Prochiral systems

Chiral or asymmetric synthesis generates a single enantiomer from a prochiral precursor by using some chiral influence. This chiral influence is often added to the prochiral system first (chiral auxiliary) or it may already be present within the prochiral precursor as another chiral centre. The advantage of chiral synthesis is that like resolution it provides better, more suitable chiral materials but in addition the process is not wasteful because all of the material is converted into the desired single enantiomer (ideally). 

Diastereotopism indicates prochirality, as exemplified by glycerol (25, Fig. 2.23). Other examples of this include diethylacetals, in which the OC//2 protons are diastereotopic on account of the prochiral acetal-C atoms, thus forming AB systems of quartets because of coupling with the methyl protons. 

If a tetrahedral center in a molecule has two identical substituents, it is referred to as prochiral since, if either of the like substituents is converted to a different group, the tetrahedral center then becomes chiral. Consider glycerol the central carbon of glycerol is prochiral since replacing either of the —CH9OH groups would make the central carbon chiral. Nomenclature for prochiral centers is based on the (R,S) system (in Chapter 3). To name the otherwise identical substituents of a prochiral center, imagine... 

In order to broaden the field of biocatalysis in ionic liquids, other enzyme classes have also been screened. Of special interest are oxidoreductases for the enan-tioselective reduction of prochiral ketones [40]. Formate dehydrogenase from Candida boidinii was found to be stable and active in mixtures of [MMIM][MeS04] with buffer (Entry 12) [41]. So far, however, we have not been able to find an alcohol dehydrogenase that is active in the presence of ionic liquids in order to make use of another advantage of ionic liquids that they increase the solubility of hydrophobic compounds in aqueous systems. On addition of 40 % v/v of [MMIM][MeS04] to water, for example, the solubility of acetophenone is increased from 20 mmol to 200 mmol L ... 

Diboration of terminal alkenes has also been studied with other d " metals (Fig. 2.12) including the Ag and Au complexes 75-77 and the Pt" complexes 78-79. Styrene is diborylated with 100% selectivity and good conversions in THF (46% for 75 and 94% for 77 at 5 mol%, 60 h) using equimolecular amounts of (Bcat)j. The difference in activity between the Ag and Au complexes has been ascribed to the increased lability of the Ag-NHC bond, which may lead to catalyst decomposition under the reaction conditions, hi both catalytic systems it is believed that the active species involves only one coordinated NHC ligand. Complex 77 is less active than 74 and 75, possibly due to steric reasons. The enantioselectivity of 77 in the diboration of prochiral alkenes is very low [63]. 

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],... 

Whereas general activities and selectivities for hydrogenations of ketones are similar to those of aldehydes, one big difference exists between the two. The hydrogenation of prochiral ketone carbonyls produces chiral carbons. Over symmetrical catalysts, racemic alcohols are formed however, over unsymmet-rical surfaces, enantioselectivity may occur. Enantioselective hydrogenations of ketones is an increasingly active research held and is covered in Chapter 3. Here we discuss that aspect of stereoselectivity associated with ring systems. 

Among the most active catalysts for the asymmetric transfer hydrogenation of prochiral ketones and imines to chiral alcohols and amines are arene-ruthenium(II) amino-alcohol (or primary/ secondary 1,2-diamine)-based systems, with an inorganic base as co-catalyst, developed by Noyori139-141 and further explored by others (Scheme 27).142-145... 

The effect of surfactant on enantioselective hydrogenation has been thoroughly investigated. Rhodium complexes of phosphinated glucopyranosides were used for hydrogenation of prochiral dehydroaminoacid derivatives in aqueous systems in the presence of sodium dodecylsulfate (SDS)... 

Prochiral imines can be hydrogenated to the corresponding amines with extremely high enan-tioselectivities in H20/ethyl ethanoate biphasic systems, using Rh1 complexes of sulfonated phosphines 342 The cationic rhodium complex [Rh(NBD)(131)]+ was an active catalyst for hydrogenation of 2-ethanamido-propenoic acid in aqueous solution.343... 

Prochiral derivatives of propenoic acid were reduced by hydrogen transfer from aqueous solutions of M[HCOO] (M = K+, Na+ and [NH4]+) catalyzed by Rh1 complexes of (117) or the tetrasulfonated cyclobutanediop (132) 345 Aldehydes were reduced in a phase transfer catalytic system having [RuCl2(PPh3)3] as the catalyst in the organic phase (for example chlorobenzene) and the hydrogen donor (Na-methanoate) in the aqueous phase.346... 

The cA-PtCl2(diphosphine)/SnCl2 constitutes the system mostly used in catalyzed hydroformylation of alkenes and many diphosphines have been tested. In the 1980s, Stille and co-workers reported on the preparation of platinum complexes with chiral diphosphines related to BPPM (82) and (83) and their activity in asymmetric hydroformylation of a variety of prochiral alkenes.312-314 Although the branched/normal ratios were low (0.5), ees in the range 70-80% were achieved in the hydroformylation of styrene and related substrates. When the hydroformylation of styrene, 2-ethenyl-6-methoxynaphthalene, and vinyl acetate with [(-)-BPPM]PtCl2-SnCl2 were carried out in the presence of triethyl orthoformate, enantiomerically pure acetals were obtained. 

If kinetic resolution is being studied, the ratio of pseudo-e nantiomers can be measured by MS, allowing for the determination of ee-values (and/or of selectivity factors E). The same applies to the reaction of pseudo prochiral compounds. This system has been used successfully in the directed evolution of enantioselective enzymes. However, it should work equally well in the case of asymmetric transition metal catalyzed reactions. In the original version about 1,000 ee-deter-minations were possible per day (Figure 6).94 The second-generation version based on an 8-channel multiplexed spray system enables about 10,000 samples to be handled per day, the sensitivity being 2% ee.96... 

When a chiral ansa-type zirconocene/MAO system was used as the catalyst precursor for polymerization of 1,5-hexadiene, an main-chain optically active polymer (68% trans rings) was obtained84-86. The enantioselectivity for this cyclopolymerization can be explained by the fact that the same prochiral face of the olefins was selected by the chiral zirconium center (Eq. 12) [209-211]. Asymmetric hydrogenation, as well as C-C bond formation catalyzed by chiral ansa-metallocene 144, has recently been developed to achieve high enantioselectivity88-90. This parallels to the high stereoselectivity in the polymerization. 

The asymmetric organosilane reduction of prochiral ketones has been studied as an alternative to the asymmetric hydrogenation approach. A wide variety of chiral ligand systems in combination with transition metals can be employed for this purpose. The majority of these result in good to excellent chemical yields of the corresponding alcohols along with a trend for better ee results with aryl alkyl ketones than with prochiral dialkyl ketones. 

The bis-DIOP complex HRh[(+)-DIOP]2 has been used under mild conditions for catalytic asymmetric hydrogenation of several prochiral olefinic carboxylic acids (273-275). Optical yields for reduction of N-acetamidoacrylic acid (56% ee) and atropic acid (37% ee) are much lower than those obtained using the mono-DIOP catalysts (10, II, 225). The rates in the bis-DIOP systems, however, are much slower, and the hydrogenations are complicated by slow formation of the cationic complex Rh(DIOP)2+ (271, 273, 274) through reaction of the starting hydride with protons from the substrate under H2 the cationic dihydride is maintained [cf. Eq. (25)] ... 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

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