In:
Angewandte Chemie International Edition, Wiley, Vol. 58, No. 32 ( 2019-08-05), p. 10990-10994
Kurzfassung:
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.
Materialart:
Online-Ressource
ISSN:
1433-7851
,
1521-3773
DOI:
10.1002/anie.201905452
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2019
ZDB Id:
2011836-3
ZDB Id:
123227-7
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