Alkyl Substituent Effects on Pipecolyl Amide Isomer Equilibrium:  Efficient Methodology for Synthesizing Enantiopure 6-Alkylpipecolic Acids and Conformational Analysis of TheirN-AcetylN‘-Methylamides

Abstract

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.

Cyclopropane Pipecolic Acids as Templates for Linear and Cyclic Peptidomimetics: Application in the Synthesis of an Arg‐Gly‐Asp (RGD)‐Containing Peptide as an αvβ3 Integrin Ligand

“…Although our spectra were recorded in CDCl 3 and some solvent effect cannot be completely ruled out, in our case, the prevalence of the cis isomer could be due to further unfavorable interactions between the α‐Me group and the large, axially oriented, OTIPS group at C‐4 (position δ of the pipecolic amino acid) in the trans isomer. This is in accordance with data reported for N ‐acetyl‐ N ′‐methyl pipecolinamide (in water) in which there is an increase in the cis isomer from 28 to 43 % when the ε position of the pipecolic amino acid bears a tert ‐butyl group 47. Hydrolysis of the ester group provided acid 46 (Scheme ), which was coupled to O ‐benzyl‐protected glycine by using DEPBT as the coupling reagent to afford tripeptide 47 in 84 % yield.…”

“…However, a hydrogen bond between the glycine NH and the alanine CO that forms a seven‐membered cycle should stabilize the trans isomer, too (Figure 6). 47 The deshielded signal assigned to the glycine NH, which resonates at δ =7.2 ppm, is consistent with the presence of this hydrogen bond, whereas in the cis isomer the NH resonates at δ =6.6 ppm. Final removal of the TIPS group provided tripeptide 48 in 58 % yield after chromatography in which the cis / trans isomeric ratio, despite our expectations (owing to the lack of the sterically encumbered 4‐OH protecting group) remained practically unchanged (1:1.2).…”

Degradation of rapamycin and its ring-opened isomer: Role of base catalysis

“…The amide bond isomerization in simple derivatives and short peptides containing L-pipecolic acid has characteristic times within the second range. 32,33 A similar time scale may be expected for the trans → cis isomerization in 2 based on the fact that it is a linear molecule and the process is not energetically prohibited (trans/cis ratio close to 1). Notice that the trans form dominates in rapamycin solutions.…”

Homoserine‐derived cyclic sulfamidate as chiral educt for the diversity‐oriented synthesis of lactam‐bridged dipeptides

“…The configurational assignments for sulfamidites 7 were made on the basis of their proton NMR spectra with comparison to sulfamidate 8 (Figure 2). 17 Saturated N ‐PhF‐amino six‐membered heterocycles such as 7 and 8 adopt normally chair conformations in which the α‐carboxylate and PhF groups are oriented axial and equatorial, respectively 17, 25–29. In the proton spectrum of 8 , the axial cumyl ester singlets (1.95, 2.07 ppm), the C‐6 β‐proton (4.80 ppm), and the PhF resonances (7.20–8.07 ppm) all were shifted downfield because of the anisotropy of the sulfamidate.…”