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dc.contributor.authorBentler, Patrick
dc.contributor.authorBergander, Klaus
dc.contributor.authorDaniliuc, Constantin G
dc.contributor.authorMück-Lichtenfeld, Christian
dc.contributor.authorJumde, Ravindra P
dc.contributor.authorHirsch, Anna K H
dc.contributor.authorGilmour, Ryan
dc.date.accessioned2019-08-21T13:19:20Z
dc.date.available2019-08-21T13:19:20Z
dc.date.issued2019-08-05
dc.identifier.citationAngew Chem Int Ed Engl. 2019 Aug 5;58(32):10990-10994. doi: 10.1002/anie.201905452. Epub 2019 Jul 3.en_US
dc.identifier.issn1521-3773
dc.identifier.pmid31157945
dc.identifier.doi10.1002/anie.201905452
dc.identifier.urihttp://hdl.handle.net/10033/621917
dc.description.abstractFluorinated motifs have a venerable history in drug discovery, but as C(sp3 )-F-rich 3D scaffolds appear with increasing frequency, the effect of multiple bioisosteric changes on molecular recognition requires elucidation. Herein we demonstrate that installation of a 1,3,5-stereotriad, in the substrate for a commonly used lipase from Pseudomonas fluorescens does not inhibit recognition, but inverts stereoselectivity. This provides facile access to optically active, stereochemically well-defined organofluorine compounds (up to 98 % ee). Whilst orthogonal recognition is observed with fluorine, the trend does not hold for the corresponding chlorinated substrates or mixed halogens. This phenomenon can be placed on a structural basis by considering the stereoelectronic gauche effect inherent to F-C-C-X systems (σ→σ*). Docking reveals that this change in selectivity (H versus F) with a common lipase results from inversion in the orientation of the bound substrate being processed as a consequence of conformation. This contrasts with the stereochemical interpretation of the biogenetic isoprene rule, whereby product divergence from a common starting material is also a consequence of conformation, albeit enforced by two discrete enzymes.en_US
dc.language.isoenen_US
dc.publisherWiley-VCHen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectbiocatalysisen_US
dc.subjectconformationen_US
dc.subjectfluorineen_US
dc.subjectgauche effecten_US
dc.subjectmolecular recognitionen_US
dc.titleInverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism.en_US
dc.typeArticleen_US
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germanyen_US
dc.identifier.journalAngewandte Chemie - International Editionen_US
refterms.dateFOA2019-08-21T13:19:20Z
dc.source.journaltitleAngewandte Chemie (International ed. in English)


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