Fluorinated Organocatalysts for the Enantioselective Epoxidation of Enals: Molecular Preorganisation by the Fluorine‐Iminium Ion Gauche Effect

Abstract

The fluorine-iminium ion gauche effect is triggered upon union of a secondary β-fluoroamine and an α,β-unsaturated aldehyde, providing a useful strategy for controlling the molecular topology of intermediates that are central to organocatalytic processes. The β-fluoroamine (S)-2-(fluorodiphenylmethyl)pyrrolidine (1) is an effective catalyst for the enantioselective epoxidation of α,β-unsaturated aldehydes. A process of structural editing has revealed that the efficiency of this catalyst is due to the (fluorodiphenyl)methyl group when it is embedded in a β-fluoroiminium motif. Epoxidations of challenging cyclic α,β-disubstituted, β,β-disubstituted and α,β,β-trisubstituted enals catalysed by 1 proceed with excellent levels of enantiocontrol (up to 98% ee).

Modulating NHC catalysis with fluorine

“…3) [42]. In previous analyses of ( S )-2-(fluorodiphenylmethyl)pyrrolidine derivatives, the synclinal-endo conformation was almost exclusively observed in the solid state [13,15–16 18,21–22]. This was also found to be the case in triazolium salt 5 (Φ NCCF −54.0°), with the diphenylfluoromethyl group adopting a quasi -equatorial orientation, presumably to minimise non-bonding interactions as a consequence of the sterically demanding phenyl groups.…”

Chemistry without Bo(a)rders

“…A process of structural editing has revealed that the efficiency of this catalyst is due to the (fluorodiphenyl)methyl group. [14] Furthermore, the epoxidation and aziridation of challenging cyclic α,β-disubstituted, β,β-disubstituted and α,β,β-trisubstituted enals catalysed by (S)-2-(fluorodiphenylmethyl)-pyrrolidine proceeded with excellent levels of enantiocontrol (up to 99% ee). [13,14] Furthermore, we were able to extend this principal to chiral DMAP analogues, showing that by invoking the fluorine gauche effect we could predictably control molecular space, by hindering rotation around the only rotatable sp 3 -sp 3 bond.…”

“…[14] Furthermore, the epoxidation and aziridation of challenging cyclic α,β-disubstituted, β,β-disubstituted and α,β,β-trisubstituted enals catalysed by (S)-2-(fluorodiphenylmethyl)-pyrrolidine proceeded with excellent levels of enantiocontrol (up to 99% ee). [13,14] Furthermore, we were able to extend this principal to chiral DMAP analogues, showing that by invoking the fluorine gauche effect we could predictably control molecular space, by hindering rotation around the only rotatable sp 3 -sp 3 bond. [15] This design approach was verified by X-ray analysis as well as computational methods, where a clear preference for the gauche conformation (φNCCF ≈ 60°) was apparent.…”

Chiral imidazolidinone and proline-derived surface modifiers for the Pt-catalysed asymmetric hydrogenation of activated ketones

“…The synthesis of the following compounds has been described in the literature: 6 [11], 11 [12], 18 [13], 19 [14], 20-21 [15], 22 [16], 23-24 [17], 25-26 [18], 29-31 [19], and 32-35 [20].…”