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Emulating Natural Product Conformation by Cooperative, Non‐Covalent Fluorine Interactions
Author(s) -
Scheidt Felix,
Selter Philipp,
Santschi Nico,
Holland Mareike C.,
Dudenko Dmytro V.,
Daniliuc Constantin,
MückLichtenfeld Christian,
Hansen Michael Ryan,
Gilmour Ryan
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201604632
Subject(s) - vicinal , chemistry , covalent bond , natural product , ether , molecule , fluorine , stereochemistry , function (biology) , expansive , combinatorial chemistry , organic chemistry , materials science , compressive strength , evolutionary biology , composite material , biology
Pervasive in Nature, the propane unit is an essential component of numerous bioactive molecules. These range from acyclic systems, such as the neurotransmitter γ‐aminobutyric acid, through to the bicyclic nuclei of various chromanes and dihydrobenzofurans. In the latter case, cyclisation via cyclic ether formation ensures a highly pre‐organised structure, whilst linear scaffolds display more dynamic conformational behaviour resulting from rotation about the two internal C(sp 3 )–C(sp 3 ) bonds. In this study, the replacement of ‐[CH 2 ]‐ units by ‐[CHF]‐ centres is evaluated as a strategy to achieve acyclic conformational control by hindering these internal rotations. Reinforcing, non‐covalent fluorine interactions are validated as powerful design features that result in programmable conformational behaviours: These are encoded by the relative configuration of each centre. By exploiting cooperative neighbouring stereoelectronic effects in a multi‐vicinal fluoroalkane it is possible to emulate the overall conformation of the dihydrobenzofuran scaffold found in a variety of natural products with an acyclic mimic. This is described as a function of two bond vectors at the chain termini and validated by combined theoretical, crystallographic and spectroscopic analyses. In view of the favourable physicochemical properties associated with fluorine introduction, this approach to bioactive scaffold design may prove to be expansive.