Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis

Abstract

Common anionic nucleophiles such as those derived from inorganic salts have not been used for enantioselective catalysis because of their insolubility. Here, we report that merging hydrogen bonding and phase-transfer catalysis provides an effective mode of activation for nucleophiles that are insoluble in organic solvents. This catalytic manifold relies on hydrogen bonding complexation to render nucleophiles soluble and reactive, while simultaneously inducing asymmetry in the ensuing transformation. We demonstrate the concept using a chiral bis-urea catalyst to form a tridentate hydrogen bonding complex with fluoride from its cesium salt, thereby enabling highly efficient enantioselective ring opening of episulfonium ion. This fluorination method is synthetically valuable considering the scarcity of alternative protocols and points the way to wider application of the catalytic approach with diverse anionic nucleophiles.

Shielding Effect of Micelle for Highly Effective and Selective Monofluorination of Indoles in Water

“…Functional groups such as benzyloxycarbonyl (Cbz) ( 28 – 30 ) and ketone ( 32 ) were well tolerated. In the substrates containing Cbz residue, fluorination was exceptionally selective, that is, ortho to this residue, which possibly occurred owing to the delivery of fluorine atom through hydrogen bonding . Notably, with the reported methods, 31 could be only synthesized through a multistep functional‐group interconversion strategy, which produced overall low yield and an enormous amount of waste .…”

“…In the substrates containing Cbz residue, fluorination was exceptionally selective, that is, ortho to this residue, which possibly occurred owing to the delivery of fluorine atom through hydrogen bonding. [14] Notably,w itht he reported methods, 31 could be only synthesized through am ultistep functional- Table 2. Substrate scope for CÀHm onofluorinationofi ndoles.…”

2nd PSL Chemical Biology Symposium (2019): At the Crossroads of Chemistry and Biology

“…[44,45] This pioneering work led her group to developt he first example of catalytic enantioselective fluorination with the most cost-effectivef luorides ources, CsF and KF.T his chemistry uses new BINAM-derived urea organocatalysts capable of transporting fluoridef rom the solid phase into solution in the form of at ri-coordinated hydrogen-bonded F-urea complex. [46] This novel catalytic manifold,w hich she coined Hydrogen BondingP hase Transfer Catalysis, provides ag enerals olution enablingt he use of cost-effective insoluble inorganic salts as reagents for synthesis. [47] Conclusion This year,w ewere impressed by the diversity and quality of the science that was presented, and we are grateful to the speakers ( Figure 1) who enthusiastically described some sensitive unpublished work showing that science still provides af ertile ground in which peoplec an agree,d isagree, and share ideas with others.L ectures were spread over two days with ample time for scientific discussions, relaxing breaks, poster sessions, and evening drinks.…”

“…This pioneering work led her group to develop the first example of catalytic enantioselective fluorination with the most cost‐effective fluoride sources, CsF and KF. This chemistry uses new BINAM‐derived urea organocatalysts capable of transporting fluoride from the solid phase into solution in the form of a tri‐coordinated hydrogen‐bonded F–urea complex . This novel catalytic manifold, which she coined Hydrogen Bonding Phase Transfer Catalysis, provides a general solution enabling the use of cost‐effective insoluble inorganic salts as reagents for synthesis …”

Enantioselective, Catalytic Vicinal Difluorination of Alkenes

“…[4] Ac ogent bioisostere of vicinal diols ( Figure 1, right), this motif displays an inverse temperature dependent dipole moment (dm/dT < 0) [5] that is inextricably linked to the stereoelectronic gauche effect (s CÀH !s CÀF *), [6] and is apowerful physicochemical modulator in drug discovery. [10] Whilst achiral vicinal difluorination reactions of alkenes employing F 2(g) [11] or XeF 2 [12] have also been documented, their translation to an enantioselective paradigm is doubtful. [8] Consequently, stoichiometric strategies that are predicated on stereoselective oxidation/ deoxyfluorination sequences [9] are employed, where efficiencyi sf requently compromised by the loss of configurational integrity.R eagent cost, tempered nucleophilicity,and solubility issues must also be considered.…”