Satoshi Ushida

Asymmetric Synthesis of α-Amino Acids

It has been emphasized that the most important factor determining the efficiency of asymmetric induction by a chiral NAD(P)H-model compound is the effectiveness in discriminating between the re- and si-faces of the dihydropyridine ring. A similar effect also operates in the stereochemistry of transamination mediated by pyridoxamine, vitamin B6.

Asymmetric Reduction by Model Compounds of NAD(P)H

Within a molecule of NAD(P)H, the 1,4-dihydronicotinamide moiety acts as a reducing reagent. Thus, a 1,4-dihydropyridine derivative where the ring nitrogen is substituted by a simple substituent, such as 1-propyl-1,4-dihydronicotinamide (PNAH), 1-benzyl-1,4-dihydronicotinamide (BNAH), or Hantzsch ester (HEH), can be considered as a model compound for NAD(P)H.

Polar Effect Exerted by Other Asymmetric Reactions

The authors have proposed that the dipole-dipole interaction is more important than the steric effect in the reduction with the 1,4-dihydropyridine derivative. Especially, this is true when the magnesium ion is present in the reduction system. The idea is different from the traditional one which insists that steric bulk is the most important factor in determining the steric course of a reaction. All of them, the Prelog model (Prelog 1953), Cram model (Cram and Abd Elhafez 1952 a,b), Karabatsos model (Karabatsos and Hsi 1965, 1967, Karabatsos and Krumel 1967, Karabatsos and Fenoglio 1969a,b, Karabatsos et al. 1967), Felkin model (Cherest et al. 1968, Cherest and Felkin 1968), and other similar models are stereo-models for transition states that predict the stereochemistry of the reaction from the viewpoint of a steric effect.

Asymmetric Reduction in a Chiral Reaction Field

Stereospecificity in the enzymatic reduction with NADH or NADPH as a reducing agent is due largely to the effect from the environment around the 1,4-dihydropyridine moiety. The active site of the enzyme is surrounded by amino acid residues that form a chiral environment so as to achieve the asymmetric reduction of substrates. One of the attempts to mimic the system conveniently is to introduce one chirality into a 1,4-dihydropyridine derivative. This has been successful in constructing a specific chiral field for the reduction with the aid of Mg(II). Based on the fact that an enzyme exhibits its catalytic activity by binding to a substrate with a large association constant, it is expected that a good result will be obtained by introducing a mimic of the binding site within a molecule of a 1,4-dihydropyridine derivative. At the same time, if the binding site incorporates chirality, stereoselective reduction should be achieved. One of the most effective NAD(P)H model compounds of this type is that which has a macrocyclic moiety in the molecule. The compound was designed with the intention of binding a substrate or a metal ion at the macrocyclic moiety.

Stereochemistry in NAD(P) + -Dependent Dehydrogenases

One of the most outstanding features in enzyme-catalyzed reactions is stereochemical completeness. A high percentage of stereospecific reactions, such that only one chiral product is formed in an excellent enantiomer excess (e.e.) and that only one of two enantiomers is available as a substrate, readily take place. In addition, the spectacular feature that an enzyme can also differentiate enantiotopic groups or faces that are nonenzymatically (chemically) equivalent has also been found. For example, enzymes distinguish two hydrogens attached to a prochiral carbon, >CH2. Even the three hydrogens of a methyl group are sometimes nonequivalent within an enzyme. As will be discussed below, such phenomena, which could not be proved without using an isotope labeling technique, tell us that the active site of an enzyme provides a specific environment for the substrate.

NAD(P)H as a Coenzyme

Nicotinamide adenine dinucleotide and its phosphate derivative are widely distributed as coenzymes for biological redox reactions. Structures of their oxidized and reduced forms are depicted above. Within the coenzyme molecule, the nicotinamide moiety which is linked with a ribose moiety through a β-glycosidic bond* acts as a shuttle redox reagent by interconverting between 1,4-dihydropyridine and pyridinium cation structures. The remaining part of the coenzyme mainly acts as the binding site for the apoenzyme.

Diastereo-Differentiation at the 4 Position of 1,4-Dihydropyridine

It is concluded, as described in the previous section, that the most important factor for the stereoselectivity of reduction is the selection of the transferring hydrogen from the prochiral position.

Recent Progress in Asymmetric Reactions Mediated by an Enzyme

At the end of this review, it is worthwhile surveying asymmetric organic reactions mediated by an enzyme in which a biological material is used as one of the chemical reagents for an organic reaction. Oxidoreduction mediated by an microorganism was reviewed recently by Sih and Chen (1984) and the reader is recommended to consult that review for this particular topic.

Stereochemical Course of the Reduction

As mentioned above, it is reasonable to consider that the reduction by a 1,4-dihydropyridine derivative catalyzed by metal ions proceeds via a ternary complex as shown in Fig. 3. In the reduction by PNPH, the factor which determines the stereochemistry of the product is the mode of approach of the substrate to PNPH. Namely, the relative orientation between the 1,4-dihydropyridine ring and the substrate in the ternary complex is important. There are many possibilities for the molecular arrangement in the ternary complex as well as for the fashion of the coordination of Mg(II) to PNPH. Here we will discuss what kind of complexation and approach should be considered in order to understand the magnitude and direction of the induced chirality, or the mechanism of chirality induction.