Optical Resolutions via Derivatives

0-Acyl Cleavage Carboxypeptidases (EC 3.4) are exopeptidases, which catalyze the release of C-terminal (S)-amino acids from peptides. Carboxypeptidase variants include A (for neutral and acidic amino acids), B (for basic amino acids) and Y (accepting a broad 

Selective hydrolysis of esters is a well-established procedure for the resolution of chiral carboxylic acids. Enzymes such as hydrolases, lipases and proteases are utilized. Due to their high selectivity for (5)-amino acids, proteases have been widely used in the selective transformations of amino acids and their derivatives. a-Chymotrypsin- a serine protease -catalyzes not only the hydrolysis of amide bonds, but also the cleavage of various esters, including a-alkyl-a-amino acid esters. One application is the synthesis of (5)-a-[ C]-methyltryptophan The anion synthesized by LDA-deprotonation of M-benzylidene tryptophan methyl ester (T) was alkylated with [ CJmethyl iodide to obtain the methyl A-benzylidene derivative 2, which was hydrolyzed under acidic conditions. Subsequent selective cleavage of the ester group with a-chymotrypsin provided the enantiomerically pure (5)-amino acid 3 in 33% radiochemical yield. 

COOEt H- NHAc COOEt AcHN-4—H COOH AcHN l—H coo  

Reaction conditions 1. separation by HPLC 2. a-chymotrypsin, MeOH, 0.5 M NH4OAC, pH 6.9 24 h 3. 1 M trifluoroacetic acid reflux, 6 h 

Other enzymes widely used in organic syntheses are lipases. Lipases are serine hydrolases that catalyze the hydrolysis of lipids to fatty acids. An example of their use is in the resolution of racemic methyl 4-benzyloxy-2-(hydroxymethyl)[l- C]butyrate (8), an intermediate for the carbon-13 labeling of the antiviral agents penciclovir and famciclovir. From a limited number of candidates Candida cylindracea lipase turned out to be the enzyme of choice. At optimal reaction conditions (pH 5-7, 35 °C) no nonenzymatic hydrolysis was detectable. Due to insufficient enzymatic stereospecificity, however, the hydrolysis provided the unreacted dextrorotary ester 2 at an optical purity of 94% e.e. and the hydrolyzed levorotary acid 10 at an optical purity of 70% e.e. 

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