ZnI₂-Mediated cis-Glycosylations of Various Constrained Glycosyl Donors: Recent Advances in cis-Selective Glycosylations

Abstract

An efficient and versatile glycosylation methodology is crucial for the systematic synthesis of oligosaccharides and glycoconjugates. A direct intermolecular and an indirect intramolecular methodology have been developed, and the former can be applied to the synthesis of medium-to-long-chain glycans like that of nucleotides and peptides. The development of a generally applicable approach for the stereoselective construction of glycosidic bonds remains a major challenge, especially for the synthesis of 1,2-cis glycosides such as β-mannosides, β-L-rhamnosides, and β-D-arabinofuranosides with equatorial glycosidic bonds as well as α-D-glucosides with axial ones. This review introduces the direct formation of cis-glycosides using ZnI₂-mediated cis-glycosylations of various constrained glycosyl donors, as well as the recent advances in the development of stereoselective cis-glycosylations.

1. Introduction

Stereoselective 1,2-cis O-glycosylation is one of the most essential issues in synthetic carbohydrate chemistry for the construction of various glycans with biological functions [1,2,3,4,5,6,7,8,9]. The preparation of 1,2-trans O-glycoside became possible using a stereoselective glycosylation method based on the effect of neighboring group participation from acyl carbonyl functionality at the 2-position of the glycosyl donor [10,11,12,13,14,15,16,17,18]. By the activation of the glycosyl donor, the kinetically favored cis-participation of the acyl group at the 2-position of the donor to the anomeric carbon at the 1-position occurs, followed by the nucleophilic attack of the acceptor from the opposite side to afford the 1,2-trans O-glycoside stereoselectively. Compared to the 1,2-trans O-glycosylations, the highly stereoselective synthesis of 1,2-cis glycosides is far less straightforward. The stereochemical outcome of a chemical glycosylation reaction is influenced by multiple chemical and environmental factors, including the structure of the glycosyl donor, the type and position of protecting groups installed on the donor, the nucleophilicity of the acceptor, the solvent in which the reaction is performed, the concentration of substrates, and the reaction temperature, and is determined by the specific combination of these factors [19,20,21,22,23,24,25,26,27,28,29]. The 1,2-cis-configured O-glycosidic linkages, such as α-glucopyranoside, β-mannopyranoside, β-L-rhamnopyranoside, β-D-arabinofuranosides, and 2-azido-2-deoxy-α-D-glucopyranoside, are found in natural glycans, especially in glycoconjugates (glycoproteins, glycolipids, proteoglycans, and microbial polysaccharides) and glycoside natural products [30,31,32,33,34,35]. Chemical glycosylation is a useful method to obtain these glycosidic linkages as the alternative way of isolation from natural sources. However, the strictly controlled formation of these 1,2-cis glycosides is generally difficult, and the key factors controlling the stereoselectivity of glycosylation are not fully understood. This review introduces a direct formation of cis glycosides using recently developed ZnI₂-mediated cis glycosylations of various constrained glycosyl donors [36,37,38,39,40,41] (Figure 1).

Recent Development of Stereoselective cis Glycosylations

In recent years, further progress has been made in the development of stereoselective O-glycosylation as well as orthogonal techniques using various methods [42,43] as stereoselective C-glycosylations have been extensively developed in recent publications [44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62]. Glycosyl iodide as an intermediate generated from glycosyl 2,2,2-trifluoro-N-phenylacetimidate [CF₃C(=NPh)–O–] (3) with trimethylsilyl iodide (TMSI) could be complexed with triphenylphosphine oxide (Ph₃P=O) [63] to afford cis glycosides (6, α:β = >20:1) through the direct interaction of Ph₃P=O with the C1 position (4→5) [64,65] (Figure 2A). Glycosyl bromide generated from thioglycoside with Br₂ in the presence of silver trifluoromethanesulfonate (AgOTf) and 2,4,6-collidine afforded 1,2-cis glycoside which has been applied to a synthesis of a repeating unit of Bacteroides fragilis zwitterionic polysaccharide A1 [66]. Stereoselective glycosylations from 3,5-dimethyl-4-(2′-phenylethynylphenyl)phenyl glycoside (7) under N-iodosuccinimide (NIS)–trifluoromethanesulfonic acid (TfOH) conditions [67] (Figure 2B), as well as the Pd- or Cu-catalyzed activation system of donors through the cyclization of some aglycons [68,69], have been developed. For the synthesis of heparin pentasaccharide, [3+2] fragment coupling using the methodology of [67] has been applied to give the α-selective formation of the pentasaccharide (8). The glycosylation of 7 proceeds via an unprecedented dearomative cyclization mechanism initiated by the activation of the triple bond with I⁺, resulting in side product 9. Benzylthio/seleno glycosides (10) with an activation system using benzyne (12), generated in situ from o-TMS-phenol (11) with trifluomethanesulphonate, KF, and 18-Crown-6 [70] (Figure 2C), have also been developed. The benzyne promotes the activation of the donor as well as the acceptor (ROH) through proposed intermediates (14→16) for an effective S_N2 reaction. Gluco-, galacto-, and mannosyl as well as 2-deoxyglucosyl donors can be applied to afford S_N2 products (13). Phenylseleno (PhSe-) 2-azidoglycosides (17) could be converted to 1,2-cis glycosides (19) with N-iodosuccinimide in the presence of a catalytic amount of Cu(OTf)₂ and N,N-bis-[(2,4-trifluoromethyl)phenyl]thiourea (18) [71] (Figure 2D). The reagent combination forming the metal–organocatalyst complex (20) can activate selenoglycoside by the liberation of iodonium ion. The resultant α-selenonium salt analog (α-21) is converted to β-isomer (β-21), which seems to be the key intermediate for cis glycosylation without neighboring group participation.

Recent developments were reported about the effective participation of solvents [72,73,74,75,76,77] and additives [78,79] as well as intramolecularly participating groups [79,80,81,82,83] to induce cis glycosides. The participation of special functionalities such as the 2-(diphenylphosphinoyl)acetyl group (DPPA) with an acceptor has been shown to afford the cis glycoside (24) effectively through a participating intermediate (23) of the phosphine oxide (–Ph₂P=O) functionality of donor (22) with the acceptor (ROH), as developed by Li [84,85] (Figure 2E).

By the action of M⁴⁺ Lewis acids such as SnCl₄ and TiCl₄, the glycosylation of a 2,3,4,6- tetra-O-benzyl-α-D-glucopyranosyl trichloroacetimidate (25) afforded α- and β-D-glucopyranoside (27) depending on the amount of M⁴⁺ (Figure 2F) [86]. When a catalytic amount of M⁴⁺ was used, β-D-glucopyranoside (β-27) was obtained predominantly through a proposed intermediate (26). The use of 3.0 equiv. of M⁴⁺ resulted in the formation of α-D-glucopyranoside (α-27) in one-pot from the donor (25). Since the initially obtained β-D-glucopyranoside (β-27) was isomerized to α-D-glucopyranoside (α-27) under M⁴⁺ conditions, the excess M⁴⁺ accelerated the anomerization through a proposed endo-cleavage intermediate (28), followed by cyclization to thermodynamically more stable α-glucoside (α-27). As reported by Santrsa et al., the ZnBF₄-catalyzed glycosylation of α-imidate donor without 4,6-O-tethered structure in CH₂Cl₂ at −78 °C also afforded the β-glycoside of various donor moieties, including D-Glcp, and D-Galp, through S_N2 reaction without isomerization [87].

The combination of the donor, the leaving groups, and the reagent as a promotor [24,88] should be optimized. Recent progress on the orthogonal [89] one-pot procedure [90,91,92,93,94,95,96,97] using stereoselective glycosylation methods in combination with orthogonal activation systems [64,98,99,100,101,102,103,104] has afforded oligosaccharides containing 1,2-cis glycosidic linkages. Alternatively, 1,2-cis glycosylation using the naphthyl methyl ether-mediated intermolecular aglycon delivery (IAD) method [1,105,106,107,108,109,110,111,112,113,114,115,116,117] was applied to the selective 1,2-cis α-D-allopyranosylation using the D-allopyranosyl donor (29) with the 1,3,4,6-tetra-O-benzoyl-D-psicofuranose acceptor (30) through a mixed acetal intermediate (31) [118], which is the first example of the synthesis of non-reducing disaccharides (32) comprising only rare D-sugars by IAD using protected ketose (Figure 2G).

2. ZnI₂-Mediated Glycosylations

Zinc iodide (ZnI₂) has been used as a catalyst in various organic reactions [119] such as the Simmons–Smith cyclopropanation [120]. In the field of carbohydrate chemistry, both methyl glycoside and 1-O-benzoate have been converted to thioglycoside by the action of ZnI₂, tetra-n-butyl ammonium iodide (TBAI), and alkylthiotrimethylsililane (TMSSR) [121,122,123,124], which are useful transformations for obtaining the key stable intermediate for glycosidic bond formation (Figure 3A,B). Methyl D-rhamnopyranoside (33) was treated with TMSSPh in the presence of ZnI₂ and TBAI to give α-thioglycoside (34) in 73% [122] (Figure 3A). Benzoyl (Bz)- or tri-t-butyldimethylsilyl (TBS)-protected 1,6-anhydroglucose derivative (35, 36) could be used as the substrate to obtain thioglycoside (37, 38) by treatment under TMSSPh in the presence of ZnI₂ without TBAI, respectively (Figure 3B).

1-O-Benzoate and phosphate-protected glycosyl donors (39, 41) could be used for O-glycosylation activated by ZnI₂ with I₂–(TMS)₂ [125,126] or TMSI [125,127] (Figure 3C), and ZnI₂ [128] (Figure 3D), respectively, with glycosyl iodide as the intermediate [129]. The neighboring group participation effect of the 2-O-Bz group resulted in the predominant formation of 1,2-trans glycoside (40) (Figure 3C) [125]. During the screening of 1,2-trans glycosylation using dibutyl 2-O-pivaloyl-3,4,6-tri-O-benzyl-D-glucopyranosyl phosphate (41) reported by Seeberger and coworkers [128], ZnI₂ in CH₂Cl₂–THF was indicated to afford β-glucoside (43) in 30% yield via the neighboring group participation of the 2-O-pivaloyl group, followed by the nucleophilic attack of an acceptor (42) (Figure 3D).

2.1. cis-Selective Glycosylations by the Action of ZnI₂

The 1-O-trichloroacetimidate moiety [7,130,131,132,133] can be used as a leaving group of a glycosyl donor by the action of a cheap and mild Lewis acid, such as ZnI₂ for cis glycosylation [1,89,134,135], and Zn(BF₄)₂ [136], B(C₆F₅)₃ [137] and pyrylium salt [138] for 1,2-trans glycosylation. However, optimizations for the stereoselective construction of cis glycosides should be carried out. The conformational strain on the donor moiety caused by cyclic protective groups [139] is one of the important factors for cis-glycosylation [19,20,21]. There have been many recent advances in the development of ZnI₂-mediated O-glycosylation reactions especially for cis-selective glycosylations, including α-D-glucoside, β-D-mannoside, β-D-rhamnoside, β-D-galactoside, and 2-azido-2-deoxy-α-D-glucoside formation.

2.2. 1,2-cis Mannosylation Using C-2-o-TsNHbenzyl Ether (TAB)

When trichloroacetimidates are used as a convenient and common leaving group of the bimodal donor equipped with C-2-o-TsNHbenzyl ether (TAB) groups for gluco- [140,141], galacto- [140], and manno-sides [36], the examination of activators on the mannosylation suggested the proposed unique donor activation pathway with coordination to the donor (44⇄45) by ZnI₂ for the stereo-direction toward 1,2-cis glycosidic bond formation [36] (Figure 4). Zn²⁺ not only activates the donor leaving group but also coordinates to oxygens at the 2- and 3-positions to induce the effective interaction of TAB with an incoming nucleophile during 1,2-cis-β-mannosylation (44→47).

2.3. ZnI₂-Mediated 1,2-cis α-Glucosylation

Easily accessible and common 4,6-O-tethered glucosyl donors (1^Glc) were found to be useful for highly stereoselective 1,2-cis α-glucosylation mediated by ZnI₂ [37] (Figure 1). The 4,6-O-tethering constrains a pyranose ring of the glycosyl donors for stereoselective 1,2-cis glycosylation [19]. The versatility and effectiveness of the α-glucosylation strategy was demonstrated successfully with various acceptors. This approach demonstrates the feasibility of the modular synthesis of α-glucans with both linear and branched backbone structures. DFT calculations (vide infra) indicated that both the activation of trichloroacetimidate and the coordination between 2–O in the donor moiety and the hydroxy group in the acceptor could be carried out by Zn²⁺, and that 1,2-cis selective glycosylation proceeded through the proposed transition state (TS) structure (Glc TS) after activation to afford α-glucoside (α-2^Glc).

2.4. ZnI₂-Mediated 1,2-cis β-D-Mannopyranosylation and β-L-Rhamnopyranosylation

The ZnI₂-mediated method could be applied to the synthesis of 1,2-cis β-glycosides such as β-D-mannopyranosides (β-2^Man) [38] (Figure 5A) and β-L-rhamnopyranosides (β-2^L-Rha) [39] which are 6-deoxy-β-L-mannopyranosides [142] (Figure 5B). The 1,2-cis β-manno- and β-L-rhamno-sylation mediated by ZnI₂ employed easily accessible 4,6-O-tethered mannosyl and L-rhamnosyl trichloroacetimidate donors (1^Man and 1^L-Rha). The versatility and effectiveness of this strategy were demonstrated with successful β-mannosylation of a wide variety of alcohol acceptors, including complex natural products, amino acids, and glycosides.

Through iterative ZnI₂-mediated mannosylation with a chitobiosyl azide acceptor, followed by the site-selective deprotection of the mannosylation product, this novel methodology enables the modular synthesis of a key intermediate trisaccharide with a β-D-Man-(1→4)-β-D-GlcNAc-(1→4)-β-D-GlcNAc linkage for N-glycan synthesis [38]. The core repeating tetrasaccharide unit with an α-L-Rhap-(1→2)-β-D-Galp-(1→4)-β-L-Rhap-(1→4)-α-D-Glcp linkage of the Streptococcus pneumoniae 23F capsule polysaccharide has been successfully synthesized using ZnI₂-mediated 1,2-cis β-L-rhamnosylation with a convergent [2 + 2] strategy [39].

DFT calculations also suggested similar activation and coordination via the key coordinated-intermediates (Man TS and L-Rha TS) in the aforementioned α-glucosylation. Theoretical investigations using DFT calculations (vide infra) delved into the mechanistic details of this β-selective glycosylation and elucidated the essential roles of two zinc cations as the activating agent of the donor and the principal mediator of the cis-directing intermolecular interaction [38,39].

2.5. ZnI₂-Mediated 1,4/6-cis β-D-Galactopyranosylation

Although the ZnI₂-mediated method has been applied to the synthesis of α-D-galactopyranosides, the β-anomer (β-2^Gal) was obtained from the 4,6-O-tethered 2,3-di-O-benzyl-D-galactopyranosyl trichloroacetimidate donor (1^Gal) in the presence of ZnI₂ in a 1,2-trans glycosylation fashion [40] (Figure 5C). The unexpected formation of β-D-galactopyranosides (β-2^Gal) [143] could be explained by the favored coordination of Zn²⁺ to the conformationally fixed 4-O or 6-O of the galactopyranosyl donor instead of 2-O as in the expected cases. Suggested by DFT calculations (vide infra), the stability of the key intermediate for the stereodirection was proposed to be enhanced by the coordination of Zn²⁺ to 4-O or 6-O on the β-face that controlled the approach of the acceptor from the β-side. This β-D-galactopyranosylation should occur through 1,4/6-cis glycosylation under ZnI₂ conditions via Gal TS. By using this ZnI₂-mediated β-galactosylation strategy, the tetrasaccharide fragment β-D-Galp-(1→6)-3-O-[α-L-Araf-(1→)]-β-D-Galp-(1→6)-β-D-Galp linkage of arabinogalactan, derived from the plant polysaccharide of Stevia rebaudiana and Silybum marianum, was synthesized efficiently with high stereoselectivity [40].

2.6. ZnI₂-Mediated 1,2-cis 2-azido-2-deoxy-α-D-Glucopyranosylation

The synthesis of the 1,2-cis 2-acetamido-2-deoxyglucoside (D-GlcNAc) core of the capsular polysaccharide (CPS) remains challenging. The tetraisopropyldisiloxane (TIPDS)-protected 2-azido-2-deoxy-D-glucosyl donor (1^GlcN3) afforded the α-glycoside (2^GlcN3) (α:β = >20:1) predominantly in maximum yield [41] (Figure 5D). This approach applies to a wide acceptor substrate scope, including various aliphatic alcohols, sugar alcohols, and natural products. The reaction mechanism was explored by combined experimental variable-temperature NMR (VT-NMR) studies, mass spectrometry (MS) analysis, and DFT calculations (vide infra), and the results suggested the formation of a covalent α-C1^GlcN3-iodide intermediate in equilibrium with a separated oxocarbenium–counter ion pair, followed by an S_N1-like α-nucleophilic attack most likely from the separated ion pairs by the ZnI₂-activated acceptor complex under the influence of the 2-azido gauche effect [144] via GlcN₃ TS. The α-D-GlcNAc-linked core structure of the CPS repeating fragments from Acinetobacter baumannii was synthesized by employing the developed reaction as the key step for constructing the 1,2-cis 2-azido-2-deoxy glycosidic linkage.

2.7. ZnI₂-Mediated 1,2-cis β-D-Arabinofuranosylation

In the case of D-arabinofuranosylation using a D-arabinofuranosyl trichloroacetimidate as the donor, tris(pentafluorophenyl)borane [B(C₆F₅)₃] conditions resulted in better 1,2-cis stereoselectivity compared to the ZnI₂-mediated reaction [145] (Figure 6). The reaction of D-arabinofuranosyl trichloroacetimidate (1D-Araf) under ZnI₂ activation conditions proceeded 1,2-cis stereoselectively via the proposed TS structure (D-Araf TS1) when the donor was protected as an 8-membered 3,5-O-xylylene group [146,147,148] such as the 9-membered 3,5-O-tetra-i-propyldisiloxanylidene (TIPDS) group [149,150,151]. Since the 3,5-O-xylylene-protected donor gave higher yield, the optimization of the conditions including the promotor suggested that B(C₆F₅)₃ [142,152,153,154,155] could activate the α-imidate and directly afford the glycosidic bond through an S_N2-like mechanism via D-Araf TS2 from α-D-arabinofuranosyl trichloroacetimidate at −78 °C in CH₂Cl₂. This method was applied to the synthesis of β-D-Araf linkages with various acceptors including the acceptor for producing a non-reducing terminal structure of mycobacterial arabinan fragment (2D-Araf) [145,156].

2.8. Density Functional Theory (DFT) Calculations for ZnI₂-Mediated Reactions

2.8.1. DFT Calculations for ZnI₂-Mediated Glucosylation and Mannosylation

The TSs of each ZnI₂-mediated reaction were obtained by density functional theory (DFT) computations with Gaussian 16 software package [157] and the detailed conditions are as follows. For GlcTS (Figure 1) and ManTS (Figure 2A), structures of plausible reagents, products, and intermediates species were preoptimized at the PM6-d3 level of theory [158,159] at the gas phase, and then subjected to geometry optimization at the PBE0/def2-TZVP level of theory [160,161,162], with Grimme’s DFT-D3(BJ) empirical dispersion correction [163] applied to account for the dispersion interactions, and the implicit solvation model based on density (SMD) [164] applied to describe the solvent effect exerted by diethyl ether. A short intrinsic reaction coordinate scan with the local quadratic approximation [165] method and 0.1 Bohr step-size was performed on the optimized TS structures at the same level of theory for 30 steps on each side to ensure that the TS structures correspond to energy maxima along the reaction routes connecting the immediately reacting intermediates and product structures. The accurate electronic energy of the chemical species was calculated from the optimized structures with single-point calculation at the M06-2X/ma-def2-TZVPP/SMD (solvent = diethyl ether) level of theory [166,167,168] with an ultrafine integration grid, and the thermal energy terms associated with various thermal motions of the molecule as well as the solvation of the molecules in diethyl solvent were calculated from the frequency analysis output using Shermo [169], with scale factors [170] applied to adjust for the errors arising from the harmonic oscillation assumption. The Gibbs free energy of each chemical species was calculated as the sum of the accurate electronic energy and thermal energy terms.

2.8.2. DFT Calculations for ZnI₂-Mediated l-Rhamnosylation, 2-azido-2-deoxy-α-d-Glucopyranosylation and for B(C₆F₅)₃-Mediated d-Arabinofuranosylation

For L-Rha TS, GlcN₃ TS (Figure 5B,D) and D-Araf TS² (Figure 6), the geometries were optimized at the theory level of B3LYP [171,172]//BS1 (BS1 = 6-31G(d) [173,174] for main group elements and Lanl2dz [175] for Zn, Si, I, and Sn) in the gas phase. Solvation free energies were calculated using the SMD [164] solvation model (solvent = diethyl ether or DCM) under ωB97XD [176] or M06 [177]//BS2 (BS2 = 6-311 + G** [173,174] for main group elements and SDD [178] for Zn, Si, I, and Sn). The Gibbs free energy present in this paper is the sum of single-point energy at ωB97XD [173] or M06 [174] //BS2, thermodynamic correction at B3LYP//BS1, and solvation free energy.

2.8.3. DFT Calculations for ZnI₂-Mediated D-Galactopyranosylation

For Gal TS (Figure 5C), DFT computations at the TPSS/def-TZVP/SMD and diethyl ether [173,174,175] level of theory, with Grimme’s empirical correction to account for dispersion D3(BJ) [163], were carried out.

3. Conclusions

For a 1,2-trans selective glycosylation, methodologies have been further developed using 2-(2-propylsulfinyl)benzyl 1,2-orthoester glycosides [179] activated by trifluoromethanesulfonic anhydride (Tf₂O) with DTBMP, N-(1,1-dimethylpropargyl)carbamate by chloro[tris(2,4-di-t-butyphenyl)-phosphite]gold and AgOTf [180,181,182] and diphenyl phosphate by bis-thiourea type molecule catalyst with high site-selection [183].

There have been extremely valuable reports on the synthesis of large glycans with over 20 monosaccharide units [184] composed of pyranosides [185,186,187,188,189,190,191,192], furanosides [193,194,195,196,197], and both isomers [198]. Both the synthesis and the application of biosynthetic incorporation and selective labeling [199,200,201] of mycobacterial cell walls [202,203] related to tuberculosis [204,205] should be noted as recent advances in remodeling glycoconjugates containing cis glycosides.

This review summarizes recent stereoselective glycosylation methods including the very simple and efficient ZnI₂-mediated cis-glycosylation methodology using constrained glycosyl trichloroacetimidate donors such as D-Glcp, D-Manp, L-Rhap, and 2-azido-2-deoxy-D-Glcp in a 1,2-cis selective manner, and D-Galp in a 1,4/6-cis selective manner. In addition, other findings for β-D-Araf formation using a constrained donor in the presence of B(C₆F₅)₃ instead of ZnI₂ as well as the synthesis of branched terminal D-arabinan hexasaccharide fragment using tricloroacetimidate donor-B(C₆F₅)₃ combination were also effective enough. These methodologies, mainly based on ZnI₂-mediated cis-glycosylation with optimization, could be used in investigations focused on elucidating the biosynthetic pathways and function of these glycans, and conjugating them to a protein carrier for vaccine generation in the case of antigenic glycans from pathogenic bacteria. Further exploration of applications of this methodology for the synthesis of other complex oligosaccharides containing cis linkages is the focus of continuing investigation for synthetic carbohydrate chemists.