Probing the Origin of Affinity in the GM1-Cholera Toxin Complex through Site-Selective Editing with Fluorine.

Carbohydrates regulate an inimitable spectrum of biological functions, yet successfully leveraging this therapeutic avenue continues to be frustrated by low affinities with glycan-specific proteins. A conspicuous exception is the interaction of monosialotetrahexosylganglioside (GM1) with the carbohydrate-recognition domain of cholera toxin from : this is one of the strongest protein-carbohydrate interactions known. To establish the importance of a long-discussed key hydrogen bond between C2 of the terminal galactose of GM1 and the B subunit pentamer of cholera toxin (CTB), the total synthesis of a selectively fluorinated GM1 epitope was conducted in 19 steps.

A Fluorinated Sialic Acid Vaccine Lead Against Meningitis B and C.

Inspired by the specificity of α-(2,9)-sialyl epitopes in bacterial capsular polysaccharides (CPS), a doubly fluorinated disaccharide has been validated as a vaccine lead against serogroups C and/or B. Emulating the importance of fluorine in drug discovery, this molecular editing approach serves a multitude of purposes, which range from controlling α-selective chemical sialylation to mitigating competing elimination. Conjugation of the disialoside with two carrier proteins (CRM197 and PorA) enabled a semisynthetic vaccine to be generated; this was then investigated in six groups of six mice.

-Selective dearomatization of phenols by I(i)/I(iii) catalysis-based fluorination.

The regio- and enantio-selective dearomatization of phenols has been achieved by I(i)/I(iii) catalysis enabled fluorination. The process is highly -selective, guiding the fluoride nucleophile to the distal C4 position of the substrate to generate fluorinated cyclohexadienones in an operationally simple manner. Extensive optimization has revealed key parameters that orchestrate enantioselectivity in this historically challenging transformation.

Skeletal Ring Contractions via I(I)/I(III) Catalysis: Stereoselective Synthesis of -α,α-Difluorocyclopropanes.

The clinical success of α,α-difluorocyclopropanes, combined with limitations in the existing synthesis portfolio, inspired the development of an operationally simple, organocatalysis-based strategy to access -configured derivatives with high levels of stereoselectivity (up to >20:1 :). Leveraging an I(I)/I(III)-catalysis platform in the presence of an inexpensive HF source, it has been possible to exploit disubstituted bicyclobutanes (BCBs) as masked cyclobutene equivalents for this purpose. generation of this strained alkene, enabled by Brønsted acid activation, facilitates an unprecedented 4 → 3 fluorinative ring contraction, to furnish -α,α-difluorinated cyclopropanes in a highly stereoselective manner (up to 88% yield).