Premium
Inverting Small Molecule–Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism
Author(s) -
Bentler Patrick,
Bergander Klaus,
Daniliuc Constantin G.,
MückLichtenfeld Christian,
Jumde Ravindra P.,
Hirsch Anna K. H.,
Gilmour Ryan
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201905452
Subject(s) - chemistry , selectivity , stereochemistry , fluorine , stereoselectivity , molecule , kinetic resolution , pseudomonas fluorescens , lipase , combinatorial chemistry , enzyme , enantioselective synthesis , organic chemistry , biology , bacteria , genetics , catalysis
Fluorinated motifs have a venerable history in drug discovery, but as C(sp 3 )−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.