Prochiral substrate

The research group of Muzart and Henin studied extensively the palladium-catalyzed EDP of allyl- or benzyl-carboxylated compounds. Mainly two types of substrates, prochiral enol carbonates A and racemic (3-keto esters B, were used to afford enols C as transient species [25]. In the presence of a chiral proton source, asymmetric protonation/tautomerization of enols led to enantioenriched ketones D... 

Interestingly, none of the stereoselective reactions described previously assembles a new chiral center instead, the applied strategies rely on previously existing, special chiral characteristics of the substrates (prochiral moieties or fluxional axial chirahty). In contrast to these approaches, a recently published report relies solely on catalyst design to generate a new stereocenter in the product through chelate-assisted hydroarylation (Scheme 23.54) [166]. The most selective Rh catalyst 31 uses a biaryl-substituted Cp ring as the structural element to induce enantioselectivity. After the reaction, the hydroarylation product with a new quaternary stereocenter can be isolated in 87% yield and 91% ee. 

FIGURE 17 14 (a) Binding sites of enzyme discriminate between prochiral faces of substrate One prochiral face can bind to the enzyme better than the other (b) Reaction attaches fourth group to substrate producing only one enantiomer of chiral product... 

The situation is different if the substrate is a prochiral or meso compound. Since these molecules have a center or plane of symmetry the binding of pro-S or pro-R forms is equivalent. The chirahty appears only as a result of the transformation. Hence, at least theoretically, the compound can be converted to one enantiomer quantitatively. 

Reductive alkylation with chiral substrates may afford new chiral centers. The reaction has been of interest for the preparation of optically active amino acids where the chirality of the amine function is induced in the prochiral carbonyl moiety 34,35). The degree of induced asymmetry is influenced by substrate, solvent, and temperature 26,27,28,29,48,51,65). Asymmetry also has been obtained by reduction of prochiral imines, using a chiral catalyst 44). Prediction of the major configurational isomer arising from a reductive alkylation can be made usually by the assumption that amine formation comes via an imine, not the hydroxyamino addition compound, and that the catalyst approaches the least hindered side (57). 

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. 

The second group of studies tries to explain the solvent effects on enantioselectivity by means of the contribution of substrate solvation to the energetics of the reaction [38], For instance, a theoretical model based on the thermodynamics of substrate solvation was developed [39]. However, this model, based on the determination of the desolvated portion of the substrate transition state by molecular modeling and on the calculation of the activity coefficient by UNIFAC, gave contradictory results. In fact, it was successful in predicting solvent effects on the enantio- and prochiral selectivity of y-chymotrypsin with racemic 3-hydroxy-2-phenylpropionate and 2-substituted 1,3-propanediols [39], whereas it failed in the case of subtilisin and racemic sec-phenetyl alcohol and traws-sobrerol [40]. That substrate solvation by the solvent can contribute to enzyme enantioselectivity was also claimed in the case of subtilisin-catalyzed resolution of secondary alcohols [41]. 

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. 

It had been known for a long time that CFIMO can also be used as catalysts in the enantioselective air-oxidation of some but not all prochiral thioethers [97]. Therefore, directed evolution of the CFIMO from Adnetohacter sp. NCIMB 9871 was applied in those cases in which the WT fails [32]. An example is substrate (40), which reacts with an enantiomeric excess of only 14% in slight favor of (R)-41 (see Scheme 2.12). 

Figure 6.4 Hydrolase-catalyzed desymmetrization of a prochiral (a), a meso (b), or a centrosymmetric (c) substrate.

In an asymmetric synthesis, the enantiomeric composition of the product remains constant as the reaction proceeds. In practice, ho vever, many enzymatic desymmetrizations undergo a subsequent kinetic resolution as illustrated in Figure 6.5. For instance, hydrolysis of a prochiral diacetate first gives the chiral monoalcohol monoester, but this product is also a substrate for the hydrolase, resulting in the production of... 

Esterases, proteases, and some lipases are used in stereoselective hydrolysis of esters bearing a chiral or a prochiral acyl moiety. The substrates are racemic esters and prochiral or meso-diesters. Pig liver esterase (PLE) is the most useful enzyme for this type of reaction, especially for the desymmetrization of prochiral or meso substrates. 

The biocatalytic differentiation of enantiotopic nitrile groups in prochiral or meso substrates has been studied by several research groups. For instance, the nitrilase-catalyzed desymmetrization of 3-hydroxyglutaronitrile [92,93] followed by an esterification provided ethyl-(Jl)-4-cyano-3-hydroxybutyrate, a useful intermediate in the synthesis of cholesterol-lowering dmg statins (Figure 6.32) [94,95]. The hydrolysis of prochiral a,a-disubstituted malononitriles by a Rhodococcus strain expressing nitrile hydratase/amidase activity resulted in the formation of (R)-a,a-disubstituted malo-namic acids (Figure 6.33) [96]. 

In the above cases, an optically active reducing agent or catalyst interacts with a prochiral substrate. Asymmetric reduction of ketones has also been achieved with an achiral reducing agent, if the ketone is complexed to an optically active transition metal Lewis acid. ... 

Encapsulated rhodium complexes were prepared from Rh-exchanged NaY zeolite by complexation with (S)-prolinamide or M-tert-butyl-(S)-prolinamide [73,74]. Although these catalysts showed higher specific activity than their homogeneous counterparts in non-enantioselective hydrogenations, the hydrogenation of prochiral substrates, such as methyl (Z)-acetamidocinnamate [73] or ( )-2-methyl-2-pentenoic acid [74], led to low... 

Of the two former processes shown in Scheme 5.2, the kinetic resolution of race-mates has found a much greater number of applications than the desymmetrization of prochiral or meso compounds. This is due to the fact that racemic substrates are much more common than prochiral ones. However, kinetic resolution suffers from a number of drawbacks, the main being the following ... 

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