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 β‐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.