DFT Mechanism Studies: Biomimetic 1,4-NADH Chemoselective, Co-factor Regeneration with [Cp*Rh(bpy)H]+, in Tandem with the Biocatalysis Pathways of a Core Model of the (HLADH)-Zn(II) Mediated Enzyme, in the Enantioselective Reduction of Achiral Ketones to Chiral S-Alcohols

Abstract

Quantum Chemical (QC) calculations, utilizing Density Functional Theory (DFT), were performed to investigate the mechanistic aspects of the chemoselective catalyzed reaction of [Cp*Rh(bpy)H]+ with the biomimetic NAD+ analogues, N-benzylnicotinamide triflate, 1, and β-nicotinamide ribose-5′-methyl phosphate, 2, in the conversion to their 1,4-NADH analogues, 1,4-dihydro-N-benzylnicotinamide, 4, and β-1,4-dihydronicotinamide-5′-ribose methyl phosphate, 5. This reaction was in tandem with the 1,4-NADH dependent HLADH-Zn(II)-catalyzed reduction of achiral ketones to chiral S-alcohols. The [Cp*Rh(bpy)H]+ complex, and not its equilibrium tautomer, [η4-Cp*HRh(bpy)]+, was found to control the hydride transfer during the biomimetic NAD+/1,4-NADH conversion, through the non-covalent interactions of the biomimetic co-factors with [Cp*Rh(bpy)H]+. The thermodynamics and kinetics for the chiral reduction of the Zn(II) bound ketones, 2-pentanone and 4-phenyl-2-butanone, with co-factor, 4, catalyzed by Zn(SCH3)2(Imidazole), a core model of the Zn(II)-based catalytic center of HLADH, was also investigated by the evaluation of two possible reaction pathways: (1) formation of a ZnH from the C4-H hydride transfer of co-factor, 4, followed by reaction of the postulated ZnH with the bound 2-pentanone or 4-phenyl-2-butanone substrate, and (2), the direct C4-H transfer to the bound achiral ketone substrates, to provide the dominant chiral alcohols, S-2-pentanol or S-4-phenyl-2-butanol. The latter pathway was found most viable, and DFT calculations also revealed an essential η2-coordination of the 5,6 double bond of co-factor, 4, to the HLADH-Zn(II) metal ion center, upon imidazole decomplexation, providing an asymmetric differentiation of S-η2-5,6-1,4-NADH-Zn(II) binding. A proposed new paradigm for the Zn(II)'s non-innocent role in the HLADH-Zn(II) biocatalysis reduction mechanism, for enantioselective hydride transfer to a Zn(II) bound ketone, providing S-alcohols.