Kinetic Resolutions of Esters

The potential analgesic and replacements of the opiate-agonist tramadol, e-hydroxyl-tramadol, was resolved enzymatically [43, 45]. Screening of several enzymes revealed that selective enzymes for both enantiomers were available. While pig liver esterase (PLE) hydrolysed the ester of the active enantiomer, 

The atom efficiency of a kinetic resolution is increased if the starting material is not an ester but a lactone. Indeed, kinetic resolutions of lactones are used on an industrial scale. Fuji/Daiichi Chemicals produces D-pantothenic acid on a multi-ton scale based on such a resolution. D-Pantolactone is hydrolysed at pH 7 by a hydrolase from Fusarium oxysporum yielding D-pantoic acid with an ee of 96% while L-pantoic acid was barely detectable. The immobilized Fusarium oxysporum cells were recycled 180 times and retained 60% of their activity, demonstrating the great stability of this catalytic system [47-50]. 

---

Figure 2.9 Schematic summary of the directed evolution of enantioselective lipase variants originating from the WT PAL used as catalysts in the hydrolytic kinetic resolution of ester rac-1. CMCM = Combinatorial multiple-cassette mutagenesis [8c,22],...

Efforts were also made to invert the sense of enantioselectivity in the hydrolytic kinetic resolution of ester (1) using PAL with preferential formation of (R)-2 [40,411-Using epPCR and DNA shuffling, an (R)-selective mutant showing an E value of 30 was evolved by screening about 45 000 clones for the (R) enantiomer. The best mutant is characterized by 11 mutations, which are different from those of the best (S)-selective variant X [41]. 

The above-mentioned facts have important consequences on the stereochemical outcome of the kinetic resolution of asymmetrically substituted epoxides. In the majority of kinetic resolutions of esters (e.g. by ester hydrolysis and synthesis using lipases, esterases and proteases) the absolute configuration at the stereogenic centre(s) always remains the same throughout the reaction. In contrast, the enzymatic hydrolysis of epoxides may take place via attack on either carbon of the oxirane ring (Scheme 7) and it is the structure of the substrate and of the enzyme involved which determine the regioselec-tivity of the attack [53, 58-611. As a consequence, the absolute configuration of both the product and substrate from a kinetic resolution of a racemic... 

UV/visible/Quick-E-test kinetic resolution of esters 14... 

Fluorescence/enzyme coupled kinetic resolution of esters 26... 

To assess the applicability of FTIR spectroscopy for determining ee values for a given substrate, especially with regard to accuracy, the best position at which isotopes are introduced needs to be determined. For illustration, the lipase- or esterase-catalyzed kinetic resolution of esters is considered here, although the method is not restricted to this type of reaction.13C labeling of carbonyl groups is ideal for several reasons ... 

General Assay for Kinetic Resolution of Esters (Kazlauskas Test)... 

Figure 11. Dynamic kinetic resolutions of esters and alcohols...

Kinetic Resolutions of Esters Combined with Inversions... 

The enantioselective formation and hydrolysis of esters has been very heavily investigated using enzymatic methods, and has been well reviewed elsewhere. The use of nonenzymatic methods for the kinetic resolution of ester formation and hydrolysis is becoming increasingly important. A range of new catalysts has been shown to have good levels of enantioselectivity. ... 

---