An Efficient Synthesis of the Optical Isomers of Nipradilol

An efficient synthesis of all four optical isomers of nipradilol has been achieved. Thus, 8-methoxy-3-chromanone was reduced enantioselectively with baker's yeast to afford (3R)-8-methoxy-3-chromanol, which, after derivation to (3R)-8-acyloxy-3-chromanol, was led to (3S)- or (3R)-8-hydroxy-3-chromanyl nitrate (7 or 9) by selecting a reaction with retention (using acetyl nitrate) or inversion (using Bu4N+NO3-) of configuration. Futher, (3S)- and (3R)-8-methoxy-3-chromanol, prepared via chemical resolution of 8-methoxy-3-chromanyl N-mesyl-L-phenylalanylate, were also led to 7 or 9 in the same manner. Using 7 and 9, four optically active glycidyl ether derivatives (11-14) were synthesized by using a novel Me4N+Cl--catalyzed etherification reaction of phenol with (S)- and (R)-epichlorohydrin. Subsequent amination of 11-14 with isopropylamine afforded the four optical isomers of nipradilol.