Stereochemistry of hydride transfer

Dehydrogenases and reductases are enzymes that catalyze the reduction of carbonyl groups. The natural substrates of the enzymes are alcohols, such as ethanol, lactate, glycerol, and the corresponding carbonyl compounds however, unnatural ketones can also be reduced enantioselectively. To exhibit catalytic activities, the enzymes require a coenzyme such as NADH or NADPH from which a hydride is transferred to the substrate carbonyl carbon. 

Distance between chiral carbon and reaction center 

The chiral carbon and the reaction center is separated by 1 atom. 

---

Gogte, V. N., Salama, M. A., and Tilak. B. D., Synthesis of nitrogen hetcrocyclics. VI. Stereochemistry of hydride transfer in acid catalysed disproportionation of 3,4-disubstituted... 

The additional stereochemical control available in carbanions relative to alkoxides arises both from the extra ligation about carbon and the contributions of the metal. The stereochemistry of hydride transfer from organostannanes has been particularly well investigated. Coordinatively saturated metals like tin function less well as Lewis acids in a cyclic mechanism, and tend to induce hydride loss through an anti-... 

Figure 5 Stereochemistry of hydride transfer from NADPH to the product of the Methanocaldococcus jannaschii reductase. Oniy deuterium from the 4(R)-position of NADPH is transferred into the 1 -proS position of the product 5 (ieft side). ...

The stereochemistry of hydrogen transfer has been studied with the liver enzyme by using the labeled NAD derivative354 (91). The reduced pyridine nucleotide was shown to have the structure 92, thus indicating that both hydride ions that are transferred from 89a... 

In this synthesis, the reactant was chosen to control stereochemistry and give an equatorial alcohol, due to an intermediate axial radical use of hydride-transfer reagents would tend to afford predominantly the axial alcohol. 

Homer and Balzer had earlier reported 32) that reduction of optically active phosphine oxides with either trichlorosilane (HSiCls), HSiClj/pyridine, or HSiCls/N, N-diethylaniline affords phosphines with overall retention of configuration, whereas reduction with HSiCls/triethylamine affords phosphine with inversion of configuration at phosphorus. In summary, it was suggested 32) that this difference in overall stereochemistry of reduction reflected a difference in the mode of hydride transfer from silicon to phosphorus intra- and intermolecular hydride transfer led to retention and inversion, respectively. The essential features of these mechanistic rationalizations are represented by Eq. (3). The intramolecular hydride transfer mechanism ), which may include pseudorotation (see Sect. 3) if intermediate phospho-HSiClj + O=PR3 - 0 PRj PRj + [ClsSiOH]... 

The regioselective and stereospecific construction of C-20 stereochemistry is explained by the following mechanism. The Pd(0) species attacks the ( )-/3-carbonate 616 from the a-side by inversion to form the Tr-allylpalladium species 620, which has a stable syn structure[392]. Then concerted decarboxylation-hydride transfer as in 621 takes place from the a-side to give the unnatural configuration in 617. On the other hand, the Tr-allylpalladium complex 622... 

The r/zreo-3-deutero-2-trimethylstannylbutane that Hannon and Traylor158 used to determine the stereochemistry of the hydride transfer reaction and to shed light on the mechanism of this reaction was synthesized using the reactions in Scheme 22. Each of the reactions in Scheme 22 is stereo specific and the analysis showed that the product was at least 97% r/rreo-3-deutero-2-trimethylstannylbutane. If the elimination reaction from t/zreo-3-deutero-2-trimethylstannylbutane occurs with an awh -periplanar stereochemistry, the products shown in Scheme 23 will be obtained. Thus, if the elimination occurs by an awft -periplanar stereochemistry, all the fraws-2-butene will be monodeuterated while the ds-2-butene will not be deuterated. A syw-periplanar elimination from f/zreo-3-deutero-2-trimethylstannylbutane, on the other hand, would give the products shown in Scheme 24. If this occurs, the cw-2-butene will contain one deuterium atom and the fraws-2-butene will contain none. 

Hydride Transfer in NAD+- and NADP -Dependent Enzymes. The transfer of the hydride ion in redox reaction of NAD+- and NADP+-dependent enzymes can occur either to the re- or the xi-face of the pyridine ring of the coenzyme . Such stereochemistry is crucial in the characterization of these enzymes. The same enzymes from different sources can express different stereospecificities. For example, E. coli NAD(P)+ transhydrogenase expressed one form of stereospecificity whereas the Pseudomonas aeruginosa enzyme catalyzes the identical reaction with the other NAD form . 

Other methods are also available for generation of boron enolates. Dialkylboranes react with acyclic enones to give Z-enolates by a 1,4-reduction.19 The preferred Z-stereochemistry is attributed to a cyclic mechanism for hydride transfer ... 

Reaction Pathway. The simplest pathway is illustrated by the /3-keto ester substrate in Scheme 50. As suggested by reaction with RuCl2[P(C6H5)3]3 as the catalyst precursor (40c, 96), this hydrogenation seems to occur by the monohydride mechanism. The catalyst precursor has a polymeric structure but perhaps is dissociated to the monomer by alcoholic solvents. Upon exposure to hydrogen, RuC12 loses chloride to form RuHCl species A, which, in turn, reversibly forms the keto ester complex B. The hydride transfer in B, from die Ru center to the coordinated ketone to form C, would be the stereochemistry-determining step. Liberation of the hydroxy ester is facilitated by the al-... 

Each of the syntheses of seychellene summarized in Scheme 20 illustrates one of the two important methods for generating vinyl radicals. In the more common method, the cyclization of vinyl bromide (34) provides tricycle (35).93 Because of the strength of sjp- bonds to carbon, the only generally useful precursors of vinyl radicals in this standard tin hydride approach are bromides and iodides. Most vinyl radicals invert rapidly, and therefore the stereochemistry of the radical precursor is not important. The second method, illustrated by the conversion of (36) to (37),94 generates vinyl radicals by the addition of the tin radical to an alkyne.95-98 The overall transformation is a hydrostannylation, but a radical cyclization occurs between the addition of the stannyl radical and the hydrogen transfer. Concentration may be important in these reactions because direct hydrostannylation of die alkyne can compete with cyclization. Stork has demonstrated that the reversibility of the stannyl radical addition step confers great power on this method.93 For example, in the conversion of (38) to (39), the stannyl radical probably adds reversibly to all of the multiple bond sites. However, the radicals that are produced by additions to the alkene, or to the internal carbon of the alkyne, have no favorable cyclization pathways. Thus, all the product (39) derives from addition to the terminal alkyne carbon. Even when cyclic products might be derived from addition to the alkene, followed by cyclization to the alkyne, they often are not found because 0-stannyl alkyl radicals revert to alkenes so rapidly that they do not close. 

As shown in the biosynthesis of granaticin, a hydride shift occurs intramolecularly. This process is mediated by an enzyme-bond pyridine nucleotide. A concerted abstraction of H-4 as a hydride in la and a C-5 deprotonation in 2a leads to the 4,5-enol ether 3a. The reduced form of the pyridine nucleotide transfers the hydride to C-6, simultaneously releasing a hydroxide to give 4a. Final tautomerization yields the dTDP-4-keto-6-deoxy-sugar in v-xylo configuration 4a. In other enzymes of the oxidoreductase type, the active site may show a different configuration. Thus, the intermediate 3a can be protonated from above at C-5 to yield the l-arabino isomer of 4a [2]. The stereochemistry of this mechanism was demonstrated by double labelling (cf. l-4b series), and as a net result proved a suprafacial 4—>6 hydride shift. 

Table 2. Stereochemistry of the hydrid transfer catalyzed by alcohol dehydrogenases...

---