedure represents new methodology for the stereoselective syntheses of tetrahydronaphthyridines.