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- Title
Chiral Chlorohydrins from the Biocatalyzed Reduction of Chloroketones: Chiral Building Blocks for Antiretroviral Drugs.
- Authors
de Miranda, Amanda S.; Simon, Robert C.; Grischek, Barbara; de Paula, Gabriel C.; Horta, Bruno A. C.; de Miranda, Leandro S. M.; Kroutil, Wolfgang; Kappe, C. Oliver; de Souza, Rodrigo O. M. A.
- Abstract
E. coli cells that contain overexpressed alcohol dehydrogenases (ADHs) were screened as biocatalysts for the stereoselective reduction of chloroketones 5 a- d, the corresponding halohydrins 6 a- d of which are building blocks in the synthesis of antiretroviral drugs. Among them, ADH from Sphingobium yanoikuyae was found to reduce chloroketone 5 c with a high stereoselectivity (90 % de) and conversion (85 %) to furnish threo halohydrin ( R, S)- 6 c. ADH from Ralstonia sp. (RasADH) was able to reduce 5 a and 5 b with complementary diastereoselectivity to provide access to both threo and erythro halohydrins through 'substrate-based' stereocontrol. The RasADH-catalyzed reductions were optimized to provide ( R, S)- 6 a with 98 % conversion and 84 % diastereomeric excess ( de) and ( S, S)- 6 b with 95 % conversion and 86 % de. Molecular modeling studies showed that 5 b, which features a carboxybenzyl protecting group, is able to bind to the enzyme catalytic site in an 'inverted' mode in comparison to tert-butyloxycarbonyl- and methyloxycarbonyl-protected substrates 5 a and 5 c, which sheds light on the observed switching of the stereopreference. RasADH-catalyzed reductions were optimized to provide ( R, S)- 6 a with 98 % conversion and 84 % de and ( S, S)- 6 b with 95 % conversion and 86 % de.
- Subjects
CHLOROHYDRINS; CHIRALITY; BIOCATALYSIS; ANTIRETROVIRAL agents; ESCHERICHIA coli; DEHYDROGENASES; HALOHYDRINS
- Publication
ChemCatChem, 2015, Vol 7, Issue 6, p984
- ISSN
1867-3880
- Publication type
Article
- DOI
10.1002/cctc.201403023