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Efficient Deracemization of Pipecolic Acid Amides through Enantioselective Protonation of Their Lithium Enolates: Insights into the Origin of the Transferred Proton
Author(s) -
Martin Juliette,
Plaquevent JeanChristophe,
Maddaluno Jacques,
Rouden Jacques,
Lasne MarieClaire
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.200900726
Subject(s) - chemistry , enantioselective synthesis , protonation , pipecolic acid , enantiomer , enantiomeric excess , reagent , superbase , lithium (medication) , medicinal chemistry , alkoxide , lithium amide , triflic acid , quenching (fluorescence) , combinatorial chemistry , organic chemistry , catalysis , amino acid , medicine , ion , biochemistry , physics , quantum mechanics , endocrinology , fluorescence
A detailed study of the deracemization of pipecolic acid amides is reported. Enantioselective protonation of the lithium enolates of these amides with use of commercially available ephedrines led to enantiomeric excesses ( ee values) higher than 99 %. The success of the reaction was strongly dependent on the following parameters: the base, the reaction temperature, the structure of the chiral source, and the achiral quenching reagent. s BuLi and the bimetallic base “potassium alkoxide/ n BuLi” were the only bases to allow complete formation of the enolate in conjunction with high stereocontrol of the protonation. Experiments with (+)‐ or(–)‐ephedrine derivatives as chiral sources and deuteriated reagents gave evidence that both the OH and NH protons of ephedrine were involved in the stereoinduction. External delivery of the proton was mainly operative with the aniline derivative (+)‐ 5 , as shown by deuterium labeling experiments, whereas internal quenching was the major pathway observed with ephedrine ( 6 ). Finally, the deracemization procedure was successfully applied to prepare both enantiomers of N ‐protected pipecolic acid from racemic pipecolic acid (51 % overall yield, 99 % ee ).(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)