English

• C-Glycosides exhibit remarkable potential as drug mimics in pharmacological research owing to their substantial physiological effect and excellent stability against chemical and enzymatic hydrolysis [1-7]. To date, a multitude of C-glycosides of highly diverse structures have been systematically assessed for their biological activities (Fig. 1a) [8-11]. The escalating realization of the research significance of C-glycosides leads to the growing demand for the synthesis of these compounds. Consequently, the imperative to develop highly robust and efficient C-glycosylation methods has become evident to encounter the inherent synthetic challenge.

  Figure 1

  

  Figure 1.  (a) Selected alkyl and C-indolyl-glycosides with biological activities. (b) Our previous work on O-, S-, and N-glycosylation. (c) This work: catalytic strain-release C-glycosylation. Bn: benzyl, ⁱPr: isopropyl, Ac: acetyl, Me: methyl, Nu: nucleophiles, R: functional groups.

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  Over the past decades, considerable efforts have been devoted to the advancement of C-glycosylation protocols. Catalytic C-glycosylation with the exemption of excess promoters not only improves the atom economy of the reaction but also minimizes the environmental impact [12]. The radical pathway to acquire C-glycosides under cross-coupling or photo-induced conditions represents a well-explored and established strategy in recent years [13-36]. Notwithstanding the mild reaction condition, many of the radical-based C-glycosylation methods are sensitive to air, which creates great troubles in the tedious pretreatment of the reaction vessels and reagents, thereby hindering their application in scaled production. On the other hand, the C-glycosylation via oxocarbenium cation serves as an operationally much simpler way while keeping the mildness and robustness with careful choice of reaction conditions. Nevertheless, despite several impressive reports, this strategy has been relatively under-explored in recent years entailing stoichiometric promoters, as exemplified by the elegant works by Tang, Xiong and Ye [37,38]. Thus, the essential roles of C-glycosides pose an urgent need for the development of catalytic C-glycosylation via oxocarbenium. A notable instance was reported by Yu’s research group in 2016, where a glycosyl ortho-alkynylbenzoate donor underwent smooth C-glycosylation catalyzed by gold(I) species [39]. In 2021, Mandal and co-workers developed a catalytic protocol using glycosyl trichloroacetimidate as donors and an organo-boron compound B(C₆F₅)₃ as the catalyst for the synthesis of C-indolyl-glycosides [40]. Kancharla and co-workers evaluated the capability of their ortho–[1–(para–methoxyphenyl)vinyl]benzoates (PMPVB) donors in the synthesis of alkyl [41] and indolyl [42] C-glycosides in 2022 and 2023, respectively. In 2023, Sun and fellow researchers reported a novel glycosylation protocol utilizing ortho-methoxycarbonylethynylphenyl thioglycosides (MCEPTs) as donors and examined the C-glycosylation potential of it [43]. Hence, inspired by these elegant protocols, we noticed the emphasized necessity to delve into innovative catalytic C-glycosylation methods capable of surmounting challenges posed by the sensitivity of reagents and radical reaction intermediates, all while maintaining good efficiency and substrate scope. As a continuation of our long-lasting interests in catalytic strain-release glycosylation reactions, we hypothesized that the acceptor scope of this reaction could be readily extended to various C-nucleophiles, developing a novel genre of catalytic C-glycosylation reactions (Fig. 1b) [44-49]. Herein, we disclose our development of the efficient C-glycosylation of various C-nucleophiles with glycosyl CCBz donors. Allyltrimethylsilane, differentially substituted silyl enol ethers, and indoles were all competent acceptors, affording structurally diverse C-glycoarchitectures. The deprotection of C-indolyl-glycosides was conducted to yield free sugar derivatives, which were then subjected to antibacterial investigations. The results indicated that these C-glycosides showed promising antibacterial potentials (Fig. 1c).

  Built upon our hypothesis, we commenced our study with the optimization of reaction conditions. Although the reaction between donor 1a and allyltrimethylsilane (2a) gave only 49% yield, this was a successful proof-of-concept experiment that unequivocally revealed the feasibility of our strategy in C-glycosylation (Table 1, entry 1). Subsequent screening of reaction conditions resulted in improved yield for the model reaction. With a 3.0 equiv. of C-acceptor, the model reaction provided 80% isolated yield and excellent stereoselectivity at a concentration of 0.1 mol/L (Table 1, entry 3). Changing the solvent to Et₂O or toluene diminished the reaction yield significantly, although Et₂O showed slightly better α-selectivity (Table 1, entries 4 and 5). We also tested if a disarmed donor 1f could be used as a suitable donor in the reaction, and unfortunately, no product could be detected from the reaction system (Table 1, entry 6). Of note, when silyl enol ether 2b was subjected to reaction under the aforementioned optimal condition, the reaction failed to provide us with a satisfactory yield (Table 1, entry 7). As silyl enol ethers are also commonly used as C-nucleophiles, we deemed it imperative to include this type of acceptor in the model reaction study. Upon realizing the sensitivity of silyl enol ethers to acids, we speculated that the low yield observed might be attributed to the decomposition of silyl enol ether under the acidic condition, thereby leading to the increased hydrolysis product and incompletely consumed donor 1a. Therefore, we embarked on further optimizing the reaction condition for silyl enol ether substrates by regulating the acidity of the reaction system. Reducing the catalyst load did not ameliorate the situation, as this led to incomplete donor consumption (Table 1, entry 8). We speculated that increasing the basicity of the environment might facilitate the glycosylation of silyl enol ethers, thus 4 Å molecular sieve with stronger basicity was added to the reaction. To our delight, this minor modification provided a much better reaction yield of 70% with 7.1:1 anomeric selectivity (Table 1, entry 9). Ultimately, we opted for a slightly higher load of Sc(OTf)₃ with 4Å MS as the desiccant. Under this condition, donor 1a could be transformed to the desired C-glycoside 3ab in 82% yield with good anomeric selectivity (Table 1, entry 10). We also evaluated the possibility of using acceptor 2b’, as TBS is a more stable protection than TMS. While the result was satisfactory enough, the lower yield and anomeric selectivity indicated that TMS was the optimized protection for silyl enol ether (Table 1, entry 11). We finally noticed the potential chemoselectivity in the current protocol as acetophenone 2b” did not participate in the reaction, and donors remained unreacted in the reaction system (Table 1, entry 12).

  Table 1

  

  Table 1.  Optimization of reaction condition^a.

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  Entry	Acceptor	Solvent	Time (h)	Yield (%)	α:β
  1b, c	2a	DCM	2	49	10.4:1
  2b	2a	DCM	2	67	16.0:1
  3	2a	DCM	2	80	21.9:1
  4	2a	Et2O	2	67	24.2:1
  5	2a	Toluene	2	62	19.1:1
  6d	2a	DCM	Overnight	N.R.	–
  7	2b	DCM	Overnight	46	5.3:1
  8e	2b	DCM	Overnight	42	5.3:1
  9f	2b	DCM	Overnight	70	7.1:1
  10g	2b	DCM	Overnight	82	11.0:1
  11	2b’	DCM	Overnight	71	7.6:1
  12	2b”	DCM	Overnight	N.R.	–
  a Unless otherwise stated, the reactions were carried out with 1.0 equiv. of 1a, 3.0 equiv. of indicated acceptor in the presence of Sc(OTf)3 (0.1 equiv.) and 5 Å molecular sieve in the corresponding solvent (0.1 mol/L) for an indicated time at room temperature. All yields were calculated based on 1a and represent isolated yields. The anomeric ratio was determined via 1H NMR analysis. DCM = dichloromethane, N.R. = no reaction. b 1.5 equiv. acceptor. c 0.05 mol/L. d 1f (1.0 equiv.) was used as donor. e 0.05 equiv. Sc(OTf)3. f 4 Å MS. g 4 Å MS and 0.15 equiv. Sc(OTf)3.

  With the optimized reaction conditions in hand, we then proceeded to evaluate the generality of our C-glycosylation method (Fig. 2). Versatile C-nucleophiles, including substituted silyl enol ethers (2c–2n), derivatized indole compounds (2o–2v), and trimethylsilyl cyanide (2w), were subjected to reaction with donor 1a under either condition A or B. To our delight, the reaction showed excellent functional group tolerance when various silyl enol ethers and indoles bearing colorful functionalities, including halides, typical electron donating/withdrawing groups, heteroaromatic furan ring, naphthalene ring, and commonly used N-substituents, were subjected to the reaction. Of note, the theoretically more nucleophilic methoxy–substituted acceptor 2g gave a significantly lower yield. Considering the silyl enol ethers are acid-sensitive by nature, the poor reaction outcome of acceptor 2g might be due to its more severe decomposition under acidic conditions. Improving the acid tolerance of the substrate by using a more stable TBS protection was found beneficial to the yield. Reaction involving acceptor 2h, which bears a cyanide group in its structure, gave worse results compared with other electron-deficient acceptors. Since the cyanide group is a coordinating group to transition metals, we presumed that the cyanide group may have coordinated with the Sc(Ⅲ) catalyst, thereby influencing the catalytic activity and leading to decreased reaction yield. Reaction with differently N-protected-2-substituted indole acceptors gave moderate to good yields with noteworthy change of the ring conformation from ⁴C₁ to ¹C₄ in some cases. In both conformations, the thermodynamically more stable anomers with aglycons occupying the equatorial positions were identified as the predominant products. While the reaction proceeded unsurprisingly smoothly with the substrates bearing different N-substitutions and functionalizations at C5 on the indole ring, we realized that utilization of different substituents could significantly impact the reaction yields. Notably, the application of different substituents may also lead to the change conformations of products, probably due to the equatorial-equatorial gauche interaction resulting from the steric effect of the substituents [50]. These results illustrated that various C-nucleophiles, such as silyl enol ethers, indoles, and trimethylsilyl cyanide, can all be utilized as acceptors, suggesting the extensive acceptor scope.

  Figure 2

  

  Figure 2.  Scope of C-nucleophiles. Unless otherwise stated, all reactions were carried out using either optimized conditions A or B as described below. Condition A: 1.0 equiv. of 1a, 3.0 equiv. of C-nucleophile and 0.1 equiv. of Sc(OTf)₃ were stirred for 2 h in the presence of 5 Å molecular sieve in anhydrous DCM (0.1 mol/L) at room temperature. Condition B: 1.0 equiv. of 1a, 3.0 equiv. of C-nucleophile and 0.15 equiv. of Sc(OTf)₃ were stirred overnight in the presence of 4 Å molecular sieve in anhydrous DCM (0.1 mol/L) at room temperature. All yields were calculated based on 1a and represent isolated yield. The anomeric ratio was determined by ¹H NMR analysis. ^a Reaction time: 3 h.

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  The donor scope of the present C-glycosylation method was evaluated by glycosylating three types of C-nucleophiles, including allyltrimethylsilane (2a), silyl enol ether 2b, and indole 2o with four glycosyl CCBz donors (Fig. 3). As expected, the reaction could be applied to various CCBz donors, including D-galactosyl, D-mannosyl, 2-deoxy-d-glucosyl, and D-ribosyl donors, and most of the reactions delivered the desired C-glycosides in good yields. Although the anomeric selectivity of the reactions involving acceptor 2b was moderate, other acceptors generally yielded the C-glycosides in satisfactory anomeric ratios. The crossover experiments persuasively demonstrated the feasibility of the current protocol in the C-glycosylation of pyranose and furanose.

  Figure 3

  

  Figure 3.  Scope of glycosyl CCBz donors. Unless otherwise stated, all reactions were carried out using either optimized conditions A or B as described below. Condition A: 1.0 equiv. of 1a, 3.0 equiv. of C-nucleophile and 0.1 equiv. of Sc(OTf)₃ were stirred for 2 h in the presence of 5 Å molecular sieve in anhydrous DCM (0.1 mol/L) at room temperature. Condition B: 1.0 equiv. of 1a, 3.0 equiv. of C-nucleophile and 0.15 equiv. of Sc(OTf)₃ were stirred overnight in the presence of 4 Å molecular sieve in anhydrous DCM (0.1 mol/L) at room temperature. All yields were calculated based on 1a and represent isolated yield. The anomeric ratio was determined by ¹H NMR analysis. ^a Reaction time: 3 h.

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  To explore the potential synthetic application of the current method, we attempted the one-pot global deprotection to obtain the free C-indolyl-glycosides (Fig. 4). Direct debenzylation of compound 3ao by catalytic hydrogenolysis with palladium hydroxide on carbon as catalyst and acetic acid as additive gave the desired free glycoside 4a in 94% yield without influencing the anomeric configuration. We then tested the one-pot deprotection of both benzoyl and benzyl groups on compound 3as. Treatment with in-situ generated sodium methoxide from sodium hydride and methanol followed by hydrogen gas in the presence of palladium hydroxide on carbon afforded 4b in 88% yield with the anomeric indole untouched. We also realized the importance and demand of synthesizing optically pure C-glycoside. Therefore, we evaluated the anomer resolution efficiency in the deprotection of compound 3av, which was obtained in 14.5:1 anomeric selectivity. Notably, the β-anomer resolution by silica gel column chromatography was surprisingly smooth after the debenzoylation step. Subsequent hydrogenolysis provided 4c with excellent anomeric purity. To further showcase the synthetic potential of the current method, a one-pot glycosylation and global deprotection sequence was performed with acceptor 2x and donor 1a, affording 4d in 70% yield over three steps with excellent β-selectivity.

  Figure 4

  

  Figure 4.  One-pot deprotection and one-pot synthesis toward free C-indolyl-glucosides.

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  The colorful biological potentials of sugars bearing indole moiety have been well established in past reports, mainly their anticancer and antidiabetic functions [51-55]. More notably, the tryptophan C-mannosylation at the 2-position of the indole ring is the only known protein C-glycosylation [55]. Nevertheless, the antibacterial potential of C-indolyl-glycoside is rarely investigated. To demonstrate the important role of C-glycoside in discovering new biological activities as well as our efficient and convenient C-glycosylation protocol, we were keen to explore the antibacterial possibilities of readily accessible 4a–4d C-indolyl-glycosides. We conducted in vitro antibacterial assays to evaluate the efficacy of sample compounds 4a–4d against Gram-positive bacterium Staphylococcus aureus (S. aureus) and Gram-negative bacterium Escherichia coli (E. coli) (Fig. 5). Upon treatment with the C-indolyl-glycosides, both S. aureus and E. coli exhibited reasonable sensitivity to 4a, 4c, and 4d, while 4b showed no significant inhibitory effect. Remarkably, compound 4a with a phenyl substituent on C2 of indole displayed the most effective inhibition on E. coli, achieving a 40% reduction in growth. Conversely, S. aureus was most susceptible to 4d having an electron-donating methoxy group, with a 27% inhibition rate. Moreover, the comparable inhibitory effects of 4c and 4d were detected on E. coli, with inhibition rates of 20% and 23%, respectively. Compounds 4a and 4c showed similar suppressed effects on the growth of S. aureus. These preliminary results on the structure-activity relationship underscored the potential of these C-indolyl-glycosides compounds as antimicrobial agents and provided a direction for further development and optimization of their antibacterial properties.

  Figure 5

  

  Figure 5.  Growth inhibitory effects of compounds 4a-4d on S. aureus and E. coli. See Supporting information for experimental details.

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  To conclude, we have achieved a novel Sc(Ⅲ) catalyzed C-glycosylation using trailblazing glycosyl CCBz donors. The glycosyl donor could be easily activated under mild conditions through the release of ring strain energy. The protocol was demonstrated with an extensive substrate scope and could serve as a general method for the preparation of versatile C-glycosides bearing different aglycons and functionalities. We have also investigated the antibacterial potentials of several selected synthesized C-indolyl-glucosides, which shed light on the way to further development.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Yuhan Zhang: Writing – review & editing, Writing – original draft, Methodology, Investigation. Xiao-Lin Zhang: Writing – review & editing, Writing – original draft, Investigation. Han Ding: Writing – review & editing, Writing – original draft, Investigation, Conceptualization. Yuan Xu: Writing – review & editing, Investigation. Xue-Wei Liu: Writing – review & editing, Writing – original draft, Supervision, Resources, Project administration, Conceptualization.

  Acknowledgment

  We thank the Ministry of Education (MOE-T2EP30120-0007, Tier-1 RG107/23) of Singapore for the financial support.

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110560.

  
  
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• 

  Figure 1  (a) Selected alkyl and C-indolyl-glycosides with biological activities. (b) Our previous work on O-, S-, and N-glycosylation. (c) This work: catalytic strain-release C-glycosylation. Bn: benzyl, ⁱPr: isopropyl, Ac: acetyl, Me: methyl, Nu: nucleophiles, R: functional groups.

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  Figure 2  Scope of C-nucleophiles. Unless otherwise stated, all reactions were carried out using either optimized conditions A or B as described below. Condition A: 1.0 equiv. of 1a, 3.0 equiv. of C-nucleophile and 0.1 equiv. of Sc(OTf)₃ were stirred for 2 h in the presence of 5 Å molecular sieve in anhydrous DCM (0.1 mol/L) at room temperature. Condition B: 1.0 equiv. of 1a, 3.0 equiv. of C-nucleophile and 0.15 equiv. of Sc(OTf)₃ were stirred overnight in the presence of 4 Å molecular sieve in anhydrous DCM (0.1 mol/L) at room temperature. All yields were calculated based on 1a and represent isolated yield. The anomeric ratio was determined by ¹H NMR analysis. ^a Reaction time: 3 h.

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  Figure 3  Scope of glycosyl CCBz donors. Unless otherwise stated, all reactions were carried out using either optimized conditions A or B as described below. Condition A: 1.0 equiv. of 1a, 3.0 equiv. of C-nucleophile and 0.1 equiv. of Sc(OTf)₃ were stirred for 2 h in the presence of 5 Å molecular sieve in anhydrous DCM (0.1 mol/L) at room temperature. Condition B: 1.0 equiv. of 1a, 3.0 equiv. of C-nucleophile and 0.15 equiv. of Sc(OTf)₃ were stirred overnight in the presence of 4 Å molecular sieve in anhydrous DCM (0.1 mol/L) at room temperature. All yields were calculated based on 1a and represent isolated yield. The anomeric ratio was determined by ¹H NMR analysis. ^a Reaction time: 3 h.

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  Figure 4  One-pot deprotection and one-pot synthesis toward free C-indolyl-glucosides.

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  Figure 5  Growth inhibitory effects of compounds 4a-4d on S. aureus and E. coli. See Supporting information for experimental details.

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  Table 1.  Optimization of reaction condition^a.

  Entry	Acceptor	Solvent	Time (h)	Yield (%)	α:β
  1b, c	2a	DCM	2	49	10.4:1
  2b	2a	DCM	2	67	16.0:1
  3	2a	DCM	2	80	21.9:1
  4	2a	Et2O	2	67	24.2:1
  5	2a	Toluene	2	62	19.1:1
  6d	2a	DCM	Overnight	N.R.	–
  7	2b	DCM	Overnight	46	5.3:1
  8e	2b	DCM	Overnight	42	5.3:1
  9f	2b	DCM	Overnight	70	7.1:1
  10g	2b	DCM	Overnight	82	11.0:1
  11	2b’	DCM	Overnight	71	7.6:1
  12	2b”	DCM	Overnight	N.R.	–
  a Unless otherwise stated, the reactions were carried out with 1.0 equiv. of 1a, 3.0 equiv. of indicated acceptor in the presence of Sc(OTf)3 (0.1 equiv.) and 5 Å molecular sieve in the corresponding solvent (0.1 mol/L) for an indicated time at room temperature. All yields were calculated based on 1a and represent isolated yields. The anomeric ratio was determined via 1H NMR analysis. DCM = dichloromethane, N.R. = no reaction. b 1.5 equiv. acceptor. c 0.05 mol/L. d 1f (1.0 equiv.) was used as donor. e 0.05 equiv. Sc(OTf)3. f 4 Å MS. g 4 Å MS and 0.15 equiv. Sc(OTf)3.

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