Summary
A key intermediate (S(−) 2-cyclohexyl-1,3-propanediol monoacetate) was made with high optical purity for the total synthesis of a new angiotensin converting enzyme inhibitor, Fosinopril. The stereoselective hydrolysis of 2-cyclohexyl-1,3-propanediol diacetate (I) and 2-phenyl-1,3-propanediol diacetate (II) was carried out with lipases. Among various lipases evaluated, only porcine pancreatic lipase (PPL) and Chromobacterium viscosum lipase demonstrated efficient conversion and gave the desired enantiomer of monoacetate. In aqueous solution, the desired S(−) monoacetate exhibited an optical purity of 65%–80% (30%–60% enantiomeric excess [e.e.]). However, when the same reactions were conducted in a biphasic system, the product S(−) monoacetate exhibited an optical purity of 99%–100% (98%–100% e.e.). The high purity product was achieved with 65 mol% yield at 1% substrate concentration. Among various solvents evaluated in biphasic systems, efficient hydrolysis was achieved in toluene, cyclohexane, and trichloro-trifluoroethane. The crude PPL was partially purified and two lipase fractions (A and B) were identified. Lipases A and B had a molecular mass of 38 000 and 40 000 daltons, respectively, and both were found to catalyze the hydrolysis of I and II to the appropriate monoacetate in a biphasic system.
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References
Barlett PA (1980) Stereocontrol in the synthesis of acyclic systems: applications to natural product synthesis. Tetrahedron Lett 36:2–72
Chen CS, Sih CJ (1989) General aspect and optimization of enantioselective biocatalysis in organic solvents: the use of lipases. Angew Chem Int Ed Engl 28:695–707
Eliel EL, Otsaka S (1982) Asymmetric reactions and process in chemistry. American Chemical Society, Washington, DC
Jones J (1986) Enzymes in organic synthesis. Tetrahedron 42:3351–3403
Khmelnitsky YL, Levashov AV, Klyachko NL, Martinek K (1988) Engineering biocatalysis system in organic media with low water content. Enzyme microb Technol 10:710–724
Klibanov AM (1986) Enzymes that work in organic solvent. Chemtech 6:354–359
Laumen K, Schneider M (1985) Enantioselective hydrolysis of cis-1,2-diacetoxycycloalkanedimethanols: enzymatic preparation of chiral building blocks from prochiral meso-substrate. Tetrahedron Lett 26:2073–2076
Mohr P, Waespe-Sarcevic N, Tamm C (1983) A study of stereoselective hydrolysis of symmetrical diesters with pig liver esterase. Helv Chim Acta 66:2501–2511
Mosher HS, Morrison TD (1983) Current status of asymmetric synthesis. Science 221:1013–1019
Morrison TD, Mosher HS (1971) Asymmetric organic reactions. Prentice Hall, New York
Tombo GMR, Schar HP, Busquets XF, Ghisalba O (1986) Synthesis of both enantiomeric forms of 2-substituted 1,3-propanediol monoacetates starting from a common prochiral precursors, using enzymatic transformation in aqueous and organic media. Tetrahedron Lett 21:5707–5710
Whitesides GH, Wong C (1985) Enzymes as catalyst in synthetic organic chemistry. Angew Chem Int Ed Engl 24:617–638
Yamada H, Shimizu S (1988) Microbial and enzymatic processes for the production of biologically and chemically useful compounds. Angew Chem Int Ed Engl 27:622–642
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Patel, R.N., Robison, R.S. & Szarka, L.J. Stereoselective enzymatic hydrolysis of 2-cyclohexyl-and 2-phenyl-1,3-propanediol diacetate in biphasic systems. Appl Microbiol Biotechnol 34, 10–14 (1990). https://doi.org/10.1007/BF00170915
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DOI: https://doi.org/10.1007/BF00170915