NADH Analogs

Two-step(electron - hydrogen atom) hydride transfer  

Three-step (electron - proton - electron) hydride transfer 

However, the authors of that paper conceded that this tautomerization might require the involvement of at least one molecule of water to occur spontaneously [20]. 

Of course, the barrier is even wider and higher in 8 K (O- H distance 2.78 A, 

---

Zincke salts have played an important role in the synthesis of NAD /NADH coenzyme analogs since a 1937 report on the Zincke synthesis of dihydropyridine 7 for use in a redox titration study.The widely utilized nicotinamide-derived Zincke salt 8, first synthesized by Lettre was also used by Shifrin in 1965 for the preparation and study of NAD /NADH analogs. In 1972, Secrist reported using 8 for synthesis of simplified NAD analogs such as 10 for use in spectroscopic studies (Scheme 8.4.4). Subsequent utilization of 8 is discussed later in this article. 

The utility of the Zincke reaction has been extended to the preparation of various NAD and NADH analogs. Holy and co-workers synthesized a series of NAD analogs containing nucleotide bases as a means to study through-space interaction between the pyridinium and base portions. Nicotinamide-derived Zincke salt 8 was used to link with various adenine derivatives via tethers that contained hydroxyl (105 —> 106, Scheme 8.4.35), phosphonate (107—>108, Scheme 8.4.36), and carboxylate "... 

Utilizing the Zincke reaction of salts such as 112 (Scheme 8.4.38), Binay et al. prepared 4-substituted-3-oxazolyl dihydropyridines as NADH models for use in asymmetric reductions. They found that high purity of the Zincke salts was required for efficient reaction with R-(+)-l-phenylethyl amine, for example. As shown in that case (Scheme 8.4.38), chiral A-substituents could be introduced, and 1,4-reduction produced the NADH analogs (e.g. 114). 

Reduction of l,10-phenanthroline-2-aldehyde to 1,10-phenanthroline-2-carbinol is efficiently accomplished by a dihydronicotinamide derivative in acetonitrile solution catalyzed by zinc ions. This was the first example of the reduction of an aldehyde by a NADH analog in a nonenzymic system. It also supports the catalytic function of the metal ion in the enzymic system.359 l,10-Phenanthroline-2-carbinol, obtained by sodium borohydride reduction of 2-carbomethoxy-1,10-phenanthroline, is phosphorylated by adenosine triphosphate in the presence of zinc ions.360... 

Although a number of substrates can be reduced by AcrH2 photochemically [50-52] or by acid catalyis [53,54], neither thermal acid catalysis nor the use of the excited states of NADH analogs is effective for the reduction of Me2SO, which is commonly used as an inert solvent. 

The problem of biomimetic model design simulating the action mechanism of corresponding enzymes is based on the idea of structural-functional conformity. In 1971, alcohol dehydrogenase was primarily synthesized [123], In this biomimetic system the product is formed due to direct electron transfer from the reduced co-factor (NADH) analog to aldehyde. Note that the display of alcohol dehydrogenase catalytic activity requires the presence of zinc (II) ion. 

Fig. 13.10 Plot of logfcet vs. -AC0, for electron transfer from anthracene radical anion to C60, C70 and l,4-t-Bu(PhCH2)C60 in PhCN (closed circle) [18], electron transfer from C60 to a-chloranil in PhCN (closed triangle) [28], electron transfer from NADH analogs to [3]C60 and [3]C70 in PhCN (open triangle)...

The catalytic activity of the immobilized flavin was determined using the oxidation of an NADH-analog, namely 1-benzyl-1,4-dihydronicotinamide (BNAH), as a model reaction (Figure 8). If a potential of +0.9 V is applied to the system, hydrogen peroxide, which is formed in the aerobic oxidation of BNAH by flavin, can be oxidized... 

It is possible to interpret these results in terms of the model proposed by Saveant for the deprotonation of NADH analog radical cations, where the dynamics of the deprotonation process in the radical cation are controlled by the homolytic C-H bond dissociation energy [137, 139]. 

Syntheses and functional properties of bridged structures including an TV-hetero-aromatic fragment, in particular NADH analogs 03YGK352. 

Classic work by Powell and Bruice (37) established the hydride-transfer nature of the interaction of flavins with nicotinamide cofactors. Among several lines of evidence, a very impressive experiment (Eq. (4.11)) involved the exposure in tert-butyl alcohol solvent at 30 °C of various NADH analogs to the N,N-bridged flavin analog shown in Eq. (4.11a), which resulted in quick and complete reduction, and exposure to the radical cation shown in Eq. (4.11b), which gave no direct reduction product at all, although as explained below the observations required careful analysis. 

Finally it was reasoned that if the mechanism of Eq. (4.11a) involved an electron transfer or a hydrogen-atom transfer from the NADH analog to the acridinium species, then such processes should surely occur in the system of Eq. (4.11b). The fact that this did not occur, in spite of the electron transfer being thermodynamically favorable, demonstrated the extreme propensity of the NADH/flavin system for hydride-transfer reaction. 

Powell, M. F. Beuice, T. C. 1982 J. Am. Chem. Soc. 104, 5834-5836 Reinvestigation of NADH analog reactions in acetonitrile Consequences of isotope scrambling on kinetic and product isotope effects. 

Shinkai and Bruice (21, 22) recently have described the first example of a zinc-ion-catalyzed reduction of aldehyde by NADH and NADH analogs in aqueous solution. They found that 3-hydroxypyridine-4-carboxaldehyde derivatives are reduced by 1,4-dihydropyridines in aqueous methanol (52% by weight) at 30°. Furthermore, this reaction is subject to catalysis by divalent metal ions, including Zn(II), Eq. (9). The following apparent relative order for metal ion effectivenes was observed Ni2+>Co2+>Zn2+>Mn2+>Mg2+>control. 

Fukuzumi reported a detailed mechanistic study of quinone reduction catalyzed by protonated amino acids [245]. Kinetic experiments, EPR spectroscopy and cyclic voltammetry were employed to illustrate the role protonated histidine plays in mediating electron transfer between NADH analog 9,10-dihydro-10-methy-lacridine (AcrH2) and l-(p-tolylsulfinyl)-2,5- benzoquinone (TolSQ). Cyclic voltammetry experiments demonstrate a 0.55-V positive shift in the one-electron reduction potential of TolSQ in the presence of 5.0 x 10 M of protonated... 

Anne, A., Hapiot, P., Moiroux, J., Neta, P., and Saveant, J.-M., Dynamics of proton transfer from cation radicals. Kinetic and thermodynamic acidities of cation radicals of NADH analogs, /. Am. Chem. Soc., 114, 4694, 1992. 

---