Cooperative Catalysis in Stereoselective O- and N-Glycosylations with Glycosyl Trichloroacetimidates Mediated by Singly Protonated Phenanthrolinium Salt and Trichloroacetamide

Abstract

The development of small-molecule catalysts that can effectively activate both reacting partners simultaneously represents a pivotal pursuit in advancing the field of stereoselective glycosylation reactions. We report herein the development of the singly protonated form of readily available phenanthroline as an effective cooperative catalyst that facilitates the coupling of a wide variety of aliphatic alcohols, phenols, and aromatic amines with α-glycosyl trichloroacetimidate donors. The glycosylation reaction likely proceeds via an S_N2-like mechanism, generating β-selective glycoside products. The developed protocol provides access to O- and N-glycosides in good yields with excellent levels of β-selectivity and enables late-stage functionalization of O- and N-glycosides via cross-coupling reactions. Importantly, this method exhibits excellent β-selectivity that is unattainable through a C2-O-acyl neighboring group participation strategy, especially in the case of glycosyl donors already containing a C2 heteroatom or sugar unit. Kinetic studies demonstrate that the byproduct trichloroacetamide group plays a previously undiscovered pivotal role in influencing the reactivity and selectivity of the reaction. A proposed mechanism involving simultaneous activation of the glycosyl donor and acceptor by the singly protonated phenanthrolinium salt catalyst with the assistance of the trichloroacetamide group is supported by kinetic analysis and preliminary computational studies. This cooperative catalysis process involves four consecutive hydrogen bond interactions. The first interaction occurs between the carbonyl oxygen of the trichloroacetamide group and the hydroxyl group of alcohol nucleophile (C═O···HO). The second involves the trichloroacetamide-NH₂ forming a hydrogen bond with the nitrogen atom of the phenanthroline (NH···N). The third involves the donor trichloroacetimidate (═NH) engaging in a hydrogen bond interaction with the phenanthrolinium-NH (NH···N═H). Lastly, the protonated trichloroacetimidate-NH₂ forms a hydrogen bond with the fluorine atom of the tetrafluoroborate ion.

Graphical Abstract

INTRODUCTION

The selective synthesis of carbohydrate-based biomolecules has been a long-standing challenge in glycosciences.¹ Carbohydrates play a crucial role in a wide range of biochemical processes.² The highly variable, structurally complex, and densely polyoxygenated nature of these molecules makes their synthesis a significant challenge in glycosylation reactions (Figure 1A) due to the inherent difficulty in controlling stereoselectivity.^3,4 Further, the formation of a new stereogenic bond at the C1 position of the sugar product adds to the complexity. Recent advancements in the development of small-molecule catalysts have provided promising solutions to these glycosylation challenges, offering new opportunities for achieving selective coupling.⁵ These catalysts effectively utilize hydrogen bond interactions^6,7 or covalent interactions⁸ with either the glycosyl electrophile or the nucleophile (Figure 1B).

Figure 1.

(A) Glycosylation reactions. (B) Interactions between the organocatalyst and the electrophile or the nucleophile. (C) Cooperative interactions of the organocatalyst with both the nucleophile and the electrophile. (D) Singly protonated phenanthrolinium as a cooperative small-molecule catalyst.

The development of small-molecule catalysts that activate both the nucleophile and the electrophile in stereoselective glycosylation has opened new horizons in recent years. This innovative approach was pioneered by Fairbanks,⁹ Schmidt,¹⁰ Toshima,¹¹ Taylor,^12,13 Jacobsen,^14–16 Pedersen,¹⁷ and Kancharla¹⁸ (Figure 1C). The potential of cooperative catalysis in stereoselective glycosylation has been demonstrated by employing the commonly used glycosyl halide, phosphate, and trichloroacetimidate donors.^10–19 The glycosylation reactions occur through S_N2-like mechanisms that involve the nucleophiles stereospecifically displacing the halide, phosphate, or trichloroacetimidate leaving groups of the donors via electrophile-catalyst-nucleophile complexes. This idea offers great potential for advancing stereoselective glycosylation reactions, especially with the widely used glycosyl trichloroacetimidates.¹⁹ However, designing small-molecule catalysts that simultaneously activate both reacting partners to produce the coupling products with high levels of stereoselectivity remains a considerable challenge. The cooperative catalysts developed by Toshima¹¹ (phosphoric acid) and Kancharla (hindered pyridinium salt),¹⁸ have proven to be effective in mediating stereoselective coupling of alcohol acceptors with glycosyl trichloroacetimidate donors only at temperatures below −40 °C. Fairbanks’ phosphoric acid cooperative catalyst has been applied with only galactosyl trichloroacetimidate.⁹ While Schmidt’s thiourea cocatalyst exhibited cooperative behavior in promoting the S_N2-like reactions of aliphatic alcohols with glycosyl trichloroacetimidate donors at room temperature, using carbohydrate alcohol acceptors resulted in moderate selectivity.¹⁰ Pedersen’s pyrylium salt catalysts displayed varying degrees of stereoselectivity in the coupling of alcohols and phenols with glycosyl trichloroacetimidates.¹⁷ In some cases, reactions were carried out with a gradual increase in temperature (−78 to 23 °C) to achieve high levels of β-selectivity. Acetonitrile was occasionally utilized as a solvent to enhance β-selectivity since acetonitrile can form a covalent adduct with the glycosyl oxocarbenium ion from the α-face, making a nucleophilic attack from the β-face more preferential.²⁰

Herein, we report a 1,2-trans glycosylation technique utilizing a readily available phenanthrolinium salt in its singly protonated form as a catalyst (Figure 1D). This catalyst functions as both a Brønsted acid and a Brønsted base to organize and activate the reacting components effectively.^21,22 The N–H proton of phenanthrolinium salt serves as a Brønsted acid, which activates the trichloroacetimidate leaving group of the glycosyl donor. Previously unrecognized in glycosyl trichloroacetimidate methodology, the presence of the trichloroacetamide byproduct was observed to accelerate the reaction rate. Amides play a critical role in determining a protein’s secondary structure, whose stability stems from the strong hydrogen bond formed between the amide proton and the carbonyl oxygen, as well as the planar geometry of amide.²³ Additionally, trichloroacetimidate has been utilized as a leaving group in catalytic reactions and has been observed to act as a directing group.²⁴ Its byproduct, trichloroacetamide, has been found to serve as a ligand for the metal ion.²⁴ Consequently, we postulated that the phenanthroline nitrogen acts as a hydrogen bond acceptor to interact with the trichloroacetamide-NH₂ group. The nucleophile is then likely activated through a hydrogen bond interaction with the carbonyl oxygen of the trichloroacetamide. The cooperative hydrogen bond interactions between the catalyst, the trichloroacetamide, and the reacting partners can create a stable transition state complex, influencing the reaction’s reactivity and selectivity. This catalytic system’s unique characteristics set it apart from single hydrogen-bond donor catalysts with similar acidity. Moreover, the acidic nature of the N–H bond (pK_a ~ 5.0) of phenanthrolinium salt can enhance the activation of the trichloroacetimidate group of a glycosyl donor through a strong hydrogen bond interaction, compared to dual hydrogen-bond donor thiourea (pK_a ~ 8.5).^7,25 These distinctive attributes of a singly protonated phenanthrolinium salt catalyst can help drive stereoselective glycosylation forward and broaden its applications to a range of potential reacting partners. Our findings present the first example of the trichloroacetamide byproduct serving as a cocatalyst. We illustrate that singly protonated phenanthrolinium salt, with the assistance of trichloroacetamide, facilitates β-selective couplings of alkyl alcohols, phenols, and anilines with α-glycosyl trichloroacetimidate donors through electrophile-catalyst-trichloroacetamide-nucleophile intermediates.

RESULTS AND DISCUSSION

Reaction Development.

Glycosyl trichloroacetimidates are typically activated using a catalytic amount of a Lewis acid, such as BF₃·OEt₂ and TMSOTf.³ The high reactivity of the imidate donor and the strong affinity of BF₃·OEt₂ or TMSOTf to the trichloroacetimidate leaving group results in the formation of the coupling product, with the selectivity highly dependent on the reaction temperature. Conducting the reaction at low temperatures is crucial for optimal stereoslectivity, as high temperatures frequently lead to inconsistent selectivity. For instance, when glycosyl trichloroacetimidate 1a reacted with alcohol 2a in the presence of 10 mol % TMSOTf or 10 mol % BF₃·OEt₂ at 0 °C, product 3a was obtained as a 1:1 α/β mixture of isomers in both cases (Table 1). Schmidt and co-workers discovered that gold(III) chloride is a highly effective Lewis acidic metal salt catalyst that strongly interacts with the alcohol acceptor–OH but weakly with the trichloroacetimidate leaving group.²¹ The AuCl₃ catalyst facilitates the highly β-selective formation of O-glycoside products at temperatures below −60 °C. When AuCl₃ was used as the catalyst in the reaction of alcohol 2a with donor 1a at a higher temperature (0 °C) under the conditions described in Table 1, product 3a was obtained with low anomeric selectivity (α:β = 1:2).

Table 1.

Evaluation of Catalysts for the Coupling of an Alcohol with Glycosyl Trichloroacetimidate^a

^aAll reactions were conducted with donor 1a (0.12 mmol) and acceptor 2a (0.10 mmol) in Et₂O (0.2 M) at 0 °C.

^bIsolated yields are reported.

^cDiasteroselectivities (α:β) were determined by ¹H NMR.

We predicted that by using a singly protonated phenanthrolinium salt as a cooperative catalyst, O-glycoside products could be formed with high β-selectivity. It has been reported that Brønsted acids with pK_a < 5.0 effectively activate trichloroacetimidate donors.²⁶ Based on this observation, we postulated that the N–H bond of the catalyst, with a pK_a value of 4.8–5.2,²⁷ could function as a suitable Brønsted acid. This phenanthrolinium salt would not only activate the donor but also mitigate the rapid dissociation of the leaving group, that would lead to the formation of the oxocarbenium ion which favors a S_N1-like pathway. The selectivity of the coupling reaction would instead be determined through the cooperative interactions of the catalyst with both the glycosyl donor and acceptor in an S_N2-like transition state.²⁸

After an initial screening of a variety of catalysts, solvents, reaction temperatures, and counterions (Tables S3–S5), we identified three singly protonated phenanthrolinium and two bipyridinium salts as highly selective catalysts in the coupling of alcohol 2a with glucosyl trichloroacetimidate 1a (Table 1). The parent singly protonated phenanthroline catalyst, [PhenH]⁺[BF₄]⁻,²⁹ displayed the highest reactivity and selectivity, producing 3a in 91% yield with α:β = 1:23. For comparison, we conducted experiments with two other catalysts lacking a second nitrogen, benzo[h]quinolinium salt ([BenzoH]⁺[BF₄]⁻), and pyridinium salt ([PyrH]⁺[BF₄]⁻) (Table 1). We found that these catalysts mediated O-glycosylation with lower yields and β-selectivity than the [PhenH]⁺[BF₄]⁻ catalyst,²⁹ validating the critical role of the second nitrogen atom on the phenanthrolinium salt in influencing the reaction’s reactivity and selectivity.

Our objective is to establish adaptable protocols that allow scientists to select their preferred catalysts for synthesizing their desired targets.¹ As a result, we performed the coupling of alcohol 2a with donor 1a, utilizing cooperative catalysts previously published and readily available, under our optimized conditions for phenanthrolinium salt, [PhenH]⁺[BF₄]⁻ (Table 1).

We studied the cooperative catalysis phenomenon using a chiral phosphoric acid first developed by Fairbanks⁹ and then later modified by Toshima,¹¹ for the coupling of alcohol 2a with trichloroacetimidate 1a. The reaction was slow and produced 3a in 83% yield with good β-selectivity (α:β = 1:7). Even though the achiral 4-nitro-phosphoric acid reacts faster (36 h) compared to the chiral phosphoric acid (48 h), the ratio of α:β was moderate (α:β = 1:3). The combination of thiourea cocatalyst and 4-nitro-phosphoric acid catalyst developed by Schmidt¹⁰ was more reactive (3 h) and produced 3a in slightly higher yield and β-selectivity (85%, α:β = 1:6). This result is consistent with a previous report by Schmidt, where the reaction was conducted in methylene chloride at room temperature.¹⁰ The use of a chiral phosphoric acid catalyst in combination with a thiourea cocatalyst has not been documented. This prompted us to investigate whether such a combination could enhance the selectivity. This combination resulted in a higher β-selectivity for 3a (α:β = 1:11) compared to the combination of achiral 4-nitro-phosphoric acid and thiourea (α:β = 1:6). As a control, we conducted the glycosylation reaction mediated by thiourea only. The reaction was sluggish (48 h) and produced 3a in 57% yield as a 1:1 α/β mixture. The pyrylium salt catalyst developed by the Pedersen group exhibited higher reactivity than the other catalysts. However, it was moderately β-selective (α:β = 1:4).¹⁷ The (3,5-bis(trifluoromethyl) phenyl)boronic acid catalyst, reported by the Taylor group for the couplings of azole heterocycles with trichloroacetimidates, exhibited lower reactivity compared to other catalysts. The reaction resulted in a 15% yield of 3a with a α/β ratio of 1:8 after 48 h.¹³ This result is in line with Taylor’s findings, where the reaction required a temperature of 75 °C for 24 h to achieve high yield and selectivity.

It is important to note that all these comparison studies with previously reported cooperative catalysts were conducted under the optimal conditions for the phenanthrolinium salt, [PhenH]⁺[BF₄]⁻, where product 3a was obtained in 91% yield with excellent levels of selectivity (α:β = 1:23, Table 1). As previously demonstrated, it is evident that the yield and selectivity for product 3a may vary under the optimal conditions developed for each of the previous cooperative catalysts.

Substrate Scope.

The scope of alcohol acceptors in glycosylation reactions using glucosyl donor 1 and the catalyst [PhenH]⁺[BF₄]⁻ was examined (Table 2). The optimized procedure proved effective, resulting in the desired products 3b–3j, 3l, and 3m in good yields and high β-selectivity. For instance, both primary and secondary pyranose and furanose-derived alcohol acceptors underwent glycosylation, selectively producing the β-disaccharides 3b–3e, 3h–3j (α:β > 1:25). Additionally, the primary alcohol of N-protected carbamate serine residue proved to be an effective acceptor, producing glycoconjugate 3f in 81% yield with α:β = 1:12. The reaction conditions were equally effective with the primary and secondary alcohol acceptors, dexamethasone, cholestanol, and oleanolic acid, resulting in the highly selective β-glycosides 3g, 3l, and 3m, respectively, (α:β = 1:13 to >1:25).

Table 2.

Phenanthrolinium-Catalyzed Stereoselective Glycosylations with Alcohols^a

^aReactions were conducted with donor (0.12 mmol) and acceptor (0.10 mmol) in Et₂O (0.2 M).

^bIsolated yields are reported.

^cThe α:β ratios were determined by ¹H NMR.

^dReactions were conducted with 5 mol % TMSOTf at 0 °C for 1 h.

^eReactions were conducted at 25 °C for 24 h.

^fA 1:1 mixture of Et₂O and DCM was used as a solvent.

^gReactions were conducted with 15 mol % [PhenH]⁺[BF₄]⁻ at 25 °C for 24 h.

Next, the developed catalytic protocol was examined with different α-glycosyl trichloroacetimidate donors, including 2-fluoro³⁰ and 2-azido d-glucose substrates (1n–1p), 2-fluoro d-galactose (1r),³¹ and d-xylose (1s). We observed that these substrates performed well, yielding 3n–3p, 3r, and 3s in good yields with excellent β-selectivity (α:β = 1:17–1:25). The 2-fluoro and 2-azido derived donors displayed lower reactivity than the parent glucose and galactose, requiring room temperature and longer reaction times. Nonetheless, our method demonstrates excellent β-1,2-trans selectivity for these substrates, which cannot be achieved through a C2-O-acyl neighboring group participation strategy, as it does not apply to these substrates.³² We also conducted a few control reactions mediated by TMSOTf, which resulted in the preferred formation of the α-isomer of products 3d (α:β = 2:1), 3e (α:β = 6:1), 3n (α:β = 2:1), and 3s (α:β = 1:1). Overall, the phenanthrolinium-catalyzed protocol has demonstrated a significant increase in β-selectivity compared to the standard TMSOTf activation protocol, which exhibited a slight bias toward α-selectivity in the cases examined. Moreover, in reactions with moderate yields, we have observed that a portion of the trichloroacetimidate donor undergoes hydrolysis to form the corresponding hemiacetal while the unreacted acceptor remains intact.

Next, we examined the reactivity and selectivity of phenol nucleophiles with a variety of d- and L-glycosyl trichloroacetimidate electrophiles (Table 3A). β-O-aryl glycosides have demonstrated antitumor, anti-HIV, and antibiotic properties.³³ However, achieving the selective synthesis of O-aryl glycosides via nucleophilic substitution between a carbohydrate electrophile and phenol is challenging,³⁴ due to the electron-withdrawing nature of the aromatic ring, the presence of substituents on phenol, and the facile rearrangement of O-aryl glycosides to C-aryl glycosides.³⁵ As such, there is a continued interest in the development of glycosylation methods to generate O-aryl glycosides with enhanced levels of efficiency, selectivity, and functional group tolerance.^15,36 Considering the developed protocol is highly β-selective for the couplings of various aliphatic alcohols, we assessed [PhenH]⁺[BF₄]⁻ as a catalyst in the reactions of phenols with several donors (Table 3A). The α/β selectivity of O-aryl glycoside products 5a–5n was consistently high (1:16–1:25) across the range of phenols tested. Phenols with electron-donating or electron-withdrawing substituents yielded β-O-aryl glycosides with similar yields and selectivities. In addition, the stereochemical features and the substitution pattern of the glycosyl donor did not affect the reaction’s selectivity. With this catalytic protocol, we also observed high β-selectivity for medicinally relevant phenols, including estrone (5f, α:β = 1:17), N-carbamate-protected tyrosine residue (5g, α:β = 1:14), and capsaicin (5h, α:β > 1:25).

Table 3.

Phenanthrolinium-Catalyzed Stereoselective Glycosylations with Phenols and Anilines^a

^aFor phenols, donor (0.10 mmol) and acceptor 4 (0.40 mmol) in THF (0.2 M); for anilines, donor (0.12 mmol) and acceptor 6 (0.10 mmol) in Et₂O (0.2 M).

^bIsolated yields are reported.

^cThe α:β ratios were determined by ¹H NMR.

We also explored the couplings of aromatic amine nucleophiles (Table 3B). N-aryl glycosides, in which a sugar is attached to a nitrogen atom of an aromatic ring, are a significant subclass of the nucleoside adenosine, a vital component of RNA.³⁷ N-aryl glycosides are being explored as potential candidates for developing antiviral and anticancer drugs.³⁸ The majority of synthetic efforts have been focused on the synthesis of O-aryl glycosides. As a result, strategies for the stereoselective synthesis of N-aryl glycosides are still underdeveloped.^13,39 The optimized protocols proved effective for various acyclic and cyclic secondary anilines (Table 3B). The N-aryl products (7a–7e) were stereoselectively formed in high yield with α:β > 1:25 across the series of the arylamines tested. The use of other glycosyl donors also led to the production of products 7f–7l in high yield with exceptional β-selectivity (α:β = 1:20 to >1:25). Given that aniline is more nucleophilic than phenol and alcohol, we hypothesized that aniline would exhibit inherent β-selectivity irrespective of the catalyst’s structure. Therefore, we conducted control experiments using pyridinium catalysts. The result showed that N-methyl aniline, when reacted with glucosyl trichloroacetimidate 1a and catalyzed by pyridinium catalysts, exhibited similar yield and β-selectivity as when the reaction was catalyzed by [PhenH]⁺[BF₄]⁻ (see Table S9). Furthermore, aliphatic amine, 1,2,3,4-tetrahydroisoquinoline, was determined to be unreactive. This lack of reactivity was attributed to the transfer of the proton from phenanthrolinium salt to tetrahydroisoquinoline (pK_a ~ 11, see Scheme S10 and Figure S1), effectively quenching the catalyst.

Overall, our findings indicate that aromatic amine couplings show a greater preference for β-products than phenol and alcohol nucleophiles, regardless of the stereochemical patterns of the donors. Furthermore, compared to alcohols, we observed that phenols and aromatic amines display higher β-selectivity for L-arabinosyl and L-fucosyl trichloroacetimidates (donors that traditionally exhibit slight bias toward α-selectivity) despite the greater complexity of the alcohols used. For example, the reactions of 4-methoxy phenol and indoline with L-arabinosyl and L-fucosyl donors produced β-phenolic glycosides (5m and 5n, Table 3A) and β-aryl-N-glycosides (7k and 7l, Table 3B) with excellent selectivity (α:β = 1:16–1:20). In contrast, reactions of aliphatic alcohol 2a with these donors yielded O-glycosides (3t and 3u, Table 5, vide infra) with lower selectivity (α:β = 1:3–1:6).

Table 5.

Influence of Trichloroacetamide on Various Donors and Acceptors^a

^aReactions were conducted with donor (0.12 mmol) and acceptor 2 (0.10 mmol) in Et₂O (0.2 M), 0 °C, 6 h.

^bIsolated yields are reported.

^cThe α:β ratios were determined by ¹H NMR.

^dReactions were conducted with 15 mol % [PhenH]⁺[BF₄]⁻ at 25 °C for 24 h.

^eReactions were conducted with 15 mol % of trichloroacetamide as an additive.

^fThe reaction time was 24 h.

^gAcetonitrile was used as the solvent.

^hReactions were conducted with donor (0.10 mmol) and acceptor 4 (0.40 mmol) in THF (0.2 M) 0 °C, 1 h.

ⁱReactions were conducted with donor (0.12 mmol) and acceptor 6 (0.10 mmol) in Et₂O (0.2 M), 0 °C, 6 h.

The effectiveness of [PhenH]⁺[BF₄]⁻-catalyzed glycosylation was further illustrated in the stereoselective synthesis of tetrasaccharide 9 (87%, α:β > 1:25). This tetrasaccharide was produced by the coupling of alcohol 2a with the trisaccharide unit of the natural saponin lablaboside F, a potential vaccine adjuvant (Scheme 1A).⁴⁰ The method illustrates remarkable selectivity that is unattainable through a C2-acyl neighboring group participation strategy,³² particularly with regard to the trisaccharide substrate 8, which carries a C2-disaccharide unit adjacent to its electrophilic center. In addition, the ability to produce O- and N-aryl β-glycoside products via [PhenH]⁺[BF₄]⁻ catalyzed reactions offers a rapid method to generate carbohydrate building blocks from the common precursor 1a. To demonstrate this potential application, we conducted the couplings of 4-bromo-phenol 4o (Scheme 1B) and 4-bromo-N-methylanline 6m (Scheme 1C) with glucosyl donor 1a. We then elaborated the O- and N-aryl glycoside products 5o and 7m in a one-pot reaction via Suzuki–Miyaura cross-coupling⁴¹ or the Sonogashira reaction.⁴² Excellent stereoselectivity (α:β > 1:20) was observed in each transformation. Motifs like those found in cross-coupling products 11–13 (Schemes 1B–C) may now be prepared using sequential catalytic stereoselective glycosylation and transition-metal-catalyzed cross-coupling reactions.

Scheme 1. Applications toward Oligosaccharide and Carbohydrate Building Block Syntheses.

^aIsolated yields are reported. ^bThe α:β ratios were determined by ¹H NMR.

Mechanistic and Computational Studies.

Stereochemical Outcomes.

To probe the stereospecific nature of [PhenH]⁺[BF₄]⁻-catalyzed glycosylation, we examined the impact of the donor’s anomeric composition on the reaction’s selectivity by utilizing both the α- and β-isomers of the trichloroacetimidate donor (Table 4). It was observed that reducing the anomeric purity of the α-donor decreased the β-selectivity, indicating a dominant S_N2-like pathway. When alcohol 2a was reacted with donor 1-β, product 3a was produced as a 1:1 α/β mixture (entry 5) in contrast to the highly β-selective formation of 3a from donor 1-α (entry 1). Moreover, the rate of conversion of 1-β (entry 5) was significantly slower than that of 1-α (entry 1). Although product 3a was obtained in good yield from both diastereomeric donors, the highly pure α-donor reaction was completed within 6 h (entry 1), whereas the reaction of the highly pure β-isomer required 36 h (entry 5b). Stopping the reaction at 6 h yielded product 3a with only a 21% yield, alongside unreacted starting material 1-β (entry 5a). Notably, the presence of the isomer 1-α was not detected. The reactions were not entirely stereospecific, possibly due to competition with a S_N1-like pathway or donor anomerization.^3,43 To determine if donor anomerization was probable, we carried out a control reaction using donor 1-β and 5 mol % [PhenH]⁺[BF₄]⁻ in the absence of an acceptor. After 24 h at 0 °C, we observed a mixture of α-trichloroacetimidate 1-α, β-trichloroacetimidate 1-β, and some hemiacetal (see Scheme S12). The findings indicate that donor anomerization may occur under the specified reaction conditions, forming the αisomer that in turn reacts rapidly with the alcohol nucleophile.

Table 4.

Influence of the Donor’s Anomeric Composition on the Selectivity and Reactivity of the Reaction^a

Entry	Imidate 1α/1λ α:β ratio	Time (h)	Product 3a Yield (%)b	Product 3a α:β ratioc
1	100:0	6	91	1:23
2	20:1	6	90	1:17
3a	10:1	6	81	1:8
3b	10:1	7 (completion)	91	1:8
4a	3:1	6	57	1:5
4b	3:1	10 (completion)	88	1:5
5a	0:100	6	21	1:1
5b	0:100	36 (completion)	91	1:1

^aReactions were conducted with donor (0.12 mmol) and acceptor (0.10 mmol) in Et₂O (0.2 M).

^bIsolated yields.

^cThe α:β ratios were determined by ¹H NMR.

Kinetics.

The coupling of alcohol acceptor 2a with trichloroacetimidate donor 1a* was monitored by ¹H NMR spectroscopy in CDCl₃ using 1,3,5-trimethoxybenzene as an internal standard with varying concentrations of the acceptor (Figure 2A), the donor (Figure 2B), and [PhenH]⁺[BF₄]⁻ catalyst (Figure 2C). In this study, 2,3,4,6-tetra-benzyl-d₇-glycosyl trichloroacetimidate 1a* was employed as the electrophile to obtain an unobstructed view of the anomeric region in ¹H NMR. As demonstrated in Figures 2A–C, the rate of the formation of product 3a* increases as the concentration of each reaction component increases. The rate of the reaction showed first-order dependence on the donor, acceptor, and catalyst.¹⁴

Figure 2.

Concentration of 3a* (M) vs time (min) as determined by ¹H NMR analysis in CDCl₃ using 1,3,5-trimethoxybenzene as an internal standard (A) with variation of the initial concentration of acceptor 2a, (B) with variation of the initial concentration of donor 1a*, and (C) with variation of the initial concentration of [PhenH]⁺[BF₄]⁻ catalyst.

We additionally monitored the reaction progress using 0.2 M of alcohol acceptor 2a, 0.2 M of trichloroacetimdiate donor 1a, and 0.01 M of the [PhenH]⁺[BF₄]⁻ catalyst (Figure 3A). Interestingly, the kinetic study results revealed that the product concentration exhibited a sigmoidal kinetic profile over time, with an observed induction period of about 20 min (Figure 3A). One possible explanation for the sigmoidal kinetic profile is that the product 3a* or the byproduct, trichloroacetamide generated in the reaction, may accelerate the reaction rate by acting as a cocatalyst.⁴⁴ To test this hypothesis, the reaction rate was monitored with the addition of either 3a* or trichloroacetamide. Figure 3B illustrates the reaction profile with the addition of product 3a* (15 mol %). The resulting kinetic profile (Figure 3B) was identical to the original profile (Figure 3A), indicating that the addition of the product 3a* does not eliminate the induction period. On the other hand, the addition of trichloroacetamide (15 mol %) eliminated the induction period (Figure 3C), indicating that the byproduct trichloroacetamide serves as a cocatalyst to accelerate product formation.

Figure 3.

Concentration of 3a* (M) vs time (min) as determined by ¹H NMR analysis in CDCl₃ using 1,3,5-trimethoxybenzene as an internal standard (A) with 0.2 M 1a*, 0.2 M 2a, and 0.01 M [PhenH]⁺[BF₄]⁻; (B) with 0.2 M 1a*, 0.2 M 2a, 0.01 M [PhenH]⁺[BF₄]⁻, and 0.03 M 3a*; and (C) with 0.2 M 1a*, 0.2 M 2a, 0.01 M [PhenH]⁺[BF₄]⁻, and 0.03 M trichloroacetamide. (D) Overlay of (A), (B), and (C).

Furthermore, we observed significant changes in the α/β ratio of product 3a* for the standard reaction (0.2 M donor 1a*, 0.2 M acceptor 2a, and 0.01 M [PhenH]⁺[BF₄]⁻ catalyst, Et₂O, 0 °C) after the induction period versus the end of the reaction. After the induction period, the selectivity was measured at α:β = 1:11 (Scheme S13). By the end of the reaction, the selectivity had increased to α:β = 1:23 (Table 1). These results clearly demonstrate the critical role trichloroacetamide has in enhancing the β-selectivity of the reaction. Figure 3A, Figure 3B, and Figure 3C are overlaid in Figure 3D to visually demonstrate that the addition of the product did not alter the kinetic profile, whereas the addition of trichloroacetamide eliminated the induction period and exhibited a similar rate to the standard reaction after the induction period.

Some limitations of the developed protocol were identified (Table 5). For instance, when primary alcohol 2a was combined with both d-galactosyl and L-fucosyl trichloroacetimidate donors, it resulted in disaccharide products 3q and 3u with a low β-selectivity (α:β = 1:3). On the other hand, coupling 2a with L-arabinosyl donor and coupling the C3-hydroxyl group of glucoside 2k with d-glucosyl donor 1a produced disaccharides 3t and 3k, respectively, with moderate β-selectivity (α:β = 1:5–1:6). Inspired by our kinetic results, we investigated whether adding the byproduct trichloroacetamide into the reaction mixture could improve the β-selectivity of the product. We initially conducted the coupling of alcohol 2a with galactosyl trichloroacetimidate 1q, while varying the amount of trichloroacetamide added (Table S8). The diastereoselectivity of disaccharide product 3q showed a slight increase as the amount of trichloroacetamide added increased, with the highest α/β ratio of 1:6 observed with 15 mol % of trichloroacetamide. Any further increase in the amount of trichloroacetamide added had no effect on the selectivity. As a control, we determined that using 15 mol % of trichloroacetamide in the absence of [PhenH]⁺[BF₄]⁻ resulted in no reaction (Table S8). We conducted several reactions with the addition of 15 mol % of trichloroacetamide, the results of which are summarized in Table 5. Using a secondary alcohol, we observed that product 3k exhibited a slight increase in β-selectivity (α:β = 1:5 → 1:7). Similarly, when combining the L-arabinosyl and L-fucosyl donors with the primary alcohol 2a, we obtained products 3t (α:β = 1:6 → 1:8) and 3u, (α:β = 1:3 → 1:5) with improved β-selectivity. The impact of trichloroacetamide on the reaction’s selectivity was most evident with the D-mannosyl donor (Table 5). Without trichloroacetamide, the desired disaccharide 3v was obtained with high α-selectivity (α:β = 11:1). However, in the presence of 15 mol % of trichloroacetamide, the α-selectivity decreased from α:β= 11:1 to α:β = 7:1. Furthermore, conducting the reaction in acetonitrile with the addition of 15 mol % of trichloroacetamide, the α-selectivity decreased even further (α:β = 3:1). In the case of the phenol acceptor 4b, the β-selectivity of the product 5b increased from 1:16 to 1:19 with the addition of 15 mol % of trichloroacetamide. Moreover, we noted the addition of trichloroacetamide yielded a slight increase in the β-selectivity of product 7j, obtained from the glycosylation of aniline acceptor 6j with the xylosyl donor (α:β = 1:20 → 1:21).

Computational Studies.

We utilized density functional theory (DFT) to perform a preliminary computational evaluation of our proposed transition state forthe selective glycosylation of methanol with 2,3,4,6-tetra-O-methyl-α-d-glucopyranosyl trichloroacetimidate (Figure 4). The crystal structure of singly protonated phenanthroline reveals an N–H···N angle of 104 degrees, which differs from the near-linear angle of traditional hydrogen bonds (see Figures 1D and S10). This result suggests that the proton of phenanthrolinium is likely stabilized by a strong electrostatic interaction with the adjacent nitrogen atom. The crystal structure of [PhenH]⁺[BF₄]⁻ also shows interactions between the phenanthrolinium proton and the tetrafluoroborate, BF₄⁻, ion.²⁹

Figure 4.

Proposed transition states B (TS-B) and C (TS-C) for the singly protonated phenanthrolinium-catalyzed stereoselective glycosylation of a methanol acceptor with a glycosyl trichloroacetimidate donor. Bond lengths are labeled in green and reported in Å. Hydrogen bond angles are labeled in pink. The Gaussian 16 program package⁴⁵ at the M06–2X/def2-TZVPP//M06–2X/def2-SVP level of theory,⁴⁶ using diethyl ether with SMD implicit solvation,⁴⁷ was employed to model the transition state.

Attempts to locate transition state (TS-A) involving direct hydrogen bond interactions between methanol and the nitrogen atom of the phenanthroline salt were unsuccessful (see Figure S11). In our hypothesis, the two nitrogen atoms of protonated phenanthroline are rigidly fixed at a small bite angle. This makes it unlikely that the transition state will allow simultaneous hydrogen bonding between the methanol acceptor and the trichloroacetimidate donor.

Our kinetic results suggest that the selectivity of the reaction is lower during the induction period when the concentration of the byproduct trichloroacetamide is low and increases substantially after the induction period (Figure 3A,D). Based on these observations and the crystal structure of singly protonated phenanthrolinium, we conducted calculations in the presence of a trichloroacetamide group and a BF₄⁻, ion. Our analysis revealed a potential transition state structure (Figure 4) involving a strong hydrogen bond between the carbonyl oxygen of the trichloroacetamide and the methanol hydroxyl group (C═O···HO-Me), as well as between the trichloroacetamide-NH₂ group and the phenanthroline nitrogen atom (TS-B). Consequently, we hypothesized that the lower selectivity during the induction period is due to a competing S_N1-like mechanism, as indicated by the result obtained with product 3a (α:β = 1:11, Scheme S13) at the end of the induction period. However, as the concentration of trichloroacetamide increases, the S_N2-like TS-B becomes the favored mechanism, based on the higher β-selectivity of product 3a at the end of the reaction (α:β = 1:23, Table 1). In the TS-B model, the phenanthrolinium is positioned favorably to interact with both the protonated trichloroacetimidate leaving group of the donor and the amide-methanol complex through strong hydrogen bond interactions. The counterion BF₄⁻ is situated at the backside, forming a strong hydrogen bond with the protonated trichloroacetimidate leaving group.

As a comparison, we modeled an S_N2-like reaction pathway using a 2,3,4,6-tetra-O-methyl-β-d-glucopyranosyl trichloroacetimidate which resulted in the α-O-glycoside product (TS-C). Our findings revealed that phenanthrolinium was also positioned in a way that allowed it to interact with both the leaving group and the amide-methanol complex. However, we observed a stronger hydrogen bond between phenanthrolinium and the amide-methanol complex in TS-B (1.89 Å and 171°) compared to TS-C (2.25 Å and 134°). Furthermore, the BF₄⁻ ion did not play a significant role in TS-C and was positioned above the donor.

The formation of the TS-B and TS-C complexes is proposed to occur through a series of discrete steps. Initially, the nucleophile and a free trichloacetamide form a complex, followed by the formation of another complex involving the trichloroacetimidate and protonated phenanthrolinium. Subsequently, these two complexes combine to create the larger transition state complex, ultimately leading to an S_N2-like reaction. It is important to note that the energy barrier of the transition state was determined by calculating the total energies of the individual starting materials, with the presented energy barrier value representing an amalgamation of the small amount of energy contributions required for each sequential complexation. This comprehensive approach is reflected in the total energy barrier. Although the high energy barriers suggest that additional mechanistic studies are needed to gain further insights into the reaction pathway, the predicted transition states serve as valuable models for explaining the observed selectivities.

When comparing the transition states TS-C and TS-B, it was observed that TS-C has a significantly higher energy level than TS-B (Figure 4). The higher energy barrier (55.2 kcal/mol) for TS-C renders this transition state unrealistic, explaining the observed anomeric mixture and sluggish reaction (Table 4, entries 5a and 5b). Under our optimized conditions, the β-trichloroacetimidate donor is less reactive than its α-anomer counterpart, supporting that an S_N2-like substitution with a β-trichloroacetimidate donor is unlikely. On the other hand, the more reasonable energy barrier for TS-B (33.0 kcal/mol) supports the proposed mechanism (Figure 4), where the synergistic effect of both the singly protonated phenanthrolinium salt and trichloroacetamide could facilitate the β-selective glycosylation process by activating the donor and acceptor simultaneously.

The substantial difference in energy between the two transition states may also be attributed to the non-participation of the BF₄⁻ ion in TS-C. In contrast, the counterion BF₄⁻ interacts with the positive charge formed on the trichloroacetimidate leaving group in TS-B. To elucidate the role of BF₄⁻ on selectivity, we added 5 mol % of tetrabutylammonium tetrafluoroborate to the glycosylation of 1a and 2a employing [PhenH]⁺[ClO₄]⁻ as the catalyst. Consequently, we observed a significant increase in β-selectivity (Table S4, α:β = 1:3 → 1:10). This finding indicates the significant impact that BF₄⁻ plays in modulating the stereoselectivity of the reaction.

CONCLUSION

We have developed a highly β-selective glycosylation method that allows for the coupling of a variety of aliphatic alcohols, phenols, and anilines with stereochemically distinct α-trichloroacetimidates. This catalytic process utilizes a readily available phenanthrolinium salt to produce O- and N-glycosides in high yields with excellent β-selectivity in most cases. Moreover, the established protocol demonstrates outstanding selectivity for glycosyl donors with a C2-azido or fluoro group adjacent to the electrophilic center, as well as for branched trisaccharide donors containing a C2-disaccharide unit. In contrast, the widely used C2-O-acyl neighboring group participation method may not be suitable for synthesizing β-1,2-trans selective glycosidic bonds with these donor substrates. Our kinetic studies and preliminary computational modeling indicate that the β-selectivity of the glycosylation reaction arises from an S_N2-like mechanism involving the phenanthrolinium salt catalyst and the trichloroacetamide cocatalyst, which activates both the sugar electrophile and nucleophile simultaneously. Furthermore, it has been demonstrated that the BF₄⁻ counterion improves the β-selectivity of the product by participating in hydrogen bonding with the protonated trichloroacetimidate in the transition state. An important discovery of our study is that the displaced trichloroacetamide group from the glycosyl donor significantly influences the reactivity and selectivity of the reaction by acting as a cocatalyst. This occurs through the formation of a hydrogen bond complex with both the glycosyl donor and acceptor. This finding is supported by kinetic studies and DFT calculations. The discovery of the significant impact of the trichloroacetamide group has not been previously reported in the literature, which warrants further investigation into its role in catalytic stereoselective glycosylation.