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A Computational Study of the Stereoselective Decarboxylation in the Synthesis of Naproxen
Author(s) -
Drees Markus,
Kleiber Lillian,
Weimer Martin,
Strassner Thomas
Publication year - 2002
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 - 10.1002/1099-0690(200207)2002:14<2405::aid-ejoc2405>3.0.co;2-1
Subject(s) - chemistry , decarboxylation , protonation , enantioselective synthesis , stereoselectivity , enantiomer , naproxen , quantum chemical , stereochemistry , computational chemistry , medicinal chemistry , organic chemistry , catalysis , molecule , ion , alternative medicine , pathology , medicine
The antiinflammatory drug Naproxen has been synthesized via several enantioselective routes. The recently published synthesis involving the asymmetric decarboxylation of 2‐cyano‐2‐(6‐methoxy‐naphth‐2‐yl)propionic acid (H. Brunner, P. Schmidt, Eur. J. Org. Chem. 2000 , 2119) was investigated by quantum‐chemical calculations. It was found that the stereochemistry of the products was determined by a concerted protonation/decarboxylation reaction. According to quantum‐chemical gas‐phase calculations, C−H ··· O and N−H ··· O interactions between the chiral base and the substrate in the transition state stabilize the ( S ) enantiomer by 3.7 kcal/mol. The postulated planar ketenimine anion intermediate could be ruled out on the basis of B3LYP/6‐31G(d) calculations. (© Wiley‐VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)