Kinetic Resolution of Alcohols, Amines, and Amino Acids

Dynamic Kinetic Resolution of Alcohols, Amines, and Amino Acids 

Jusuk Lee, Yoon Kyung Choi, Jaiwook Park, and Mahn-joo Kim 

Department of Chemistry, Pohang University of Science and Technology, Pohang, South Korea 

The classical enzymatic kinetic resolution of a racemic substrate provides two enantiomers as the product and unreacted substrate. In this case, the theoretical maximum yield for one enantiomer is 50%. To improve the yield, tite opposite enantiomer is racemized and then recycled for the second enzymatic kinetic resolution. The racemi-zation-recycling process should be repeated at least three times to achieve more than a 90% yield. In the metalloenzymatic DKR, the enzymatic kinetic resolution occurs simultaneously with the metal-catalyzed racemization, so all tiie substrates can be converted to the products to provide a near 100% yield in a single operation. Each DKR process, however, gives only single enantiomeric products. Accordingly, two stereocomplementary enzymes are needed for the synthesis of a pair of enantiomeric products via DKR. 

---

DYNAMIC KINETIC RESOLUTION OF ALCOHOLS, AMINES, AND AMINO ACIDS... 

Of the six main classes of enzymes, hydrolases, oxidoreductases and transferases have been the three most useful in kinetic resolution. Among the hydrolases, lipases are extensively used. The molecular machinery of lipases consists of a catalytic triad of the amino acids serine, histidine, and aspartic (or glutamic) acid. The enzyme first transfers the acyl group of an ester to the hydroxyl group of the serine residue to form the acylated enzyme. The acyl group is subsequently transferred to an external nucleophile with the return of the enzyme to its pre-acylated state to start the process again. A variety of nucleophiles can participate in this process water results in hydrolysis, an amine results in amidation, an alcohol results in esterification or transesterification, and hydrogen peroxide results in the formation of perac-id. Another reason which favored the relatively wide applicability of lipases in enzymatic... 

On the other hand, the Yu group reported a kinetic resolution via a Pd-catalyzed enantioselective C—H bond iodination of racemic benzylic amines rac-61 by the Pd VMPAA catalytic system." In addition to simple arylalkyl-amines, a wide range of 3-amino acids and 3-amino alcohols are compatible... 

Transaminases are most powerful tools for the synthesis of chiral amines, amino acids, and amino alcohols, hi this chapter several approaches for tiie preparation of fine chemicals or building blocks for pharmaceuticals were discussed, like asymmetric synthesis or kinetic resolution. The main limitations of transaminase-catalyzed reactions are the need to shift the equihbrium to the product side and substrate and product inhibition. Some solutions to overcome such inhibition were presented here for example, multienzyme cascades or biphasic extraction of the product. Protein engineering by directed evolution or rational enzyme design is a promising option to find transaminases with different substrate specificities and enantiopreferences. This is becoming more and more important for the pharmaceutical industry. Furthermore, it is a way to alter enzyme properties known so far, like thermostability and solvent and pH stability. Protein engineering has been assisted by the recently solved structures of certain transaminases. 

The separation of amino acids into particular enantiomers was the subject of mass spectrometric studies but also ESI MS was applied to determine by kinetic resolution the enantiomeric excess of optically active alcohols and amines in nanoscale by diastereoselective derivatization with optically active acids [38], This method has several distinctive features among others, easily available chiral acids can be used (the authors used A -benzoyl proline derivatives), no chromatographic separations are required, it is insensitive to certain impurities, it is fast and requires only small amount of substrate (10 nmol or less). The method can take an advantage when accuracy of enantiomeric excess measurement is sufficient within 10% limits. 

---