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Emulating Natural Product Conformation by Cooperative, Non‐Covalent Fluorine Interactions

2016; Wiley; Volume: 23; Issue: 25 Linguagem: Inglês

10.1002/chem.201604632

1521-3765

Felix Scheidt, Philipp Selter, Nico Santschi, Mareike C. Holland, Dmytro Dudenko, Constantin G. Daniliuc, Christian Mück‐Lichtenfeld, Michael Ryan Hansen, Ryan Gilmour,

Carbohydrate Chemistry and Synthesis

Abstract 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.