Common anionic nucleophiles such as those derived from inorganic salts have not been used for enantioselective catalysis because of their insolubility in organic solvents. We herein present the successful development of a novel activation mode for these nucleophiles which relies on the merge between hydrogen bonding and phase-transfer catalysis (HB PTC). By employing readily available alkali metal fluorides as fluorinating reagents, we disclose a class of organocatalysts whose main role is to render the anion soluble and reactive while simultaneously providing an asymmetric environment. Following a brief introduction on nature’s only known fluorinase, this novel bio-inspired catalytic manifold will be presented. By using a chiral bis-urea catalyst to form a tridentate hydrogen bonding complex with fluoride from its alkali metal salt, we demonstrate for the first time that alkali metal salts are suitable fluorinating reagents for asymmetric catalysis. We then apply this concept to the desymmetrization of in situ formed episulfonium and aziridiniums ions using both CsF and KF (up to 98% yield, 97:3 e.r and 50 g-scale) to access pharmaceutically relevant compounds such as enantiopure β-fluoroamines. Furthermore, we present our recent advances in the use of ionic substrates, namely azetidinium triflates for asymmetric phase-transfer catalysis, to access enantioenriched γ-fluoroamines in high yields and enantiopurity. Finally, our most recent experimental (X-ray and NMR) and computational mechanistic insight will be presented thus highlighting the key features of the catalytic system and the broad applicability of this manifold beyond fluorination chemistry. .

Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis

ACS Spring 2022

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