Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines.

ABSTRACT: Selective fluorination of the pyrrolidine ring in proline motifs has been found to induce significant conformational changes that impact the structure and biological roles of modified peptides and proteins. Vicinal difluorination of fluoroproline, for example, in (3S,4R)-3,4-difluoroproline, serves to mitigate the inherent conformational bias of the pyrrolidine ring by inducing stereoelectronic effects that attenuate this conformational bias. In this investigation, we present a quantumchemical analysis of the conformational equilibrium and effects that are induced in difluorinated pyrrolidines, with a particular focus on exploring the impact of gauche and anomeric effects on the conformer stabilities of different stereo- and regioisomers. Initially, we conducted a benchmark assessment comparing the optimal density functional theory method with coupled cluster with single and double excitations (CCSD) calculations and crystallographic data using the 3-fluoropyrrolidinium cation and 3-fluoropyrrolidine. Subsequently, we explored the relative energy of all favored conformations of all different stereoisomers of 2,3-, 2,4-, and 3,4-difluoropyrrolidines at the B3LYP-D3BJ/6-311++G** level. A generalized anomeric effect, arising from n_N→σ*_CF electron delocalization, is particularly important in modulating the energetics of the α-fluoro isomers and imparts a strong conformational bias. In contrast, the fluorine gauche effect assumes a secondary role, as it is overshadowed by steric and electrostatic interactions, referred to as Lewis interactions from a natural bond orbital perspective.

SUBMITTER: Silva AFC 

PROVIDER: S-EPMC11250193 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature