In:
Angewandte Chemie International Edition, Wiley, Vol. 58, No. 32 ( 2019-08-05), p. 10990-10994
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1433-7851
,
1521-3773
DOI:
10.1002/anie.201905452
Language:
English
Publisher:
Wiley
Publication Date:
2019
detail.hit.zdb_id:
2011836-3
detail.hit.zdb_id:
123227-7
Bookmarklink