Radical Pathway Glycosylation Empowered by Bench-Stable Glycosyl Donors

Abstract

Conspectus The study of carbohydrates has emerged as a crucial research area in various disciplines due to their pivotal roles in cellular processes. To facilitate in-depth exploration of their biological functions, chemical glycosylation reactions that allow facile access of glycoconjugates to a broad research community are highly needed. In classical glycosylation reactions, a glycosyl donor is activated by an acid to generate a reactive electrophilic intermediate, which subsequently forms a glycosidic bond upon reaction with a nucleophilic acceptor. Such an ionic pathway glycosylation has been the mainstay technique for glycoconjugate synthesis and allowed the synthesis of numerous intricate structures. Nevertheless, limitations still exist. For instance, when labile glycosyl donors or harsh activating conditions are required, these methods show limited tolerance to hydroxyl groups that are abundant on sugar rings. In addition, achieving good stereocontrol represents another longstanding obstacle. In recent years, new modes of donor activation have been sought to tackle the above challenges. We noted that glycosylation methods passing through the intermediacy of glycosyl radicals via a cascade of single-electron transfer steps possess significant but underexplored potential. Progress in this area has been slow due in large part to a dearth of handy methods to generate and maneuver glycosyl radicals. Most existing methods call for either forcing conditions or unstable/inconvenient starting materials. In order to better exploit the power of the radical pathway glycosylation, we have developed a range of glycosyl donorsnamely, glycosyl sulfoxides, glycosyl sulfones, and glycosyl sulfinatesthat are bench stable and can be readily prepared from simple starting materials. These donors can be activated to form glycosyl radicals under mild conditions. Enabled by the use of these donors, we have developed a series of glycosylation methods that could be used for making O-, S-, or C-glycosides, some of which were previously difficult to access. In many cases, no protecting group on glycosyl donors is required. As an illustration of their potential utility, our methods have been adopted in the preparation of sugar–drug conjugates, sugar–DNA conjugates, glycopeptides, and even glycoproteins. While in most cases the intrinsic reactivity of glycosyl radical intermediates can be explored to access axially configured products, some of the methods also allow the utilization of external, delicate reagents, or catalysts to override such innate preference and achieve catalyst-controlled stereoselectivity. We believe that radical pathway glycosylation has enormous potential and can inspire the development of novel methods for glycoside synthesis. In this Account, we highlight the design principles for the development of our glycosyl donors, summarize our recent advancements in radical pathway glycosylation enabled by their use, and provide an outlook on the future directions of this field.

Palladium catalysis enables cross-coupling–like S N 2-glycosylation of phenols

“…Unlike phosphine-based ligands, nitrogen-based ligands and N -heterocyclic carbene ligands we tried were less effective (see SM, section 4). Addition of a stoichiometric amount of TEMPO was fully tolerated, essentially excluding a radical-based mechanism (entry 14) ( 22 , 37 ).…”

“…Among the venues to overcome these obstacles, developments include the Yu group ( 11 ), which exploits selective gold-alkyne interactions; the Jacobsen group ( 12 , 13 ), which explores mild hydrogen-bond catalysis; the Miller group ( 14 , 15 ), which harnesses the strong Ca–F bond-forming energy; the Nguyen group ( 16 ) that employs Lewis base catalysis; and the Codée ( 17 ), Takemoto ( 18 ), and Loh groups ( 19 ), which utilize halogen-bond catalysis, and others based on transition metal catalysis ( 20 , 21 ). We have reported radical activation of glycosyl donors ( 22 ). Despite this progress, there is still a high demand for methods with a general scope to prepare stereodefined glycosides in a simple and predictable manner, which continues to fuel mechanistic and methodological advancements.…”

Recent Advances in First-Row Transition Metal-Catalyzed Reductive Coupling Reactions for π-Bond Functionalization and C-Glycosylation

“…Amid the established glycosylation methodologies, glycosyl radical functionalization stands as a mild and powerful tool for the synthesis of C-glycosides and glycoconjugates, finding numerous applications in synthetic drug discovery, materials science, and chemical biology. Noteworthy contributions from Gagné et al, Gong et al, and Niu et al have significantly propelled this field, by conceiving Ni-catalyzed glycosylation protocols that capitalize on the aforementioned glycosyl radical intermediates to facilitate the diversified synthesis of C–alkyl, C–acyl, and C–aryl glycosides .…”

“…Such transformations often involve glycosyl cations, anions, radicals, or glycosyl–transition metal complexes as key intermediates. Notably, C-glycosylation via the intermediacy of glycosyl radicals offers a milder approach to ionic pathways and exhibits excellent compatibility with most polar functionalities …”

Synthesis of 2-Indolyl C-Glycoside Neopetrosins A and C and Congeners via Ni-Catalyzed Photoreductive Cross-Coupling

“…Reaction of glucose-, galactose-, lactose-, and maltose-derived glycosyl bromides gave rise to the corresponding C -glycosides ( 12d – e , 12i – j , 12m , and 12p ) with α/β selectivities ranging from 1.6:1 to 1:5. The interaction of the lone electron pair of the endocyclic oxygen with the antibonding orbital of the anomeric C–Ni bond might stabilize the sterically congested α-glycosyl nickel intermediate, so as to increase the product distribution of the 1,2- cis α-anomers. , Meanwhile, it was also possible that the steric clashes between the indole unit and sugar moiety in α-glycosyl nickel intermediate hampered its reductive elimination, making the formation of 1,2- trans β-anomers more facile. ,, …”