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Enantioselective 1,3‐Dipolar Cycloaddition Reactions of C ‐Carboxy Ketonitrones and Enals with MacMillan Catalysts: Evidence of a Nonconcerted Mechanism
Author(s) -
Ben Ayed Kawther,
Laurent Mathieu Y.,
Martel Arnaud,
Selim Khalid B.,
Abid Souhir,
Dujardin Gilles
Publication year - 2017
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201701307
Subject(s) - chemistry , cycloaddition , enantioselective synthesis , diastereomer , nitrone , iminium , steric effects , reaction mechanism , stereochemistry , medicinal chemistry , catalysis , organic chemistry
Highly diastereo‐ and enantioselective 1,3‐dipolar cycloadditions between functional ketonitrones and β‐substituted enals are promoted by MacMillan imidazolidinium organocatalysts. A study of the reaction scope shows that high selectivities are conserved if the N‐protecting group or the ester function is varied. However, the reaction is sensitive to steric interactions with the C substituent of the nitrone. In all cases, the reaction proceeds with high exo selectivity. In most cases, a third diastereomer, incompatible with a concerted mechanism, was also observed, albeit in minute amounts. DFT calculations suggest that the cycloaddition proceeds in a nonconcerted fashion by an initial oxa‐Michael‐type addition of the nitrone to the double bond followed by a cyclization. This mechanism explains the formation of the observed minor diastereomers. In addition, the diastereo‐ and enantioselectivities of the reaction were shown to be intermediately thermodynamically controlled, and the diastereomeric ratio is modulated by the kinetics of iminium hydrolysis.