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Chiral 2‐ endo ‐Substituted 9‐Oxabispidines: Novel Ligands for Enantioselective Copper(II)‐Catalyzed Henry Reactions
Author(s) -
Breuning Matthias,
Hein David,
Steiner Melanie,
Gessner Viktoria H.,
Strohmann Carsten
Publication year - 2009
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200901789
Subject(s) - enantioselective synthesis , piperidine , chemistry , substituent , catalysis , tricyclic , yield (engineering) , bicyclic molecule , copper , diol , stereochemistry , medicinal chemistry , ring (chemistry) , organic chemistry , materials science , metallurgy
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.