A versatile route towards 6-arylpipecolic acids

Abstract

Pipecolic acid is known as a non-proteinogenic amino acid with a secondary amine. It contains a six-membered ring and is, like its five-membered correlate, known for its secondary structure inducing properties, which are particularly useful in the design of peptide conformations. We present a new and improved way to generate enantiomerically pure pipecolic acid derivatives with aryl modifications in C⁶ position by utilising the chiral pool of a non-proteinogenic amino acid in combination with transition metal-catalysed cross-coupling reactions. Moreover, we present an in-depth NMR analysis of the key intermediate steps, which illustrates the conformational constraints in accordance with coupling constants and resulting dihedral angles.

Keywords: Suzuki–Miyaura cross-coupling; conformational restraints; dihedral angle NMR; half-chair conformation; modified amino acids; pipecolic acid; stereoselective hydrogenation.

Scheme 1

ᴅ-2-Aminoadipic acid (1) can be used to generate C⁶ aryl and alkynyl-modified pipecolic acid derivatives.

Scheme 2

Methyl ester formation, followed by cyclization, N-formylation, as well as bromination under Vilsmeier–Haack conditions.

Scheme 3

Suzuki–Miyaura cross-coupling reaction between bromide 2 and a variety of boronic acids 8.

Scheme 4

Reaction of 3a to (2R,6S)-9a and (2R,6R)-9a. The chromatograms prove the simple diastereoselection.

Figure 1

The minor diastereomer of the catalytic hydrogenation was assigned as (2R,6R)-9, based on the analysis of the coupling constants for H² and H⁶.

Figure 2

¹H NMR spectra with both signal sets for the chair and half-chair configuration as well as Newman projection for both protons H² and H⁶ with corresponding dihedral angles ϕ for a) (2R,6S)-9, b) saponification product (2R,6S)-10.

Figure 3

¹H NMR spectra with signal set for the chair configuration as well as Newman projection for both protons H² and H⁶ with corresponding dihedral angles ϕ for deformylated product (2R,6S)-11 with one signal set.

Scheme 5

a) Sonogashira–Hagihara cross-coupling reaction followed by b) NaBH₃CN reduction of the N-acyliminium species and c) deprotection.

Figure 4

¹H NMR with Newman projection for both protons H² and H⁶ with corresponding dihedral angles ϕ for a) both signal sets of two half-chair conformations for (2R,6S)-13 and b) for the chair conformations of (2R,6R)-13.

Scheme 6

Overview of reduction and deprotection to the final pipecolic acid derivatives (2R,6S)-5.