Alkyl Substituent Effects on Pipecolyl Amide Isomer Equilibrium: Efficient Methodology for Synthesizing Enantiopure 6-Alkylpipecolic Acids and Conformational Analysis of Their N-Acetyl N'-Methylamides.
Enantiopure 6-alkylpipecolic acid hydrochlorides 1a-e were synthesized in five steps and 15-59% overall yields from alpha-tert-butyl beta-methyl N-(PhF)aspartate (3) via an approach featuring selective hydride reduction to the corresponding aspartate beta-aldehyde 2, aldol condensations with the enolates of various methyl alkyl ketones, and diastereoselective intramolecular reductive aminations. The influence of the 6-position substituent on the equilibrium and the energy barrier for isomerization of the amide N-terminal to pipecolate was then explored via the synthesis of N-acetyl N'-methylpipecolinamide (16) and its (2S,6R)-6-tert-butylpipecolinamide counterpart 17, and their conformational analysis by proton NMR spectroscopy and coalescence experiments. The presence of the tert-butyl substituent augmented the population of the amide cis-isomer and lowered the barrier for pipecolyl amide isomerization in water. Compared with the results from our previous examination of N-acetyl-5-tert-butylproline N'-methylamides (Beausoleil, E.; Lubell, W. D. J. Am. Chem. Soc. 1996, 118, 12902), the consequences of the bulky 6-alkyl substituent on the acetamide geometry and isomerization barrier were less pronounced in the pipecolate series relative to the respective proline amides.
Swarbrick
Martin E.
ME
Département de chimie, Université de Montréal C. P. 6128, Succursale Centre Ville, Montréal, Québec, Canada H3C 3J7.
Gosselin
Francis
F
Lubell
William D.
WD