Enantiomers reactions with racemic mixtures

Reaction of an achiral reagent with a molecule exhibiting enantiotopic faces will produce equal quantities of enantiomers, and a racemic mixture will result. The achiral reagent sodium borodeuteride, for example, will produce racemic l-deM/eno-ethanol. Chiral reagent can discriminate between the prochiral faces, and the reaction will be enantioselective. Enzymatic reduction of acetaldehyde- -[Pg.106]

KR is the total or partial separation of two enantiomers from a racemic mixture [5]. KR is based on the different reaction rates of the enantiomers with a chiral molecule (a reagent, a catalyst, etc). In the ideal case, the difference in reactivity is large, and one of the enantiomers reacts very fast to give the product, whereas the other does not react at all (Figure 4.1). 

The hydrolytic kinetic resolution (HKR) of terminal epoxides using Co-salen catalysts provides a convenient route to the synthesis of enantioemiched chiral compounds by selectively converting one enantiomer of the racemic mixture (with a maximum 50% yield and 100% ee) (1-3). The use of water as the nucleophile makes this reaction straightforward to perform at a relatively low cost. The homogeneous Co(III) salen catalyst developed by Jacobsen s group has been shown to provide high... 

Partial or complete separation of enantiomers within a racemic mixture as a result of unequal rates of reaction with another agent. The latter reagent, catalyst, solvent, or micelle must itself exhibit chirality, resulting in its stereoselective or stereospecific action on the racemic compound. 

By contrast with the enantioselective deprotonation of meso oxiranes, there is only a limited number of reports on the kinetic resolution of unsymmetrically substituted oxiranes. This reaction involves the preferential recognition of one of the two enantiomers of a racemic mixture by a chiral reagent to provide both the starting material and the product in enantioenriched form . Several HCLA bases developed for enantioselective deprotonation have been tested as chiral reagent in stoichiometric or catalytic amount for the kinetic resolution of cyclic and linear oxiranes. 

Although the reaction sequence is shown for only one of the enantiomers of the racemic mixture it must hold for the other, except that the configurations of the products are reversed. This is invariably the case in the reaction of optically active compounds with symmetric reagents. Thus since the final step causes the loss of the asymmetric centres, all distinction between the path vanishes and the same product appears. 

Another resolution method that is sometimes employed involves the selective reaction of one enantiomer of a racemic mixture with one enantiomer of a chiral reagent,... 

A recent discovery that has significantly extended the scope of asymmetric catalytic reactions for practical applications is the metal-complex-catalyzed hydrolysis of a racemic mixture of epoxides. The basic principle behind this is kinetic resolution. In practice this means that under a given set of conditions the two enantiomers of the racemic mixture undergo hydrolysis at different rates. The different rates of reactions are presumably caused by the diastereo-meric interaction between the chiral metal catalyst and the two enantiomers of the epoxide. Diastereomeric intermediates and/or transition states that differ in the energies of activation are presumably generated. The result is the formation of the product, a diol, with high enantioselectivity. One of the enantiomers of... 

The development of new methodologies for asymmetric synthesis is of crucial importance and in this context the new strategy of parallel kinetic resolution (PKR), whereby both enantiomers of a racemic mixture can be converted to useful products via simultaneous reaction with two different chiral reagents, is particularly promising. Pedersen and co-workers have recently reported the first asymmetric Horner-Wadsworth-Emmons procedure that allows the parallel kinetic resolution of racemic aldehydes. These workers have used two alternative approaches. In the first approach (Scheme... 

Kinetic resolution The separation (or partial separation) of enantiomers due to a difference in the rate of reaction of the two enantiomers in a racemic mixture with an nonracemic chiral reagent. 

For the enantioselective dehydrogenation of the ( -enantiomer from a racemic mixture of 3-hydroxybutyrate three different methods were used to regenerate NADP (Table 27) (83). The first method worked with catalytic concentrations of NADP and anthraquinone-2.6-disulphonate. NADPH was reoxidized by oxidized anthraquinone-2.6-disulphonate catalysed by AMAPOR (Reaction [31a]). The reduced anthraquinone-2.6-disulphonate was electrochemically reoxidized. In experiment 2 a method described by the Whitesides group (106) was applied for NADP regeneration. Oxidized anthra-quinone-2.6-disulphonate could also be used in stoichiometric concentrations (exp. 3). In such a case its electrochemical reoxidation was not necessary. Obviously in experiment 1 the product isolation is especially simple. 

Thus the very process of crystallization leads to separation of excess enantiomer and of racemic mixture In different crystals. In order to achieve enantiomeric enrichment, one has need to separate the materials constituting these two types of crystals. This Is achieved by Irradiation the racemic, exclmer-formlng crystals undergo reaction to yield photodimers which are highly Insoluble. Extraction with a suitable solvent removes residual monomer, which Is the excess enantiomer. 

Another approach, called kinetic resolution, depends on the different rates of reaction of two enantiomers with a chiral reagent. A very effective form of kinetic resolution uses enzymes as chiral catalysts to selectively bring about the reaction of one enantiomer in a racemic mixture (enzymatic resolution). Lipases, or esterases, enzymes that catalyze ester hydrolysis, are often used. In a typical procedure, one enantiomer of the acetate ester of a racemic alcohol undergoes hydrolysis and the other is left unchanged when hydrolyzed in the presence of an esterase from hog liver. 

Because kinetic resolutions provide a means to separate the two enantiomers of a racemic mixture, the maximum yield of enantiopure product from a kinetic resolution is 50%. For this reason, an increased emphasis has been placed on enantioselective catalysis over kinetic resolution (enantioselective catalysis can generate 100% yield of enantioemiched product, at least in principle). However, the continued use of KR and development of syn-theticaUy valuable new kinetic resolutions attests to the utility of these classes of reactions. KR is often the best option when the racemate is inexpeiwive, when no practical enantioselective route to the single enantiomer is available, or when classical resolution does not provide the desired material with high ee. ... 

Kinetic resolutions of allylic esters have also been conducted. As noted in Chapter 14, in most cases, catalysts that are selective for kinetic resolution of substrates containing one type of functional group are also selective for reactions of meso substrates and vice versa.The enantioselective reaction of one acetate of a meso substrate involves similar stereochemical recognition to reaction of two enantiomers of a racemic mixture of allylic esters. In one illustrative example, an allylic acetate underwent reaction with a pivalate nucleophile to form the allylic pivalate product, which is less reactive than the starting compound (Equation 20.54). Reaction of one enantiomer of the racemic allylic acetate occurs preferentially, and the pivalate product is formed enantioselec-tively. The product of the resolution in Equation 20.54 was carried forward to form (+)-cyclophellitol. 

Two examples of enzymatic resolutions with selectivities of = 5 and = 20 are depicted in Fig. 2.4. The curves show that the product (P -E Q) can be obtained in its highest optical purities before 50% conversion, where the enzyme can freely choose the weU-fitting enantiomer from the racemic mixture. So, the well-fitting enantiomer is predominantly depleted from the reaction mixture during the course of the reaction, leaving behind the poor-fitting counterpart. Beyond 50% conversion, the enhanced relative concentration of the poor-fitting counterpart leads to... 

This book is about the separation of enantiomers by synthetic methods, which is to say methods involving some chemical transformation as part of the separation process. We do not in this book cover chromatographic methods for the separation of enantiomers [1]. Nor do we focus on methods based on crystallizations as these have been amply reviewed elsewhere (see below). We are concerned mainly therefore with resolutions that involve a synthetic component, so mostly with the various flavours of kinetic resolutions through to more modern methods such as divergent reactions ofa racemic mixture (DRRM).This introduction briefly clarifies the scope of the book. 

Scheme 2.1 indicates a general presentation of the KR of a racemic compound (R, S) when the product is chiral (case I) or achiral (case II). In both cases, the KR process is characterized by two competitive reactions going with different rates on the two enantiomers of the racemic mixture. Each rate depends on the concentrations of the reactants, the rate constants and the kinetic law. A common situation is a kinetic law first-order in substrate, here the (R) and (S) enantiomers (Scheme 2.1). 

Notice that the stereochemistry of the product of the osmium tetroxide oxidation of lrans-2-butene is opposite that formed on the addition of bromine to lra s-2-butene. Osmium tetroxide oxidation gives the glycol as a pair of enantiomers forming a racemic mixture. Addition of bromine to trcms-2-butene gives the dibromoalkane as a meso compound. A similar difference is observed between the stereochemical outcomes of these reactions with ds-2-butene. The difference in outcomes occurs because bromination of an alkene involves anti addition, whereas oxidation by osmiinn tetroxide involves syn addition. 

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