Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines.

Vladimir Kubyshkin

doi:10.3762/bjoc.16.151

Abstract

Fluorine-containing analogues of proline are valuable tools in engineering and NMR spectroscopic studies of peptides and proteins. Their use relies on the fundamental understanding of the interplay between the substituents and the main chain groups of the amino acid residue. This study aims to showcase the polarity-related effects that arise from the interaction between the functional groups in molecular models. Properties such as conformation, acid–base transition, and amide-bond isomerism were examined for diastereomeric 4-fluoroprolines, 4-(trifluoromethyl)prolines, and 1,1-difluoro-5-azaspiro[2.4]heptane-6-carboxylates. The preferred conformation on the proline ring originated from a preferential axial positioning for a single fluorine atom, and an equatorial positioning for a trifluoromethyl- or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pKa values, lipophilicity, and the kinetics of the amide bond rotation. The study also provides a set of evidences that the transition state of the amide-bond rotation in peptidyl-prolyl favors C4-exo conformation of the pyrrolidine ring.

Highlights

Polarity is among the key features essential for understanding the behavior of organic molecules of biological origin
The classification of the amino acid residues by hydrophobic/hydrophilic usually refers to the variable part, which locates in the side chain
It has been shown that fluoroprolines can alter donor–acceptor interactions of the proline ring with a tryptophan residue [59]. All these findings indicate that polarity effects should be taken into account in the characterization of proline analogues containing fluorinated groups

Summary

Introduction

Polarity is among the key features essential for understanding the behavior of organic molecules of biological origin. There is a set of polarity-related issues in the chemistry of amino acids, while the latter are key actors in multiple biochemical processes. For example, 20 (+2) amino acids are utilized for polymerizing them into a primary structure of a protein. Most of these structures share the same key elements with the structure of alanine, which constitute the backbone features. The classification of the amino acid residues by hydrophobic/hydrophilic usually refers to the variable part, which locates in the side chain. The introduction of an aliphatic or an aromatic group into the side chain usually renders an amino acid hydrophobic, while the introduction of a polar or an ionizable group makes it hydrophilic

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Conclusion