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Inverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H?F Bioisosterism.


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 (???*). 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.

SUBMITTER: Bentler P 

PROVIDER: S-EPMC6771710 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Inverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism.

Bentler Patrick P   Bergander Klaus K   Daniliuc Constantin G CG   Mück-Lichtenfeld Christian C   Jumde Ravindra P RP   Hirsch Anna K H AKH   Gilmour Ryan R  

Angewandte Chemie (International ed. in English) 20190703 32


Fluorinated motifs have a venerable history in drug discovery, but as C(sp<sup>3</sup> )-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 we  ...[more]

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