Chiral 2-endo-substituted 9-oxabispidines: novel ligands for enantioselective copper(II)-catalyzed Henry reactions.

A flexible approach, applicable on a gram scale, to chiral 2-endo-substituted 9-oxabispidines was developed. The key intermediate, a cis-configured 6-aminomethylmorpholine-2-carbonitrile, was prepared from (R)-3-aminopropane-1,2-diol and 2-chloroacrylonitrile. The 2-endo substituent was introduced by Grignard addition, cyclization, and exo-selective reduction, thus furnishing the enantiomerically pure bi- and tricyclic 9-oxabispidines in 19-59 % yield. The CuCl(2) complex of the tricyclic 9-oxabispidine, which carries an 2-endo,N-anellated piperidine ring, is an excellent catalyst for enantioselective Henry reactions giving the S-configured beta-nitro alcohols in 91-98 % ee (13 examples). Surprisingly, the analogous copper complexes of the bicyclic 9-oxabispidines delivered the enantiocomplementary R-configured products in 33-57 % ee. The respective transition states were discussed.