Prochiral model substrates

Hydrosilylation reactions are formal additions of Si-H units across multiple bonds. They are fundamental reactions in organosilicon chemistry. Despite early reports of Marinetti and Ricard on Pd-catalysed hydrosilylation of alkenes with phosphetanes (up to 65% ee with styrene) and of Zhang and co-workers on Ru-catalysed hydrosilylation of ketones (up to 54% ee with acetophenone), most of the work on enantioselective hydrosilylation with P-stereogenic ligands has been carried out with Rh(I) complexes and prochiral ketones as substrates. Initially, silyl ethers are formed but they are usually cleaved under acidic conditions affording alcohols. As a result, hydrosilylations of ketones are formally identical to hydrogenations but do not involve the manipulation of dihydrogen. The model substrate for enantioselective hydrosilylation is acetophenone (Scheme 7.17). 

Hydrogen transfer reactions consist of formal transfers of two hydrogen atoms from a hydrogen donor to a prochiral substrate, catalysed by ruthenium(II) complexes under basic conditions. The model substrate for hydrogen transfer of ketones is once again acetophenone with isopropanol as hydrogen source and potassium tcrt-butoxide or KOH as base (Scheme 7.18). 

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]. 

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). 

Addressing the origins of enantioselectivity requires a chiral model. We chose [Rh((/ ,/ )-Me-DuPHOS)]+ (12) for the model system because of its relative simplicity and high selectivity. As in the previous study, we used the simplified substrate, a-formamidoacrylonitrile (13). Since the double bond in 13 is prochiral, there are two different catalyst-enamide diastereomers as shown in Figure 1. 

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. 

The rates of asymmetric sulfoxidation of thioanisole in nearly anhydrous (99.7%) isopropyl alcohol and methanol catalyzed by horseradish peroxidase (HRP) were determined to be tens to hundreds of times faster than in water under otherwise identical conditions (Dai, 2000). Similar effects were observed with other hemo-proteins. This dramatic activation is due to a much higher substrate solubility in organic solvents than in water and occurs even though the intrinsic reactivity of HRP in isopropyl alcohol and in methanol is hundreds of times lower than in water. In addition, the rates of spontaneous oxidation of the model prochiral substrate thioanisole in several organic solvents was observed to be some 100- to 1000-fold slower than in water. This renders peroxidase-catalyzed asymmetric sulf-oxidations synthetically attractive. 

In discussing the appearence of diastereoselectivity in natural systems, the rule of three-point contact is frequently used11). This rule implies that a prochiral substrate becomes a chiral one, when it is fixed on three nonidentical points on the enzyme system. On the other hand, the well-known lock-key model is mainly based on a specific spacial arrangement and does not take into account specific types of bonding to the matrix12). For a discussion of diastereoselectivity in reactions with metal complexes, it seems more appropriate to use such a lock-key model. 

Many achiral or chiral substituted382 and bridged 1,4-dihydropyridines383 have been prepared by a reduction of quaternary pyridium salts with sodium hydrosulphite as NADH models for enantioselective reduction of some prochiral substrates. A lithium aluminium hydride reduction of Af-acylenamines has also been observed384-386. 

The mechanism of asymmetric hydrogenation of dehydroaminoacids has been studied by a combination of kinetic and spectroscopic methods, mainly by Halpern et al. [38] and Brown et al. [39]. It was proved that the substrate bound by both the double bond and the amide group. It was surprising to see that the major diastereomeric rhodium-alkene complex detected in solution was the less reactive one towards hydrogen. This showed the inaccuracy of previous models of the lock and key type between the prochiral double bond and the chiral... 

Because of the results with numerous prochiral diesters and diols, which have been subjected successfully to hydrolase-catalyzed enantioselective hydrolysis and acylation, respectively, and because of the desire to predict the sense of the asymmetric induction in the conversion of a new substrate, active-site or substrate models have been developed for the hydrolases pig liver esterase171 731, pig pancreas... 

Ogston [20,21], seemingly unaware of the Easson-Stedman model, proposed a similar three-point attachment model to rationalize the observed stereoselectivity in the enzymatic transformation of symmetrical prochiral substrates, e.g., citrate and aminomalonate (Fig. 3) [22]. Similarly, Dalgleish [23], also unaware of the Easson-Stedman model [17], rationalized his observations concerning the resolution of the enantiomers of a number of amino acids on paper chromatography by a three-point attachment. In a subsequent telephone conversation with Bentley [24], Dalgleish stated that he was terribly impressed by the Ogston hypothesis. It is therefore... 

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