Is Simpler Better? Synthetic Nicotinamide Cofactor Analogues for Redox Chemistry

The topic of synthetic nicotinamide cofactor analogues is resurfacing as new approaches are being explored, especially in the areas of organic chemistry and biocatalysis. By changing the adenine dinucleotide moiety for a simpler alkyl or aryl group and taking advantage of their ability for hydride transfer, these cofactor biomimetics are used in redox reactions in catalytic or stoichiometric amounts. Alteration of the amide functional group on the pyridine ring, thus varying their electronic properties, and the presence of divalent metal ions also enable rate acceleration in enzyme-catalyzed and chemical reactions. Herein, an overview of the synthesis, mechanism, and applications of nicotinamide cofactor NAD(P)H analogues in redox chemistry, particularly 1,4-dihydronicotinamide derivatives and their oxidized counterpart, is presented. These compounds have been extensively studied as models of NAD(P)H for enzymatic reactions with oxidoreductases as well as nonenzymatic reactions, and the focus of this review is placed mainly on the scope and limitations of these synthetic analogues in biocatalysis.