Selective Transformations of Carbohydrates Inspired by Radical-Based Enzymatic Mechanisms

Abstract

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.

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

“… , The regioselectivity of deoxygenation is reliably predicted by the presence of an axial hydroxyl substituent alpha to the position of radical generation (Figure A, inset). Effective p somo → σ* orbital overlap has previously been noted as essential for efficient radical migration and C–O bond scission in both synthetic and enzymatic systems. ,− …”

α-C–H Photoalkylation of a Glucose Derivative in Continuous Flow

“…Carbohydrates are intrinsically attractive substrates for radical-based reactions involving the carbon skeleton, because the hydroxy groups themselves are not very reactive in such a setting. 5 Nevertheless, the challenge of site-selectivity remains.…”

“…With the advent of synthetically attractive photoredox chemistry (3), (4) , siteselective photoalkylation has come into play as a powerful strategy to extend the carbon framework of carbohydrates. Carbohydrates are intrinsically attractive substrates for radicalbased reactions involving the carbon skeleton, because the hydroxy groups themselves are not very reactive in such a setting (5) . Nevertheless, the challenge of site-selectivity remains.…”

Synthesis of Ketodeoxysugars from Acylated Pyranosides Using Photoredox Catalysis and Hydrogen Atom Transfer

“…21,48 Extending this mode of reactivity to other groups capable of 1,2-migration in radical intermediates (e.g., phosphatoxy groups 41 ) and/or to aminosugar derivatives is another potential avenue for further study. In broader terms, it is becoming clear that enzyme-catalyzed radical reactions of sugars can serve as a source of inspiration for the development of new synthetic processes 16 and that there is potential for further innovation and exploration along this line.…”

“…Opportunities exist to take advantage of radical hydroxy-lyaselike reactivity in the development of laboratory protocols to access ketodeoxysugars, which are valuable building blocks for the synthesis of nucleoside analogues and “rare” sugars . In particular, recent advances in the combined application of photoredox catalysis and hydrogen atom transfer (HAT) reactivity have revealed new ways to generate sugar-derived radicals directly from readily available glycosides by site-selective C–H bond cleavage. − In 2020, Murakami and co-workers disclosed a method for the synthesis of 2-deoxyaldonates from unprotected aldoses using a benzophenone photocatalyst (Scheme a) . In the same year, our group reported a method for the site-selective transformation of furanosides to 2-keto-3-deoxysugars using an iridium photoredox catalyst, quinuclidine as the HAT mediator, and a boronic acid cocatalyst (Scheme b) .…”