Nucleic acids, proteins, and polysaccharides constitute the three fundamental classes of biomolecules essential for life. Among these, polysaccharides play critical roles in numerous biological processes, including bacterial and viral infections, cell recognition, immune regulation, inflammatory responses, and cancer metabolism [
1–
3]. Advances in understanding carbohydrate-receptor interactions have spurred significant progress in the synthesis of carbohydrate analogs and mimetics [
4–
7]. Nonetheless, significant challenges remain in glycoscience, particularly in achieving the efficient and stereoselective synthesis of bioactive oligosaccharides and glycoconjugates. Addressing these challenges requires the development of innovative synthetic platforms capable of generating diverse carbohydrate-based structures, thereby bridging the gap between fundamental glycoscience and its medical applications.
In recent years, electrochemical organic synthesis has emerged as a powerful tool for green synthesis, offering advantages such as high atom economy, mild reaction conditions, and scalability [
8–
17]. These attributes make electrochemical methods particularly attractive for glycosylation reactions [
18–
28].
Glycals represent an important class of polyhydroxylated chiral synthons that serve as versatile synthetic intermediates in the synthesis of oligosaccharides, glycoconjugates, and bioactive natural products [
29–
34]. They are broadly classified into two categories:
Endo-glycals, which contain an endocyclic carbon-carbon double bond, and
exo-glycals (or 1-methylene sugars), featuring an exocyclic double bond (
Fig. 1a) [
35].
Endo-glycals have been extensively explored and widely employed in
O- and
C-glycosylation reactions [
20,
21,
26,
34,
36–
52]. In medicinal chemistry,
exo-glycals are valued as glycosidase inhibitors [
53–
55] and have been used in the synthesis of
C-glycoside analogs
via various strategies, including hydroboration/Suzuki cross-coupling [
56], Stille cross-coupling [
57], Heck reactions [
58], radical addition [
59], epoxidation [
60], and others methods [
56–
66].
In contrast,
O-glycosylation reactions employing
exo-glycals as glycosyl donors remain underdeveloped [
67–
73]. Existing approaches are largely limited to two conventional pathways: (a) Lewis acid-catalyzed direct
O-glycosylation [
72,
73] and (b) Lewis acid-promoted rearrangement reactions [
69,
70], both of which have been applied to synthesize biologically relevant 1′-
C-methyl-
O-glycosides. These methods, however, suffer from several drawbacks, including narrow substrate scope, limited stereocontrol, and harsh reaction conditions. Thus, the development of efficient and stereoselective strategies for synthesizing 1′-
C-methyl-
O-glycoside analogs is highly desirable.
Our group recently reported an electrochemical method for glycosylation using
endo-glycal, which afforded products in high yields with excellent selectivity, offering an efficient and novel strategy for
O-glycosylation (
Fig. 1d) [
20]. Inspired by the structural similarities between the double bonds in
exo- and
endo-glycals, and encouraged by the efficiency and sustainability of electrochemical synthesis, we sought to extend this electro-promoted approach to achieve efficient and stereoselective
O-glycosylation of
exo-glycals (1-methylene sugars) to form 1′-
C-methyl-
O-glycosides (
Fig. 1e). Herein, we present an electrochemical method for the efficient synthesis of
O-glycoside analogs from
exo-glycals and nucleophilic acceptors. The electrochemical method exhibits a combination of broad substrate scope, outstanding functional group tolerance (especially for alkenes), excellent stereocontrol, and enhanced reaction efficiency. In addition, this strategy not only expands the synthetic utility of
exo-glycals but also aligns with green chemistry principles by reducing environmental impact.
We initiated our investigation by examining the electrochemical glycosylation of benzyl protected-1-methylenesugars
1a and
2a in an undivided electrochemical cell (
Table 1). Under initial conditions using Bu
4NOTf as the electrolyte, a graphite anode, a platinum plate cathode, CH
3CN as the solvent, room temperature, and a constant current of 2 mA, the target product
3a was achieved with 44% yield and exclusive α-selectivity (entry 1). Solvent screening revealed a significant influence on the reaction outcome (entries 2–4). Low or negligible yields were observed with 1,2-dimethoxyethane (DME), diethyl ether, or 1,4-dioxane. Subsequent evaluation of electrolytes, including Bu
4NBF
4, Bu
4NOAc, Bu
4NBr, KOTf and NaOTf, identified KOTf and NaOTf as superior, affording
3a in 51% and 50% yields, respectively (entries 5–9). Based on these results, KOTf (2.0 equiv.) was selected for further optimization. We then evaluated alternative electrode configurations. Employing graphite for both electrodes resulted in a diminished yield of 31% (entry 10), while a Pt/Pt setup completely inhibited the reaction (entry 11). Notably, reversing the electrodes to a Pt anode and graphite cathode significantly improved the yield to 87% (entry 12). Varying the current intensity did not lead to further enhancement (entries 13 and 14). Control experiments confirmed that both electricity and electrolyte are essential, as no reaction occurred in their absence (entries 15 and 16).
Having established the optimal electrochemical conditions, we next evaluated the scope of glycosyl donors (
Table 2). Firstly, we synthesized a series of
exo-glycals, including
gluco– (
1a and
1g),
galacto- (
1b),
manno- (
1c),
rhamno-(
1d),
fuco- (
1e) and
lacto- (
1f), following established literature procedures [
35,
63,
74]. Under the standard conditions, the reaction between 1-methylidene-2,3,4,5-tetra-
O-benzyl-d-glucopyranoside (
1a) and acceptor
2a afforded disaccharide
3a in 87% yield (entry 1). Notably, a variety of perbenzylated 1-methylene sugars (
1b-
1e) acted as competent donors, yielding the corresponding disaccharides
3b-
3e in excellent yields ranging from 90% to 97% (entries 2–5). Trisaccharide
3f was also obtained in good yield when
lacto-derived donor
1f was employed (entry 6). Furthermore, the 1-ethylsugar was found to be compatible with the system, furnishing glycoside
3g in 75% yield (entry 7).
We then explored the acceptor scope of the transformation (
Table 3). Both primary and secondary non-sugar alcohols were suitable reaction partners under the standard conditions, delivering glycosides
4a-
4d in 71%−95% yields. Among these, product
4d was obtained with an
α/
β selectivity of 22/1 (entry 4), while the others were exclusively
α-configuration. Notably, the reaction could be scaled up to furnish
4b in 86% yield (739 mg, entry 2). Reactions of cyclododecanol with either
exo-glucal or
exo-galcal donors provided
4c and
4d in 71% and 73% yields, respectively (entries 3 and 4). Acceptors containing a free C-6 hydroxyl group underwent smooth glycosylation to afford disaccharides
4e-
4f in 83%–91% yields (entries 5 and 6). Reactions with acceptors containing free C-3 or C-2 hydroxyl groups were less effective at room temperature; however, reducing the temperature to −30 ℃ improved the yields of products
4g and
4h to moderate to good levels (entries 7 and 8). Di-glycosylation of 1,1-bis(hydroxymethyl)cyclopropane and 1,12-dodecanediol with
exo-glucal afforded
4i and
4j in 87% and 77% yields, respectively (entries 9 and 10).
To further demonstrate the practical utility of this method, we applied the electro-glycosylation reaction to the late-stage glycosylation of natural products (
Table 4). Epiandrosterone was successfully coupled with
exo-glucal donor under standard reaction conditions to afford
5a in 61% yiled. Similarly, podophyllotoxin was glycosylated to give
5b in 60% yield. Beta-sitosterol was also modified using different glycosyl donors (
1a and
1b), yielding products
5c and
5d in 84% and 85% yields, respectively. Cholesterol proved to be a suitable substrate as well, providing glycosides
5e and
5f in good yields.
To gain further insight into the reaction mechanism, a series of mechanistic experiments were conducted (
Scheme 1). First, control experiments confirmed the essential role of electrical current and electrolyte, as no glycosylation occurred in their absence (Schemes 1a and b). Subsequently, the introduction of the radical scavenger TEMPO under standard conditions completely suppressed the formation of product
3a. Notably, intermediates
6 and
7 were detected
via ESI-MS, suggesting the involvement of radical species and a radical-inhibited pathway (
Scheme 1c).
Deuterium labeling experiments provided additional insight into the source of the methyl hydrogen in the product. When the reaction between
1a and
2a was performed in CD
3CN, no deuterium incorporation was observed in the product, ruling out the solvent as the hydrogen source (
Scheme 1d). In a complementary experiment, reaction of
1a with CD
3OD in CH
3CN afforded deuterated product
8, confirming that the methyl proton originates from the nucleophilic acceptor (
Scheme 1e).
Based on these experimental results, along with supporting evidence from cyclic voltammetry (Figs. S7-S9 in Supporting information) and previous literature reports [
73,
75–
80], a plausible reaction mechanism is proposed (
Fig. 2). Initially, the glycosyl donor
1 is oxidized at the anode to form a radical cation intermediate
Ⅰ. Concurrently, the alcohol nucleophile is reduced at the cathode, generating a hydrogen radical and an alkoxide ion. The hydrogen radical combines with intermediate
Ⅰ to form carbocation intermediate
Ⅱ. The approach of acetonitrile is directed by the anomeric effect preferentially from the
α-face, leading to the selective formation of intermediate
Ⅲ. In acetonitrile solvent,
Ⅲ predominates due to effective stabilization. Significant steric hindrance from the C1-methyl group prevents nucleophilic approach from the
β-face, while favoring minor dissociation back to intermediate
Ⅱ. Ultimately, the alkoxide attacks intermediate
Ⅲ from the sterically accessible
α-face, resulting in the thermodynamically favored
α-glycoside product.
In concluding, we have developed an electrochemical glycosylation method for the stereoselective synthesis of O-glycosides using exo-glucals and various nucleophilic acceptors. This approach operates under simple conditions in an undivided cell, employing KOTf as the electrolyte to afford the corresponding glycosylation products in high yields with excellent selectivity. The reaction accommodates a broad range of glycosyl and non-glycosyl acceptors, consistently yielding products with exclusive α-selectivity. Scalability was demonstrated through gram-scale synthesis without compromising yield or stereoselectivity. Furthermore, the method proved effective for the late-stage glycosylation of natural products and pharmaceuticals, highlighting its potential for the discovery of carbohydrate-based drugs. This electrochemical strategy thus represents an efficient and attractive platform for synthesizing O-glycosides.
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