Enzyme-catalyzed resolution of 3,8-dioxatricyclo[3.2.1.0]octane-6-carboxylic esters and the application to the synthesis of 3-epishikimic acid |
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| Authors: | Manabu Hamada Yoshikazu Inami Yasuhito Nagai Toshinori Higashi Mitsuru Shoji Seiichiro Ogawa Kazuo Umezawa Takeshi Sugai |
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| Affiliation: | aDepartment of Applied Chemistry, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan;bFaculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo 105-8512, Japan;cDepartment of Chemistry, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan;dDepartment of Bioscience and Bioinformatics, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan |
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| Abstract: | 3,8-Dioxatricyclo[3.2.1.02,4]octane-6-carboxylic acid, whose racemic form is readily available on a large scale, is a versatile starting material for the synthesis of carbasugars and carbocyclic biologically active natural products. In this study, the enzyme-catalyzed kinetic resolution was attempted on a variety of corresponding carboxylic esters. The hydrophobic and hydrophilic properties of ester substituents greatly affected the rate of reaction and the enantioselectivity. Hydrolysis of the corresponding 2′-chloroethyl ester with pig liver esterase worked well in a highly enantioselective manner (E = 116) to give the hydrolyzate (90.6% ee) and unreacted ester recovery (99.4% ee). The hydrolyzate is a precursor for (−)-oseltamivir phosphate, and a route to (3S,4S,5R)-(−)-3-epishikimic acid was developed from the recovered ester. |
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