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Highly Diastereo‐ and Enantioselective Aldol Reactions in Common Organic Solvents Using N ‐Arylprolinamides as Organocatalysts with Enhanced Acidity
Author(s) -
Moorthy Jarugu Narasimha,
Saha Satyajit
Publication year - 2009
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.200800960
Subject(s) - chemistry , stereocenter , electrophile , enantioselective synthesis , aldol reaction , amide , steric effects , aryl , hydrogen bond , ring (chemistry) , cyclohexanone , aldehyde , medicinal chemistry , stereochemistry , catalysis , organic chemistry , molecule , alkyl
A broad set of N ‐arylprolinamides 1 – 8 with increasing NH acidity and steric crowding has been synthesized and its catalytic activity explored for enantioselective aldol reactions. In DMF containing 10 mol‐% of TFA, all arylamides are found to catalyze the reaction between cyclohexanone and a variety of electrophilic aldehydes leading to aldols in excess of 90 % yield and >95 % enantioselectivity. The perfluorophenyl catalyst 8 is found to perform best with a broad substrate scope as compared to all other N ‐arylamides 1 – 7 . It is shown that 8 can indeed be employed in highly nonpolar as well as polar solvents including brine to afford high yields of aldols with excellent diastereo‐ as well as enantioselectivity. The results observed for 8 are amongst the best reported so far for prolinamides that do not contain additional stereogenic center(s) and hydrogen‐bonding site(s). The molecular structures of 7 and 8 , determined by X‐ray crystallography and presumed to reflect the most stable conformations, reveal a notable difference in the conformations of the N ‐aryl rings; the aryl ring exhibits tendency to lie coplanar with the amide functionality in the case of 7 , while the perfluorophenyl ring twists almost orthogonally with respect to the plane of the amide of functionality in 8 . The superior performance of the latter is attributed to, in addition to the enhanced NH acidity, the tendency of the perfluorophenyl ring to lie orthogonally to the amide group, which may facilitate a stronger binding of the electrophilic aldehyde via hydrogen bonding in the transition state.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)