Use of Novel Homochiral Thioureas Camphor Derived as Asymmetric Organocatalysts in the Stereoselective Formation of Glycosidic Bonds

We synthesized six new camphor-derived homochiral thioureas 1–6, from commercially available (1R)-(−)-camphorquinone. These new compounds 1–6 were evaluated as asymmetric organocatalysts in the stereoselective formation of glycosidic bonds, with 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl and 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates as donors, and several alcohols as glycosyl acceptors, such as methanol, ethanol, 1-propanol, 1-butanol, 1-octanol, iso-propanol, tert-butanol, cyclohexanol, phenol, 1-naphtol, and 2-naphtol. Optimization of the asymmetric glycosylation reaction was achieved by modifying reaction conditions such as solvent, additive, loading of catalyst, temperature, and time of reaction. The best result was obtained with 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates, using 15 mol% of organocatalyst 1, in the presence of 2 equiv of MeOH in solvent-free conditions at room temperature for 1.5 h, affording the glycosidic compound in a 99% yield and 1:73 α:β stereoselectivity; under the same reaction conditions, without using a catalyst, the obtained stereoselectivity was 1:35 α:β. Computational calculations prior to the formation of the products were modeled, using density functional theory, M06-2X/6-31G(d,p) and M06-2X/6-311++G(2d,2p) methods. We observed that the preference for β glycoside formation, through a stereoselective inverted substitution, relies on steric effects and the formation of hydrogen bonds between thiourea 1 and methanol in the complex formed.


Introduction
Biologically functional carbohydrates have diverse structures, and it is necessary to obtain homogeneous and well-defined materials for their study.The isolation and purification of such natural carbohydrates implies laborious steps, therefore synthetic organic chemistry has been identified as a potential tool to prepare complex oligosaccharides [1].Glycosylation reactions are fundamental processes for joining monosaccharides, which are essential in the synthesis of oligosaccharides.This process involves the displacement of a leaving group from a glycosyl donor to a glycosyl receptor, generally aimed at a promoter or activator (Figure 1) [2].These reactions are influenced by various factors affecting its result, including solvent [3], temperature [4], reactant concentration [5], activation method [6], chemical, stereo, and electronic properties of the donor and acceptor [7].

O (PO)n
LG Among the most commonly used donors are glycosyl iodides [8], thioglycosides [3], glycosyl thioimidates [9], carboxybenzyl glycosides [10,11], and trichloroacetimidates [12].The trichloroacetimidates have been suitable glycosyl donors due to their easy preparation in basic media and moderate chemical stability at room temperature.In the last two decades, there has been an enormous growth in the development of new glycosylation methodologies, whose efficiency have been generally evaluated by measuring chemical yield, regioselectivity, and stereoselectivity α/β [13][14][15][16][17][18].Despite numerous advances throughout the last few years, there is not a universal protocol that permits the formation of glycosidic bonds and the main challenge is stereoselectivity [19].Glycosylation methodologies can be classified depending on the promoter or activator into four different groups as follows [20]: transition metals catalysis [21], photochemical reactions [13], reactions in the presence of designed modulators to control selectivity [22], and reactions with organocatalysts [16,[23][24][25][26][27][28][29].Organocatalysts as activators are environmentally friendly and are ease functionalized.Organocatalytic glycosylation can be classified into three principal groups based on the type of catalyst used as follows: Brønsted acids, organoboron, and thioureas [30].Thioureas, as organocatalysts, offer important advantages, because they act as donors of hydrogen bonds and weak acids resulting in higher tolerance to several functional groups, chemoselectivity, and stereocontrol.These kinds of catalyst are synthesized through construction blocks that are commonly available and easily modifiable; usually the groups attached to N can be changed to syntonize the organocatalyst.The electronic nature of thiourea is also modified with the insertion of chiral components [30].Park et al. designed macrocyclic bis-thioureas (R,R)-9, which catalyzed the stereospecific inverted substitution using glucosyl chlorides as the donor and cyclohexanol as the acceptor, affording an 88% yield of the glycosylation product at rt for 6 h, adding IBO and solvent (Scheme 1) [26].Among the most commonly used donors are glycosyl iodides [8], thioglycosides [3], glycosyl thioimidates [9], carboxybenzyl glycosides [10,11], and trichloroacetimidates [12].The trichloroacetimidates have been suitable glycosyl donors due to their easy preparation in basic media and moderate chemical stability at room temperature.In the last two decades, there has been an enormous growth in the development of new glycosylation methodologies, whose efficiency have been generally evaluated by measuring chemical yield, regioselectivity, and stereoselectivity α/β [13][14][15][16][17][18].Despite numerous advances throughout the last few years, there is not a universal protocol that permits the formation of glycosidic bonds and the main challenge is stereoselectivity [19].Glycosylation methodologies can be classified depending on the promoter or activator into four different groups as follows [20]: transition metals catalysis [21], photochemical reactions [13], reactions in the presence of designed modulators to control selectivity [22], and reactions with organocatalysts [16,[23][24][25][26][27][28][29].Organocatalysts as activators are environmentally friendly and are ease functionalized.Organocatalytic glycosylation can be classified into three principal groups based on the type of catalyst used as follows: Brønsted acids, organoboron, and thioureas [30].Thioureas, as organocatalysts, offer important advantages, because they act as donors of hydrogen bonds and weak acids resulting in higher tolerance to several functional groups, chemoselectivity, and stereocontrol.These kinds of catalyst are synthesized through construction blocks that are commonly available and easily modifiable; usually the groups attached to N can be changed to syntonize the organocatalyst.The electronic nature of thiourea is also modified with the insertion of chiral components [30].Park et al. designed macrocyclic bis-thioureas (R,R)-9, which catalyzed the stereospecific inverted substitution using glucosyl chlorides as the donor and cyclohexanol as the acceptor, affording an 88% yield of the glycosylation product at rt for 6 h, adding IBO and solvent (Scheme 1) [26].In 2013, Geng et al. presented the cooperative catalysis of glycosylation reactions using O-trichloroacetimidate donors [25].Specifically, thiourea as co-catalysts exhibit a cooperative performance with a strong effect on reaction velocity, yield, and selectivity of glycosylation reactions.Dubey et al. ( 2019) demonstrated a fast glycosylation method, which is highly selective and efficient for preparing β-glycosides using a cooperative promoter system of N-benzoylglycine/thiourea (I) [31].The reaction is highly applicable to a variety of glycosyl donors, and the nucleophile receptors proceed with high selectivity Scheme 1. Glycosylation reaction catalyzed by a macrocyclic bis-thiourea 9.
In 2013, Geng et al. presented the cooperative catalysis of glycosylation reactions using O-trichloroacetimidate donors [25].Specifically, thiourea as co-catalysts exhibit a cooperative performance with a strong effect on reaction velocity, yield, and selectivity of glycosylation reactions.Dubey et al., (2019) demonstrated a fast glycosylation method, which is highly selective and efficient for preparing β-glycosides using a cooperative promoter system of N-benzoylglycine/thiourea (I) [31].The reaction is highly applicable to a variety of glycosyl donors, and the nucleophile receptors proceed with high selectivity and a high yield, tolerating the most common protective groups.These reaction conditions can be an attractive alternative to existing procedures.Achiral thiourea, as a co-catalyst, exhibits a cooperative performance, having a strong effect on the reaction velocity, yield, and selectivity of glycosylation (Scheme 2).
In 2013, Geng et al. presented the cooperative catalysis of glycosylation reactions using O-trichloroacetimidate donors [25].Specifically, thiourea as co-catalysts exhibit a cooperative performance with a strong effect on reaction velocity, yield, and selectivity of glycosylation reactions.Dubey et al. (2019) demonstrated a fast glycosylation method, which is highly selective and efficient for preparing β-glycosides using a cooperative promoter system of N-benzoylglycine/thiourea (I) [31].The reaction is highly applicable to a variety of glycosyl donors, and the nucleophile receptors proceed with high selectivity and a high yield, tolerating the most common protective groups.These reaction conditions can be an a ractive alternative to existing procedures.Achiral thiourea, as a co-catalyst, exhibits a cooperative performance, having a strong effect on the reaction velocity, yield, and selectivity of glycosylation (Scheme 2).Solvent-free methodologies have been developed recently in stereoselective glycosylation reactions [32]; however, these procedures are uncommon in carbohydrate chemistry and have only directed very few applications to glycosylation reactions [33].Solvent-free reactions avoid the use of polluting, high-boiling, toxic, and commonly used organic solvents; such approaches allowed a great simplification and improvement [34,35].
Meanwhile, camphor is a privileged chiral construction block in asymmetric catalysis because of its availability in both enantiomeric forms; additionally, it can suffer an ample Scheme 2. Glycosylation reaction co-catalyzed by achiral thiourea I.
Solvent-free methodologies have been developed recently in stereoselective glycosylation reactions [32]; however, these procedures are uncommon in carbohydrate chemistry and have only directed very few applications to glycosylation reactions [33].Solvent-free reactions avoid the use of polluting, high-boiling, toxic, and commonly used organic solvents; such approaches allowed a great simplification and improvement [34,35].
Meanwhile, camphor is a privileged chiral construction block in asymmetric catalysis because of its availability in both enantiomeric forms; additionally, it can suffer an ample variety of chemical transformations [36], allowing the synthesis of compounds with diverse structures and functionalities [37,38].
Herein, we report the synthesis and application of homochiral thioureas 1-6, using camphor as the construction skeleton.We evaluated them in the stereoselective glycosylation reaction, which has been optimized using several reaction conditions.We performed computational calculations to validate the preference of the formation of βglycosylation product.
a Yield determined after purification by flash silica gel chromatography.
a Yield determined after purification by flash silica gel chromatography.

Homochiral Thioureas 1-6 as Organocatalysts in Glycosylation Reaction
Once compounds 1-6 were synthesized, we investigated the potential of homochiral thioureas as organocatalysts in the stereoselective glycosylation reaction.For the optimization of the reaction conditions, we performed the glycosylation reaction of 2,3,4,6tetra-O-benzyl-D-galactopyranosyl trichloroacetimidate 15 [28] (1 equiv) as the glycosyl donor and 2 equiv of methanol as the glycosyl acceptor in the presence of organocatalysts 1 (Table 2), modifying conditions such as the following: solvent, temperature, organocatalyst loading, and additives.
First, we decided to use several polar aprotic solvents such as CH3CN, CH2Cl2, and THF.In all cases, the glycosylation reaction afforded the product after 120 h, in poor to low yields (15-40%), favoring selective inversion of the configuration of the anomeric center in the range of 1:8 to 1:13 (α/β) (Table 2, entries 1-3).
Second, the reaction was performed in the presence of non-polar aprotic solvents such as ethyl ether, tert-butyl methyl ether, and toluene.Ethyl ether and tert-butyl methyl ether after 120 h afforded the expected product in poor to low yields (12-47%), favoring selective inversion of the configuration of 1:12 and 1:15 (α/β), respectively (Table 2, entries  4 and 5).The reaction did not proceed to reveal the presence of toluene as solvent (Table 2, entry 6).

Homochiral Thioureas 1-6 as Organocatalysts in Glycosylation Reaction
Once compounds 1-6 were synthesized, we investigated the potential of homochiral thioureas as organocatalysts in the stereoselective glycosylation reaction.For the optimization of the reaction conditions, we performed the glycosylation reaction of 2,3,4,6-tetra-Obenzyl-D-galactopyranosyl trichloroacetimidate 15 [28] (1 equiv) as the glycosyl donor and 2 equiv of methanol as the glycosyl acceptor in the presence of organocatalysts 1 (Table 2), modifying conditions such as the following: solvent, temperature, organocatalyst loading, and additives.
First, we decided to use several polar aprotic solvents such as CH 3 CN, CH 2 Cl 2 , and THF.In all cases, the glycosylation reaction afforded the product after 120 h, in poor to low yields (15-40%), favoring selective inversion of the configuration of the anomeric center in the range of 1:8 to 1:13 (α/β) (Table 2, entries 1-3).Second, the reaction was performed in the presence of non-polar aprotic solvents such as ethyl ether, tert-butyl methyl ether, and toluene.Ethyl ether and tert-butyl methyl ether after 120 h afforded the expected product in poor to low yields (12-47%), favoring selective inversion of the configuration of 1:12 and 1:15 (α/β), respectively (Table 2, entries 4 and 5).The reaction did not proceed to reveal the presence of toluene as solvent (Table 2, entry 6).Second, the reaction was performed in the presence of non-polar aprotic solvents such as ethyl ether, tert-butyl methyl ether, and toluene.Ethyl ether and tert-butyl methyl ether after 120 h afforded the expected product in poor to low yields (12-47%), favoring selective inversion of the configuration of 1:12 and 1:15 (α/β), respectively (Table 2, entries 4 and 5).The reaction did not proceed to reveal the presence of toluene as solvent (Table 2, entry 6).
Based on these results, we decided to perform the reaction in solvent-free conditions using no added solvent except for 2 equiv of MeOH, which is polar and protic.The reaction finished after only 1.5 h, affording a 99% yield and 1:73 α/β, i.e., circa 99% stereospecific inverted substitution product (Table 2, entry 7).
The following experiments were centered on examining the influence of lower temperatures (Table 2, −25 and 0 • C, entries 8 and 9, respectively), affording the product in a lower yield and lower selectivity compared to room temperature.We observed that the reaction time was longer as the temperature diminished (Table 2, 24 and 2 h, entries 8 and 9, respectively).
Then, we proceeded to determine the influence of catalyst loading on selectivity.We modified the amount of organocatalyst 1 from 15 mol% to 5, 10, and 20 mol%, and achieved the best results with 15 mol% of catalyst loading (Table 1, entries 10-12).
To explore the scope of this methodology, we also performed the reaction in the optimized conditions using 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidate 15 [28] (1 equiv) as the glycosyl donor with 2 equiv of several acceptors such as ethanol, 1propanol, 1-butanol, 1-octanol, iso-propanol, tert-butanol, cyclohexanol, phenol, 1-napthol, and 2-naphtol.We observed the formation of the glycosylation products in all cases.Methanol showed the highest β-selectivity due to the lowest steric hindrance (Table 5, entry 1).It is important to note that β-selectivity decreases as the carbon chain is larger (Table 5, entries 2-5) or the bulkiness of the carbon chain is bigger (Table 5, entries 6-7).We observed that in the cases of 1-propanol and 1-butanol, the reaction occurred almost to completion in 4 h (Table 5, 95 and 96%, entries 3 and 4, respectively), and in the case of 1-octanol, the reaction was carried out in 3 h with a yield of 76% (Table 5, entry 5).When cyclohexanol was employed, a significant decrease in yield was observed, resulting in an α:β ratio of 1:3 in 4 h (Table 5, 25%, entry 8).When solid alcohols such as phenol, 1-naphthol, and 2-naphthol were utilized, the reactions were solubilized in TBME, a solvent that yielded the best result in previous studies (Table 2, entry 5).With phenol, a 1:1.3 α:β ratio was achieved at a 39% yield (Table 5, entry 9).Finally, with 1-naphthol and 2-naphthol, an increase in reaction time was observed (6 h), leading to the formation of the anomeric mixture in low yields (Table 5, entries 10 and 11).We explored the scope of this methodology performing the reaction with 2,3,4,6tetra-O-benzyl-α-D-glucopyranosyl trichloroacetimidate 17 [41] as the glycosyl donor (1 equiv) and with MeOH as the glycosyl acceptor (2 equiv), in solvent-free reaction conditions, catalyzed by 15 mol% of thioureas 1-6.The reaction was followed by TLC until the total consumption of raw material, affording the stereoselective glycosylation product with moderate to high yields (58-92%) and β-selectivity from low to high (1:6 to 1:58).On the one hand, thiourea 1 showed the highest efficiency, with an 81% yield and 1:58 α/β stereoselectivity (Table 4, entry 1).On the other hand, organocatalyst 2 gave the worst result, i.e., the mismatched diastereomer of compound 1, affording a 58% yield and 1:6 βselectivity (Table 4, entry 2).Thioureas 3-6 afforded the glycosylation product in good yields (83-92%) and low to high β-selectivity 1:12-1:57 α/β (Table 4, entries 3-6).To explore the scope of this methodology, we also performed the reaction in the optimized conditions using 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidate 15 [28] (1 equiv) as the glycosyl donor with 2 equiv of several acceptors such as ethanol, 1-propanol, 1-butanol, 1-octanol, iso-propanol, tert-butanol, cyclohexanol, phenol, 1-napthol, and 2-naphtol.We observed the formation of the glycosylation products in all cases.Methanol showed the highest β-selectivity due to the lowest steric hindrance (Table 5, entry 1).It is important to note that β-selectivity decreases as the carbon chain is larger (Table 5, entries 2-5) or the bulkiness of the carbon chain is bigger (Table 5, entries 6-7).We observed that in the cases of 1-propanol and 1-butanol, the reaction occurred almost to completion in 4 h (Table 5, 95 and 96%, entries 3 and 4, respectively), and in the case of 1-octanol, the reaction was carried out in 3 h with a yield of 76% (Table 5, entry 5).When cyclohexanol was employed, a significant decrease in yield was observed, resulting in an α:β ratio of 1:3 in 4 h (Table 5, 25%, entry 8).When solid alcohols such as phenol, 1-naphthol, and 2-naphthol were utilized, the reactions were solubilized in TBME, a solvent that yielded the best result in previous studies (Table 2, entry 5).With phenol, a 1:1.3 α:β ratio was achieved at a 39% yield (Table 5, entry 9).Finally, with 1-naphthol and 2-naphthol, an increase in reaction time was observed (6 h), leading to the formation of the anomeric mixture in low yields (Table 5, entries 10 and 11).To explain the formation of a 1:73 ratio (α:β) that favors product β-16, related to α-16 (Figure 5), we modeled the possible interaction between the three structures involved in the reaction, i.e., the donor, acceptor, and organocatalyst, before the formation of β-16.To explain the formation of a 1:73 ratio (α:β) that favors product β-16, related to α-16 (Figure 5), we modeled the possible interaction between the three structures involved in the reaction, i.e., the donor, acceptor, and organocatalyst, before the formation of β-16.First, we look for the lowest energy local minimum for the complex involving the three species 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidate 15, MeOH, and organocatalyst 1. Computational calculations have suggested two structures with the lowest energy, both of which are stabilized by various hydrogen bonds (Figure 6).The orientation of the organocatalyst 1 is the difference in both complexes.Optimizations were performed using the M06-2X/6-31G(d,p) method and all atoms were considered without any restriction of motion or geometry.Energies were computed using the M06-2X/6-311++G(2d,2p) method [42,43].All calculations were performed using Gaussian 16 [44].The IEFPCM solvation model [45] was used and methanol was the solvent.Complex 1 is stabilized by three hydrogen bonds, two of the type O--H-O and one O--H--S, while complex 2 only shows a hydrogen bond, O--H--S.This explains why complex 1 has the lowest energy.Also, these structures were modeled in the presence of a solvent in order to know the effect of methanol on the energies; the result was a decrease in the difference between the values of the energies, but it was confirmed that complex 1 is more stable.Figure 7 shows the internal interactions of the hydrogen bonds and O1--C1 (orange dotted line) distances.Methanol O1 has a good orientation to attack the C1 of the six-membered heterocycle because of less steric agglomeration observed in that position (Figure 7).This O1--C1 distance has a value of 3.212 Å.In addition, different internal hydrogen bonds that stabilize the geometry can be observed in more detail.First, we look for the lowest energy local minimum for the complex involving the three species 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidate 15, MeOH, and organocatalyst 1. Computational calculations have suggested two structures with the lowest energy, both of which are stabilized by various hydrogen bonds (Figure 6).The orientation of the organocatalyst 1 is the difference in both complexes.Optimizations were performed using the M06-2X/6-31G(d,p) method and all atoms were considered without any restriction of motion or geometry.Energies were computed using the M06-2X/6-311++G(2d,2p) method [42,43].All calculations were performed using Gaussian 16 [44].The IEFPCM solvation model [45] was used and methanol was the solvent.First, we look for the lowest energy local minimum for the complex involving the three species 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidate 15, MeOH, and organocatalyst 1. Computational calculations have suggested two structures with the lowest energy, both of which are stabilized by various hydrogen bonds (Figure 6).The orientation of the organocatalyst 1 is the difference in both complexes.Optimizations were performed using the M06-2X/6-31G(d,p) method and all atoms were considered without any restriction of motion or geometry.Energies were computed using the M06-2X/6-311++G(2d,2p) method [42,43].All calculations were performed using Gaussian 16 [44].The IEFPCM solvation model [45] was used and methanol was the solvent.Figure 6.Relative energies of complexes 1 and 2 in the gas phase and methanol as solvent.Color codes were used to identify different atom types as follows: dark gray for carbon (C), red for oxygen (O), light gray for hydrogen (H), yellow for sulfur (S), green for chlorine (Cl), and blue for nitrogen (N).The blue dots represent weak interactions known as hydrogen bonds.
Complex 1 is stabilized by three hydrogen bonds, two of the type O--H-O and one O--H--S, while complex 2 only shows a hydrogen bond, O--H--S.This explains why complex 1 has the lowest energy.Also, these structures were modeled in the presence of a solvent in order to know the effect of methanol on the energies; the result was a decrease in the difference between the values of the energies, but it was confirmed that complex 1 is more stable.Figure 7 shows the internal interactions of the hydrogen bonds and O1--C1 (orange dotted line) distances.Methanol O1 has a good orientation to attack the C1 of the six-membered heterocycle because of less steric agglomeration observed in that position (Figure 7).This O1--C1 distance has a value of 3.212 Å.In addition, different internal hydrogen bonds that stabilize the geometry can be observed in more detail.Complex 1 is stabilized by three hydrogen bonds, two of the type O--H--O and one O--H--S, while complex 2 only shows a hydrogen bond, O--H--S.This explains why complex 1 has the lowest energy.Also, these structures were modeled in the presence of a solvent in order to know the effect of methanol on the energies; the result was a decrease in the difference between the values of the energies, but it was confirmed that complex 1 is more stable.Figure 7 shows the internal interactions of the hydrogen bonds and O1--C1 (orange dotted line) distances.Methanol O1 has a good orientation to attack the C1 of the six-membered heterocycle because of less steric agglomeration observed in that position (Figure 7).This O1--C1 distance has a value of 3.212 Å.In addition, different internal hydrogen bonds that stabilize the geometry can be observed in more detail.The preference for β-glycoside formation relies on steric effects and the formation of hydrogen bonds (complex 1), which help in stabilization.The final product was modeled as complex 3 (Figure 8).This molecular complex is stabilized by three main hydrogen bonds, two in which hydrogen participates in O2 with methanol, oxygen, and sulfur, and the third is formed by the exiting fragment of C1 with the oxygen of the -OPh group.With the prepared models, it is evident that the formation of complexes 3 and 2 is favored by steric effects because the attack is performed opposite to O3, which is less sterically hindered.Finally, to understand the poor effectiveness of organocatalyst 2 (mismatch diastereomer of thiourea 1), complex 4 has been modeled, in which it can be observed that the entry of methanol is stereoelectronically impeded by the thiourea group; moreover, this complex is stabilized, similar to complex 1, by multiple hydrogen bonds (Figure 9).It The preference for β-glycoside formation relies on steric effects and the formation of hydrogen bonds (complex 1), which help in stabilization.The final product was modeled as complex 3 (Figure 8).This molecular complex is stabilized by three main hydrogen bonds, two in which hydrogen participates in O2 with methanol, oxygen, and sulfur, and the third is formed by the exiting fragment of C1 with the oxygen of the -OPh group.With the prepared models, it is evident that the formation of complexes 3 and 2 is favored by steric effects because the attack is performed opposite to O3, which is less sterically hindered.The preference for β-glycoside formation relies on steric effects and the formation of hydrogen bonds (complex 1), which help in stabilization.The final product was modeled as complex 3 (Figure 8).This molecular complex is stabilized by three main hydrogen bonds, two in which hydrogen participates in O2 with methanol, oxygen, and sulfur, and the third is formed by the exiting fragment of C1 with the oxygen of the -OPh group.With the prepared models, it is evident that the formation of complexes 3 and 2 is favored by steric effects because the attack is performed opposite to O3, which is less sterically hindered.Finally, to understand the poor effectiveness of organocatalyst 2 (mismatch diastereomer of thiourea 1), complex 4 has been modeled, in which it can be observed that the entry of methanol is stereoelectronically impeded by the thiourea group; moreover, this complex is stabilized, similar to complex 1, by multiple hydrogen bonds (Figure 9).It Finally, to understand the poor effectiveness of organocatalyst 2 (mismatch diastereomer of thiourea 1), complex 4 has been modeled, in which it can be observed that the entry of methanol is stereoelectronically impeded by the thiourea group; moreover, this complex is stabilized, similar to complex 1, by multiple hydrogen bonds (Figure 9).It is important to note that in this complex, the distance O1-C1 is much longer with a value of 4.026 Å. is important to note that in this complex, the distance O1-C1 is much longer with a value of 4.026 Å.

Materials and Methods
All chemicals were obtained from commercial suppliers and used without purification.Liquid chemicals, solutions, or solvents were added using a syringe (mL) or a micropipette (µL).Reactions were followed by thin-layer chromatography using silica gel 60 F254 plates supported in aluminum (Merck, Rahway, NJ, USA, Telos) and were revealed by UV light (254 nm) using phosphomolybdic acid in ethanol (0.25 g/mL), or with iodide vapors.The products obtained were concentrated using Rotavapor Büchi R-300 (bath temperatures above 40 °C) and reduced pressure depending on the solvent used.
1 H and 13 C NMR spectra were obtained in CDCl3 using a Bruker (Billerica, MA, USA) AscendTM (400 MHz) spectrometer with tetramethylsilane (TMS) as a reference at 0 ppm.Optical rotation recordings were measured using an Autopol III (Rudolph Research Analytical, Hackettstown, NJ, USA) polarimeter at 20 °C and 589 nm, using CHCl3 as the blank and solvent, and concentrations were calculated in g/mL.Infrared (IR) spectra were obtained using an FTIR Cary 630 spectrophotometer (Agilent Technologies, Santa Clara, CA, USA).
Single-crystal XRD analysis was performed as a single crystal of each compound was mounted on a loop plastic fiber.Diffraction analyses were carried out on an Oxford Diffraction Gemini "Atlas" diffractometer, Agilent Technologies (Oxford, UK), equipped with a charge-coupled device area detector, sealed X-ray tube (λMoKα = 0.71073 Å), and a graphite monochromator.The CrysAlis PRO (v38.46) and CrysAlis RED (Version 1.171.35.11) software packages were used for data collection and integration.The collected data were corrected for absorbance using an analytical numerical correction [46] with a multifaceted crystal model.Structure solution and refinement were carried out using Olex2 software [47].To prepare the material for publication, Mercury 4.0 and Olex2 software were used [48].

Materials and Methods
All chemicals were obtained from commercial suppliers and used without purification.Liquid chemicals, solutions, or solvents were added using a syringe (mL) or a micropipette (µL).Reactions were followed by thin-layer chromatography using silica gel 60 F 254 plates supported in aluminum (Merck, Rahway, NJ, USA, Telos) and were revealed by UV light (254 nm) using phosphomolybdic acid in ethanol (0.25 g/mL), or with iodide vapors.The products obtained were concentrated using Rotavapor Büchi R-300 (bath temperatures above 40 • C) and reduced pressure depending on the solvent used.
1 H and 13 C NMR spectra were obtained in CDCl 3 using a Bruker (Billerica, MA, USA) AscendTM (400 MHz) spectrometer with tetramethylsilane (TMS) as a reference at 0 ppm.Optical rotation recordings were measured using an Autopol III (Rudolph Research Analytical, Hackettstown, NJ, USA) polarimeter at 20 • C and 589 nm, using CHCl 3 as the blank and solvent, and concentrations were calculated in g/mL.Infrared (IR) spectra were obtained using an FTIR Cary 630 spectrophotometer (Agilent Technologies, Santa Clara, CA, USA).
Single-crystal XRD analysis was performed as a single crystal of each compound was mounted on a loop plastic fiber.Diffraction analyses were carried out on an Oxford Diffraction Gemini "Atlas" diffractometer, Agilent Technologies (Oxford, UK), equipped with a charge-coupled device area detector, sealed X-ray tube (λMoKα = 0.71073 Å), and a graphite monochromator.The CrysAlis PRO (v38.46) and CrysAlis RED (Version 1.171.35.11) software packages were used for data collection and integration.The collected data were corrected for absorbance using an analytical numerical correction [46] with a multifaceted crystal model.Structure solution and refinement were carried out using Olex2 software [47].To prepare the material for publication, Mercury 4.0 and Olex2 software were used [48].

General Methodology for Glycosylation Reaction
In a 25 mL flask with magnetic stirring, 1 equiv of trichloroacetimidate and the corresponding organocatalysts (15 mol%) were weighed.Both were dissolved in solvent (2 mL), and the MeOH was added (2 equiv).The reaction mixture was maintained at room temperature.The reaction was completed by adding triethylamine to the flask (0.5 mL) and washing with a saturated solution of NaCl, followed by ulterior extractions with CH 2 Cl 2 (3 × 20 mL).The organic phase was dried over Na 2 SO 4 , and the solvent was eliminated using reduced pressure.The crude reaction was analyzed using 1 H NMR to measure the α:β ratio.

General Methodology for Solvent-Free Glycosylation Reaction [32]
The trichloroacetimidate donor and the corresponding organocatalyst were added as a solution in the smallest possible amount of technical grade CH 2 Cl 2 ; the flask was heated at the required temperature and the solvent was distilled off.Then, the acceptor (2 equiv) was added and the reaction was followed by TLC until the disappearance of the raw material.The reaction was completed by adding triethylamine to the flask (0.5 mL) and washing with a saturated solution of NaCl, followed by ulterior extractions with CH 2 Cl 2 (3 × 20 mL).The organic phase was dried over Na 2 SO 4 , and the solvent was eliminated using reduced pressure.The crude reaction was analyzed using 1 H NMR to measure the α:β ratio.

Conclusions
Our research group has developed new camphor-derived organocatalysts 1-6, which proved to be effective in the stereoselective glycosylation reaction.We observed the best results with thiourea 1 and worst with thiourea 2, which is the mismatch diastereomer of thiourea 1 and is due to the chiral center present in the methylbenzyl group.Thioureas 3-6 have a similar performance compared to 1, even though these organocatalysts have structures with important stereo and electronic differences.Glycosylation reaction conditions were optimized, finding that the best yield and selectivity were afforded at room temperature and in solvent-free conditions.We extended the scope of the methodology for the stereoselective glycosylation reaction using methanol as the acceptor with two glycosyl donors 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidate 15 and 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl trichloroacetimidate 17, observing that 15 gave a higher yield and selectivity than 17 due to less steric hindrance.Our group extended the scope of the methodology using donor 15 in the presence of several alkyl alcohols as acceptors besides methanol, such as the following: 1-propanol, 1-butanol, 1-octanol, isopropanol, tert-butanol, cyclohexanol, phenol, 1-naphtol, and 2-naphtol, and observed that methanol was the best acceptor due to less steric hindrance and had the best hydrogen bond formation ability.In the glycosylation reaction described here, we observe that α-imidates provide β-selectivity; therefore, we consider that the organocatalyzed reaction by chiral thioureas 1-6 might proceed through a S N 2 mechanism, where, initially, the acceptor forms an adduct with the catalyst, followed by the activation of the imidate in a stereoselective manner to provide β-glycosides.
Theoretical calculations were performed to explain the formation of β anomer in the glycosylation reaction product with organocatalysts 1 and 2. Our findings indicate that β anomer is favored with organocatalyst 1 for steric effects and the formation of hydrogen bonds that helped to the stabilization of the glycosylation product, meanwhile thiourea 2 presents the worst performance as an organocatalyst because a stereoelectronic hindrance occurs in the activation complex produced by the chiral center (R) of the thiourea.The reaction conditions used are mild and widely applicable to diverse glycosyl donors and acceptors.Nowadays, our group is focused on the improvement of organocatalytic systems that might be applicable to a larger scope.

Figure 6 .
Figure 6.Relative energies of complexes 1 and 2 in the gas phase and methanol as solvent.Color codes were used to identify different atom types as follows: dark gray for carbon (C), red for oxygen (O), light gray for hydrogen (H), yellow for sulfur (S), green for chlorine (Cl), and blue for nitrogen (N).The blue dots represent weak interactions known as hydrogen bonds.

Figure 6 .
Figure 6.Relative energies of complexes 1 and 2 in the gas phase and methanol as solvent.Color codes were used to identify different atom types as follows: dark gray for carbon (C), red for oxygen (O), light gray for hydrogen (H), yellow for sulfur (S), green for chlorine (Cl), and blue for nitrogen (N).The blue dots represent weak interactions known as hydrogen bonds.

Figure 7 .
Figure 7. Hydrogen bonds in complex 1 and their distances (Å).The orientation of methanol toward C1 is also represented.Each type of atom is indicated by specific colors, namely dark gray (C), red (O), light gray (H), yellow (S), green (Cl), and blue (N).The blue dots represent weak interactions known as hydrogen bonds.

Figure 8 .
Figure 8. Complex 3 structure, which is stabilized by three main hydrogen bonds.Color code for each atom is as follows: dark gray (C), red (O), light gray (H), yellow (S), green (Cl), and blue (N).The blue dots represent weak interactions known as hydrogen bonds.

Figure 7 .
Figure 7. Hydrogen bonds in complex 1 and their distances (Å).The orientation of methanol toward C1 is also represented.Each type of atom is indicated by specific colors, namely dark gray (C), red (O), light gray (H), yellow (S), green (Cl), and blue (N).The blue dots represent weak interactions known as hydrogen bonds.

Molecules 2024 , 19 Figure 7 .
Figure 7. Hydrogen bonds in complex 1 and their distances (Å).The orientation of methanol toward C1 is also represented.Each type of atom is indicated by specific colors, namely dark gray (C), red (O), light gray (H), yellow (S), green (Cl), and blue (N).The blue dots represent weak interactions known as hydrogen bonds.

Figure 8 .
Figure 8. Complex 3 structure, which is stabilized by three main hydrogen bonds.Color code for each atom is as follows: dark gray (C), red (O), light gray (H), yellow (S), green (Cl), and blue (N).The blue dots represent weak interactions known as hydrogen bonds.

Figure 8 .
Figure 8. Complex 3 structure, which is stabilized by three main hydrogen bonds.Color code for each atom is as follows: dark gray (C), red (O), light gray (H), yellow (S), green (Cl), and blue (N).The blue dots represent weak interactions known as hydrogen bonds.

Figure 9 .
Figure 9. Electronic structure for complex 4, with organocatalyst 2. Color code for each atom is as follows: dark gray (C), red (O), light gray (H), yellow (S), green (Cl), and blue (N).The blue dots represent weak interactions known as hydrogen bonds.

Figure 9 .
Figure 9. Electronic structure for complex 4, with organocatalyst 2. Color code for each atom is as follows: dark gray (C), red (O), light gray (H), yellow (S), green (Cl), and blue (N).The blue dots represent weak interactions known as hydrogen bonds.