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 CuCl2 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. Regarding Henry: The tricyclic 9‐oxabispidine is an excellent ligand for copper(II)‐catalyzed enantioselective Henry reactions; it gives β‐nitro alcohols in up to 98 % ee (see scheme). This diamine and several other bicyclic 2‐endo‐substituted 9‐oxabispidines are available in a few steps from a 2‐cyanomorpholine as the key intermediate.