Abstract

Stereoselective hydride transfer to N5,N10-bridged pterins exhibits opposite facial preferences under enzymatic and non-enzymatic conditions. While enzymatic systems preferentially involve hydride delivery to the face, non-enzymatic reductions with NaBH4 proceed predominantly via the Si face. Here, density functional theory calculations combined with activation-strain analysis and symmetry-adapted perturbation theory are used to investigate the origin of this intrinsic stereochemical preference in non-enzymatic hydride transfer reactions. The results show that noncovalent interactions, particularly repulsive contributions arising from the spatial orientation of the pterinic oxygen, favor hydride attack on the Si face. This preference persists for neutral donor models, indicating that geometric constraints inherent to the pterin scaffold play a central role in shaping the potential energy surface. These findings demonstrate that the non-enzymatic stereochemical outcome is governed by intrinsic electronic and geometric factors, and that alternative selectivities observed in enzymatic environments must arise from additional interactions or constraints beyond those present in the isolated substrate-donor system.