Microbial approach to the practical monofluorinated chiral synthons

Abstract

The synthetic approach to (+)-and (-)-Z-fluoro-Z-substituted malonic acid monoesters, based on the enantiotopic specificity of lipases and/or cellulases, which catalyze the stereospecific hydrolysis of the ester group in monofluorinated malonic acid diesters, is described. This microbial approach to the monofluorinated chiral synthons provides a new synthetic route for introduction of a center of chirality in fluorinated organic compounds.The asymmetric synthetic opportunities provided by the catalytic activity of enzymes have increased in recent years.'-" Developments in microbial synthesis, especially, oxidative, reductive, carbon-carbon bond-forming reactions, and/or asymmetric hydrolysis, are remarkable. The importance of microbial behavior of halogen-containing compounds, which are hardly decomposed by microorganisms, has been recognized in living system^.^^^ However, with the exception of the asymmetric reduction of halogen-containing carbonyl compounds by baker's no reports concerning the use of microbially transformed halogenated compounds in synthetic reaction have appeared.We recently outlinedg-" the possibility of microbial transformation of fluorinated compounds under stereocontrol such as asymmetric induction with reductive and/or carbon-carbon bond-forming reactions and asymmetric hydrolysis. Recently considerable attention has been focused on the search for chiral synthetic tools for the preparation of fluorinated bioactive molecule^.'^^^^ As part of our continuing effort to develop stereocontrolled syntheses of fluorinated compounds with high optical purity by use of microorganisms, we have found the microbial hydrolysis of 2-fluoro-2-substituted malonic acid diesters with several lipases or cellulases yields (+)-or (-)-2-fluoro-2-substituted malonic acid monoesters. Results and DiscussionAsymmetric hydrolysis of prochiral compounds with enzymes of microbial or animal origin has been extensively s t~d i e d . '~-~~ However. it is difficult to transform halo-(1) Jones, J. B. "Enzymic and Non-Enzymic Catalysis"; Dunnill, P., (4) Retey, J.; Robinson, J. A. "Stereospecificity in Organic Chemistry and Enzymology"; Verlag-Chemie: Basel, 1982. (5) Motosugi, K.; Souda, K. Kagaku (Kyoto) 1982,37, 544 and references cited therein. (6) Filler, R.; Kobayashi, Y. 'Biomedicinal Aspects of Fluorine Chemistry"; Kodansha and Elsevier Biomedical: 1983. (7) Bucciarelli, M.; Forni, A.; Moretti, I.; Torre, G. J . Chem. SOC., Chem. Commun. 1978, 456. (8) Bucciarelli, M.; Forni, A.; Moretti, I.; Torre, G. Lee, L. F. H.; Mittal, R. S. D.; Ravikumar, P. R.; Chan, J. A.; Sih, C. J.; Capsi, E.; Eck, C. R. J . Am. Chem. SOC. 1975,97, 4144. (15) Chen, C. S.; Fujimoto, Y.; Sih, C. J. J . Am. Chem. SOC. 1981,103, 3580. (16) Schneider, M.; Engel, N.; Boensmann, H. Angew. Chem., Int. Ed. Engl. 1984, 23 and references cited therein. (17) Francis, C. J.; Jones, J. B. J. Chem. Soc., Chem. Commun. 1984, 579.Table I. Asymmetric Hydrolysis with Pig Liver Esterase R yield, 9i (mmHg) (MeOH), deg purity, % ee bp, "C [fflD optical Me 61 10...

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Asymmetric Fluorination of Enolates with Nonracemic N-Fluoro-2,10-Camphorsultams

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A New Catalyst for a Pd Catalyzed Alder Ene Reaction. A Total Synthesis of (+)-Cassiol

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