Radical Tools to Transform Biomass Sugars

Abstract

Carbohydrates are implicated in essential biological processes – cell recognition, cell signaling, mechanical structure, and energy storage – and play essential roles in the potency and selectivity of bioactive natural products and pharmaceutical compounds. While some biomass-derived carbohydrates are extracted on commercial scales (e.g. D-glucose, D-xylose, D-galactose), there are > 500 ’rare’ sugars that feature prominently and are difficult to isolate from natural sources. Instead, these rare glycosides are typically prepared through multistep chemical syntheses which commonly rely on protecting group manipulations to achieve selective reaction outcomes. Currently, the lack of reliable and selective chemical tools to rapidly access diverse sugar building blocks presents a bottleneck in the synthesis and evaluation of unusual and unnatural sugars. New, selective methods are needed for the expedient synthesis of rare sugars. This thesis describes the development of selective radical reactions to transform unprotected and minimally-protected biomass-derived carbohydrates into diversely functionalized monosaccharides and glycans. We specifically targeted epimerization reactions and radical rearrangements to achieve broad synthetic access to sugar isomers and deoxygenated sugars, respectively.

We have achieved the direct synthesis of rare sugar epimers through site-selective radical epimerization. Mechanistic studies establish that these reactions proceed under kinetic control through two distinct and sequential H atom transfer steps: H atom abstraction and H atom donation. We have developed complementary methods to achieve equatorial-to-axial and axial-to-equatorial diastereoselectivity by employing two compositionally distinct H atom abstraction catalysts. The distinct reactivity profile of the catalysts was found to arise from a change in mechanism: equatorial-to-axial epimerization is achieved by a minimally selective H atom abstraction and diastereoselective H atom donation while axial-to-equatorial epimerization is achieved by a site-selective and diastereoselective H atom abstraction.

Furthermore, we accessed deoxygenated sugars by leveraging a manganese-promoted 1,2 radical migration, which proceeds via a sugar radical intermediate accessed by H atom abstraction. The resulting deoxyketopyranosides feature chemically distinguishable functional groups and are readily transformed into diverse carbohydrate structures.

This work validates the potential for radical intermediates to facilitate the selective transformation of carbohydrates and showcases the step and efficiency advantages attendant to synthetic strategies that minimize reliance upon protecting groups.