Racemate separation

Racemate separation by stereoselective ligand exchange occurs when a chiral matrix complex has additional coordination sites that are capable of readily exchanging a racemic substrate ligand. The chiral induction, i. e., the efficiency of the matrix complex, is related to the product distribution which depends on the relative stabilities of the complexes with the two enantiomers of the racemic substrate (Fig. 8.1). The problem to be solved in the design of effective chiral matrix complexes for specific racemic substrates is therefore related to isomeric analyses of the type discussed in Section 8.1. 

An important condition for chiral matrices is that they need to form labile interactions with the substrate in order to facilitate both the recovery of the enantiose-lectively coordinated substrate ligand and the recycling of the chiral matrix. Usually copper(II) complexes have been used12341. Due to the problems involved in the modeling of Jahn-Teller distorted copper(II) complexes (see Chapter 12 for 

Chiral matrix a) Racemic substrate a Calculated (%) Observed (%) Reference 

The difference between calculated and experimentally determined distributions is generally not larger than 5 %. This accuracy is clearly reasonable in the light of the approximations discussed above. More importantly, the error limit of ca. 5% seems to be general[221 223], i.e., the method is reliable. Two additional factors emerge from Table 8.2  

Instructive examples for cases where simple intuition might fail are the reversal of selectivity of Mn+((5),( S)-ppm) with respect to rac-pn for M = Co(III) and Ni(II) (see Table 8.2 for ligand abbreviations), the increased selectivity towards rac-pam of Nin((S),(S)-epm) compared to Nin((5),(5)-ppm), and a reversal of selectivity with the same matrix complexes towards rac-pn (see Table 8.2). All of these effects are accurately predicted with molecular mechanics. 

Jahn-Teller effects), nickel(II) complexes have been used in the molecular mechanics design. They too are labile enough. Some of the systems discussed in the literature are presented in Table 7.2. 

The problem to be solved in the design of effective chiral matrix complexes for specific racemic substrates is therefore related to isomeric analyses of the type discussed in Section 8.1. 

An important condition for chiral matrices is that they need to form labile interactions with the substrate in order to facilitate both the recovery of the 

Chiral matrix Racemic substrate Calculated %) S R Observed %) S R Reference 

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Racemate Separation factor a Resolution Note factor R S Refe- rence... 

Table 7.2. Racemate separation by stereoselective ligand exchange.

The application of molecular mechanics to enantio- and diastereo-selective synthesis is less straightforward, and publications in this area have started to appear only recently. In the case of the racemate separations described above, the isomer abundances of equilibrated solutions are taken to be related to the energy of all local minima. In contrast, in order to predict the enantiomeric excesses arising from chiral syntheses, the reaction mechanisms and the basic structure of relevant intermediates or transition states have to be known since their relative energies need to be computed in order to predict the expected enantiomeric excesses. 

There are various methods for the prediction of stereoselectivities, both in racemate separation (thermodynamics, usually computed by force field methods) and enantioselective catalysis (reactivity, usually computed by quantum mechanics)18. Promising recent developments, primarily based on force field and statistical methods, but also involving QM modeling, are based on stereocartography, the computation of the chirality content and the evaluation of chirophores.151 154... 

The use of chiral auxiliaries to induce enantioselectivity was unsuccessful, as was attempted racemic separation via chiral HPLC stationary phase. It should be noted, however, that this is an excellent example of the utility of the convergent process coupled with controlled deprotection of a core unit. 

To verify this idea the methyl substituted phosphate complex 62 was synthesized and separated into its optical antipodes. The reaction with protons was not regiospecific but to a certain extent stereoselective, and the isolation of optically active phosphorane 63 was greatly helped by fortunate incursion of a spontaneous racemate separation 73>. 

A recent example of a racemate separation process (D,L-methionine) by immobilized acylase has been described 53) indicating the upcoming trend of enzyme technology in amino acid production (Fig. 2, Table 3). 

The examples shown in Table 8.2 do not show a particularly high enantioselec-tivity. However, with an enantiomeric excess of 50 % (75/25), material of acceptable optically purity can be obtained in five cycles, and for chromatographic resolutions, separation factors greater than one are sufficient for efficient resolution processes [222,223l Nickel(II) complexes of the type shown in Table 8.2 have been used to modify ion-exchange resins that were used for racemate separations[222], and derivatives of (S),(with functional groups that may be fixed to supports are readily available12 5]. 

The starting material for the acylase process is a racemic mixture of N-acetyl-amino acids 20 which are chemically synthesized by acetylation of D, L-amino acids with acetyl chloride or acetic anhydride in alkaU via the Schotten-Baumann reaction. The kinetic resolution of N-acetyl-D, L-amino acids is achieved by a specific L-acylase from Aspergillus oryzae, which only hydrolyzes the L-enantiomer and produces a mixture of the corresponding L-amino acid, acetate, and N-acetyl-D-amino acid. After separation of the L-amino acid by a crystallization step, the remaining N-acetyl-D-amino acid is recycled by thermal racemization under drastic conditions (Scheme 13.18) [47]. In a similar process racemic amino acid amides are resolved with an L-spedfic amidase and the remaining enantiomer is racemized separately. Although the final yields of the L-form are beyond 50% of the starting material in these multistep processes, the effidency of the whole transformation is much lower than a DKR process with in situ racemization. On the other hand, the structural requirements for the free carboxylate do not allow the identification of derivatives racemizable in situ therefore, the racemization requires... 

This racemate separation method was applied to synthesis of the fi-lactam 29 starting from the commercially available (Z)-DL-Ser-OH (28) (85JCS(P 1)2361). 

Michor H, Gamse T, Marr R. Enzyme catalysis in supercritical carbon dioxide racemate separation of D,L-menthol. Chem IngTechnol 1997 69 690-694. 

Kinetic resolution of alcohols and esters with hydrolases has opened up a new dimension for the synthesis of enantiomerically pure alcohols, esters and carboxylic acids, and in consequence the importance of resolution as a method for the attainment of enantiomerically pure compounds has been increased considerably. Hydrolase-catalyzed resolution is amenable to large-scale production l33-351, as was impressively demonstrated much earlier by the acylase-catalyzed racemate separation of N-acyl amino acids (not discussed in this chapter)ls4]. 

In lipase-catalyzed racemate separation of alcohols the same enantiomer preference is usually observed in acylation and hydrolysis (Scheme 11.1-15)[SG. ... 

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