Conformational Properties of a Peptidic Catalyst: Insights from NMR Spectroscopic Studies

Abstract

Peptides have become valuable as catalysts for a variety of different reactions, but little is known about the conformational properties of peptidic catalysts. We investigated the conformation of the peptide H-dPro-Pro-Glu-NH, a highly reactive and stereoselective catalyst for conjugate addition reactions, and the corresponding enamine intermediate in solution by NMR spectroscopy and computational methods. The combination of nuclear Overhauser effects (NOEs), residual dipolar couplings (RDCs), J-couplings, and temperature coefficients revealed that the tripeptide adopts a single predominant conformation in its ground state. The structure is a type I β-turn, which gains stabilization from three hydrogen bonds that are cooperatively formed between all functional groups (secondary amine, carboxylic acid, amides) within the tripeptide. In contrast, the conformation of the enamine intermediate is significantly more flexible. The conformational ensemble of the enamine is still dominated by the β-turn, but the backbone and the side chain of the glutamic acid residue are more dynamic. The key to the switch between rigidity and flexibility of the peptidic catalyst is the COH group in the side chain of the glutamic acid residue, which acts as a lid that can open and close. As a result, the peptidic catalyst is able to adapt to the structural requirements of the intermediates and transition states of the catalytic cycle. These insights might explain the robustness and high reactivity of the peptidic catalyst, which exceeds that of other secondary amine-based organocatalysts. The data suggest that a balance between rigidity and flexibility, which is reminiscent of the dynamic nature of enzymes, is beneficial for peptidic catalysts and other synthetic catalysts.

Catalysis-Enabled Access to Cryptic Geldanamycin Oxides

“…C (32) 116 (15) 115 (16) 114 15-1 628 71 6C (33) 190(20) 150 (40) 60 2020 (30) 40 (18) 40 20C (34) 210 (30) 210 (30) 210 (30) 0 (6) 55 101 6C (35) 240 (30) 210 50190 4020 (40) 100 (30) 60 30C (36)…”

4‐Naphthylmethyl Proline Forms a Channel Structure

“…Supporting information for this article is available on the WWW under https://doi.org/10.1002/hlca.201900052 Our research group has been using the unique structural and functional properties of proline and proline derivatives bearing substituents at C(γ) for applications in chemical biology, supramolecular chemistry, and asymmetric catalysis. [5,[12][13][14][15][16][17] Recently, we became interested in peptides containing methylaryl substituents at C(γ) for their value as selective binders of the bacterial second messenger c-di-GMP. [18] Specifically, peptides consisting of cationic residues and (2S,4R)-4-[(naphthalen-2-yl)methyl]proline exhibit excellent binding affinity and selectivity towards c-di-GMP.…”

Effect of β3‐Amino Acids on the Performance of the Peptidic Catalyst H‐dPro‐Pro‐Glu‐NH2

“…[19] Recently, we analyzed the conformation of the ground state catalyst H-DPro-Pro-Glu-NH 2 and the respective enamine intermediate. [21] [22] NMR Spectroscopic studies showed that the peptide adopts a single predominant conformation in its ground state. This structure is a type I β-turn, which is stabilized by three hydrogen bonds that are formed cooperatively between all functional groups -the secondary amine, the carboxylic acid, and the amide groups (Scheme 1,a).…”

“…This structure is a type I β-turn, which is stabilized by three hydrogen bonds that are formed cooperatively between all functional groups -the secondary amine, the carboxylic acid, and the amide groups (Scheme 1,a). [22] The conformation of the enamine intermediate is more flexible as revealed by NMR spectroscopic and computational studies. A β-turn is still the dominant structure but the interaction of the CO 2 H group with the N-terminal amine is broken up.…”

“…The data suggests that this interplay between rigidity, which is inscribed in the DPro-Pro motif, and flexibility of the peptidic catalyst is important for its high reactivity and stereoselectivity. [22] β 3 -Amino acids are homologues of α-amino acids with an additional methylene group next to the carboxylic acid moiety and thus an additional degree of freedom around the θ dihedral angle (Scheme 1,b). Incorporation of β 3 -amino acids into α-peptides affects their conformational properties.…”