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Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines.
Silva, Ana Flávia Candida; Martins, Francisco A; Freitas, Matheus P.
Afiliación
  • Silva AFC; Department of Chemistry, Institute of Natural Sciences, Federal University of Lavras, 37200-900, Lavras, MG, Brazil.
  • Martins FA; Department of Chemistry, University of Houston, Houston, TX, USA.
  • Freitas MP; Department of Chemistry, Institute of Natural Sciences, Federal University of Lavras, 37200-900, Lavras, MG, Brazil.
Beilstein J Org Chem ; 20: 1572-1579, 2024.
Article en En | MEDLINE | ID: mdl-39015619
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 nN→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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Beilstein J Org Chem Año: 2024 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Alemania

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Beilstein J Org Chem Año: 2024 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Alemania