Prochiral substrates, reactions

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. 

CHMO is known to catalyze a number of enantioselective BV reactions, including the kinetic resolution of certain racemic ketones and desymmetrization of prochiral substrates [84—87]. An example is the desymmetrization of 4-methylcyclohexanone, which affords the (S)-configurated seven-membered lactone with 98% ee [84,87]. Of course, many ketones fail to react with acceptable levels of enantioselectivity, or are not even accepted by the enzyme. 

The similarities of above experimental results inspired us to investigate the role of SE in heterogeneous catalytic enantioselective hydrogenation reactions. In heterogeneous catalytic reaction the SE means that a given template molecule interacts with the prochiral substrate in the liquid phase in such a way that one of the prochiral sites is preferentially shielded. If the substrate is shielded then its adsorption onto the metal can take place with its unshielded site resulting in ED. 

The efficiency of the new ligands was examined in enantioselective hydrogenation of some prochiral substrates. Itaconic ester hydrogenation using in situ prepared Rh-complexes was the first test reaction chosen. The best results from... 

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 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. 

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]. 

Table 10.3 Effect of deviations of the standard enantioselective enzymatic conversion on the enantiomeric excess. The standard conversion is a single irreversible batch reaction in a homogeneous solution starting form racemic or prochiral substrate. (+)=positive effect, (-)=negative effect, (o)=no effect.

Usually the enantiomeric excess is calculated for a standard conversion process a single irreversible batch reaction in a homogeneous solution starting from racemic or prochiral substrate. However, if the assumptions that were used for the derivation of Eqns. (10.14), (10.15) and (10.17) do not hold, different equations apply, and the enantiomeric excess may be higher or lower. Table 10.3 shows an overview of some modifications, including some potential improvements (substrate racemization) and problems (equilibration) that were treated in Chapter 2. Clearly, many modifications will lead to a decrease rather than to an increase of the enantiomeric excess. 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

In ordinary reagent- or catalyst-based enantioselective reactions of prochiral substrates (equations 4 and 5, respectively), 100% enantiomeric purity of the chiral source is assumed, and the major concern is the efficiency of the chirality transfer from the chiral source to the substrate, namely, optical yield. In some special cases, however, a chiral metal complex can even amplify chirality (equation 6). A catalyst that is itself only partially resolved may form a chiral product with very high enantiomeric purity (24) (Chapter 5). 

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