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Inverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism.
Bentler, Patrick Bergander, Klaus Daniliuc, Constantin G Mück-Lichtenfeld, Christian Jumde, Ravindra P Hirsch, Anna K H Gilmour, Ryan
Bentler, Patrick
Bergander, Klaus
Daniliuc, Constantin G
Mück-Lichtenfeld, Christian
Jumde, Ravindra P
Hirsch, Anna K H
Gilmour, Ryan
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2019-08-05
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Abstract
Fluorinated 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.
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Angew Chem Int Ed Engl. 2019 Aug 5;58(32):10990-10994. doi: 10.1002/anie.201905452. Epub 2019 Jul 3.
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en
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1521-3773
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Attribution-NonCommercial-ShareAlike 4.0 International