Chirality prochiral substrates

The hand-in-glove fit of a chiral substrate into a chiral receptor is relatively straightforward, but it s less obvious how a prochiral substrate can undergo a selective reaction. Take the reaction of ethanol with NAD+ catalyzed by yeast alcohol dehydrogenase. As we saw at the end of Section 9.13, the reaction occurs with exclusive removal of the pro-R hydrogen from ethanol and with addition only to the Re face of the NAD+ carbon. 

We can understand this result by imagining that the chiral enzyme receptor again has three binding sites, as was previously the case in Figure 9.17. When green and gray substituents of a prochiral substrate are held appropriately, however, only one of the two red substituents—say, the pro-S one— is also held while the other, pro-R, substituent is exposed for reaction. 

In a catalytic asymmetric reaction, a small amount of an enantio-merically pure catalyst, either an enzyme or a synthetic, soluble transition metal complex, is used to produce large quantities of an optically active compound from a precursor that may be chiral or achiral. In recent years, synthetic chemists have developed numerous catalytic asymmetric reaction processes that transform prochiral substrates into chiral products with impressive margins of enantio-selectivity, feats that were once the exclusive domain of enzymes.56 These developments have had an enormous impact on academic and industrial organic synthesis. In the pharmaceutical industry, where there is a great emphasis on the production of enantiomeri-cally pure compounds, effective catalytic asymmetric reactions are particularly valuable because one molecule of an enantiomerically pure catalyst can, in principle, direct the stereoselective formation of millions of chiral product molecules. Such reactions are thus highly productive and economical, and, when applicable, they make the wasteful practice of racemate resolution obsolete. 

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

The subject of asymmetric synthesis generally (214, 215) gained new momentum with the potential use of transition metal complexes as catalysts. The use of a complex with chiral ligands to catalyze a synthesis asymmetrically from a prochiral substrate is advantageous in that resolution of a normally obtained racemate product may be avoided, for example,... 

As outlined in Section II,E, ketone and imine groups are readily hydrogenated via a hydrosilylation-hydrolysis procedure. Use of chiral catalysts with prochiral substrates, for example, R,R2C=0 or R,R2C=N— leads to asymmetric hydrosilylation (284, 285 Chapter 9 in this volume) and hence optically active alcohols [cf. Eq. (41)]. 

When the optically active catalyst [Rh((—)-BINAP)]+ was employed, a prochiral substrate was transformed to the corresponding chiral aldehyde with 18% ee (Scheme 23).45 Since the enantioselectivity-determining step in this... 

Although several noble-metal nanoparticles have been investigated for the enantiomeric catalysis of prochiral substrates, platinum colloids remain the most widely studied. PVP-stabilized platinum modified with cinchonidine showed ee-values >95%. Several stabilizers have been also investigated such as surfactants, cinchonidinium salts and solvents, and promising ee-values have been observed. Details of a comparison of various catalytic systems are listed in Table 9.16 in one case, the colloid suspension was reused without any loss in enantioselectiv-ity. Clearly, the development of convenient two-phase liquid-liquid systems for the recycling of chiral colloids remains a future challenge. 

Figure 6-3. Mechanism for the hydrogenation of a prochiral substrate methyl acet-amidocinnamate (MAC) with a catalyst containing a chiral chelating diphosphine ligand...

Homogeneous enantioselective hydrogenation constitutes one of the most versatile and effective methods to convert prochiral substrates to valuable optically active products. Recent progress makes it possible to synthesize a variety of chiral compounds with outstanding levels of efficiency and enantioselectivity through the reduction of the C=C, C=N, and C=0 bonds. The asymmetric hydrogenation of functionalized C=C bonds, such as enamide substrates, provides access to various valuable products such as amino acids, pharmaceuticals, and... 

One of the first attempts to explain e.s. was made by Wells and coworkers [234], who proposed that the L-shaped modifier could generate a chiral surface, by adsorption on Pt in ordered nonclose-packed arrays, allowing preferential adsorption on the metal surface of one of the faces of the prochiral substrate (template model). 

The asymmetric synthesis of allenes by stereoselective manipulations of enantio-merically pure or enriched substrates relies on the availability of such optically active substrates. In contrast, a direct synthesis of allenes by the reaction of prochiral substrates in the presence of an external asymmetric catalyst is an almost ideal process [102]. Most of the catalytic asymmetric syntheses in organic chemistry involve the creation of chiral tetrahedral carbon centers [103], whereas the asymmetric synthesis of allenes requires the construction of an axis of chirality. 

Related to these enzyme -catalysed reactions are electroreductions of acetophenone in the presence of chiral crown ethers. The low optical yields (<3%) are attributed to association of the prochiral substrate and the chiral crown ether salt complex in the electrochemical double layer (Horner and Brich, 1978). 

Reaction of an achiral (and prochiral) substrate with a chiral reagent. 

A much more efficient procedure consists in the deprotonation of prochiral substrates 4 by chiral base 5 (equation 2). The removal of the enantiotopic protons in 4 proceeds through diastereotopic transition states having different energies AG and thus yielding the diastereomeric carbanions 6 and epi-6 in unequal amounts (equation 2). 

Enantioselective enzyme-catalyzed reactions may involve the transformation of a prochiral substrate into a chiral product, in which case the selectivity is measured by the enantiomeric excess (ee). The transformations can also involve kinetic resolution of racemic substrates, in which case enantioselectivity is measured by the selectivity factor E reflecting the relative rates of reaction of the R)- and (5)-enantiomer. 

Reetz and coworkers developed a highly efficient method for screening of enantioselectivity of asymmetrically catalyzed reactions of chiral or prochiral substrates using ESI-MS [60]. This method is based on the use of isotopically labeled substrates in the form of pseudo-enantiomers or pseudo-prochiral compounds. Pseudo-enantiomers are chiral compounds which are characterized by different absolute configurations and one of them is isotopically labeled. With these labeled compounds two different stereochemical processes are possible. The first is a kinetic separation of a racemic mixture, the second the asymmetric conversion of prochiral substrates with enantiotopic groups. The conversion can be monitored by measuring the relative amounts of substrates or products by electrospray mass spectrometry. Since only small amounts of sample are required for this method, reactions are easily carried out in microtiter plates. The combination of MS and the use of pseudo-enantiomers can be used for the investigation of different kinds of asymmetric conversion as shown in Fig. 3 [60]. 

For our initial studies we chose to evaluate the hydrogenation of two unsaturated carbonyl model prochiral substrates with rhodium complexes of chiral ferrocene diphosphine and tetraphosphine ligands using a standard set of conditions. The substrates screened were methyl a-acetamido cinnamate (MAC) and dimethyl iticonate (DIMI). The substrates, catalysts, conditions, and experimental results are shown in Table 1. 

Such oligocyclizations have also been carried out on prochiral substrates such as 132 with asymmetric induction by chiral ligands on palladium. With (spirocyclic system 133 was obtained in good yield with an enantiomeric excess (ee) of 45% (Scheme 35). ... 

In the preceding Section we considered the catalytic asymmetric synthesis. In this connection the induction of asymmetry by catalytic amounts of chiral information (= amino acids or their derivatives) was treated. The chiral information was transferred into a prochiral substrate. 

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