Fluorine‐Directed Automated Mannoside Assembly

Abstract

Automated glycan assembly (AGA) on solid support has become invaluable in reconciling the biological importance of complex carbohydrates with the persistent challenges associated with reproducible synthesis. Whilst AGA platforms have transformed the construction of many natural sugars, validation in the construction of well-defined (site-selectively modified) glycomimetics is in its infancy. Motivated by the importance of fluorination in drug discovery, the biomedical prominence of 2-fluoro sugars and the remarkable selectivities observed in fluorine-directed glycosylation, fluorine-directed automated glycan assembly (FDAGA) is disclosed. This strategy leverages the fluorine atom for stereocontrolled glycosylation on solid support, thereby eliminating the reliance on O-based directing groups. The logical design of C2-fluorinated mannose building blocks, and their application in the fully (α-)stereocontrolled automated assembly of linear and branched fluorinated oligomannosides, is disclosed. This operationally simple strategy can be integrated into existing AGA and post-AGA protocols to augment the scope of programmed carbohydrate synthesis.

Rapid Measurement of Heteronuclear Coupling Constants in Complex NMR Spectra

“…A further demonstration of the power and usefulness of IPAP-FESTA is provided by a study of solvent effects on the conformational equilibria in a physically inseparable (due to exchange between isomers) mixture of cis - and trans -fluorohydrins. Fluorohydrins have attracted interest in organofluorine chemistry 44 as precursors to a range of biologically active fluorinated analogues 45 and as probes for use as biomarkers. 46 In solution, 3-fluorotetrahydro-2 H -pyran-2-ol, referred to here as fluorohydrin, is in a fast conformational equilibrium dominated by eq–eq and ax–ax conformers for the trans isomer and by eq–ax and ax–eq conformers for the cis isomer ( Scheme 2 ).…”

A Fluorinated Sialic Acid Vaccine Lead Against Meningitis B and C

“…Inspired by the success of fluorination as a molecular editing strategy in pharmaceutical design, it was reasoned that judicious installation of a C­(sp 3 )-F bond proximal to the glycosidic linkage may play a multitude of roles in vaccine development. These include regulating glycosylation, increasing enzymatic stability and providing a valuable NMR active nucleus to facilitate structural determination . Collectively, these attributes provide a compelling argument for the strategic use of fluorinated sugars in vaccine development.…”