Synthesis of carbohydrate building blocks via regioselective uniform protection/deprotection strategies

Abstract

Discussed herein is the synthesis of partially protected carbohydrates by manipulating only one type of a protecting group for a given substrate. The first focus of this review is the uniform protection of the unprotected starting material in the way that only one (or two) hydroxyl groups remain unprotected. The second focus involves regioselective partial deprotection of uniformly protected compounds in the way that only one (or two) hydroxyl groups become liberated.

Graphical Abstract

Scope 1: sugar is uniformly protected leaving only one (or two) free hydroxyl;

Scope 2: uniformly protected sugar is deprotected to liberate only one (or two) hydroxyl

1. Introduction and basic considerations

Carbohydrates are the most abundant molecules among the four essential classes of biomolecules that also include nucleic acids, lipids, and proteins. Unlike proteins and nucleic acids, which follow template-driven synthetic pathways, there is no general route to the synthesis of carbohydrates. Monosaccharides are polyhydroxylated molecules, and regioselective protection and deprotection of specific hydroxyl groups over others represents one of the major challenges in carbohydrate chemistry.^1–3 During sequencing of simple monosaccharides into larger oligomeric networks, most of the functional groups need to be temporarily blocked by protecting groups. On the other hand, functional groups involved in the coupling process need to be left unprotected or regioselectively liberated. Therefore, it is significant to develop regioselective methods to simplify the preparation of partially or differentially substituted synthetic intermediates.⁴ As a consequence, regioselective protection and deprotection of carbohydrates has been a vibrant area of research. Orthogonal or selectively removable protecting group manipulations have been extensively employed in oligosaccharide synthesis.^5,6 However, these strategies require a specialized knowledge of various protecting groups, reaction conditions for their installation and removal, and application strategies to different sugar series.

Despite a significant progress in this area, and the availability of streamlining one-pot processes,^7–12 in a majority of the applications a large number of protecting group manipulation steps are required to obtain the desired regioselectively substituted product. While orthogonal, semi-orthogonal, or selectively removable protecting groups represent a very important direction of carbohydrate synthesis, discussed herein in the synthesis of partially protected carbohydrates by manipulating only one type of a protecting group for a given derivative. While some overlap with orthogonal protecting group strategies is inevitable, a more comprehensive coverage of the topic is available in a number of excellent recent reviews.^5,10,13–16 Two major focuses of this review article are depicted in Scheme 1. The first focus is the protection of the unprotected starting material in the way that only one (or two) hydroxyl groups remain unprotected. The second focus leads to the formation of the same type of derivatives, but it rather involves regioselective partial deprotection of uniformly protected compounds. At times, we chose to discuss these two major focus areas in application to differentially protected carbohydrates. These examples include some new reactions that have only been applied to such molecules, but in our opinion could also be generally relevant to the uniformly protected systems.

Scheme 1.

The overview of protecting group strategies described herein

The application of partially protected building blocks is fundamental to oligosaccharide synthesis. Mono-hydroxylated building blocks can be directly utilized as glycosyl acceptors in glycosylation reactions. Di-hydroxylated building blocks can also be utilized as glycosyl acceptors, for example, for the synthesis of branched glycan sequences. Alternatively, the diols are useful synthetic intermediates for further transformations because the differentiation between two hydroxyls is typically much simpler than that of fully unprotected sugars containing four or more hydroxyls.

Inherent difference in reactivity of various hydroxyl groups in carbohydrates have been investigated to achieve selective protection. Primary hydroxyl groups are sterically less hindered than their secondary counterparts, which offers an opportunity for their regioselective protection.¹⁷ The best-known examples is the use of bulky (trityl, silyl) protecting groups to selectively protect primary hydroxyl groups in the presence of secondary ones. Steric hindrance, as well as the electronic effects, can also be utilized to some extent to discriminate between certain secondary hydroxyl groups.¹⁸ In addition, hydrogen bond networks were also proposed as a possible driving force for the regioselective protection.

Early studies by Williams and co-workers revealed general reactivity trends of various hydroxyls.¹⁹ These studies also gave an appreciation that even similarly positioned hydroxyls of different sugar series may have different reactivities towards regioselective protection. Thus, the order of reactivity towards benzoylation was determined to be: 2-OH > 3-OH > 4-OH for D-gluco, 3-OH > 2-OH > 4-OH for D-manno, and 2-OH, 3-OH > 4-OH for the D-galacto series. In 1990, Hanessian attempted partial acetylation of methyl α-D-glucopyranoside 1 with and without the use of zinc chloride additive.²⁰ Compared with the control experiment, the addition 1 equiv of zinc(II) chloride enhanced the selectivity of the formation of the 3,4-diol product (Scheme 2). However, the regioselectivity and the product distribution was below preparative value for mainstream application in carbohydrate synthesis. This example clearly illustrates the challenge that synthetic chemists dealing with regioselective protection of carbohydrates face.

Scheme 2.

Partial acetylation of methyl α-D-glucopyranoside 1 provides a mixture of products

2. Synthesis of partially substituted building blocks by uniform regioselective protection

This section is focused on discussing those methods wherein the unprotected (or polyol) starting material is regioselectively protected in the way that only one (or two) hydroxyl groups remain unprotected.

2.1. Ester groups

Ester protecting groups are ubiquitous in carbohydrate chemistry because acylation of hydroxyl groups is typically an efficient and high-yielding process. Common methods of esterification utilize an acid chloride or an acid anhydride as the acylating reagent in the presence of pyridine. Sometimes, more reactive nucleophilic catalysts such as DMAP are also employed. In 1975, Williams and co-workers observed that benzoylation of α-D-glucose with benzoyl chloride (4.2 equiv) in anhydrous pyridine at −35 °C provided 1,2,3,6-tetrabenzoate (4-OH derivative) 2 in 37% yield (Scheme 3). When similar conditions were applied to α-D-mannose, the respective 4-OH derivative 3 was obtained in 51% yield.²¹ The synthesis of 1,2,3,6-tetrabenzoate 4 from α-D-galactose using benzoyl chloride in pyridine at low temperature was achieved in 38% yield.^22,23 These results clearly demonstrate that 4-OH is typically the least reactive hydroxyl access these sugar series. In contrast, a very recent report describes selective benzoylations of various α-D-galactopyranosides 5 with benzoyl cyanide to produce 3-OH compound 6 in good yields of 61–67%.²⁴ The regioselectivity achieved was rationalized by the existence of the “cyanide effect” that favors 4-O-benzoylation and “the alkoxy group mediated diol effect” that favors 2-O-benzoylation with BzCN in the presence of DMAP.

Scheme 3.

Regioselective benzoylation

An efficient method for regioselective benzoylation of diols and polyols was developed by Dong and co-workers.²⁵ This regioselective method does not rely on any amine bases or metal-based catalysts. Thus, benzoylation of methyl glycosides of the D-gluco, D-galacto, and D-manno series with benzoic anhydride catalyzed by tetrabutylammonium benzoate led to 2,4-diols in 70–91% yield.

Tin-mediated acylation was initially developed and used for monoacylations of polyhydroxylated compounds.^26,27 The tin-mediated reactions of carbohydrates with acylating reagents has been an effective way to acheive differentiation between 1,2- and 1,3-diol pairs.²⁸ More recently, Zhang and Wong performed regioselective polyacylation reactions of various sugars using an excess of BzCl and Bu₂SnO at higher temperatures (70–100 °C).²⁹ The stannylene acetal was proposed as an intermediate of the reaction of methyl α-D-glucopyranoside 1 with O-2 coordinating with the anomeric methoxy and O-6 coordinating with the ring oxygen. This reaction produced 4-OH glucoside 7 with high regioselectivity in 91% yield (Scheme 3). Interestingly, while a comparable outcome was achieved with the D-manno substrate, the D-galacto counterpart gave much lower regioselectivity.²⁹ Tosylation and benzylation can also be achieved regioselectively using a similar approach.³⁰ The principles and applications of tin-mediated reactions have been extensively reviewed.^31–34

Regioselective acetylation can be achieved by using iodine with ether-protected sugar derivatives.³⁵ Upon the treatment of 3-O-benzyl glucose 8 with acetic anhydride containing iodine at rt, 1,6-di-O-acetate 9 was obtained in 90% yield (Scheme 4). The reaction rate was improved at higher temperatures, but the regioselectivity was not affected. Many methods have been known to perform selective acetylation. Joseph et al. developed a regioselective one-pot silylation and acetylation method to form a partially acetylated sugar.³⁶ After TMSOTf-catalyzed silylation of D-glucose with HMDS, followed by acetylation, 6-O-acetyl glucopyranose 10 was formed as the major product via per-O-trimethylsilylated intermediate (Scheme 4). When per-O-TMS protected sugar in a mixture of pyridine and acetic anhydride is treated with acetic acid, regioselective exchange of TMS for acetate protecting groups occurs.³⁷ This process was termed as Regioselective Silyl Exchange Technology (ReSET). This method has been applied to glucose,³⁸ galactose, mannose, lactose,³⁷ and sialic acids.³⁹ Regiocontrol is achieved by limiting the equivalents of acetic acid, varying thermal conditions and using microwave assistance.

Scheme 4.

Examples of regioselective acetylation

Besides the ReSET approach, many catalysts such as 1-acetylimidazole,⁴⁰ C₂-symmetric chiral 4-pyrrolidinopyridine,⁴¹ copper(II),⁴² tetrabutylammonium acetate,⁴³ Mitsunobu conditions,⁴⁴ borinic acids,^45,46 and cyanides⁴⁷ can help to achieve regioselective acylation. However, very few of them can protect free sugars in one step and leave only one hydroxyl group free. MoCl₅ has been used as an effective catalyst for selective 3-acetylation of methyl 6-deoxyhexoses.⁴⁸ Acetylation with Ac₂O in the presence of catalytic MoCl₅ produced 3-O-acetyl derivative 12 regioselectively in 91% yield from methyl α-L-rhamnopyranoside 11 (Scheme 4). Kulkarni and co-worker also studied acylation of rhamnosides.⁴⁹ In particular, acetylation of phenylthio β-L-rhamnopyranoside with acetyl or benzoyl chloride (1.1 equiv) in the presence of catalytic Me2SnCl2 at rt afforded the corresponding 3-O-acylated derivatives in 95–98% yield. When the same starting material was benzoylated with 2.1 equiv of BzCl in pyridine at −30 °C, 2,3-di-O-benzoylated rhamnoside was produced in 71% yield.⁴⁹

When Kurahashi et al. treated octyl α- and β-glucopyranosides with a sub-stoichiometric amount of acetic anhydride in the presence of a catalytic amount of DMAP, 3-, 4- and 6-nonoacetylated glucosides were obtained in a 2/2/1 ratio.⁵⁰ Recently, Ren et al. described a method for selective acetylation of glycosides using tetrabutylammonium acetate as catalyst.⁴³ However, all these investigations of inherent reactivity differences and partial protections of glycoside hydroxyl groups did not provide products with exclusive regioselectivity. More recently, mono-hydroxyl building blocks were synthesized by reagent-dependent regioselectively controlled poly-acetylation.⁵¹ For methyl β-D-galactopyranoside 13, the use of Ac₂O or AcCl as acetylating reagents lead to the formation of 2-OH compound 14 or 4-OH compound 15, respectively (Scheme 5). For methyl β-D-glucopyranoside 16, either acetylating reagent gave 4-OH compound 17 as the major product. When treated with 3.3 equiv. of Ac₂O in acetonitrile solvent, both methyl α-D-glucopyranoside 1 and methyl α-D-mannopyranoside 19 gave the corresponding 4-OH products 18 and 20 in 90% yield. To explain the regioselectivity obtained, reagent-dependent thermodynamic and kinetic control and dynamic assistance mechanisms were proposed.⁵¹ Thus, when acetyl chloride was used as the acylating a monodentate chlorostannane complex was generated, whereas acylation with acetic anhydride proceeded via a less reactive bidentate acetoxystannane.

Scheme 5.

Reagent-dependent tin-mediated acetylation

The introduction of bulky ester groups was proven to be a much more promising venue. Becker and Galili prepared partially pivaloylated saccharides by using pivaloyl chloride in the presence of pyridine.⁵² 1,3,4,6-Tetra-O-pivaloyl derivative 22 was formed in 59% yield as the major product resulting from the reaction of D-mannose 21 with pivaloyl chloride in the presence of pyridine in chloroform at 35 °C (Scheme 6). Alternatively, a similar reaction performed at −10 °C produced a tetra-pivaloylated product with the free 4-OH group.⁵³ Regioselective pivaloylation of trichloroethyl galactoside 23 using pivaloyl chloride in the presence of pyridine in dichloromethane gave 4-OH product 24 in 64% yield (Scheme 6). A selective and high yielding double pivaloylation of different sugar substrates using pivaloyl chloride has also been described. See, for example, the synthesis of diols 25 and 26 depicted in Scheme 6.⁵⁴ Equatorial hydroxyl groups adjacent to axial substituents were observed have higher reactivity as they were more accessible than equatorial ones flanked by other equatorial substituents. For compound 27, which does not have any axial hydroxyl groups, selective protection occurred at the C6 and C3 positions to afford product 28.

Scheme 6.

Regioselective protection with pivaloyl groups

2.2. Alkyl and silyl groups

Alkyl group protection is widely used in carbohydrate chemistry due to its stability. Simple alkyl ethers such as methyl ethers are less preferred in complex carbohydrate synthesis because they are too stable to be removed.²⁸ Of the numerous alkyl protecting groups known, the most important are the benzyl (Bn) and allyl (All) groups and their derivatives. Direct regioselective benzylation of polyols is fairly rare. One such example was described by Koto et al⁵⁵example wherein 3-OH derivative 29 was obtained in 61% from methyl glucoside 1 by controlled heating with excess BnCl in the presence of NaH added potrionwise to 3.3 equiv total (Scheme 7).

Scheme 7.

Regioselective alkylation and silylation

In a majority of applications regioselective alkylations require metal chelating reagents and additives. Alkylations proceeding via tin intermediates is arguably the most common method to achieve regioselective protection.^{31,33,56–60} Other metal catalysts such as copper(II),⁶¹ nickel(II),⁶² and iron(III)⁶³ have also been used for regioselective alkylation. These methods are primarily used for selective mono- and di-alkylation, the formation of monohydroxylated products commonly used substrates containing other protecting groups, such as benzylidene acetals.

Recently, Vishwakarma and co-workers improved the tin-mediated alkylation method by using catalytic amount of Me₂SnCl₂ and Ag₂O as additives, which gave excellent selectivity at rt. Thus, 2,3-diol 30 was regioselectively alkylated producing 3-O-allyl and 3-O-p-methoxylbenzyl derivatives 31 and 32 in excellent yields. (Scheme 7).⁶⁴ Oshima et al. developed an alkylation method specific for the C-3 position using cyclic phenylboronate in the presence of an amine.⁶⁵ Taylor devised C-3 alkylation reaction using a diarylborinic acid derivative.⁶⁶ Iadonisi developed another method for selective benzylation that is applicable to primary hydroxyl group using stoichiometric amount of DIPEA and BnBr and catalytic amount of TBAI.⁶⁷ Some tin-mediated alkylations allow for multiple protections. Representative examples include the synthesis of 3,6-di-Bn derivative 33 from methyl galactoside 5,²⁵ and 2,6-di-Bn derivative 34 from methyl glucoside 1 (Scheme 7).⁶⁸ Benzylation of per-TMS-protected sugars via reductive etherification of benzaldehyde⁶⁹ has also received notable attention, most prominently as a part of the multi-step one-pot sequences.^9–11

Halmos et al. investigated the regioselective silylation of galactopyranosides using TBDMSCl and imidazole in the presence of DMF.⁷⁰ For both the α- and β-anomers 5 and 13, the corresponding 2,6-di-O-silylated compounds were formed predominantly. Much higher regioselectivity was observed for β-anomer 13 (Scheme 7). Schlaf and co-worker devised a silane alcoholysis method for selective trisilylation using homogeneous metal catalysts.⁷¹ High selectivity for silylation of galactoside 5 was achieved in the presence of Ir(I) catalyst. As a result, 2,3,6-tri-O-tert-butyldimethylsilyl galactoside 35 was obtained in 89% yield.

2.3. Cyclic groups

Cyclic acetals and ketals have been widely used for the protection of various diol systems in synthetic carbohydrate chemistry.^72–75 The installation of multiple acetal/ketal groups in a single monosaccharide unit is commonly used for polyols or alditols.⁷⁶ Although the double protection using cyclic acetals/ketals would have been a very effective method to obtain building blocks containing only one hydroxyl group in hexoses it remains fairly rare beyond diacetone glucofuranose (3-OH) and galactopyranose (6-OH). Thus, Rokade and Bhate devised a simple and convenient large-scale method for the synthesis of di-O-isopropylidene protected sugars by using deep eutectic solvent (DES) prepared from choline chloride and malonic acid.⁷⁷ D-Glucose can be directly converted to 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 36 in 90% yield whereas D-galactose can be converted into 1,2:3,4-di-O-isopropylidene-α-D-galactopyranose 37 in 92% yield (Scheme 8). D-Fructose can also be protected as 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose 38 using this method in 89% yield. In case of D-mannose, 2,3:5,6-di-O-isopropylidene-α/β-D-mannofuranose with the unprotected anomeric hemiacetal was formed. All these building blocks represent regioselectively protected compounds that have only one hydroxyl group. Hence, these can be used as glycosyl acceptors or intermediates for the further protection directly. In addition, one ketal is typically less stable than another, which offers a convenient opportunity for further diversification.⁷⁸ The double protection using benzylidene acetal is much less explored. In one such application, 1,2:3,4-di-O-benzylidene-D-galactopyranose could be synthesized from D-galactose using benzaldehyde and ZnCl₂.⁷⁹ Wood et al. improved the preparation of 4,6-O-benzylidene-D-glucopyranose, which lead to the formation of 1,2:4,6-di-O-benzylidene-α-D-glucopyranose as an by-product.⁸⁰

Scheme 8.

Double ketal protection of hexoses

3. Synthesis of partially substituted building blocks by regioselective deprotection of uniformly protected substrates

In addition to protection strategies, partially substituted derivatives can be obtained by regioselective deprotection of fully substituted precursors. This approach also extends to the uniformly protected precursors.

3.1. Ester group removal and migration

In general, esters are moderately stable under acidic conditions in the absence of water and other hydroxylated solvents. However, many esters are labile in the presence of nucleophiles, particularly alkoxides, amines, organometallics, and hydride transfer agents. It has been observed that essentially the same ester groups may have different stability at different positions of the ring. Thus, Haines et al. reported that a primary amine can be used for selective deacetylation of sucrose.⁸¹ Fully acetylated sucrose 39 was treated with propylamine at rt for 50 min to give diol 40 in 22% yield (Scheme 9).

Scheme 9.

Examples of regioselective deacetylation

Isopropylamine was also investigated but gave even lower yields. Ren and co-workers were able to carry out regioselective deprotections of primary acetyl esters in the presence of iodine.⁸² As depicted in Scheme 9, when various S-tolyl (Tol) glycosides 41, 43 and 45 were treated with 1% iodine–methanol solution at 70 °C for 5.5 h, 6-OH products 42, 44 and 46 were obtained in 38–43% yields. It was presumed that the electrophilic attack of iodine on the oxygen atom of the primary acetate is more favorable than that of the more hindered acetates at secondary positions. Very recently, Lecourt and co-workers achieved a similar outcome by using a combination of DIBAL-H and Cp₂ZrCl₂ to promote the regioselective cleavage of primary acetates on a variety of substrates.⁸³

Some acyl groups may undergo migration through a neighboring group effect via the formation of the respective orthoester as an intermediate. Acyl group migration has been proven to be a useful approach to obtain partially substituted building blocks for oligosaccharide synthesis.^84–86 In 1962, Helferich and Zirner⁸⁷ synthesized 1,3,4,6-tetra-O-acetyl-α-D-glucopyranose 47 from D-glucose via a three-step in-situ procedure. This synthesis requires strict control of the reaction temperature and reactant addition and still gives only 27% yield overall (Scheme 10).

Scheme 10.

The synthesis of 2-OH derivatives

A few years later, Chittenden reported a simplified method for the synthesis of 1,3,4,6-tetra-O-acetyl-α-D-galactopyranose using trifluoroacetic acid-water solution.⁸⁸ 1,2,3,4,6-penta-O-acetyl-β-D-galactopyranose 48 was treated with aqueous trifluoroacetic acid at rt for 5 h to give 1,3,4,6-tetra-O-acetyl-α-D-galactopyranose 49 in 72% yield (Scheme 10). The α-anomer of D-galactopyranose/glucopyranose pentaacetate is unreactive under these reaction conditions. When 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose was treated under the same reaction conditions, only 2,3,4,6-tetra-O-acetyl-D-glucopyranose was produced as the major product.

Recently, Demchenko et al. reinvestigated the synthesis of 2-OH glucose.⁸⁹ When acetobromoglucose 50 was treated with cerium(IV) ammonium nitrate (CAN) 2-OH glucose 47 was obtained in 51% yield (Scheme 10). This procedure was recently further improved by using AgNO₃ as the additive and glycosyl nitrates were found to be intermediates in this reaction.⁹⁰ AgNO₃ is able to convert glycosyl bromide 50 to glycosyl nitrate 51 in 77% yield within 5 min. Subsequently, 2-OH glucose 47 formed by re-dissolving compound 51 in wet MeCN (Scheme 10). The isolation of glycosyl nitrate 51 suppressed the formation of by-product 2,3,4,6-tetra-O-acetyl-D-glucopyranose. Hanessian and Kagotani found that lithium hydroperoxide could be used to remove the 2-O-acetyl group regioselectively from methyl 2,3,4,6-tetra-O-acetyl-α-D-glycoside 52 to afford 2-OH product 53 in 50% yield (Scheme 10).²⁰ For penta-O-acetyl-D-glucose, lithium hydroperoxide removed the acetyl group at C-2 position as well as at the anomeric position.

Hydrazine hydrate can also be used for selective deacetylation at C-2 position.⁹¹ On the treatment of various glycosides 52, α-54 and β-54 the corresponding 2-OH products 53, α-55 and β-55 was obtained in moderate yields of 46–49% (Scheme 10). When a bismuth(III) salt was used to promote glycosylation of allyl alcohol with glucosyl iodide 57, obtained from glucose pentaacetate 56, the corresponding 2-OH allyl glucoside 55 was formed as the major product in 57% yield instead of the anticipated tetra-O-acetylated product (Scheme 10).⁹² An allyl orthoester intermediate was suggested to form during the bismuth(III) activation step.

3.2. Ether group removal

Benzyl groups are commonly used as protecting groups in carbohydrate chemistry. Due to their general stability, these groups are considered to be “permanent” protecting groups that are only removed at the end of the target synthesis. However, it was observed that some benzyl groups may have different stability at different positions of the ring. In particular, regioselective acetolysis of 6-O-benzyl group in the presence of secondary benzyl groups is arguably the best known and most commonly applied approach.^93–95 For example, freshly fused ZnCl₂ in Ac₂O/AcOH has been used for the acetolysis of 6-O-benzyl groups in mono- and disaccharide derivatives at room temperature.⁹⁶ Per-benzylated mannoside 58 was treated with ZnCl₂ in Ac₂O/AcOH for 2 h to produce 6-O-acetyl product 59 in 85% yield (Scheme 11). The same type of a transformation can be achieved by regioselective acetolysis with toluenesulfonic acid⁹⁷ or isopropenyl acetate (IPA) in the presence of iodine or iodine/silane.⁶⁷ Thus, when a premixed solution of iodine and polymethylhydrosiloxane (PMHS) in dichloromethane was used followed by the addition of IPA as the acetylating reagent, 6-O-acetyl compound 59 was formed from per-O-benzylated mannoside 58 in 80% yield. More recently, Li and co-workers developed a highly efficient and mild method for regioselective de-O-benzylation by transforming primary benzyl ethers to silyl ethers using Co₂(CO)₈-Et₃SiH under 1 atm of CO.⁹⁸ Per-O-benzylated mannoside 58 was treated with Co₂(CO)₈/Et₃SiH/CO conditions to give 6-O-triethylsilyl compound 60 in 92% yield (Scheme 11). This method was also successfully applied to various monosaccharide substrates with different anomeric protecting groups, as well as natural disaccharides and trisaccharides including sucrose, raffinose and others. A similar protocol was applied to the regioselective removal of methyl ether protecting groups.⁹⁹ For per-O-methylated thioglucoside, primary methyl group was removed selectively and the respective 6-O-acetyl product was formed in 52% yield along with 3,6-di-O-acetyl compound was also formed as a minor side-product.

Scheme 11.

Examples of regioselective primary debenzylation

The earlier examples of regioselective de-0-benzylation include that of perbenzylated methyl lyxoside by Grignard reagent,¹⁰⁰ and perbenzylated methyl ribofuranoside with tin tetrachloride.¹⁰¹ The selective heterogeneous catalytic transfer hydrogenolysis perbenzylated 1,6-anhydrohexoses catalyzed by palladium on charcoal was developed by Martin-Lomas.¹⁰² 1,6-Anhydro-2,3,4-tri-O-benzyl-β-D-mannopyranose 61 was treated with 10% Pd/C in refluxing 2-propanol for 4 h, to produce 1,6-anhydro-3-O-benzoyl-β-D-mannopyranose 62 in 40% yield (Scheme 12). The regioselective removal of one secondary benzyl substituent in per-benzylated 1,6-anhydrohexoses by Lewis acids SnCl₄ and TiCl₄ was developed by Meguro and co-workers.¹⁰³ 1,6-Anhydro-2,3,4-tri-O-benzyl-β-D-mannopyranose 61 was treated with SnCl₄ to produce 2-OH derivative 63 in 92% along with its 3-OH regioisomers (5%). A similar result albeit lower yield of 62 due to relaxed regioselectivity were obtained with TiCl₄. Spectral studies showed the evidence of the formation of the metal-sugar complexes, thus requiring three appropriately situated alkoxyl groups for the selective de-O-benzylation.

Scheme 12.

Examples of regioselective secondary debenzylation

Catalytic transfer hydrogenation (CTH) can be performed using HCO₂NH₄ and Pd/C catalyst to selectively remove 2-O-benzyl groups in derivatives of D-glucose, D-mannose, and D-galactose.¹⁰⁴ Sinay, Sollogoub and their co-workers developed a method for regioselective de-O-benzylation of polybenzylated sugars using an excess of triisobutylaluminium (TIBAL) or diisobutylaluminium hydride (DIBAL-H).¹⁰⁵ Treatment of per-benzylated glucoside 64 with 5 equiv. of TIBAL in toluene at 50 °C led to 2-O-debenzylated product 65 in 98% yield (Scheme 12). For the reaction to occur, a 1,2-cis arrangement of adjacent oxygen atoms is required to form a chelation complex with the first mole of the aluminum reagent. The second mole of the reagent then induces the regioselectivity of the de-alkylation by coordinating preferentially to one of the oxygen atoms of the selected pair. The same transformation, albeit much slower rate, can be performed in the presence of AlMe₃.¹⁰⁶

Iadonisi and co-workers developed another method for regioselective O-debenzylation using I₂/Et₃SiH at low temperature.¹⁰⁷ The regioselectivity is dependent on the nature of the precursor and the most sterically hindered position is often deprotected. Methyl galactoside 66 was treated with 1.25 equiv. of I₂ and 1.25 equiv. of Et₃SiH at low temperature for 15 min to afford 4-OH derivative 67. In case of disaccharide 68, the 3-O-benzyl group was removed with excellent regioselectivity to produce compound 69 in 96% yield (Scheme 12).

An interesting reaction proceeding via a xanthate-mediated intramolecular 1,7-hydrogen atom transfer of a benzylic hydrogen atom to an O-silylmethylene radical was found capable of initiating the regioselective mono-de-O-benzylation of benzylated saccharides.¹⁰⁸ This method can be applied to a variety of substrates and gave moderate to good yields (Scheme 12). Xanthate 70 was treated with dilauroyl peroxide, followed by acid and TBAF in refluxing 1,2-dichloroethane to give diol 71 in 75% yield. The reaction terminates by an ionic mechanism and is general for benzylated substrates having a variety of functional groups. Intramolecular activation of per-benzylated C-glycosides to affect regioselective deprotection at C-2 can be carried out in the presence of iodine.^109,110 Boron trichloride (BCl₃) has also been investigated as a reagent to achieve regioselective deprotection of 1,2- or 1,3-cis oriented secondary benzyl ethers of poly-benzylated C-glycosyl derivatives.¹¹¹ Another method for regioselective de-O-benzylation of poly-benzylated sugars is to use CrCl₂/LiI in moist EtOAc.¹¹² The regioselectivity is dependent on the three-point coordination between the carbohydrate and Cr.

p-Methoxylbenzyl (PMB) ethers are less stable than unsubstituted benzyls. Kartha and co-workers explored a possibility for regioselective PMB removal using SnCl₄ at low temperature.¹¹³ When di-O-PMB derivative 72 was treated with SnCl₄ (0.25 mmol) in CH₂Cl₂ at −20 °C for 8 min, 2-O-PMB group was removed and mono-O-PMB ether 73 was obtained in 70% yield (Scheme 13). The initial preferential removal of the 2-O-PMB group in 72 was rationalized by the formation of a tin complex as an intermediate. Regioselective removal of p-methoxybenzyl (PMB) group at the C-5 position for hexafuranose and pentafuranose derivatives was achieved using a catalytic amount of tin chloride dihydrate (SnCl₂-2H₂O) or 0.5–10% solution of trifluoroacetic acid (TFA) in dichloromethane in good yields.¹¹⁴ For tri-O-PMB protected glucofuranose 74, the 5-O-PMB group could be removed selectively using a 0.5% solution of TFA in CH₂Cl₂ to form the 5-OH product 75 in 80% yield (Scheme 13).

Scheme 13.

Regioselective removal of PMB groups

The regioselective deprotection of a primary tert-butyldimethylsilyl (TBDMS) group of fully O-TBDMS protected monosaccharides by using boron trichloride (BCl₃) was devised.¹¹⁵ Fully O-TBDMS protected benzyl mannoside 76 was treated with BCl₃ at 25 °C for 2.8 h and gave 81% of the 6-OH product 77 (Scheme 14). The TBDMS group was also observed to migrate from the C-6 to C-4 position of glucosides under typical basic benzylation conditions.¹¹⁶ Cui et al. developed a method to selectively remove a primary trimethylsilyl (TMS) group of per-O-TMS protected carbohydrates using ammonium acetate (NH₄OAc).¹¹⁷ On the treatment of the per-O-TMS protected glucoside 78 with 2 equiv. of NH₄OAc the corresponding 6-OH product 79 was obtained in 91% yield (Scheme 14). Various monosaccharides and disaccharides were investigated under these reaction conditions giving the desired products in excellent yields. When the precursor had no primary TMS group, no reaction occurred under these reaction conditions.

Scheme 14.

Regioselective desilylation

3.3. Cyclic group removal and opening

In di-O-isopropylidene protected derivative, sometimes one ketal can be removed regioselectively over another. The regioselective removal of the acetal groups of di-O-isopropylidene-protected pyranoses was barely studied. The few known examples include the removal of 3,4-O-isopropyliden in the presence of 1,2-O-isopropylidene ketal in diacetone galactose with dilute hydrochloric acid in acetone,¹¹⁸ and with concentrated nitric acid in ethyl acetate.³⁴ Recently, Zhang et al. developed the removal of 1,2-O-isopropylidene in the presence of 3,4-O-isopropylidene ketal in diacetone galactose. Di-O-acetate 81 was obtained in 78% yield from the di-O-isopropylidene protected pyranose 80 in the presence of TFA and acetic anhydride (Scheme 15).⁷⁸ The same conditions were also successfully applied to the regioselective 4,5-O-acetolysis of 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose 82 to produce compound 83 in 76% yield. The corresponding 1,2-O-isopropylidene derivatives were obtained selectively by UV irradiation of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose and 1,2:3,5-di-O-isopropylidene-α-D-xylofuranose, respectively.¹¹⁹

Scheme 15.

Regioselective deprotection of isopropylidene

In 1994, Luh and co-workers reported that di-acetonide glucose derivative 84 can be reductively opened to produce mono-hydroxyl derivatives with high regioselectivity using MeMgI.¹²⁰ When diacetone glucose 84 was treated with 4 equiv. of MeMgI in benzene at 60 °C for 1 h, the corresponding 2-OH derivative 85 was formed in 95% yield (Scheme 15). In a similar fashion, treatment of compound 86 with MeMgI afforded 87 exclusively in 68% yield (Scheme 15). Presumably, the chelation of the Grignard reagent with the methoxy group at C-6 controls the regioselectivity.

Cyclic acetals are important protecting groups in carbohydrate chemistry and many can be opened regioselectively to form mono hydroxyl products. Many methods have been developed to dedicated to this topic,¹²¹ and a very recent review by Janssens et al. offers the most up to date coverage of the topic.¹²² Discussed herein are only some representative examples relevant to the topic of this review. In 1969, Bhattacharjee and Gorin applied the mixed hydrides in the reduction of carbohydrate series for the first time.¹²³ One molar equivalent of LiAlH₄-AlCl₃ (1/1) was used for the reduction of hexafuranose and hexapyranose acetals. After 40 h, a uniformly protected 6-OH derivative 89 was obtained in 64% yield from methyl 2,3-di-O-benzyl-4,6-O-benzylidene-β-D-glucopyranoside 88 (Scheme 16). The 2-OH derivative 91 was obtained in 56% yield from methyl 2,3:4,6-di-O-benzylidene-α-mannopyranoside 90 in 3.5 h when 2 equivalents of LiAlH₄-AlCl₃ (1/1) mixture was used. The formation of trace amounts of the 3-OH side product was also noted (Scheme 16). The study of the factors that orient the cleavage of a 4,6-O-benzylidene group undertaken by Lipták and co-workers showed that the direction of the cleavage of the benzylidene ring is affected by the bulkiness of the protecting group at C-3^124,125 and exo/endo stereochemistry of benzylidene acetal.^126,127 This was investigated on a series of 2,3-O-benzylidene protected L-rhamnopyranosides wherein 2-OH products were favored from exo-isomers whereas 3-OH products were obtained from exo-benzylidene precursors.^127–129 It was also demonstrated that the direction of cleavage is independent on the anomeric configuration or the character of the aglycone moiety.¹³⁰

Scheme 16.

Reductive opening of benzylidene acetals

Garegg et al. discovered that reductive opening of 4,6-O-benzylidene acetals of hexapyranosides using NaBH₃CN-HCl gave different regioselectivity than LiAlH₄-AlCl₃, yielding 6-O-benzyl product 4,6-O-benzylidene acetals.^131,132 6-O-Benzyl derivatives 93, 95 and 97 were obtained from the reductive cleavage of the starting materials 92, 94 and 96 in 60–95% yield (Scheme 16). This may be explained by steric factors. When a reducing agent with a greater steric demand like LiAlH₄-AlCl₃ is used, the reductive opening reaction tends to for 6OH products. When NaBH₃CN-HCl is used, the steric requirement of the electrophile is much smaller and the direction of the equilibrium is governed mainly by the relative basicities of O-4 and O-6, and the formation of the secondary 4-OH product typically prevails. The direction of regioselective opening of 4,6-O-benzylidene acetals of hexapyranosides using BH₃•Me₃N-AlCl₃ in different solvents were investigated by Ek et al.¹³³ For the reaction of 4,6-O-benzylidene derivative 92 in toluene 6OH product 98 was obtained. When THF was used as the reaction solvent, 4OH product 93 was obtained (Scheme 16). A pronounced solvent effect was also reported by Oikawa et al. who used BH₃•Me₂NH/BF₃•OEt₂ to perform a regioselective reductive opening of the 4,6-O-benzylidene acetals.¹³⁴ When the reaction was carried out in CH₂Cl₂, the 6-OH product was regioselectively obtained. Conversely, when the reaction was performed in CH₃CN, 4-OH product was predominantly formed.

Other useful methods to affect the regioselective opening of benzylidene include DIBAL,^135–138 Et₃SiH-TFA,¹³⁹ Et₃SiH-BF₃·Et₂O,¹⁴⁰ BH₃•THF-Bu₂BOTf,¹⁴¹ BH₃•NMe₃-Me₂BBr at −78 °C,¹⁴² BH₃ in combination with metal triflates at rt,¹⁴³ BH₃ or Me₂EtSiH with Cu(OTf)₂,¹⁴⁴ BH₃•THF and CoCl₂,¹⁴⁵ Et₃SiH and I₂,¹⁴⁶ among others.¹²² The development of new methods has been complemented by a variety of mechanistic investigations.^147–152 4-Methoxybenzylidene acetals can also be selectively opened in a similar fashion and using similar reagents to as benzylidene acetals.^153,154 Regioselective opening of other acetals including 4,6-O-prop-2-enylidene,¹³² fluorous benzylidene¹⁵⁵ phenylsulfonylethylidene¹⁵⁶ has also been explored. Oxidative and photooxidative methods for opening of benzylidene acetal have also been developed. N-Bromosuccinimide (NBS) was found to be an effective reagent to regioselectively open 4,6-O-benzylidene acetals to afford 6-bromo 4-benzoates.¹⁵⁷ Regioselective partial deprotection of carbohydrates protected as benzylidene acetals can be achieved by irradiation of the protected sugar with NBS in the presence of water.¹⁵⁸ Photolysis is an alternative mild and regioselective method to open an acetal protecting group. Early studies by Tănăsescu and co-workers on light-induced cleavage of o-nitrobenzylidene acetals.^159,160 have been complemented by more recent studies dedicated to photochemical conversion of cyclic acetals to the corresponding esters.^161–164

Orthoesters are other common type of protecting groups in carbohydrate chemistry. Orthoesters can be regioselectively opened to the corresponding hydroxyacetate derivatives under mild acidic conditions.¹⁶⁵ The substrate α-D-glucoside 99 was treated with a mixture of water and chloroform in the presence of TsOH, giving the corresponding 4-OH derivative 100 as the major compound in 60% yield as well as the minor product 6-OH isomer 101 in 30% yield (Scheme 17). Among other applications, orthoesters can be reduced into the corresponding acetals.^166,167 Nicolaou and co-workers showed that cyclic 1,2-carbonates can be regioselectively cleaved with organolithium reagents at low temperature to afford regioselective esters.¹⁶⁸ Thus, derivative 102 was treated with PhLi to afford 4-O-benzoyl derivative 103 in high yield (Scheme 17). A number of useful ring-opening reactions can be achieved with anhydrosugars.^{103,169–174} Thus, Hori and co-workers performed acid-catalyzed methanolysis of 1,6-anhydro-2,3,4-tri-O-benzyl-β-D-mannopyranose 61 using 7% HCl MeOH solution (Scheme 17).¹⁰³ This reaction produced methyl 2,3,4-tri-O-benzyl-α-D-mannopyranoside 104 in 77% yield together with methyl 2,4-di-O-benzyl-α-D-mannopyranoside 105 that was isolated in 14% yield. An efficient method was developed for selective 5-O-opening of 3,5-O-di-tert-butylsilylene-D-galactofuranosides to give the corresponding 5-OH derivative.¹⁷³ Thiogalactofuranoside 106 was treated with 1.1 equiv. of TBAF at −20 °C for 40 h and gave 5-OH derivative 107 in 90% yield (Scheme 17).

Scheme 17.

Regioselective ring opening of other cyclic groups.

4. Conclusions and outlook

The application of partially protected building blocks is fundamental to carbohydrate chemistry. The Glycoscience community has been working for many years on developing methods for the synthesis of building blocks. Some efforts to commercialize advanced synthetic intermediates have been made. Nevertheless, this remains an underdeveloped area of research. As Seeberger notes “differentially protected monosaccharide building blocks is currently the bottleneck for chemical synthesis”.¹⁷⁵ Indeed, most bench time in carbohydrate chemistry lab is dedicated to making building blocks. It is very common that researchers experience significant setbacks because they have to continue to remake building blocks. The synthesis of even simple compounds may require six, eight, ten or even more steps. As a result, poor accessibility to regioselectively protected building blocks hampers development of all methods, both traditional manual syntheses of glycans in solution and modern automation platforms.^176–178

This review article summarizes advances in the area made towards the regioselective protection/partial deprotection with the major focus on the synthesis of mono- or di-hydroxyl derivatives in one step form the completely unprotected or uniformly protected precursors in one step. “Unlike the synthesis of peptides and oligonucleotides, there are no universal building blocks or methods for the synthesis of all glycans”.¹⁷⁹ It is also true for methods used for the synthesis of building blocks. Some excellent methods can only be applied to the synthesis of sugars of a particular series, whereas attempts to apply certain conventions to a broader range of substrates may fail even with one different stereocenter.