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

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 )-C(sp ) bonds. In this study, the replacement of -[CH ]- 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.

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

“…This matches the geometry that was observed in the X-ray crystal structure for the anti , syn- trifluoroalkane 40a [ 17 ]. The second conformer (right) has a bent shape which provides gauche alignments between all pairs of vicinal C–F and C–N bonds, whilst avoiding any 1,3-dipolar repulsions [ 11 – 12 43 ].…”

“…The first conformer (left) has a bent structure. This provides gauche alignments between all pairs of vicinal C–F and C–N bonds, whilst avoiding 1,3-dipolar repulsion [ 11 – 12 43 ]. The second suggested conformer of 6b (right) has an extended zigzag structure.…”

Enantioselektive Synthese von 3‐Fluorchromanen durch Iod(I)/Iod(III)‐Katalyse

“…In allen Beispielen sind die Donor-C(sp 3 )-H/CH 3 -Bindungen am fluorhaltigen Kohlenstoffatom antiperiplanar zur C(sp 3 )-O-Bindung im Ring und erfüllen damit die stereoelektronischenA nforderungen des gauche-Effekts. [9] Um den Anwendungsbereich und die Grenzen der Reaktion weiter zu bestimmen und die Arbeitshypothese zu unterstützen, wurde eine Reihe von Kontrollexperimenten durchgeführt (Schema 2). Wiebereits zuvor erwähnt, war das elektronenreiche para-Methoxyderivat 22 nicht kompatibel mit den Reaktionsbedingungen (23, < 5%).…”

“…[7] Zur Vervollständigung des bioisosteren Kontinuums [H % F % OH] (Abbildung 1, Mitte) [8] sind effiziente Synthesen des 3-Fluorchromansystems nçtig, die oben genannte elegante Strategien ergänzen -a uch um das Potenzial des unsubstituierten Ringsystems in der Wirkstoffentwicklung zu erforschen. Die vicinale Beziehung des Fluoratoms und des Ringsauerstoffatoms sollte in stabilisierenden hyperkonjugativen Wechselwirkungen (s C-H !s C-F *) resultieren, [9] die sich in der Konformation dieser Wirkstoffeinheit manifestieren. Das breite Spektrum Chroman-vermittelter biologischer Aktivitäten stellt einen starken Anreiz dar,d ieses Defizit der gegenwärtigen Katalyse zu beheben.…”

Stereoelectronic Effects in Multivicinal Fluoroalkanes and Conformational Implications

“…In addition to perfluoroalkanes, multivicinal fluoroalkanes is an interesting group of fluorinated compounds whose synthesis have been extensively explored . Because of their very particular physicochemical properties, like hydrophilic behavior in some cases, they have potential to be particularly relevant to self assembly monolayers and liquid crystal applications, likewise the typical relevance of fluorinated compounds to medicinal chemistry and to mimetize natural products .…”