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.
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 β-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.
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
K
d
’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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.