Julia A. Kalow

Enantioselective Ring Opening of Epoxides by Fluoride Anion Promoted by a Cooperative Dual-Catalyst System

An enantioselective method for the synthesis of beta-fluoroalcohols by catalytic nucleophilic fluorination of epoxides is described. Mild reaction conditions and high selectivity are made possible by the use of benzoyl fluoride as a soluble, latent source of fluoride anion. A chiral amine and chiral Lewis acid serve as cooperative catalysts for desymmetrizations of five- through eight-membered cyclic epoxides, affording products in up to 95% ee. The cocatalytic protocol is also effective for kinetic resolutions of racemic terminal epoxides, which proceed with k(rel) values as high as 300.

Mechanistic investigations of cooperative catalysis in the enantioselective fluorination of epoxides.

This report describes mechanistic studies of the (salen)Co- and amine-cocatalyzed enantioselective ring opening of epoxides by fluoride. The kinetics of the reaction, as determined by in situ (19)F NMR analysis, are characterized by apparent first-order dependence on (salen)Co. Substituent effects, nonlinear effects, and reactivity with a linked (salen)Co catalyst provide evidence for a rate-limiting, bimetallic ring-opening step. To account for these divergent data, we propose a mechanism wherein the active nucleophilic fluorine species is a cobalt fluoride that forms a resting-state dimer. Axial ligation of the amine cocatalyst to (salen)Co facilitates dimer dissociation and is the origin of the observed cooperativity. On the basis of these studies, we show that significant improvements in the rates, turnover numbers, and substrate scope of the fluoride ring-opening reactions can be realized through the use of a linked salen framework. Application of this catalyst system to a rapid (5 min) fluorination to generate the unlabeled analog of a known PET tracer, F-MISO, is reported.

Synthesis of β-Fluoroamines by Lewis Base Catalyzed Hydrofluorination of Aziridines

Lewis base catalysis promotes the in situ generation of amine-HF reagents from benzoyl fluoride and a non-nucleophilic alcohol. The hydrofluorination of aziridines to provide β-fluoroamines using this latent HF source is described. This protocol displays a broad scope with respect to aziridine substitution and N-protecting groups. Examples of regio- and diastereoselective ring opening to access medicinally relevant β-fluoroamine building blocks are presented.

Nucleophilic (Radio)Fluorination of α-Diazocarbonyl Compounds Enabled by Copper-Catalyzed H–F Insertion

The copper-catalyzed H-F insertion into α-diazocarbonyl compounds is described using potassium fluoride (KF) and hexafluoroisopropanol. Access to complex α-fluorocarbonyl derivatives is achieved under mild conditions, and the method is readily adapted to radiofluorination with [(18)F]KF. This late-stage strategy provides an attractive route to (18)F-labeled biomolecules.

Rapid Aqueous Photouncaging by Red Light

This work describes three new red-photocleavable dyes. The best-performing dye exhibits a quantum yield of 5.7% in 30:70 v/v water/acetonitrile and approximately 80% release of benzoic acid using a 626 nm LED. Photo-orthogonality between this dye and a UV-activated photouncaging group was demonstrated. Additionally, a qualitative comparison between the same pair of dyes in a gel was performed, highlighting the superior penetration depth that can be achieved using the newly reported dye.

Fluoride ring-opening kinetic resolution of terminal epoxides: Preparation of (s)-2-fluoro-1-phenylethanol

(R,R)-(−)-N,N′-Bis(3,5-di-tert-butylsalicylidiene)-1,2-cyclohexanedaminocobalt(II) Styrene oxide 1.5-Diazabicyclo[4.3.0]non-5-ene Benzoyl fluoride Sodium borohydride Keywords: Fluorides; Ring-opening; Epoxides; 2-Fluro-1-phenylethanolkinetic resolution; Desymmetrization; Waste disposal; Safety