Hydrogen Bonding Phase-Transfer Catalysis with Ionic Reactants: Enantioselective Synthesis of γ-Fluoroamines.

Ammonium salts are used as phase-transfer catalysts for fluorination with alkali metal fluorides. We now demonstrate that these organic salts, specifically azetidinium triflates, are suitable substrates for enantioselective ring opening with CsF and a chiral bis-urea catalyst. This process, which highlights the ability of hydrogen bonding phase-transfer catalysts to couple two ionic reactants, affords enantioenriched γ-fluoroamines in high yields. Mechanistic studies underline the role of the catalyst for phase-transfer, and computed transition state structures account for the enantioconvergence observed for mixtures of achiral azetidinium diastereomers. The N-substituents in the electrophile influence the reactivity, but the configuration at nitrogen is unimportant for the enantioselectivity.

Hydrogen Bonding Phase-Transfer Catalysis with Potassium Fluoride: Enantioselective Synthesis of ß-Fluoroamines.

Potassium fluoride (KF) is an ideal reagent for fluorination because it is safe, easy to handle and low-cost. However, poor solubility in organic solvents coupled with limited strategies to control its reactivity has discouraged its use for asymmetric C-F bond formation. Here, we demonstrate that hydrogen bonding phase-transfer catalysis with KF provides access to valuable ß-fluoroamines in high yields and enantioselectivities. This methodology employs a chiral N-ethyl bis-urea catalyst that brings solid KF into solution as a tricoordinated urea-fluoride complex. This operationally simple reaction affords enantioenriched fluoro-diphenidine (up to 50 g scale) using 0.5 mol % of recoverable bis-urea catalyst.

Assembly of Divalent Ligands and Their Effect on Divalent Binding to Pseudomonas aeruginosa Lectin LecA.

Divalent ligands were prepared as inhibitors for the adhesion protein of the problematic Pseudomonas aeruginosa pathogen. Bridging two binding sites enables simultaneous binding of two galactose moieties, which strongly enhances binding. An alternating motif of glucose and triazole and aryl groups was shown to have the right mix of rigidity, solubility, and ease of synthesis. Spacers were varied with respect to the core unit as well as the aglycon portions in an attempt to optimize dynamics and enhance interactions with the protein. Affinities of the divalent ligands were measured by ITC, and Kd's as low as 12 nM were determined, notably for a compounds with either a rigid (phenyl) or flexible (butyl) unit at the core. Introducing a phenyl aglycon moiety next to the galactoside ligands on both termini did indeed lead to a higher enthalpy of binding, which was more than compensated by entropic costs. The results are discussed in terms of thermodynamics and theoretical calculations of the expected and observed multivalency effects.

Multigram synthesis of N-alkyl bis-ureas for asymmetric hydrogen bonding phase-transfer catalysis.

Fluorine is a key element present in ~35% of agrochemicals and 25% of marketed pharmaceutical drugs. The availability of reliable synthetic protocols to prepare catalysts that allow the efficient incorporation of fluorine in organic molecules is therefore essential for broad applicability. Herein, we report a protocol for the multigram synthesis of two representative enantiopure N-alkyl bis-urea organocatalysts derived from (S)-(-)-1,1'-binaphthyl-2,2'-diamine ((S)-BINAM). These tridentate hydrogen bond donors are highly effective phase-transfer catalysts for solubilizing safe and inexpensive metal alkali fluorides (KF and CsF) in organic solvents for enantioselective nucleophilic fluorinations. The first catalyst, characterized by N-isopropyl substitution, was obtained by using a two-step sequence consisting of reductive amination followed by urea coupling from commercially available starting materials (14 g, 48% yield and 5-d total synthesis time). The second catalyst, featuring N-ethyl alkylation and meta-terphenyl substituents, was accessed via a novel, scalable, convergent route that concluded with the coupling between N-ethylated (S)-BINAM and a preformed isocyanate (52 g and 52% overall yield). On this scale, the synthesis requires ~10 d. This can be reduced to 5 d by performing some steps in parallel. Compared to the previous synthetic route, this protocol avoids the final chromatographic purification and produces the desired catalysts in very high purity and improved yield.

Asymmetric nucleophilic fluorination under hydrogen bonding phase-transfer catalysis.

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.

Catalytic highly enantioselective transfer hydrogenation of ß-trifluoromethyl nitroalkenes. An easy and general entry to optically active ß-trifluoromethyl amines.

In the presence of a thiourea catalyst, ß-CF3 nitroalkenes react with Hantzsch esters in a highly enantioselective fashion, giving a broad range of ß-CF3 amine precursors with a tertiary stereocentre at the ß-position. This reaction represents the first general catalytic enantioselective approach to this important class of ß-CF3 amines.