A Unified Strategy to Access 2- and 4-Deoxygenated Sugars Enabled by Manganese-Promoted 1,2-Radical Migration.

The selective manipulation of carbohydrate scaffolds is challenging due to the presence of multiple, nearly chemically indistinguishable O-H and C-H bonds. As a result, protecting-group-based synthetic strategies are typically necessary for carbohydrate modification. Here we report a concise semisynthetic strategy to access diverse 2- and 4-deoxygenated carbohydrates without relying on the exhaustive use of protecting groups to achieve site-selective reaction outcomes. Our approach leverages a Mn2+-promoted redox isomerization step, which proceeds via sugar radical intermediates accessed by neutral hydrogen atom abstraction under visible light-mediated photoredox conditions. The resulting deoxyketopyranosides feature chemically distinguishable functional groups and are readily transformed into diverse carbohydrate structures. To showcase the versatility of this method, we report expedient syntheses of the rare sugars l-ristosamine, l-olivose, l-mycarose, and l-digitoxose from commercial l-rhamnose. The findings presented here validate the potential for radical intermediates to facilitate the selective transformation of carbohydrates and showcase the step and efficiency advantages attendant to synthetic strategies that minimize a reliance upon protecting groups.

Selective Transformations of Carbohydrates Inspired by Radical-Based Enzymatic Mechanisms.

Enzymes are a longstanding source of inspiration for synthetic reaction development. However, enzymatic reactivity and selectivity are frequently untenable in a synthetic context, as the principles that govern control in an enzymatic setting often do not translate to small molecule catalysis. Recent synthetic methods have revealed the viability of using small molecule catalysts to promote highly selective radical-mediated transformations of minimally protected sugar substrates. These transformations share conceptual similarities with radical SAM enzymes found in microbial carbohydrate biosynthesis and present opportunities for synthetic chemists to access microbial and unnatural carbohydrate building blocks without the need for protecting groups or lengthy synthetic sequences. Here, we highlight strategies through which radical reaction pathways can enable the site-, regio-, and diastereoselective transformation of minimally protected carbohydrates in both synthetic and enzymatic systems.

Positioning-Group-Enabled Biocatalytic Oxidative Dearomatization.

Biocatalysts have the potential to perform reactions with exceptional selectivity and high catalytic efficiency while utilizing safe and sustainable reagents. Despite these positive attributes, the utility of a biocatalyst can be limited by the breadth of substrates that can be accommodated in the active site in a reactive pose. Proven strategies exist for optimizing the performance of a biocatalyst toward unnatural substrates, including protein engineering; however, these methods can be time intensive and require specialized equipment that renders these approaches inaccessible to synthetic chemists. Strategies accessible to chemists for the expansion of a natural enzyme's substrate scope, while maintaining high levels of site- and stereoselectivity, remain elusive. Here, we employ a computationally guided substrate engineering strategy to expand the synthetic utility of a flavin-dependent monooxygenase. Specifically, experimental observations and computational modeling led to the identification of a critical interaction between the substrate and protein which is responsible for orienting the substrate in a pose productive for catalysis. The fundamental hypothesis for this positioning group strategy is supported by binding and kinetic assays as well as computational studies with a panel of compounds. Further, incorporation of this positioning group into substrates through a cleavable ester linkage transformed compounds not oxidized by the biocatalyst SorbC into substrates efficiently oxidatively dearomatized by the wild-type enzyme with the highest levels of site- and stereoselectivity known for this transformation.