Dynamic kinetic resolution carboxylic esters

Dynamic Resolution of Chirally Labile Racemic Compounds. In ordinary kinetic resolution processes, however, the maximum yield of one enantiomer is 50%, and the ee value is affected by the extent of conversion. On the other hand, racemic compounds with a chirally labile stereogenic center may, under certain conditions, be converted to one major stereoisomer, for which the chemical yield may be 100% and the ee independent of conversion. As shown in Scheme 62, asymmetric hydrogenation of 2-substituted 3-oxo carboxylic esters provides the opportunity to produce one stereoisomer among four possible isomers in a diastereoselective and enantioselective manner. To accomplish this ideal second-order stereoselective synthesis, three conditions must be satisfied (1) racemization of the ketonic substrates must be sufficiently fast with respect to hydrogenation, (2) stereochemical control by chiral metal catalysts must be efficient, and (3) the C(2) stereogenic center must clearly differentiate between the syn and anti transition states. Systematic study has revealed that the efficiency of the dynamic kinetic resolution in the BINAP-Ru(H)-catalyzed hydrogenation is markedly influenced by the structures of the substrates and the reaction conditions, including choice of solvents. 

These results, obtained with chiral substrates, agree with the general sense of enantioselective hydrogenation of prochiral 3-oxo carboxylic esters. Obviously, the chirality of the BINAP ligand controls the facial selectivity at the carbonyl function, whereas cyclic constraints determine the relative reactivities of the enantiomeric substrates. Sterically restricted transition states that lead to the major stereoisomers are shown in Scheme 66. Overall, one of four possible diastereomeric transition states is selected to afford high stereoselectivity by dynamic kinetic resolution that involves in situ racemization of the substrates. 

Quite remarkable progress has also been achieved in enantioselective transformation of cyclic anhydrides derived from a-hydroxy and a-amino carboxylic acids. By careful choice of the reaction conditions, dynamic kinetic resolution by alcoholysis has become reality for a broad range of substrates. Again, the above mentioned dimeric cinchona alkaloids were the catalysts of choice. In other words, organoca-talytic methods are now available for high-yielding conversion of racemic a-hydroxy and a-amino acids to their enantiomerically pure esters. If desired, the latter esters can be converted back to the parent - but enantiomerically pure - acids by subsequent ester cleavage. 

Kitamura, M., Tokunaga, M., Noyori, R. Quantitative expression of dynamic kinetic resolution of chirally labile enantiomers stereoselective hydrogenation of 2-substituted 3-oxo carboxylic esters catalyzed by BINAP-ruthenium(ll) complexes. J. Am. Chem. Soc. 1993,115, 144-152. 

The key step in dynamic kinetic resolutions is the in situ racemization. A number of reactions can racemize organic substrates, but most conditions are too harsh to allow a simultaneous enzyme-catalyzed reaction. In the past, the difficulty of racemizing normal alcohols and carboxylate esters restticted these dynamic kinetic resolutions to special cases. However, recent discovery of organometallic catalysts that can racemize a wide range of secondary alcohols have extended the range of these reactions [23]. 

Fulling and Sih reported one of the earliest examples to exploit racemization of carboxylic acid derivatives in order to achieve a dynamic kinetic resolution1311. The anti-inflammatory drug Ketorolac was prepared by hydrolysis of the corresponding ester. Whilst most lipases afforded the undesired enantiomer preferentially, a protease from Streptomyces griseus afforded the required (S)-enantiomer of product with good selectivity. The substrate was particularly prone to racemization since the intermediate enolate is well stabilized by resonance effects, although a pH 9 7 buffer was required to achieve a useful dynamic resolution reaction. Thus the acid was formed with complete conversion and with 76 % enantiomeric excess. 

In addition to in situ racemization of a-substituted carboxylic acid derivatives by deprotonation/reprotonation, a procedure involving halide exchange has been developed135, 361. Whilst the a-halo esters undergo racemization at a reasonable rate, the corresponding carboxylates are almost inert to racemization under the reaction conditions. Using immobilized phosphonium halide and CLEC (cross-linked enzyme crystals), a dynamic resolution procedure has been developed for the hydrolysis of a-bromo and a-chloro esters (Fig. 9-17). The enantiomeric excess in each case was similar to that achieved for simple kinetic resolution reactions using the same enzyme/substrate combinations. 

---