Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

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Site-Selective Functionalization of Hydroxyl Groups in Carbohydrate Derivatives Victoria Dimakos and Mark S. Taylor*

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Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada ABSTRACT: Methods for site-selective transformations of hydroxyl groups in carbohydrate derivatives are reviewed. The construction of oligosaccharides of defined connectivity hinges on such transformations, which are also needed for the preparation of modified or non-natural sugar derivatives, the installation of naturally occurring postglycosylation modifications, the selective labeling or conjugation of carbohydrate derivatives, and the preparation of therapeutic agents or research tools for glycobiology. The review begins with a discussion of intrinsic factors and processes that can influence selectivity in reactions of unprotected or partially protected carbohydrate derivatives, followed by a description of transformations that engage two OH groups in cyclic adducts (acetals, ketals, boronic esters, and related species). An overview of the various classes of site-selective transformations of OH groups in sugars is then provided: the reactions discussed include esterification, thiocarbonylation, alkylation, glycosylation, arylation, silylation, phosphorylation, sulfonylation, sulfation, and oxidation. Emphasis is placed on recently developed methods that employ reagent or catalyst control to achieve otherwise challenging transformations or site-selectivities.

CONTENTS 1. Introduction 2. Trends in the Relative Reactivity of Hydroxyl Groups in Carbohydrates 2.1. Steric Effects 2.2. Relative Acidities of OH Groups in Carbohydrates 2.3. Intramolecular Hydrogen Bonding 2.4. Substitution Reactions of the Anomeric OH Group: Fischer Glycosidation and Related Transformations 3. Migrations of Acyl and Silyl Groups in Carbohydrate Chemistry 3.1. Acyl Group Migrations 3.2. Silyl Group Migrations 4. Formation of Cyclic Adducts from 1,2- Or 1,3-Diol Moieties: Acetals, Ketals, Boronic Esters, and Silylenes 4.1. Acetals and Ketals 4.2. 1,2-Diacetals and Dispiroketals 4.3. Boronic Esters 4.4. Silylenes 5. Esterification 5.1. Selective Esterification with Acyl Chlorides in Pyridine 5.2. Acylating Agents: Variation of Leaving Group 5.3. Carbodiimide- and Uronium Salt-Mediated Couplings 5.4. Mitsunobu Esterifications 5.5. Organocatalyzed Acylations

B C C C D

D E F G

H H J J K L

6. 7.

L M 8. 9.

N N N

5.5.1. Catalysis by 4-(Dimethylamino)pyridine (DMAP) 5.5.2. DMAP Derivatives 5.5.3. Catalysis by Imidazoles and Related Heterocycles 5.5.4. Amine Catalysts 5.5.5. Tetraalkylammonium Salts: PhaseTransfer and Brønsted Base Catalysis 5.5.6. Oxidative Esterifications: Catalysis by NHeterocyclic Carbenes 5.6. Acylation by Complexation of OH groups: Main Group, Transition Metal, And Lanthanide-Based Promoters or Catalysts 5.6.1. Site-Selective Acylations Using Organotin Catalysts or Promoters 5.6.2. Site-Selective Acylations Using Organoboron Catalysts 5.6.3. Selective O-Acylation of Silylenes 5.6.4. Selective Acylations Promoted by Transition Metal or Lanthanide Salts 5.7. Enzyme-Catalyzed Esterification Thiocarbonylation Alkylation 7.1. Substrate Control in Selective Alkylation 7.2. Organotin Promoters and Catalysts 7.3. Transition Metal Promoters and Catalysts 7.4. Organoboron Promoters and Catalysts O-Arylation Glycosylation

N O P Q R R

S S T U U W W X X Y Y Z AA AB

Received: July 13, 2018

© XXXX American Chemical Society

A

DOI: 10.1021/acs.chemrev.8b00442 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews 9.1. Substrate Control in Site-Selective Glycosylation 9.2. Reagent-Controlled Glycosylation 9.2.1. Organotin-Promoted Glycosylation 9.2.2. Organoboron-Promoted Glycosylation 9.2.3. Calcium(II)-Promoted Glycosylation 9.3. Catalyst-Controlled Glycosylation 9.3.1. Organoboron-Catalyzed Glycosylation 9.3.2. Organotin-Catalyzed Glycosylation 9.3.3. Organocatalyzed Acetalization and Glycosylation 10. Silylation 10.1. Silyl Transfer Reactions 10.2. Reagent-Controlled Silylation 10.3. Catalysis of Silylation Reactions 11. Reactions with Phosphorus-Centered Electrophiles 11.1. Phosphorylation of Mono- And Oligosaccharides 11.2. Phosphorylation and Related Transformations of Nucleosides 11.3. Phosphorylation of Inositols 12. Reactions with Sulfur-Centered Electrophiles 12.1. Sulfonylation 12.1.1. Sulfonyl Halides in Pyridine 12.1.2. Other Sulfonylation Reagents and Conditions 12.1.3. Phase-Transfer Catalysis 12.1.4. Organotin Promoters and Catalysts 12.1.5. Transition Metal Promoters and Catalysts 12.1.6. Organoboron Catalysts 12.1.7. Organocatalysts 12.2. Sulfation 12.2.1. Direct Sulfation with SO3 Complexes 12.2.2. Installation of Masked Sulfate Groups 12.2.3. Chemoenzymatic Sulfation with Sulfotransferases 13. Oxidation 13.1. Enzyme-Catalyzed Oxidation 13.2. Oxidation Using Synthetic Reagents or Catalysts 14. Conclusions Associated Content Special Issue Paper Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

Review

with the anomeric position of a sugar-based electrophile) or indirectly (through the use of a partially protected nucleophile). In either case, chemical transformations that allow for selective functionalization of OH groups are needed. Such transformations have numerous other applications in carbohydrate chemistry, including for the preparation of rare or non-natural carbohydrate derivatives, the installation of naturally occurring sugar modifications such as ester, sulfate, or phosphate groups, and the synthesis of biological probes or potential therapeutic agents. This review aims to provide a comprehensive overview of the methods available for site-selective transformations of OH groups in carbohydrate derivatives. In general, the focus is on reactions of mono-, di-, and oligosaccharide derivatives, although examples involving nucleosides and inositols are also included, particularly for transformations such as phosphorylation where the latter two substrate classes are of particular interest. Investigations of selective transformations of sugars have been underway for more than a century, and it was recognized at an early stage that intrinsic differences in reactivity between OH groups in sugars could be exploited in useful ways. This review begins with a discussion of these differences, using representative examples to illustrate important trends. More comprehensive discussions of the early work that helped to elucidate and generalize these concepts can be found in previous review articles.1−3 Section 3 provides a brief description of acyl and silyl group migrations, processes that are important to keep in mind when interpreting the results of site-selective installations of these groups or when planning transformations of selectively protected intermediates. Reagents that engage 1,2- or 1,3-diol groups have long provided a way to distinguish between OH groups in sugars. Section 4 provides an overview of transformations of this type, including a brief discussion of the wellstudied chemistry of acetals and ketals but focusing on more recent work involving other cyclic species such as boronic esters and silylenes. The remainder of the review article is organized according to the type of functionalization reaction, with further subdivisions according to the reagent or catalyst type employed in cases where numerous approaches have been used to achieve a particular transformation. Again, an effort has been made to include a discussion of key early work, but emphasis has been placed on more recent studies. In particular, the use of reagent or catalyst control to enhance, alter, or overcome the intrinsic patterns in reactivity of OH groups in carbohydrate-derived substrates is an important emerging direction. This topic has been discussed in recent review articles,4−8 including several that focus on particular transformations,9 catalyst types,10 or substrate classes.11 We hope that by providing a comprehensive overview of this work, and by putting it into the context of more traditional approaches for distinguishing between OH groups in sugars, this review will provide a useful perspective and will point toward new challenges and opportunities. Enzyme-catalyzed reactions of sugars have clearly served as inspiration for the development of methods that employ synthetic catalysts and are also of great preparative utility. The topic of chemoenzymatic, site-selective transformations of sugar derivatives is an extensive one, and a comprehensive discussion will not be provided here. In particular, enzyme-catalyzed transformations that have been the subject of review articles, including esterification,12−15 glycosylation,16−20 and oxidation,21 will not be described in detail.

AB AD AD AD AE AE AF AG AG AG AH AH AH AI AI AK AL AM AM AM AN AN AN AO AP AP AQ AQ AR AS AS AS AT AV AV AV AV AV AV AV AV AV AV

1. INTRODUCTION Carbohydrates pose unique synthetic challenges in comparison to amino acids and nucleosides, the building blocks that compose the other major classes of biopolymers. The key issue is that each carbohydrate monomer bears several hydroxyl (OH) groups, each representing a potential site of chemical reactivity. Thus, in the construction of an oligosaccharide, the positions of the glycosidic linkages between sugar moieities must be controlled, either directly (by selective C−O bond formation B


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2. TRENDS IN THE RELATIVE REACTIVITY OF HYDROXYL GROUPS IN CARBOHYDRATES

Scheme 2. Examples of Selective Functionalizations of Secondary OH Groups in Pyranosides Attributed to Steric Control

2.1. Steric Effects

Differences in the level of steric hindrance of the various OH groups in pyranoside or furanoside derivatives can be exploited to achieve selective functionalizations, particularly in couplings with bulky electrophiles. Primary OH groups have been functionalized in the presence of secondary OH groups to install triphenylmethyl ethers,22,23 hindered silyl ethers,24,25 trimethylacetyl (pivaloyl) esters,26 and arenesulfonates (Scheme 1, α-1 → 2 and 3 → 4). Selective glycosylations of primary OH Scheme 1. Selective Functionalizations of Pyranoside and Furanoside Derivatives under Conditions of Steric Control

than the 2-OH, which is flanked by two cis substituents. Accordingly, selective 3-O-acylation of α-13 was achieved under conditions that gave a mixture of isomers from the β-anomer (Scheme 3).32 Scheme 3. Effect of Anomeric Configuration on SiteSelectivity in the Esterification of a Ribofuranoside Derivative

groups in the presence of free secondary OH groups have also been achieved.27,28 In a similar way, selectivity for secondary over tertiary OH groups has been achieved (e.g., in the glycosylation of olivomycose derivative 5).29 Steric effects can also enable differentiation of secondary OH groups in carbohydrate derivatives. In pyranosides, a preference for functionalization of equatorial over axial OH groups is often observed using bulky electrophiles (e.g., Scheme 2, 7 → 8).30 Equatorial OH groups flanked by two other equatorial substituents are often particularly resistant toward functionalization (e.g., α-9 → 10, β-11 → β-12)26,31 because electrophiles approaching in the plane of the pyranose ring engage in unfavorable interactions with the substituents. Because of these trends, both the sugar stereochemistry (gluco vs galacto, manno) and the anomeric configuration (α vs β) are important in determining the relative reactivity of OH groups in pyranosides under conditions of steric control. For furanose derivatives, selective functionalization of secondary OH substituents often hinges on steric hindrance created by adjacent substituents on the five-membered ring. The secondary OH group at the 5-position of a hexofuranoside typically shows higher reactivity than the OH groups that are bonded to the ring carbons (the 2-OH and 3-OH groups), whereas selectivity between the latter may be governed by the steric effects of adjacent, cis-configured substituents. For example, differentiation of the 2-OH and 3-OH groups of βribofuranosides is generally challenging, since the two OH groups are in roughly similar steric environments. However, in the case of the α-anomer, the 3-OH group is more accessible

2.2. Relative Acidities of OH Groups in Carbohydrates

In the presence of an appropriate base, it may be possible to selectively functionalize the most acidic OH group of a carbohydrate substrate (Scheme 4). The pKa of the hemiacetal OH at the anomeric position of a reducing sugar is appreciably Scheme 4. Examples of Selective Functionalization of the Most Acidic OH Group of a Carbohydrate Substrate under Basic Conditions

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lower than those of the alcohol groups.33 Selective anomeric Oalkylations,34,35 O-acylations,36 and nucleophilic displacement reactions37,38 have been developed to take advantage of this property (e.g., 15 → 16, Scheme 4). Monosaccharides lacking a free anomeric hemiacetal, as well as nucleosides, have been shown to undergo selective reactions at the 2-position in the presence of a strong base (e.g., α-9 → 17a).39−42 It has been suggested that the inductive electron-withdrawing effect of the anomeric center causes the 2-OH group to be the most acidic site, although calculated deprotonation enthalpies and pKa values of the OH groups in mono- and disaccharides do not always provide a clear reflection of this trend.43,44,33 A comprehensive study of the pKa values of aminodeoxysugars has been carried out by Pedersen, Bols, and coworkers.45 The results serve as a useful framework for understanding the effects of functional group position and relative configuration on the acid/base behavior of pyranose derivatives. The basicity of the amino group was found to decrease in the order 6-NH2 > 3-NH2 > 2-NH2 > 4-NH2, with antiperiplanar relationships between C−N and C−O bonds contributing to lower pKa values for the amine group. The authors also noted that axial OH or OR groups tend to result in higher amine basicities than the equatorial congeners, except in cases where the amino group is antiperiplanar to the C−O bond.

molecular hydrogen bonding interaction with O-4. In contrast, OH groups that act as acceptors of hydrogen bonds would be expected to be poorly nucleophilic.47,48 Hydrogen bond donation (either inter- or intramolecular) from the NHAc group of N-acetylglucosamine derivatives contributes to the low glycosyl acceptor reactivity of the 4-OH group in such compounds.49 Changing the hydrogen bonding pattern by incorporating a 2-picolinyl ether in place of a benzyl ether at the 3-position resulted in improved yields for glycosylation of the 4OH group. Intramolecular hydrogen bonds in carbohydrates can display cooperative effects due to the enhanced polarization of the two functional groups that engage in the interaction.50−53 Networks of hydrogen bonds have been invoked to account for trends in the reactivity of carbohydrate OH groups. For example, Yoshida and co-workers observed that the 4-OH groups of gluco- and mannopyranoside derivatives were particularly reactive, undergoing acetylation at a higher rate than the other primary and secondary OH groups (e.g., acetylation of β-20, Scheme 5).54 The authors proposed that a chain of intramolecular hydrogen bonding interactions terminating at the 4-OH group was responsible for this behavior. However, it has been noted that the calculated electron density profiles at the B3LYP/631+G(d), MPWIPW91/6-311+G(2d,p), and MP2/631+G(d) levels of theory are not consistent with intramolecular hydrogen bonding between vicinal OH groups in the 4C1 and 1 C4 conformers of β-D-glucopyranose.55 Subsequent studies have suggested that intermolecular hydrogen bonding between carbohydrate diol moieties and acetate ion is an important feature of the mechanism of acetylation using Ac2O and DMAP (see section 5.5.1 below). Moitessier and co-workers have developed “directingprotecting groups” capable of altering the reactivity of OH groups in sugars through intramolecular hydrogen bonding interactions.56 For example, the interactions depicted by dotted lines in the structure of compound 22 (Scheme 5) were proposed to be responsible for its selective acetylation at the 3position. The reaction of the corresponding trityl-protected αglucopyranoside 24 gave a complex mixture containing di- and triacetylated products in addition to the corresponding 3-Oacetate.

2.3. Intramolecular Hydrogen Bonding

Intramolecular hydrogen bonding interactions involving OH groups can potentially influence the reactivity of carbohydrate derivatives in several ways. Hydroxyl groups that act as hydrogen bond donors may display enhanced nucleophilic reactivity, since the noncovalent interaction would be expected to strengthen along the reaction coordinate for functionalization by an electrophile. An example of this type of effect is the reaction of isosorbide (18) with para-toluenesulfonyl chloride (TsCl, Scheme 5).46 The roughly 4:1 selectivity for sulfonylation of the more hindered endo-5-OH group was ascribed to its intraScheme 5. Selective Transformations of CarbohydrateDerived Substrates Attributed to Intramolecular Hydrogen Bonding Interactions

2.4. Substitution Reactions of the Anomeric OH Group: Fischer Glycosidation and Related Transformations

The OH group at the anomeric position displays unique reactivity because it is part of a hemiacetal group. Selective substitution reactions of this OH group can take place by addition−elimination mechanisms involving the acyclic hydroxy aldehyde isomer as a key intermediate. The Fischer glycosidation is a prominent example of this type of reactivity, and a useful method for the preparation of simple glycosides from unprotected monosaccharides.57,58 Typical protocols involve treating the sugar with an excess of the glycosyl acceptor alcohol (often as solvent or cosolvent, in the case of low-boiling acceptors such as methanol or ethanol) in the presence of a strong Brønsted acid catalyst. In general, pyranosides are the products of thermodynamic control for Fischer glycosidations, but conditions that favor kinetically controlled furanoside formation have been identified. This general pattern of product distributions can be understood in terms of a mechanism in which C−O bond formation proceeds by addition of the alcohol to the acyclic aldehyde intermediate, followed by cyclization to form the mixed acetal.59 Scheme 6 illustrates how the conditions D


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highest for the adducts derived from electron-rich monosaccharides. Condensation of reducing sugars with hydroxylamines, which generates acyclic carbohydrate oximes as the primary products, is a useful method for the conjugation of carbohydrates to such partners as peptides,71 prospective therapeutic agents,72 and functionalized surfaces.73 Aniline derivatives catalyze these transformations through iminium ion formation, resulting in a roughly 20-fold rate acceleration over the background reaction.74 In the case of acylhydrazides and sulfonylhydrazides, the predominant condensation products from reducing sugars are the cyclic glycosylhydrazide-type adducts. These have been employed in a variety of immobilization, tagging, and glycoconjugate synthesis applications75,76 and as donors in protective-group-free glycosidation reactions.77 Scheme 8 depicts the synthesis of glycopeptide mimetics by condensation of alanine-β-hydroxylamine and alanine-β-hydrazide-containing polypeptides with N-acetylglucosamine.78

for Fischer glycosidation can be altered to achieve the selective formation of the furanoside60 or pyranoside61 product from methanol and arabinose. Scheme 6. Synthesis of Methyl Arabinofuranoside D-25 and Methyl Arabinopyranoside L-26 by Fischer Glycosidationa

a

Amberlite IR120 H denotes the acidic form of an ion-exchange resin.

Alternative acidic catalysts/promoters62 and reaction media63 have been explored for use in Fischer glycosidations. Additives such as calcium(II) chloride, strontium(II) chloride, iron(III) chloride, and barium(II) chloride act to favor the formation of furanosides, with which they form particularly stable chelated complexes (Scheme 7).64−66 Phenylboronic acid exerts a similar

Scheme 8. Chemoselective Synthesis of Oxime- and Hydrazide-Based Glycopeptide Mimetics 29 and 30

Scheme 7. Furanoside-Selective Fischer Glycosidations Mediated by Metal Salt or Arylboronic Acid Additives

The range of chemoselective transformations of the anomeric position of free sugars continues to expand with the development of new reagents and catalysts. Additions of allylindium and related reagents to unprotected sugars in water have been employed in the synthesis of N-acetylneuraminic acid, 3-deoxyD -glycero- D -galacto-nonulosonic acid (KDN), and other carbohydrate-derived natural products.79 Other methods to achieve selective formation of a carbon−carbon bond at the anomeric position include the use of transition metal catalysis and organocatalysis.80,81 Selective carbon−carbon bond cleavage is also possible: for example, the reductive conversion of unprotected aldoses to chain-shortened alditols has been accomplished by catalytic decarbonylation using a rhodium complex.82 Furthermore, a number of processes for selective isomerization or epimerization of sugars that take advantage of hydrogen or alkyl shifts to the anomeric position have been developed.83

effect, promoting furanoside-selective Fischer glycosidations of substrates having erythro-configured OH groups at C-2 and C-3 (e.g., mannose, allose).67 Selective substitution reactions of the anomeric OH groups of free sugars can also be conducted using nitrogen-centered nucleophiles such as amines, hydrazines, and hydroxylamines. The proposed reaction mechanisms are related to that of the Fischer glycosidation in that acyclic aldehydes are invoked as intermediates. The glycosylamine-type substitution products may be in equilibrium with the acyclic carbohydrate imines and related species and may react further to generate other linkages (e.g., by the Amadori rearrangement).68 The reactions of hydroxylamines, hydrazines, and related α-effect nucleophiles are particularly useful for the preparation of glycoconjugates in complex settings because they are chemoselective and the products are less prone to rearrangements and isomerizations than those derived from amines.69 Apparent equilibrium constants for adduct formation between three monosaccharides and p-toluenesulfonylhydrazide or N-methylhydroxylamine derivatives in aqueous solution (pH 4.5, 37 °C) were found to range from 9 to 74 M−1.70 Rate constants for hydrolysis of these adducts increased with the acidity of the medium and were

3. MIGRATIONS OF ACYL AND SILYL GROUPS IN CARBOHYDRATE CHEMISTRY Partially O-functionalized carbohydrate derivatives may undergo isomerization by migration of an oxygen-bound substituent to another OH group, often in a 1,2- or 1,3-relationship. E


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carboxyl group substituent, decreasing in the order acetyl > benzoyl > pivaloyl as described above. Scheme 10 depicts an

Functional group migrations of this type can present a challenge when a kinetically controlled outcome is desired and may complicate mechanistic interpretation of the product distribution obtained under a given set of reaction conditions. On the other hand, they may provide opportunities to access products of thermodynamic control or to develop processes that combine migrations with additional functionalization steps. Migrations of several classes of carbohydrate O-substituents have been documented, including acetals and ketals,84 boronic esters,85 phosphate,86,87 and sulfonyl groups.88 This section will provide a brief overview of migrations of acyl and silyl groups, commonly employed protective groups that can be particularly prone to this type of behavior, depending on the position and orientation of free OH groups in the carbohydrate derivative.

Scheme 10. Rate Constants for Phenacyl Group Migration in α-D-Glucopyranoside Derivatives 32a−32e (D2O, pH 7.4 Phosphate Buffer)

3.1. Acyl Group Migrations

Migrations of acyl groups to neighboring sites in carbohydrate derivatives can take place by intramolecular transesterification, through the formation of cyclic, orthoester-type intermediates.89 Intermolecular transesterifications have also been documented.90 Catalysis by acidic or basic reagents is possible, although the majority of reported examples of intramolecular migration involve the latter. The identity of the carboxyl substituent influences the rate of migration, with pivaloyl and benzoyl groups generally being less prone to migration than acetyl or formyl groups. Steric hindrance in the transition states leading to the orthoester-type intermediates is likely responsible for this trend.91 The connectivity of the two positions involved in the migration (e.g., 1,2- vs 1,3-diol moiety), along with stereochemical and conformational factors, would also be expected to influence the rate of intramolecular acyl transfer. Relatively few systematic, quantitative investigations of the kinetics and thermodynamics of such processes have been reported.92−98 The majority of these focus on rearrangements of 1-O-acylglucuronates in aqueous solution, processes relevant to the metabolism of carboxylic acid drugs. Roslund, Leino, and coworkers employed NMR spectroscopy to determine the rates of migration and hydrolysis of benzyl β-D-galactopyranosidederived monoesters in D2O solution.95 Under acidic conditions (pD = 1.0−3.0), acyl group migration was slower than ester hydrolysis and thus no intramolecular acyl transfer was observed. However, under basic conditions, rate constants for acyl migration could be determined (e.g., 31a → 31d, Scheme 9). Migration across the cis-1,2-diol group (31b → 31c) occurred at a higher rate than across the 1,3-diol or trans-1,2-diol moieties, likely a reflection of the relative levels of strain associated with formation of orthoester-type intermediates at these positions. The rates of migration were dependent on the

analogous set of rate constants for migrations of the phenacyl group in the α-D-glucopyranosyl system, as determined by kinetic modeling of data from in situ 1H NMR spectroscopic analysis.98 Again, acyl migration rates were highest between OH groups in a cis-1,2 relationship (here, between the 1- and 2positions of the α-configured sugar, 32a → 32b). In cases where such isomerizations are rapid relative to attack by hydroxide or alkoxide, base-mediated cleavage of hexopyranoside-derived esters is expected to proceed by initial migration of the acyl group to the 6-position, followed by attack of this relatively unhindered electrophile. Because intramolecular acyl transfer can be relatively rapid under basic conditions, the formation of alkoxides derived from partially esterified carbohydrates is often accompanied by migration. The formation of per-acetylated methyl β-glucopyranoside 34 from 1,3,4,6-tetra-O-acetyl-D-glucopyranose 33 (Scheme 11) illustrates the type of isomerization that can Scheme 11. Acyl Migration upon Alkylation of Tetra-Oacetylated α-Glucopyranose 33

accompany alkylation of an ester-protected carbohydrate under basic conditions. In this case, the stability of the β-configured anomeric alkoxide (see section 2.2) presumably drives the migration of the acetyl group from the 1- to the 2-position and subsequent anomerization. Deng and Chang reported that combinations of tetrabutylammonium iodide with silver(I) oxide or cesium(II) trifluoroacetate are useful for promoting acyl migrations in partially esterified carbohydrate derivatives (Scheme 12).99 The combination of silver(I) oxide and tetrabutylammonium iodide likely generates a strong base (perhaps Bu4N+AgO−) that would promote alkoxide formation.100 The role of the iodide additive in the Cs(II) trifluoroacetate-mediated process is less clear. Migration of the benzoyl group from the 3-position to the 2-position in αthiogalactopyranoside 35a was accomplished in 95% yield, whereas the opposite outcome (migration to the 3-position) was favored for α-glucopyranoside derivatives (36a → 36b, Scheme 12). Factors influencing the thermodynamics of such migrations likely include the nature of the anomeric substituent (thio versus alkoxy group), the relative configuration of the OH groups in the

Scheme 9. Rate Constants for Acetyl Group Migration in Benzyl β-D-Galactopyranoside Derivatives 31a−31d (D2O, pD = 8.0, Sodium Phosphate Buffer)

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benzene) were employed for cleavage of the TBS group. Intramolecular acyl group migration was not obtained for ribofuranoside 44, presumably due to the high degree of strain that would be present in a trans-fused orthoacid-type intermediate. Related acyl group migrations accompanying desilylation reactions have been used to generate hexopyranoside derivatives having a free 4-OH group.104

Scheme 12. Migrations of Benzoyl Groups Promoted by Ag2O/Tetrabutylammonium Iodide

3.2. Silyl Group Migrations

To the extent that intramolecular silyl group transfers involve an associative mechanism at silicon, their relative rates would be expected to follow similar trends to those observed for acyl migrations. This is indeed the case, with sterically bulky groups at silicon diminishing the rate of migration and spatial proximity between oxygen atoms (e.g., in cis-1,2-diol or 1,3-diol groups) promoting faster migration. Faghih and Fraser-Reid observed the migration of a TBS group upon alkoxide formation in the synthesis of dianhydroglucose derivative 46 from 45 (Scheme 15).105 Silyl migration upon intermolecular O-alkylation was

pyranoside, and the level of steric hindrance in the ester-derived alkoxides. Acyl migrations have also been documented in the furanoside series.93,101−103 Intramolecular acyl transfer between cis-1,2configured OH groups on the furanoside ring is particularly facile: for example, the isomerization of 1-O-benzoyl-β-Larabinofuranose 37 to 2-O-benzoyl-β-L-arabinopyranose 38b (a process that was presumably initiated by migration of the benzoyl group from the 1-position to the 2-position of the furanoside) had a half-life (t1/2) of 11.6 min in 4:1 pyridine/ water at room temperature (Scheme 13). The corresponding

Scheme 15. Cyclization of an Anhydroglucose-Derived Tosylate via Silyl Group Migration

Scheme 13. Half-Lives for Migration of the Benzoyl Group from the 1-Position to the 2-Position of Arabinofuranoside 37 and Arabinopyranoside 38a

noted by Schmidt and co-workers, who found that 1-O-silylated carbohydrates having a free OH group at the 2-position served as precursors to 2-O-silylated glycosides upon treatment with sodium hydride and benzyl bromide (e.g., 47 → 48, Scheme 16).106 Scheme 16. Anomeric O-alkylation accompanied by 1 → 2-Osilyl migration

migration of 1-O-benzoyl-β-L-arabinopyranose 38a to 38b under these conditions was significantly slower, with a half-life of 1881 min. Acyl group migrations can occur between oxygen atoms having a 1,3- and 1,5-relationship in suitably configured furanoside derivatives.103 For example, ribofuranoside 39 and xylofuranoside 41 underwent 1 → 5 and 3 → 5 acyl group migrations, respectively, upon desilylation (Scheme 14). Products of intermolecular acyl transfer were also obtained, particularly when strongly basic conditions (KF/18-crown-6,

Base-promoted migrations can influence product distributions in silylation reactions of carbohydrate derivatives. Atonakis and co-workers carried out silylations of alkyl hexopyranosides with TBSCl in DMF, using either imidazole or Et3N/DMAP as the base. Imidazole-promoted migration of silyl groups between cis-diol groups was found to be relatively rapid under the former set of conditions, suggesting that thermodynamic control could play a role in certain cases.107 Arias-Perez and Santos later reported that the regioselectivities observed in the bis-silylation of α-D-mannopyranoside derivatives are dependent on the reaction conditions.108 The initially formed 3,6-bis-TBDPS ether 50a underwent isomerization to the more stable 2,6-bissilylated product 50b upon prolonged exposure to imidazole in DMF at room temperature, whereas an isomerization to the 4,6bis-silyl ether 50c could be effected by treatment of 50a with nbutyllithium at low temperature (Scheme 17). Several examples of “contrasteric” outcomes, in which the silyl group has migrated to a more sterically hindered position, have been described in the literature. The base-promoted migration of a TBS group from the primary 6-OH group to the secondary 4-OH group of fructose was observed by Miller and co-workers

Scheme 14. Examples of 1 → 5 and 3 → 5 Acyl Group Migration in Furanoside Derivatives

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electrophile, or the higher rate of five- versus six-membered ring formation, can also be exploited in this type of transformation. Cyclic adducts provide a useful way to simultaneously protect two OH groups and also serve as precursors to monofunctionalized products by selective cleavage of one of the ring bonds.

Scheme 17. Synthesis and Isomerization of Bis-Silylated Isomers of Methyl α-D-Mannopyranoside

4.1. Acetals and Ketals

The chemistry of carbohydrate-derived acetals and ketals has been reviewed in detail,84,111 and only a brief discussion will be provided below. Of this class of protective groups, isopropylidene ketals and benzylidene or arylidene acetals have been applied most extensively in carbohydrate chemistry. In general, thermodynamic control favors isopropylidene ketal formation at cis-1,2- rather than 1,3-diol motifs: formation of a 1,3-dioxane from the latter would require that one of the isopropylidene methyl groups occupy an axial position, incurring steric strain. However, kinetic control can be exploited to achieve selective isopropylidene ketal formation at the less sterically hindered 4,6diol group of a pyranoside. Scheme 20 illustrates how the 4,6- or

(Scheme 18).109 The intramolecular transfer of the silyl moiety between trans-configured hydroxymethyl and OH groups on the Scheme 18. Migration of a TBS Group from the 6-Position to the 4-Position of a Fructose Derivative

Scheme 20. Selective Preparation of the 4,6- and 3,4-OIsopropylidene Derivatives of Methyl β-D-Galactopyranoside

furanoside was presumably faciliated by the relatively long Si−O bonds, since related acyl migrations of this type are generally slow (see above). The origin of selectivity is not entirely clear, although a kinetic preference for protonation of the less hindered oxygen upon quenching, or a thermodynamic effect related to chelation of the sodium alkoxide, are potential explanations. Another apparently contrasteric silyl migration was reported by the group of Willis, who found that generation of the sodium alkoxide from xylopyranoside 52a under basic conditions was accompanied by migration of the TIPS group from the 4- to the 3-position (Scheme 19).110 Similar

3,4-O-isopropylidene derivatives of methyl β-D-galactopyranoside (β-53) can be prepared selectively by taking advantage of these factors. Treatment with 2-methoxypropene and catalytic para-toluenesulfonic acid (p-TsOH) in N,N-dimethylformamide (DMF) at −10 °C resulted in 4,6-O-isopropylidene derivative 54a, the product of kinetic control.112 The 3,4-Oisopropylidene 54b was generated using excess 2,2-dimethoxypropane and camphorsulfonic acid at room temperature, followed by selective hydrolysis of the acyclic mixed acetal group in the resulting intermediate.113 In the case of benzylidene acetals, 1,3-dioxane formation can occur without placing a sterically demanding substituent in an axial position. Accordingly, formation of 4,6-O-benzylidene derivatives of pyranosides is generally favorable on both thermodynamic and kinetic grounds. The complementary properties of benzylidene and isopropylidene groups in terms of dioxane versus dioxolane formation have been exploited to achieve the selective formation of 55 from methyl Dmannopyranoside α-49 (Scheme 21).114

Scheme 19. Silyl Group Migration to the 3-OH Group of a Xylopyranoside

distributions of O-silylated products were obtained whether the bis-alkoxide was quenched with methanol or iodomethane. The authors proposed that the cyclic, pentacoordinate organosilicon intermediate generated upon alkoxide formation underwent kinetically controlled quenching (protonation or alkylation) at the less sterically hindered site.

4. FORMATION OF CYCLIC ADDUCTS FROM 1,2- OR 1,3-DIOL MOIETIES: ACETALS, KETALS, BORONIC ESTERS, AND SILYLENES Transformations that engage both OH groups of a 1,2- or 1,3diol motif to generate a cyclic adduct are of great value in carbohydrate chemistry. Under appropriate conditions, thermodynamic control can lead to selective derivatization of a particular diol group due to minimization of steric, torsional, and angle strain, and/or maximization of favorable anomeric effects in the resulting adduct. Kinetic factors, for example, initial engagement of the less sterically hindered OH group by an

Scheme 21. Preparation of 55 from Methyl α-DMannopyranoside

H


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Selective oxidative cleavage of benzylidene acetals has also been achieved (Scheme 24). Treatment with N-bromosuccini-

Galan and co-workers have employed copper(II) trifluoromethanesulfonate (Cu(OTf)2) as a catalyst for the preparation of 4,6-O-arylidene derivatives (Ar = Ph or para-methoxyphenyl (PMP)) from pyranoside substrates.115 Sequential functionalizations were achieved by taking advantage of the activity of Cu(OTf)2 as a Lewis acid catalyst for acylation, silylation, glycosylation, and reductive ring-opening reactions (Scheme 22). Hydrogen bond donor organocatalysts (thiourea and squaramide derivatives) have also been shown to act as catalysts for the formation of pyranoside-derived arylidene acetals.116

Scheme 24. Selective Oxidative Cleavage of Benzylidene Acetals

Scheme 22. Cu(OTf)2-Catalyzed O-Arylidene Formation and Tandem Acetal Formation/Esterification

mide (NBS) and BaCO3 in CCl4/tetrachloroethane results in the 6-bromodeoxyhexopyranoside-derived benzoate ester (Hanessian−Hullar reaction, e.g., α-9 → 62).123 Protocols for oxidative cleavage of benzylidenes to monobenzoates have been reported, although achieving selectivity for the formation of either the 6- or 4-OBz derivative is often a challenge. The protective group at O-3 was found to have a significant influence on the regioselectivity of oxidative cleavage by dimethyl dioxirane (DMDO): an electron-withdrawing dichloroacetyl group resulted in the formation of the 6-OBz derivative 65, whereas a bulky, relatively electron-rich silyl group favored the formation of the 4-OBz isomer 66.124 Benzylidene acetals are key intermediates in tandem functionalization reactions that deliver orthogonally protected carbohydrate derivatives from per-O-silylated intermediates.125,126 Silyl triflates,127 copper(II) triflate,128 and iron(III) chloride hexahydrate129 have been employed in these types of protocols, which enable substitutions of trimethylsilyl (TMS) groups for acetals, esters, or other silyl groups, as well as reductive ring-opening reactions of acetals, to be conducted in a single reaction flask. Scheme 25 depicts the preparation of an orthogonally protected α-glucopyranoside derivative by sequential 4,6-O-benzylidene formation, reductive etherification, and acetylation.127

An advantageous feature of arylidene acetals is their selective ring-opening reactivity, which can be exploited to generate monofunctionalized products. Regioselective, reductive cleavage of benzylidene acetals provides access to carbohydratederived benzyl ethers (Scheme 23).117,118 For example, Scheme 23. Complementary Methods for Regioselective Ring-Opening of Benzylidene Acetal 60

treatment of 4,6-O-benzylidene acetals of hexopyranosides with LiAlH4 and AlCl3 resulted in the formation of the 4-Obenzyl ethers.119 This regiochemical outcome has also been achieved using diisobutylaluminum hydride (DIBAL−H) as the reducing agent.120 In both cases, it is likely that coordination of the Lewis acid to the less hindered oxygen of the acetal is responsible for the observed selectivity. Alternatively, the 6-Obenzyl ether can be generated by reduction with NaCNBH3 in the presence of HCl.121 It has been proposed that the regioselectivity under these conditions is controlled by the formation of the more stable oxocarbenium ion by cleavage of the benzylic C−O4 bond. Desymmetrizations of trehalose derivatives bearing arylidene acetal groups at the 4,6- and 4′,6′diol moieties have been achieved by regioselective ring-openings with DIBAL-H.122 In keeping with previous observations,120 the regiochemical outcome was influenced by the solvent employed: when the reduction was carried out in toluene, cleavage of the C−O6 bond was favored, whereas reduction in dichloromethane led to selective cleavage of the C−O4 bond.

Scheme 25. One-Pot Synthesis of an Orthogonally Protected α-Glucopyranoside Derivative

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4.2. 1,2-Diacetals and Dispiroketals

Scheme 27. Selective Protection of the 2,3- and 3,4-Diol Groups of α-D-Glucopyranoside Derivative 2 by Dispiroketal Formation with Enantiomeric Bis-Enol Ethers (S,S)- and (R,R)-73

In general, formation of cyclic acetals or ketals at trans-1,2-diol groups is unfavorable due to the strained nature of the resulting trans-fused bicyclic dioxolane derivatives. Ley and co-workers have developed 1,2-diacetals and dispiroketals as protective groups for trans-1,2-diequatorial diols in pyranoside derivatives.130 Tricylic diacetal formation at such moieties results in a stable trans-decalin-type ring system while placing the two methoxy groups in axial orientations, which is favored by the anomeric effect. Using this strategy, the 3,4-diol group of rhamnopyranoside 69 was selectively protected through the formation of a bis-acetal (70, Scheme 26).131 The conformaScheme 26. Preparation and Glycosidation of Rhamopyranoside-Derived 1,2-Diacetal 70a

occurs under relatively mild conditions, usually by heating the boronic acid and diol (in some instances, with a drying agent such as molecular sieves or MgSO4) in organic solvent, without the need for Brønsted or Lewis acid catalysts. Because of these features, boronic esters are particularly well-suited for applications in transient protection schemes, in which the intermediate species are carried through several steps without purification.138−143 Examples of selective functionalizations of OH groups in carbohydrates mediated by boronic esters as transient protective groups are depicted in Scheme 28. Disaccharide 76 was prepared from a β-galactopyranoside-derived 4,6-O-arylboronate by selective glycosylation of the most sterically accessible secondary OH group.138 The boronic ester was generated in situ from paramethoxyphenylboronic acid (PMPB(OH)2) and glycosyl acceptor β-53 in the presence of glycosyl donor 75 and 5 Å molecular sieves. Deprotection of the product-derived boronic ester was achieved by oxidative cleavage of the C−B bond with sodium perborate. Arylboronic esters have been employed for the selective preparation of pyranoside-derived sulfate esters bearing the trichloroethyl (TCE) protective group (e.g., L-77 → 79).141 In these transformations, cleavage of the phenylboronate was achieved by transesterification with pinacol. The synthesis of 80 from α-1 was accomplished by protection of the 4- and 6OH groups as an arylboronic ester and esterification of the less hindered equatorial OH group, followed by alkylation using a benzylic trichloroacetimidate.142 Conventional conditions for installation of benzyl ethers (benzylic halide, strong base) were found to be incompatible with the boronic ester group, but Lewis acid catalyzed coupling with the trichloroacetimidate proved effective, especially when conducted on an electrondeficient boronic ester. Deprotection was accomplished by a “phase-switching” protocol144 involving liquid−liquid extraction with a basic aqueous sorbitol solution. The sorbitol-derived boronate was sequestered in the aqueous phase, enabling straightforward separation from the organic-soluble protected glucopyranoside product. Boronic acid chemistry has been used to transiently anchor carbohydrate substrates to polymer resins. The group of Fréchet conducted pioneering work in this area, using a bromination/ lithiation/borylation sequence to install boronic acid groups at the para-positions of phenyl groups in cross-linked polystyrene.145 The resulting polystyrylboronic acid resin was employed in the synthesis of partially acylated carbohydrates. Boons and

a

IDCP denotes iodonium dicollidine perchlorate.

tional constraint imparted by the diacetal protective group had a deactivating (“torsional disarming”) effect on the electrophilic behavior of the anomeric center,132,133 permitting selective activation of 71 as the glycosyl donor. Incorporating chirality into the design of dispiroketal protective groups has provided a solution to the challenge of differentiating between trans-1,2-diol groups in glucopyranosides and related compounds (e.g., myo-inositol derivatives). Thus, reagent (S,S)-73 was matched with the 3,4-diol group of D-glucopyranosides such as 2, leading to an adduct having the phenyl groups in equatorial positions while maximizing the number of stabilizing anomeric effects (74b, Scheme 27).134 The 2,3-diol group was selectively protected using (R,R)-73. 4.3. Boronic Esters

Cyclic boronic esters generated by condensation of boronic acids and diols are useful protective groups in carbohydrate chemistry. In general, boronic esters can be employed to block the same types of diol moieties that are conventionally masked using acetal or ketal groups, namely, cis-1,2 or exocyclic 1,2- or 1,3-diols.135,136 However, the stability profiles and chemical reactivities of boronic esters differ from those of acetals and ketals, giving rise to distinct behavior when applied as protective groups for sugar derivatives.85,137 Hydrolysis of boronic esters is typically more facile than that of acetals or ketals, to the extent that aqueous workup procedures and purifications by silica gel chromatography are often avoided. Boronic ester formation also J


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Scheme 28. Examples of Transient Protection of Carbohydrate OH Groups As Boronic Estersa

a

Ar denotes 4-(trifluoromethyl)phenyl.

co-workers have employed polystyrylboronic acid as a solidphase protective group reagent for di- and trisaccharide synthesis.146,147 Scheme 29 illustrates a “loading−release− reloading” approach to the preparation of anomerically pure trisaccharide 83, highlighting the ease of formation and cleavage of boronic ester groups. The intermediate disaccharide 82, which was generated as a mixture of anomers, was hydrolyzed from the resin, purified by chromatography, and then reloaded onto the support for a second glycosylation. Protection of the 4,6-diol group of a mannopyranoside donor as a polystyrylboronic ester was employed by Crich and Smith to achieve the solidphase synthesis of β-mannosides.148 Whereas acetals and ketals are generally stable toward Brønsted and Lewis bases, such reagents can trigger migration or exchange reactions of boronic esters. For example, treatment of methyl α-D-galactopyranoside 4,6-O-phenylboronate (84a) with chlorotriethylsilane (TESCl) in pyridine at 0 °C led to the formation of 2,6-bis-O-silylated product 85a as the major product after phase-switching deprotection (Scheme 30).142 This product likely resulted from base-promoted rearrangement to 3,4-O-phenylboronate 84b, which underwent relatively rapid silylation at the primary OH group. The interaction of a boronic ester with a Lewis base to generate a tetracoordinate complex can activate the boron-bound oxygens toward reactions with a variety of electrophiles. This chemistry is discussed in sections 7.4 and 9.2.2.

Scheme 29. Synthesis of Trisaccharide Derivative 83 Using Polystyrylboronic Acid As a Solid Supporta

4.4. Silylenes

Cyclic silylene ethers are useful protective groups in carbohydrate and nucleoside chemistry, showing good levels of stability toward a range of Lewis acidic and electrophilic reagents. The protection of 1,3- or 1,2-diol groups as cyclic ditert-butylsilylenes generally proceeds by initial reaction of the most sterically accessible OH group with the silicon-based electrophile, followed by cyclization. As depicted in Scheme 31, the di-tert-butylsilylene group was installed selectively at the 1,3-

“PS” denotes a cross-linked polystyrene resin functionalized with boronic acid groups at the para-positions of arene repeat units.

a

diol group of triol 86 and remained intact in the presence of TMSOTf and Cp2ZrCl2/AgClO4, which were employed to K


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engagement of the 4- and 6-OH groups as the cyclic siloxane. Under acidic conditions, product 91a underwent isomerization to the more stable seven-membered ring siloxane 91b (Scheme 32).154 Another application of the TIPDS group is in the

Scheme 30. Evidence for Rearrangement of a Galactopyranoside-Derived Boronic Ester under Conditions for O-Silylation

Scheme 32. Selective Protection of Pyranoside Derivatives with the Tetraisopropyldisiloxane-1,3-diyl (TIPDS) Group

Scheme 31. Silylene Protection in the Synthesis of Disaccharide 90

selective protection of 1,2-diol groups in pentopyranosides.155 Treatment of methyl α-D-xylopyranoside α-92 with TIPDSCl2 (pyridine, room temperature) generated cyclic product α-93a, presumably initiated by the formation of a Si−O bond at the 2OH group, followed by cyclization at the 3-position. In contrast, the β-anomer led to the 3,4-cyclic product through initial interaction of the bulky reagent with the 4-OH group, as the reactivity of the 2-OH group was attenuated by presence of flanking equatorial substituents (see section 2.1).

5. ESTERIFICATION Selective acylation of OH groups in carbohydrate derivatives has been pursued in depth. Esters are among the most widely employed protective groups in carbohydrate chemistry: anchimeric assistance by such groups can be employed to influence stereoselectivity in glycosidation reactions, while their deactivating effect on the electrophilic reactivity of the anomeric position often forms the basis of “armed/disarmed” approaches to oligosaccharide synthesis.156 Glycoside and oligosaccharide esters also constitute a large and diverse class of naturally occurring carbohydrate derivatives.157,158 The protocols discussed below take advantage of distinct modes of catalysis for acceleration of esterification reactions, including activation of the acylating agent by Lewis bases159 or Lewis acids, and of OH groups by general base catalysis or alkoxide formation.

activate the trichloroacetimidate and glycosyl fluoride donors in the synthesis of 90.149 Deprotection of the silylene was accomplished using the triethylamine−hydrogen fluoride complex. When incorporated into arabinofuranoside donors, the 3,5-O-di-tert-butylsilylene group was found to promote βselective glycosidations.150 It was proposed that the silylene group favored the E 3 conformation for the furanosyl oxacarbenium ion, leading to a 1,2-cis-selective attack. Silylenes can serve as intermediates in the net monosilylation of 1,2- or 1,3-diols by selective cleavage of one of the Si−O bonds. This type of reactivity has been used to access pyranoside-derived 4-O-silyl ethers via the 4,6-O-silylenes151 and to prepare 3-O-silylated galactofuranosides.152 Like boronic esters, silylenes can be activated toward reactions with electrophiles by addition of a Lewis base. Electrophilic functionalizations of silylenes that proceed through the formation of pentacoordinate organosilicon adducts are discussed in section 5.6.3. Tetraalkyldisiloxanylidenes are another useful class of siliconbased cyclic protective groups. Initially developed for blocking the 3′- and 5′-OH groups of nucleosides,153 the tetraisopropyldisiloxane-1,3-diyl (TIPDS) moiety has also been applied in the protection of pyranosides. Treatment of glucopyranoside α1 with TIPDSCl2 (pyridine, 20 °C) resulted in selective

5.1. Selective Esterification with Acyl Chlorides in Pyridine

Several studies of the reactivity of unprotected or partially protected glycosides with acyl chlorides in pyridine solvent have been conducted. The trends in relative reactivity of the OH groups under these conditions, which appear to arise primarily from steric effects, provide a “baseline” against which the effects of catalysts or promoters of acylation reactions can be evaluated. Williams and Richardson conducted systematic studies of the reactions of pyranosides with benzoyl chloride in pyridine.160,161 At −30 or −40 °C, tri-O-benzoate ester products were obtained as major products from methyl hexopyranosides α-1, α-49, and α-53 (Scheme 33). On the basis of the product distributions, the relative reactivities of the secondary OH groups were assigned to L


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Scheme 33. Product Distributions for O-Benzoylation Reactions of Methyl α-D-Galacto-, Manno-, and Glucopyranoside

Scheme 35. Reactions of Glucopyranoside-Derived Diol α-9 with Various Benzoylating Reagents

be 2-OH > 3-OH > 4-OH for the α-glucopyranoside,162 3-OH > 2-OH > 4-OH for the α-mannopyranoside, and 2-OH, 3-OH > 4-OH for the α-galactopyranoside. The products of bisbenzoylation of the 6-deoxy derivatives (methyl α-L-fucopyranoside and methyl α-L-rhamnopyranoside L-77) were consistent with these trends.163 The relatively low reactivity of axial OH groups, and of equatorial OH groups flanked by two other equatorial substituents, are in line with the steric effects discussed in section 2.1. Using trimethylacetyl chloride (PivCl), a more sterically demanding electrophile, a variety of mono- and diesters have been synthesized in good yields from nucleosides and pyranosides.164,165 A comprehensive investigation of the reactions of pyranoside derivatives with PivCl in pyridine solvent showed that primary OH groups and secondary OH groups with an adjacent axial substituent were the most reactive positions, consistent with the studies discussed above (Scheme 34). An apparent exception to this trend is the reaction of

a modest preference for acylation of the more sterically accessible 2-OH group of substrate α-9,162 a synthetically useful 2-O-acylation was achieved using benzoylimidazole in chloroform at reflux.167 Benzoyl cyanide (BzCN: catalytic Et3N, MeCN, 23 °C),168 benzoic anhydride (Et3N, CH2Cl2, room temperature) 1-(benzoyloxy)benzotriazole (BzOBt: Et3N, CH2Cl2, 23 °C),169 and the related benzoyloxime reagent 104 (Et3N, CH2Cl2, 0° to 23 °C)170 also led to relatively high selectivities for esterification of the 2-OH group. Acylation with benzoic anhydride was dependent on the reaction conditions: the use of triethylamine as base (CH2Cl2 solvent, room temperature) favored the formation of the 2-O-benzoate,171 but a mixture enriched in the 3-O-benzoate was generated in pyridine at 20−30 °C.162 The former outcome would be consistent with activation of the more acidic OH group by the trialkylamine base (also favored by steric effects), whereas hydrogen bonding interactions between benzoate anion and the pyranoside OH groups may have played a role in the latter transformation (see section 5.5.1 below). Esterifications of mannopyranoside derivative 105 have also been conducted using the reagents discussed above (Scheme 36). The 3-O-benzoate was obtained using benzoyl chloride in pyridine172 (and the corresponding pivaloate using PivCl/ pyridine26), as anticipated for a reaction controlled primarily by steric effects, whereas BzCN and BzOBt both displayed some

Scheme 34. Selective Esterification of Carbohydrate Derivatives with Trimethylacetyl Chloride (PivCl)

Scheme 36. Reactions of α-Mannopyranoside-Derived Diol 105 with Various Benzoylating Reagents

sucrose (101) with PivCl (7 equiv, pyridine, − 40 °C), which led to the predominant formation of product 102 having free OH groups at the 2- and 4-positions of the glucopyranoside moiety (Scheme 34).166 5.2. Acylating Agents: Variation of Leaving Group

Variation of the leaving group of the acylating agent has been investigated as a way to influence site-selectivity in esterifications of carbohydrate derivatives. Scheme 35 depicts reactions of benzylidene-α-D-glucopyranoside α-9 with several benzoylating agents. Whereas benzoyl chloride (BzCl) in pyridine led to only M


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condensations of carbohydrate derivatives with carboxylic acids.175−177 An application of this reagent in the monoacylation of trehalose is shown in Scheme 39.

level of selectivity for esterification at the 2-position. It should be noted that not only the leaving group of the acylating agent but also the identity of the Brønsted base differed between these experiments. Triethylamine was used in conjunction with the less reactive electrophiles BzCN and BzOBt. The use of this relatively strong base (in comparison to pyridine) may have been responsible for the observed acylation of the 2-OH group, which is the most acidic position (see the preceding paragraph and section 2.2). When benzoylimidazole was employed for acylation of 105, a 1:1 mixture of the two isomeric monobenzoates was obtained. The authors suggested that the imidazole byproduct of the reaction catalyzed the interconversion of the two product isomers by acyl group migration (see section 3).95

Scheme 39. Site-Selective Coupling of Trehalose with Oleic Acid in the Presence of TBTU

5.3. Carbodiimide- and Uronium Salt-Mediated Couplings 5.4. Mitsunobu Esterifications

Direct, site-selective couplings between carboxylic acids and carbohydrate derivatives have been achieved using carbodiimides or uronium salts as dehydrating agents. For example, installation of a protected succinate ester group at the less sterically hindered position of diol 107 was accomplished by coupling with the corresponding carboxylic acid in the presence of dicyclohexyl carbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP, Scheme 37).173 The product was used as a

Combinations of azodicarboxylate and phosphine reagents pioneered by Mitsunobu for dehydrative couplings of alcohols with acidic pronucleophiles178 have been applied in siteselective functionalizations of carbohydrate OH groups. Glucopyranoside α-1 underwent sterically controlled esterification at the 6-OH group upon treatment with triphenylphosphine, diethyl azodicarboxylate (DEAD), and benzoic acid (1.5 equiv) in a dioxane/pyridine mixture.179 Treatment of β-1 under more forcing conditions (1.2 equiv of each reagent in THF at reflux), followed by saponification of the ester groups, resulted in methyl β-D-allopyranoside 113 in 70% yield (Scheme 40).180,181 This result can be interpreted in terms of selective

Scheme 37. Site-Selective, DCC-Mediated Ester Coupling at the Most Sterically Accessible OH Group of a TrehaloseDerived Diol

Scheme 40. Synthesis of Methyl β-D-Allopyranoside from β-1 by Site-Selective Epimerization under Mitsunobu Conditions

precursor in the synthesis of a naturally occurring glycolipid. The water-soluble carbodiimide 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), in combination with an Oxyma reagent (see section 5.2 above), has been employed to achieve selective acylations of carbohydrates and other complex molecules in mixed organic/aqueous solvent.174 Under these conditions, the O-acyl Oxyma derivative serves as the reactive acylating agent. In the example depicted in Scheme 38, the use of glyceroacetonide-derived oxime 110 was advantageous because of its straightforward separation from the desired ester product. Grindley and co-workers have identified the uronium salt 2(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as a useful coupling reagent for site-selective

formation of oxyphosphonium cations at the 6- and 3-positions. Substitution of the latter by benzoate with inversion of configuration is relatively facile due to the all-equatorial substitution pattern of the β-glucopyranoside substrate.182 Such site-selective epimerizations are of interest as a way to generate rare sugars from readily available starting materials. Mitsunobu conditions have also been employed for other siteselective displacements of OH groups in sugars by nitrogen- and sulfur-centered nucleophiles.179,183,184 As noted in section 2.2, hemiacetal OH groups at the anomeric position have been shown to participate in siteselective Mitsunobu reactions due to their relatively high acidities. For example, Juteau and co-workers achieved a direct synthesis of β-acyl glucuronides, an important class of metabolites of carboxylic acid-containing compounds, by PPh3/diisopropyl azodicarboxylate (DIAD)-mediated couplings with hemiacetal 114 (Scheme 41).185 Selective cleavage of the allyl ester group was accomplished by substitution with pyrrolidine in the presence of a palladium catalyst. Related transformations with other classes of nucleophiles have been employed to achieve O- and N-glycosylations.38

Scheme 38. Selective Monoacylation of Muramic Acid Derivative 109 in the Presence of EDCI and Oxyma 110

5.5. Organocatalyzed Acylations

5.5.1. Catalysis by 4-(Dimethylamino)pyridine (DMAP). The reactivity of Lewis bases with acylating agents N


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Scheme 41. Selective Esterification of Glucuronate 114 at the Anomeric Position under Mitsunobu Conditions

Scheme 43. Selective Acylation of the Axial OH Group of 116 Using BzCN; Calculated Structure of the 118---CN− Complex

to form covalent, electrophilic adducts186 has been exploited in catalytic, site-selective esterifications of carbohydrate derivatives. 4-(Dimethylamino)pyridine (DMAP), the most widely applied catalyst of this type, was employed to promote acetylations of the α- and β-octyl pyranosides derived from Dglucose, D-galactose, and D-mannose, using Ac2O as the electrophile.54 As described in section 2.3, the relatively high reactivity of secondary OH groups in such substrates, which would not be anticipated based on steric grounds, was proposed to arise from polarization of OH groups by networks of intramolecular hydrogen bonds. Matsumura and Kawabata later found that 6-O-protected derivatives of β-D-glucopyranoside underwent selective esterification at the 3-OH group in the presence of DMAP (isobutyric anhydride, collidine, and toluene).187 Kattnig and Albert showed that selectivity in the DMAPcatalyzed esterification of glucopyranoside β-20 is dependent on the identity of the electrophile.188 The transformation occurred primarily at the 6-OH group using AcCl but at the secondary OH groups (primarily products 21c and 21b) using Ac2O (Scheme 42). The authors suggested that the outcome using

Computional modeling of a cyanide−mannopyranoside complex provided support for this idea, with 118---CN− being identified as the lowest-energy adduct at the B3LYP/6-311+ +G(d,p) level of theory, using the polarizable continuum model (PCM) for dichloromethane. 5.5.2. DMAP Derivatives. Appending additional functional groups and/or incorporating elements of chirality to the DMAP scaffold has led to the identification of new catalysts for selective esterification of sugars. Yoshida and co-workers explored the catalytic properties of 4-aminopyridine derivatives bearing an acidic functional group (carboxylic acid or sulfonic acid) on one of the N-alkyl chains (Scheme 44).190 In the presence of catalyst Scheme 44. Selective Esterification of β-20 Catalyzed by a Functionalized DMAP Derivative

Scheme 42. Dependence of the Outcome of DMAPCatalyzed Acetylation on the Identity of the Leaving Group

119 and Ac2O, β-20 underwent selective esterification at the 6OH group, rather than at the secondary OH groups as was the case using DMAP as the catalyst (see scheme 5 above). The authors proposed that the carboxylate moiety of the catalyst acted as a Brønsted base for activation of the 6-OH group of the glucopyranoside substrate. The group of Kawabata has developed chiral derivatives of 4pyrrolidinopyridine (PPY)191 as catalysts for selective esterification reactions of pyranosides.9,192,193 With the use of C2symmetric catalyst 120, an isobutyryl group was installed selectively at the 4-position of β-20 (Scheme 45).192 The diasteromeric catalyst derived from D-tryptophan showed lower site-selectivity and an increased proportion of bis-acylated products from this substrate. On the basis of structure− selectivity relationship studies on the catalyst and substrate, the authors proposed that a hydrogen-bonding interaction between the 6-OH group of the glucopyranoside and the amide carbonyl group was important for catalyst−substrate recognition. Selective acylations of a thioglycoside, octyl β-D-mannopyranoside, and octyl β-D-galactopyranoside (products 122−124) were also achieved using this catalyst. More recently, turnover numbers as high as 6700 have been achieved for the acylation reaction shown in Scheme 45.194 The combination of isobutyryl chloride, trimethylacetic acid (PivOH), and iPr2NEt (in place of

AcCl reflected the relative nucleophilicity of the OH groups, whereas the reaction with Ac2O was influenced by a bidentate hydrogen bonding interaction between acetate anion and the 3and 4-OH groups. Schmidt and co-workers’ elucidation of the “cyanide effect” for esterifications of carbohydrate OH groups provides another illustration of the role of the leaving group in the site-selectivity of DMAP-catalyzed acylations.189 Using BzCN in the presence of DMAP (10 mol %, CH2Cl2, −78 °C), pyranoside-derived diols underwent benzoylation at the axial OH group (Scheme 43). Achieving this regiochemical outcome is a challenge because steric effects generally cause the equatorial ester to be thermodynamically and kinetically favored. The distinct behavior of BzCN, relative to BzCl, BzF, and Bz2O, all of which generated the equatorial benzoate from the βgalactopyranoside-derived diol 116 used as a test substrate, was ascribed to the ability of cyanide to form a monodentate hydrogen bond with the more acidic axial OH group. O


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alized peptoid moiety were prepared by solid-phase peptide synthesis and subjected to copper-catalyzed azide−alkyne cycloaddition prior to cleavage from the resin. The oligopeptides ranged from five to eight amino acids in length, with an acetyl group at the N-terminus and a primary amide at the C-terminus, and were composed of 11 of the canonical amino acids in addition to the DMAP-bearing peptoid group. Catalysts displaying high site-selectivity for monoacylation of a particular pyranoside-derived substrate were identified after evaluation of product distributions by 1H NMR spectroscopy. For example, selective 2-O-acylation of benzylidene α-glucopyranoside α-9 was achieved using hexapeptide 128, whereas heptapeptide 129 was optimal for installation of a benzoyl group at the 3-OH of galactopyranoside derivative α-11 (Scheme 47). Although each

Scheme 45. PPY-Derived Chiral Catalyst for Selective Acylation of Pyranosides

Scheme 47. DMAP-Bearing Peptide Catalysts for Selective Benzoylation of Pyranoside Derivatives isobutyric anhydride and sodium acetate) resulted in an appreciable rate enhancement. The authors proposed that this combination of reagents enabled rapid formation of the acylpyridinium chloride intermediate, which underwent anion exchange to generate a more reactive188 acylpyridinium pivaloate electrophile. Catalyst 120 has been employed for the installation of functionalized acyl groups derived from amino acids and gallic acid,195 the monoacylation of steroidal glycosides,196,197 and the synthesis of acylated glucopyranoside natural products.198,199 The key step in the synthesis of the phenylethanoid glycoside multifioside B (127) is shown in Scheme 46. By conducting a Scheme 46. Synthesis of Multifioside B by Organocatalytic, Site-Selective Acylation

of the products shown was also the major monobenzoate obtained using DMAP as catalyst, the latter displayed significantly lower levels of site selectivity and higher amounts of bis-acylation under otherwise identical conditions. Resinbound variants of these types of peptides also proved effective for selective monoacylations of pyranoside-derived diols, enabling simple recovery and recycling of the catalysts without apparent loss of activity or selectivity.201 5.5.3. Catalysis by Imidazoles and Related Heterocycles. Miller and co-workers have shown that short peptides bearing Lewis basic functional groups are able to serve as catalysts for a broad range of stereoselective and/or site-selective chemical transformations, including acyl transfer reactions.202 A library of 36 functionalized peptides was screened for the Oacylation of β-20 (Scheme 48).203 Pentapeptide 130, bearing two 1-alkylhistidine groups, was found to promote esterification of the 4-OH group. The primary O-acetate was obtained as the major monoester product using N-methylimidazole as catalyst in place of the peptide.

site-selective 4-O-acylation of the glucopyranoside moiety of 125 in the presence of two free primary OH groups, the authors were able to minimize the use of protective groups and avoid side reactions (β-elimination, alkene isomerization) associated with late-stage deprotection steps. Building on a general design concept explored by Miller and co-workers (see section 5.5.3), Huber and Kirsch generated a library of Lewis base organocatalysts by conjugating an azidefunctionalized 4-aminopyridine to alkyne-bearing oligopeptide derivatives.200 Catalyst candidates bearing a propargyl-functionP


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Scheme 48. Pentapeptide Catalyst for Selective Acetylation of Glucopyranoside β-20

Scheme 50. Selective Acylation of Glucopyranoside Derivative α-9 Using Enantiomeric Benzotetramisole Catalysts

N-Alkylimidazole groups also play a key functional role in the “scaffolding catalysts” developed by Tan and co-workers. These catalysts engage the substrate through a reversible covalent interaction, bringing it into proximity with a functional group that accelerates the chemical transformation. Scheme 49 Scheme 49. Catalyst-Controlled Acetylation of Either Position of the cis-1,2-Diol Group in Methyl α-LRhamnopyranoside

basis of computational modeling and an analysis of the effects of substrate structure on site-selectivity, the authors proposed that a cation−n interaction between the acylated benzotetramisole intermediate and an ether or hydroxyl oxygen of the substrate was important for selectivity. The interaction appears to be subject to relatively stringent structural constraints, requiring an equatorial OH or OR group that is not blocked by a neighboring cis-configured substituent. In the representation of the calculated transition state structure shown in Scheme 50, dotted lines indicate the important noncovalent interactions (OH---O hydrogen bonding with the isobutyrate counterion of the acylated benzotetramisole, cation−n interaction). Benzotetramisole catalyst 134 has also been used for the stereoselective synthesis of anomeric esters from free hemiacetals.207 5.5.4. Amine Catalysts. Chiral diamine catalyst 137 has been employed for selective benzoylations of OH groups in pyranoside-derived di- and triols.208 For α-D-galacto and α-Dmanno-configured triol substrates, the two enantiomers of the catalyst provided complementary regiochemical outcomes (Scheme 51). For other substrates, differences in the relative

illustrates the application of this concept to the selective acylation of methyl α-L-rhamnopyranoside (L-77).204 Using 5 mol % of oxazolidine catalyst (+)-132, high selectivity for acetylation of the 3-OH group was achieved, whereas (−)-133 was able to promote esterification of the intrinsically less reactive axial 2-OH group. The selectivity obtained using N-methylimidazole (NMI) as catalyst provided a useful benchmark for the level of catalyst control observed in these two experiments. The authors proposed a mechanism whereby the formation of a hemiaminal-type intermediate from one OH group of the cis1,2-diol positioned the neighboring OH group favorably for Brønsted base catalysis by the imidazole moiety. This class of catalysts was also employed for selective acylations of the steroidal glycoside digoxin and for transfer of silyl and sulfonyl groups to a range of carbohydrate-derived substrates (see sections 10.3 and 12.1.7). Chiral benzotetramisole 134, initially developed by Birman and co-workers as a catalyst for kinetic resolutions of secondary alcohols,205 has been used to accomplish the selective acylation of 1,2-trans-diol groups in pyranoside derivatives.206 For example, glucopyranoside α-9 could be esterified at either the 2-OH or the 3-OH group by choosing the appropriate enantiomer of the Lewis base catalyst (Scheme 50). On the

Scheme 51. Selective Benzoylation of α-Mannopyranoside Derivative 136 Using Enantiomeric Diamine Catalysts

reactivity of OH groups could not be overcome through the selection of catalyst enantiomer, although matching/mismatching effects were evident. As noted in section 5.2, triethylamine has been used as a base in conjunction with moderately reactive acylating agents (BzCN, BzOBt) to achieve acylation of the most acidic OH group in a pyranoside-derived substrate. The anomeric Oacylation of free sugars developed by Lim and Fairbanks provides another example of this type of selectivity pattern Q


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(Scheme 52).36 The proposed mechanism involves the formation of acylating agent 140 in situ from 2-chloro-1,3-

Scheme 54. Tetrabutylammonium Acetate-Catalyzed Acetylation of Pyranoside Derivatives

Scheme 52. Base-Promoted Selective Acetylation of the Anomeric OH Group of D-Mannose

dimethylimidazolium chloride (DMC) and thioacetic acid, followed by base-promoted reaction with the anomeric OH group. In certain cases, the separation of the anomeric acetates from triethylammonium salt byproducts proved to be an issue, and an alternative protocol, using sodium carbonate as base, was developed. 5.5.5. Tetraalkylammonium Salts: Phase-Transfer and Brønsted Base Catalysis. Tetraalkylammonium salts have been used as phase-transfer catalysts for selective esterification reactions of carbohydrates.209 Under these conditions, the reaction generally occurs at the most acidic OH group of the substrate. For example, selective benzoylation of the 2-OH group of α-9 was achieved under conditions of solid−liquid phase-transfer catalysis, using benzoyl chloride, tetrabutylammonium iodide, and potassium carbonate in benzene (Scheme 53).210 For related thioglycoside-derived benzylidenes such as

5.5.6. Oxidative Esterifications: Catalysis by N-Heterocyclic Carbenes. In the presence of an oxidant and an Nheterocyclic carbene (NHC) catalyst, aldehydes are converted to acylazolium salts that can serve as acylating agents.215 Studer and co-workers have employed such oxidative esterifications to achieve regioselective acylations of carbohydrate derivatives.216 After optimization of the NHC catalyst and aldehyde partner, the authors found that selective acylation (8:1 2-OAc:3-OAc) of glucopyranoside 149 could be accomplished in 85% yield using chiral NHC (S)-150 (Scheme 55). The protocol was applied to Scheme 55. Oxidative Esterification of Pyranosides with Chiral NHC Catalyst 150

Scheme 53. Selective Esterification of Pyranoside-Derived Diols α-9 and 141 under Conditions of Phase Transfer Catalysis

141, selective benzoylation of the 2-OH group was achieved in the presence of BzCl, Bu 4N+ HSO4−, and NaOH in a dichloromethane/water mixture.211 Tetrabutylammonium carboxylates have been shown to accelerate esterification reactions of carbohydrate derivatives with anhydrides through Brønsted base catalysis.212−214 For 6O-silylated α/β-gluco-, α/β-galacto-, and α-manno-configured triol substrates, selective acetylation of the 3-OH group was achieved using Ac2O and Bu4N+AcO− (Scheme 54). The proposed mechanism, which involves dual hydrogen bonding between the carboxylate and a diol group in the pyranoside substrate, is reminiscent of that advanced by Kattnig and Albert to rationalize the regiochemical outcome of the DMAPcatalyzed esterification of octyl β-glucopyranoside with Ac2O (see section 5.5.1). The authors suggested that steric effects in the hydrogen-bonded transition states played a role in determining the outcomes of these reactions.

acylations of other gluco-, galacto-, and manno-configured substrates, generally resulting in acylation of the most sterically accessible OH group. The selective O-acylation of a neodisaccharide having six secondary OH groups and one secondary amine group (product 152) is a particularly impressive example. The authors proposed that hydrogen bonding activation of the OH group by the NHC, a proposal supported by kinetic and computational studies,217 was responsible for the unusual chemoselectivity of this latter reaction. This idea of dual roles for the NHC catalyst (acylazolium formation and alcohol activation) motivated the authors to explore combinations of (S)-150 with (R)-150, or with achiral NHCs, with both approaches resulting in improvements in selectivity and/or yield. R


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5.6. Acylation by Complexation of OH groups: Main Group, Transition Metal, And Lanthanide-Based Promoters or Catalysts

Scheme 57. Selective Acylations of Secondary OH Groups in Pyranoside Derivatives via Stannylene Acetalsa

A variety of main group and transition metal-based Lewis acids have been employed in selective esterification reactions of carbohydrate derivatives. Mechanisms involving either electrophile activation (interaction with the acylating agent to generate a more reactive electrophile) or nucleophile activation (acidification of OH groups upon interaction with the Lewis acid) could be envisioned for such reactions. In general, it is the latter mechanism that has been proposed for the site-selective transformations discussed below. 5.6.1. Site-Selective Acylations Using Organotin Catalysts or Promoters. The reactivity of Sn−O bonds of stannylene acetals or stannyl ethers with electrophiles forms the basis for several well-established protocols for site-selective functionalization of carbohydrate derivatives.218,219 In 1974, Moffatt and co-workers reported the synthesis of cyclic, ribonucleoside-derived stannylene acetals, and their selective reactions with a range of electrophiles, including acid chlorides, anhydrides, TsCl, POCl3, and alkyl halides.220 For example, 3′O-benzoyluridine (153) was obtained in 78% yield from the reaction of the 2′,3′-O-stannylene acetal with benzoyl chloride (Scheme 56). Thus, the secondary OH group was acylated

a

The structures of the proposed intermediate stannylene acetals are depicted in brackets.

complexation of 1,2-trans-diols that engage only with difficulty in isopropylidene ketal formation. It should also be noted that the mechanistic details of functionalization reactions of stannylene acetals continue to be the subject of discussion.223−226 These complexes are prone to dimerization and oligomerization via Sn---O complexation in solution, and the monomer−dimer equilibria may be perturbed by interactions with anions from salts introduced deliberately as additives or formed as byproducts of the functionalization reactions. In any case, stannylene acetal chemistry provides a reliable and general way to achieve selective functionalizations of sugar derivatives using a range of electrophiles. Organotinmediated reactions of carbohydrates with other carbon-, silicon-, sulfur-, and phosphorus-centered electrophiles are discussed in sections 6, 7.2, 9.2, 9.3, 10.2, 11.1, 11.2, 12.1, and 12.2. Trialkylstannyl ethers R 3 SnOR′ also serve as useful intermediates in selective esterifications of carbohydrate derivatives. Ogawa and Matsui developed methods for partial benzoylation of mono- and disaccharide derivatives by stannylation with (Bu3Sn)2O, followed by treatment with benzoyl chloride in toluene (Scheme 58).227 In general, the results could be rationalized by invoking the formation of stannyl ethers at OH groups oriented appropriately for chelation by an adjacent oxygen atom. The stannyl ether groups reacted more rapidly with BzCl than did free OH groups. A comprehensive study of the benzoylation of pyranoside derivatives using the stannylene acetal and stannyl ether

Scheme 56. Selective Benzoylation of Uridine through Formation of a Cyclic Stannylene Acetal

efficiently despite the presence of a free primary 5′-OH group (and despite the use of methanol, a primary alcohol, as the reaction medium). This ability to activate a secondary OH group in the presence of free primary OH groups by formation of a stannylene acetal is a general, and often useful, feature of organotin-promoted and -catalyzed methods. Stannylene acetals have proved to be useful intermediates for the selective esterification of pyranosides. Formation of a dibutylstannylene acetal at a cis-1,2-diol group enabled the selective acylation of the equatorial oxygen (e.g., 154 → 155, Scheme 57).221 Munavu and Szmant showed that equatorial OH groups in free pyranosides could be functionalized via selective formation of five-membered cyclic organotin complexes.222 The presence of an axial OH or OR group adjacent to the equatorial oxygen undergoing functionalization appeared to be an important requirement for the latter types of reactions: for example, glucopyranoside α-1 underwent selective 2-Obenzoylation (Scheme 57), whereas the β-anomer was acylated primarily at the 6-position. When considering the selectivity of dialkylstannylene acetal formation from carbohydrate derivatives, it may be useful to draw parallels with isopropylidene ketal chemistry. For example, the selective complexation of cis-1,2- versus 1,3-diols is a common feature of these two types of cyclic adducts (see section 4.1). However, the relatively long Sn−O bonds of the stannylene acetals give rise to distinct behavior, such as the favorable

Scheme 58. Selective Benzoylation of Lactose by Trialkystannyl Ether Formationa

a

The structure of the proposed stannyl ether intermediate 157 is shown in brackets.

S


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methodologies was reported by Tsuda and co-workers in 1983.228 In recent years, considerable effort has been dedicated toward developing selective functionalizations of carbohydrate derivatives that employ catalytic quantities of organotin compounds. Protocols of this type offer the benefit of operational simplicity, avoiding the need for an initial complexation step to form the organotin−carbohydrate adduct, while also reducing the quantities of organotin waste generated. In 1998, Matsumura and co-workers reported that dimethyltin dichloride acted as a catalyst for selective monobenzoylations of 1,2-diols, including benzylidene α-D-glucopyranoside (α-9).229,230 A comprehensive study of the Me2SnCl2-catalyzed monobenzoylation of methyl pyranosides was reported in 2008 (Scheme 59).231 For methyl

Scheme 60. Stannylene Acetal-Catalyzed Bis-Benzoylation of Disaccharide 161, Illustrating the Effect of the 4-Substituent on Site Selectivity

showed the more typical preference for acylation at the equatorial site. 5.6.2. Site-Selective Acylations Using Organoboron Catalysts. As described in section 4.3, cyclic boronic esters are useful protective groups for diol groups in carbohydrates, enabling selective esterification, silylation, glycosylation, and other transformations. However, organoboron compounds can also be used to activate OH groups toward site-selective reactions. In particular, diarylborinic acid (Ar2BOH) derivatives act as catalysts for a range of functionalization reactions of sugars.237,238 The key to this difference in reactivity, activation with borinic acids versus protection with boronic acids, appears to be the tetracoordinate nature of borinic acid−diol complexes, which causes their nucleophilicity to be enhanced rather than attenuated relative to free OH groups. Selective esterifications of pyranosides catalyzed by 163, the ethanolamine ester of diphenylborinic acid, were reported by Lee and Taylor in 2011.239 The examples shown in Scheme 61

Scheme 59. Selective Benzoylation of Methyl Hexopyranosides Catalyzed by Me2SnCl2

α/β-galacto-, α-manno-, and α-rhamnopyranoside substrates, the benzoyl group was installed selectively at the equatorial position of the cis-1,2-diol motif, presumably via formation of stannylene acetal intermediates. In several of these instances, the equatorial OH group underwent selective esterification in the presence of a free primary alcohol (e.g., products 159 and 160). As was the case for the organotin-promoted acylations discussed above, the outcome of the reaction of methyl glucopyranoside was dependent on the configuration of the anomeric center, with α-1 undergoing esterification at the 2-OH group, versus the 6OH group for the β-anomer. In a subsequent study, Muramatsu and Takemoto showed that the relative reactivity of α- and βglucopyranosides was influenced by the choice of organotin catalyst, with Me2SnCl2 promoting selective 6-O-acylation of the β-anomer and Bu2SnCl2 favoring 2-O-acylation of the αanomer.232 Building on this observation, the authors were able to develop kinetic resolutions of mixtures of stereoisomeric carbohydrates through organotin-catalyzed esterification. Siteselective, organotin-catalyzed esterifications have been employed in the preparation of chemical probes from the complex steroidal saponin natural product OSW-1233 and the synthesis of 6-deoxy-L-sugars from L-rhamnose.234,235 The preference for functionalization of the equatorial position of carbohydrate-derived stannylene acetals may be enhanced or diminished by the steric and electronic effects of nearby substituents. For example, functionalization of the (axial) 2-OH group has been observed upon stannylene acetal activation of αmannopyranosides bearing a bulky protective group at the 4position.221 The selective, organotin-catalyzed bis-benzoylation of disaccharide 161 reported by Xia and Lowary illustrates this point (Scheme 60): the major product 162 resulted from benzoylation of the 2- and 3′-OH groups.236 The presence of a sterically encumbered mannopyranosyl substituent at the 4position impaired acylation at the 3-position of the reducing moiety, whereas the nonreducing mannopyranosyl group

Scheme 61. Selective Monoacylations of Pyranosides Catalyzed by Borinic Ester 163a

a

The proposed borinic ester intermediates are depicted below the reactions.

illustrate the selective functionalization of the equatorial position of a cis-1,2-diol motif that is generally achieved using this class of catalysts. This reactivity pattern parallels that of the diorganotin(IV) promoters and catalysts discussed in section 5.6.1. Activation of trans-1,2-diol groups (e.g., in glucopyranoside derivatives) was not observed when using borinic acidderived catalysts; whereas these moieties appear to be capable of stannylene acetal formation (e.g., Scheme 57), it appears that the relatively short B−O bond distances are not easily accommodated in the corresponding trans-fused cyclic borinic esters. Because borinic acids are also capable of binding to the 1,3-diol motif comprised of the 4- and 6-OH groups of hexopyranosides, selective monoesterifications of such substrates were conducted on derivatives having a protective group at the 6-position. T


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Diphenylborinate 163 and diphenylborinic acid Ph2BOH [or the corresponding anhydride (Ph2B)2O, as it exists in the solid state] showed similar activity and selectivity as acylation catalysts, suggesting that entry of the former into the catalytic cycle involves displacement of the ethanolamine ester. This displacement is likely triggered by the relatively rapid Nacylation of the ethanolamine ligand of 163 in the presence of BzCl.240 Numerous applications of 163 as a selective esterification catalyst in carbohydrate chemistry have been reported, including in the syntheses of complex oligosaccharides,241−244 prospective glycosyltransferase inhibitors,245 and probes for metabolic labeling.246 5.6.3. Selective O-Acylation of Silylenes. Cyclic silylene ethers are key proposed intermediates in a selective monoacetylation of carbohydrate-derived diols developed by Dong and co-workers.247 Whereas related cyclic silylenes are useful protective groups in carbohydrate chemistry (see section 4.4), the derivatives formed by condensation of diols with Me2Si(OMe)2 or MeSi(OMe)3 were activated toward O-acetylation in the presence of tetrabutylammonium acetate (Scheme 62).

Scheme 63. Selective Esterification of Pyranosides via Hg(II) Complexes

complexes with BzCl, PivCl, or AcCl.251,252 The authors found that deprotonation of the diol substrate with NaH could be avoided by using Cu(OAc)2 or Cu(acac)2 as the complexing agent in the presence of triethylamine (Scheme 64). Scheme 64. Cu(II)- and Ni(II)-Mediated Monobenzoylation of trans-1,2-Diol Motifs

Scheme 62. Organosilicon-Mediated Monoacetylation of a Galactopyranoside Derivative

Related Cu(II)-promoted esterifications were developed by Evtushenko, who employed copper(II) trifluoroacetate (1.3 equiv) in the presence of 2,4,6-collidine and Bz2O (MeCN, room temperature).253 In several of the cases examined, the most acidic OH group capable of forming a 1,2-cis-chelate with Cu(II) was functionalized selectively: thus, α-manno-, αgalacto-, and α-glucopyranosides were esterified at the 2-OH, while β-galactopyranoside derivatives underwent 3-O-benzoylation. Selective esterifications of trans-1,2-diol groups via transition metal complexes were reported by the group of Demchenko:254 in the presence of NiCl2, benzoate esters were generated selectively at equatorial OH groups having an adjacent axial oxygen-based substituent (Scheme 64). Silver(I) oxide is another metal salt that has been used to promote selective acylations of diol groups in pyranosides (Scheme 65).255 The KI additive employed in these reactions likely interacts with the Ag2O to generate AgI and a strong base, perhaps AgO−K+.100 Considering the observations of Deng and Chen regarding acyl group migrations in the presence of Ag2O and Bu4NI (section 3.1),99 it is possible that the product distributions for the Ag2O/KI-promoted acylations are controlled by the formation of the most stable monoester-derived alkoxide. Selective esterifications of carbohydrate derivatives that employ catalytic quantities of transition metal complexes have been a focus of recent research efforts. After screening several other metal salts, including CeCl3, YCl3, Cu(OCOCF3)2, and Hg(OCOCF3)2, Evtushenko identified MoCl5 as a useful

Presumably, the carboxylate additive interacts with the intermediate silylene ether, generating a pentacoordinate organosilicon adduct that serves as the reactive nucleophile. In general, the less sterically hindered position of a 1,2- or 1,3-diol group underwent selective acetylation using this protocol. 5.6.4. Selective Acylations Promoted by Transition Metal or Lanthanide Salts. Pioneering work on the selective esterification of carbohydrate−metal complexes was carried out by the groups of Avela248,249 and Schuerch.250 In these studies, a carbohydrate-derived bis-alkoxide was generated using two equivalents of strong base, and then treated with a metal salt (e.g., CuCl2, HgCl2) to generate the complex prior to quenching with the acylating agent. The highest selectivities for monoacylations of 1,3- or cis-1,2-diol groups were generally achieved using HgCl2 as the complexing agent (Scheme 63). A simple rationale for the observed selectivity is not immediately evident: for example, α-galactopyranoside 167 was acylated at the least sterically hindered 3-position, whereas benzylidene αmannopyranoside 105 was acylated at the axial position. Although the structures of the reactive Hg(II) species in these tranformations have not been elucidated, chelates of the cis-1,2diol groups are presumably involved. Building on these results, Osborn and co-workers showed that benzylidene-protected β-glucopyranosides bearing a range of anomeric substituents (SEt, SePh, and OPh) underwent selective 3-O-acylation upon treatment of their Cu(II) U


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Scheme 65. Monoesterifications of Pyranoside Diols 172 and 174 Mediated by Ag2O and KI

Scheme 67. Complementary Regiochemical Outcomes Obtained Using Cu(II) and Mo(VI) Complexes As Benzoylation Catalysts

catalyst for monoacetylation of pento- or 6-deoxyhexopyranosides (Scheme 66). 256 Another molybdenum complex, changing the configuration of the Ph-box ligand (Scheme 68).259 Catalyst control was also demonstrated in the

Scheme 66. Esterifications of Pyranosides Catalyzed by MoCl5 and MoO2(acac)2

Scheme 68. Chiral Catalyst-Controlled Benzoylation of a Pyranoside-Derived Diol

MoO2(acac)2, was used to achieve selective benzoylations of related pyranoside-derived substrates having three free secondary OH groups.257 For both the MoCl5-catalyzed acetylations and the MoO2(acac)2-catalyzed benzoylations, equatorial OH groups in cis-1,2-diol motifs were functionalized selectively, presumably through the formation of metal chelates at such sites. In a study of esterifications of benzylidene-protected hexopyranosides in the presence of transition metal complexes, Evtushenko found that both MoO2(acac)2 (catalytic, in the presence of BzCl) and Cu(OCOCF3)2 (stoichiometric, using Bz 2 O) could be employed to generate monobenzoate products.258 In certain cases, for example, the 3-O-benzoylation of 4,6-O-benzylidene-protected β-D-galactopyranosides, the same regiochemical outcome was obtained using these two protocols. However, complementary outcomes were obtained for benzoylation of benzylidene-protected methyl α-mannopyranoside 105, with the Cu(II) promoter resulting in the 2-Obenzoate 106a and the Mo(VI) catalyst generating the 3-Obenzoate 106b (Scheme 67). Following the patterns described in the preceding paragraphs, the Cu(II) system favored esterification of the most acidic chelation-prone OH group while the Mo(VI) system was selective for the equatorial position of the cis-1,2-diol group. Selective functionalizations of carbohydrate OH groups that employ catalytic quantities of Cu(II) complexes have been developed by the groups of Miller259 and Dong.260 The Cu(II)promoted esterifications discussed above, and reports by Matsumura, Onomura, and co-workers on enantioselective monofunctionalizations of 1,2-diols catalyzed by Cu(II) bis(oxazoline) (box) complexes,261 served as the basis for these studies. For the benzoylation of α-mannopyranoside diol 105, a switch in selectivity from the 2-OH group (>99:1 106a:106b) to the 3-OH group (11.5:1 106b:106a) was accomplished by

benzoylation of the corresponding α-glucopyranoside, while more modest levels of site-selectivity (but clear evidence for matching/mismatching effects for the D-sugars with the two enantiomers of the Cu(II) complex) were obtained using βgluco- and α-galacto-configured substrates. Using similar Cu(II)-Ph-box complexes, Dong and coworkers were able to accomplish selective esterifications of pyranoside-derived triols and furanoside-derived diols.260 The (S,S)-configured complexes were matched with the cis-diol groups of D-galacto- and L-rhamnopyranosides, whereas the same motifs in L-fuco- and D-mannopyranosides were matched with the (R,R)-complexes. The cis-1,2-diol group was not essential for catalysis, as α-D-glucopyranoside derivatives underwent benzoylation at the 2-OH group using an (S,S)configured pyridinebis(oxazoline) (pybox) catalyst, likely via chelation of the OH and anomeric OMe groups. Selective esterification of either the 2-OH group or the 3-OH group of methyl α-D-ribofuranoside could be achieved using the appropriate chiral Cu(II) complex (Scheme 69). In another illustration of the utility of ligand control in this system, the authors showed that an achiral Cu(II) complex of N,N,N′,N’tetramethylethylenediamine enabled selective 2-O-benzoylation of an α-galactopyranoside rather than the 3-O-benzoylation obtained using the Cu(II)-(S,S)-Ph-box catalyst. In addition to acyl groups, para-toluenesulfonyl groups were installed selectively using the Cu(II)/Ph-pybox system. Building on a method for selective acylation of 1,2-diols developed by Clarke,262,263 and Kluger and co-workers have explored the use of lanthanide(III) salts as catalysts for selective esterification of carbohydrate derivatives.264 The Kluger group V


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Scheme 69. Chiral Catalyst-Controlled Benzoylation of DRibofuranoside α-13

Scheme 71. Representative Enzyme-Catalyzed Esterifications of Carbohydrate Derivatives

rhamnopyranoside resulted in an 8% yield of a mixture favoring the 2-O-acylated product under the same conditions.

has focused on acyl phosphates as electrophiles, since these acylating agents display appreciable stability toward hydrolysis and thus can be employed in aqueous-phase reactions. In the group’s initial study, 2 equiv of the LaCl3 promoter were used because the phosphate byproduct of the acylation acted as an irreversible inhibitor of the Lewis acid catalyst.265 A variant that employed a catalytic quantity of La(OTf)3 was then developed, using Mg(OTf)2 as a phosphate-scavenging additive (Scheme 70).266 Lanthanum(III) promoters have been employed to

6. THIOCARBONYLATION Site-selective thiocarbonylation of carbohydrate derivatives is of interest because the intermediates can be employed in radical substitution reactions to achieve a net deoxygenation (BartonMcCombie reaction). Kikuchi, Tsuda, and co-workers employed stannylene acetal activation (see section 5.6.1) to effect regioselective thiocarbonylation of pyranosides with phenyl chlorothionoformate.275,276 The stannylene acetal derived from glucopyranoside α-1 underwent selective thiocarbonylation at O-2. The resulting product was acetylated and then subjected to radical substitution with Bu3SnH to generate 2-deoxysugar derivative 180 (Scheme 72). When the stannylene acetal

Scheme 70. Lanthanum(III)-Catalyzed Esterification of Glucopyranoside α-1 with Benzoyl Methyl Phosphate

Scheme 72. Deoxygenation of α-1 by Stannylene AcetalMediated Thiocarbonylation Followed by Radical Substitution achieve selective couplings of aminoacyl phosphates with the 2′and 3′-OH groups of ribonucleosides, ribonucleotides, and tRNA.267−269 5.7. Enzyme-Catalyzed Esterification

Enzymes that catalyze acyl transfer reactions have been employed in the selective esterification of carbohydrate derivatives, as well as the selective hydrolysis of per-acylated carbohydrate derivatives. This topic is extensive and has been reviewed in depth.12−15 Only a few illustrative examples will be provided here, with a focus on selective installation, rather than hydrolysis, of esters. High substrate conversions in chemoenzymatic esterifications have generally been achieved by employing an activated acylating agent, thus suppressing the reverse of the acyl transfer reaction, while avoiding aqueous solvent. Important advances included the use of trihaloethyl esters or vinyl esters as acylating agents, using lipase or protease catalysts in organic solvent.270,271 With the use of such protocols, substrates having a free primary OH group underwent esterification at this position (e.g., Scheme 71),272 but selectivity among secondary OH groups has been observed in reactions of 6-O-protected or 6deoxyhexopyranosides.273 The selective esterification of the 4OH group of methyl α-L-rhamnopyranoside (L-77, Scheme 71) is a noteworthy example: because of the presence of two flanking equatorial substituents, this position shows relatively low reactivity under conventional acylation conditions.274 A significant effect of catalyst−substrate matching/mismatching on activity and selectivity was observed, as methyl D-

protocol was applied to substrates having a cis-1,2-diol group, cyclic thionocarbonate products were obtained. After per-Oacetylation, the latter were converted to unsaturated sugar derivatives by treatment with trimethyl phosphite in a CoreyWinter-type olefination. The Miller group has shown that peptides bearing Nalkylimidazole moieties (see section 5.5.3) are useful catalysts for selective thiocarbonylations of carbohydrate and inositol derivatives.277 After establishing that N-methylimidazole and iron(III) chloride acted as cocatalysts for thiocarbonylations of alcohols in the presence of the hindered base 1,2,2,6,6pentamethylpiperidine (PEMP), the authors turned their attention to site-selective variants employing peptide-based catalysts. Thiocarbonylation of α-9 at the 2-OH group was achieved in 67% yield using catalyst 181, with optimal selectivity being obtained in the absence of the FeCl3 cocatalyst (Scheme W


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substitution with diphenylsilane in THF, initiated by triethylborane and molecular oxygen, generating fucopyranoside β-D187 in 65% yield. The outcome of the latter transformation is noteworthy: Kikuchi, Tsuda and co-workers noted that phenyl thionocarbonates at the 6-position of sugars did not undergo efficient deoxygenation in the presence of Bu3SnH and AIBN, presumably a reflection of the low stability of the primary alkyl radical intermediate.276 Organotin catalysis (see section 5.6.1) has been applied successfully to the selective thiocarbonylation of pyranosides. Muramatsu and co-workers found that dioctyltin dichloride, in the presence of tetrabutylammonium iodide, provided particularly high activity for selective functionalization of secondary OH groups in pyranosides by phenyl chlorothionoformate (Scheme 75).280 Under these conditions, the equatorial

73). Peptide 182 was able to activate the more hindered 3-OH group, giving a 53% yield of product 183b in the presence of Scheme 73. Selective Thiocarbonylation of Glucopyranoside α-9 Using Peptide-Based Catalysts

Scheme 75. Organotin-Catalyzed Thiocarbonylation of Galactopyranoside β-53

positions of cis-1,2-diol groups could be thiocarbonylated while minimizing cyclization to the corresponding dioxolane2-thiones, which were the major products from such motifs using the stoichiometric stannylene acetal protocol.276 The syntheses of representative 2-, 3-, and 6-deoxysugar products were achieved by subjecting the monothiocarbonylated products to standard Barton−McCombie conditions. As discussed in section 5.6.1 for acylation reactions, the authors found that mixtures of isomeric substrates could be thiocarbonylated selectively in the presence of an appropriate organotin catalyst: for example, Bu2SnCl2 catalyzed the thiocarbonylation of the 2-OH group of an α-glucopyranoside, while Me2SnCl2 activated the 6-OH group of the β-anomer.232

FeCl3. Products 183a and 183b were subjected to the standard Barton-McCombie protocol, leading to the corresponding deoxysugar derivatives in 70% and 72% yields, respectively. Site-selective deoxygenations of the complex glycopeptide antibiotic vancomycin were achieved using this approach.278 Dithiocarbonates derived from 2-mercapto-1,3,4-thiadiazole were found to be effective reagents for selective thiocarbonylations of pyranosides upon activation by DMAP (section 5.5.1).279 For example, galactopyranoside β-53 underwent thiocarbonylation at the 6-OH group in 92% yield using reagent 185 (Scheme 74). The product was subjected to radical

7. ALKYLATION Along with esters, ethers are the “workhorse” protective groups in carbohydrate chemistry. They are stable to a wide range of conditions, including the basic reagents generally employed for cleavage of ester groups. With dependence on the nature of the alkyl group, deprotection can be accomplished using reductants, oxidants, or acidic reagents.281 Methods for site-selective installation of ether groups are thus of great value for the preparation of building blocks for oligosaccharide synthesis. The stability of the ether linkage can also be of value in labeling or tagging applications.

Scheme 74. DMAP-Catalyzed Thiocarbonylation Using a Dithiocarbonate Electrophile

7.1. Substrate Control in Selective Alkylation

In some instances, innate differences in the relative reactivity of carbohydrate OH groups can be exploited to achieve selective alkylation. As discussed in section 2.1, installation of the triphenylmethyl ether group is subject to steric effects, enabling protection of sugar-derived primary OH groups in the presence X


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of free secondary OH groups.22,23 It is generally more difficult to achieve high levels of steric control for the formation of benzyl or substituted benzyl ethers. The combination of benzyl bromide, diisopropylethylamine, and sodium iodide has been used to generate benzyl ethers at the primary OH group of pyranosideand furanoside-derived triols.282 Selective 6-O-benzylation of glucopyranosides has also been achieved using BnBr in the presence of excess NaH, conditions that presumably favor alkylation of the most nucleophilic alkoxide group.283 In contrast, selective alkoxide formation can be exploited to achieve monoalkylation of the most acidic OH group (see section 2.2). Phase transfer catalysis with a quaternary ammonium salt is often the method of choice for achieving such monoalkylations of carbohydrate-derived polyols.34,39,41,284 However, with a few exceptions (e.g., anomeric O-alkylations of sugar-derived hemiacetals), the level of siteselectivity based on such differences in acidity is usually rather modest. For this reason, carbohydrate chemists often resort to indirect installation of benzyl ethers by regioselective, reductive cleavage of benzylidine acetals (see section 4.1),117−121 or turn to reagent- or catalyst-controlled methods.

Scheme 77. Bu2SnO-Catalyzed Alkylations

equatorial OH groups in cis-1,2-diol-containing carbohydrates could be achieved in the presence of an excess of allyl or benzyl bromide and iPr2NEt, using Bu2SnO and tetrabutylammonium bromide as cocatalysts.291 Under the optimized conditions, dibenzylated mannopyranosides, as well as gluco- and galactofuranosides, were prepared from the corresponding free reducing sugars. Dong also reported alkylation by BnBr using a catalytic Bu2SnO/Bu4N+Cl− system but in the presence of stoichiometric K2CO3 in MeCN.292 Thioglycosides, which were incompatible with the solvent-free conditions, could be selectively O-alkylated using this protocol. Further modifications to these conditions, employing either Me2SnCl2 or Bu2SnCl2 as catalysts and Ag2O or Bu4N+Br− as additives, allowed for expansions of the substrate scope to include diverse alkyl halides293,294 as well as carbohydratederived trans-1,2-diols (Scheme 78).295 The Bu4N+Br− likely

7.2. Organotin Promoters and Catalysts

Organotin-promoted alkylations have long offered reliable siteselectivities and have served as inspiration for the development of other methods for selective alkylation of sugar derivatives. Both stannylene acetals and trialkylstannyl ethers285 (see section 5.6.1) have been employed productively in reactions with benzylic, allylic, or alkyl halides, often in the presence of additives such as tetrabutylammonium bromide,286 tetrabutylammonium iodide,287 and cesium fluoride288 to increase the rates of these otherwise sluggish reactions. The formation of a nucleophilic organotin−halide complex is likely responsible for the accelerating effect of the salt additives.289 In keeping with the selectivity patterns described in section 5.6.1, the organotinmediated processes generally enable alkylation of the 3-OH groups of galacto- and mannopyranoside derivatives or the 2OH groups of α-glucopyranosides.218,220,221 Representative examples are depicted in Scheme 76.286,287,290 In 2014, the groups of Iadonisi291 and Dong292 reported the development of protocols for selective alkylation of sugars using catalytic quantities of diorganotin compounds (Scheme 77). Iadonisi and co-workers found that under solvent-free conditions, high selectivity for the mono-O-alkylation of

Scheme 78. Dialkyltin Dichloride-Catalyzed Monoalkylation Reactions

Scheme 76. Organotin-Mediated Selective Alkylation

serves to activate a transiently generated stannylene acetal intermediate as described in the preceding paragraph, whereas Ag2O acts as a halide abstracting agent, allowing for alkylation to take place at room temperature.293,296 In the case of trans-1,2diol substrates, selective alkylation took place at equatorial OH groups having an adjacent, axially oriented substituent. 7.3. Transition Metal Promoters and Catalysts

Transition metal salts also serve as useful reagents for the selective preparation of ether-protected carbohydrate derivatives (Scheme 79). Complexes of sugars with Cu(II)250−252 and Ni(II)254 have been shown to react with alkyl halides in a similar Y


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Scheme 79. Selective Etherifications Promoted by Transition Metal Salts

Scheme 80. Fe(III)-Catalyzed Selective Alkylation Reactions

a 3,4-O-boronate, formed by condensation of the carbohydrate with phenylboronic acid, was subjected to iodobutane, triethylamine, and Ag2O. The formation of a nucleophilic tetracoordinate complex was proposed to account for the activating effect of the amine additive and the observed O-3 selectivity (Scheme 81).301 By establishing that tetracoordinate organoboron-

manner to the esterification chemistry discussed in section 5.6.4. Etherification of the 3-OH group of 4,6-disubstituted pyranoside derivatives has been achieved by coordination of a dialkoxide to copper(II) and treatment of the resulting complex with an alkyl halide. Products such as 203 would be challenging to generate directly by other means, since the OH group undergoing alkylation is neither the most acidic nor capable of formation of a cis-1,2-chelate. Upon treatment with NaH and NiCl2, 4,6-O-benzylidene-protected gluco- and galactopyranosides underwent alkylation at the 2-OH and 3-OH groups, respectively, another illustration of the selective functionalization of an equatorial substituent adjacent to an axial position via a chelated intermediate. Silver(I) carbonate has been used to achieve alkylations of furanoside and pyranoside derivatives with BnBr and PMBCl.297 These reactions appear to be under steric control, perhaps due to the deprotonation of the carbohydrate substrate at the surface of the insoluble promoter. The conditions were tolerant of base-labile groups such as esters, which are prone to migration under conventional alkylation conditions. In recent years, selective alkylations of sugars using transition metal-based catalysts have begun to emerge. Dong and coworkers reported alkylations of pyranoside vicinal diols (both cis and trans) with BnBr using catalytic Fe(dibm)3 in the presence of K2CO3 at 80 °C (Scheme 80).298 The patterns of siteselectivity paralleled those of organotin promoters and catalysts: galacto- and mannopyranosides were alkylated at the 3-position, while glucopyranosides were alkylated at the 2-OH group. For each of these substrate classes, selective benzylation of the secondary OH group could be achieved in the presence of a free primary 6-OH group. Modifications of the initially developed conditions have been reported, including the use of Ag2O and Bu4N+Cl− as additives299 and the application of Fe(dipm)3, a less expensive catalyst.300 The authors proposed that the FeL3 complexes were precursors to active FeL2X species capable of complexation to a diol group in the substrate.

Scheme 81. Amine-Promoted O-Alkylation of a Carbohydrate-Derived Boronic Ester

carbohydrate complexes could serve as activated nucleophiles, this work paved the way for the borinic acid-catalyzed methods developed by Taylor and co-workers (see section 5.6.2). Indeed, borinic acid catalysis has been successfully applied to the selective monoalkylation of carbohydrate derivatives.302 Equatorial OH groups of various carbohydrates in the galacto and manno series underwent etherification with benzylic and other activated alkyl halides in the presence of Ag2O (Scheme 82). Substrates lacking a free 6-OH group were generally employed to avoid competitive borinic ester formation at the 1,3-diol group. Oxaboraanthracene 215, which generates tetracoordinate adducts of enhanced nucleophilicity relative to the Scheme 82. Borinic Acid Catalyzed O-Alkylation

7.4. Organoboron Promoters and Catalysts

Organoboron compounds have been used to achieve the siteselective activation of carbohydrate OH groups toward alkylation. Aoyama reported selective alkylations of methyl αfuco- and β-arabinopyranosides by a two-step protocol in which Z


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Scheme 83. Synergistic Organoboron−Copper Catalysis for Selective Propargylation of Carbohydrate Derivatives

displacement of an OH-derived leaving group by a phenol (with inversion of stereochemistry).308−311 It is only recently that methods for the direct, site-selective arylation of carbohydrate secondary OH groups have been reported. The Taylor group demonstrated the utility of the coppermediated Chan−Lam cross-coupling312−314 for effecting selective O-arylations of carbohydrate derivatives.315 The optimal protocol employed anhydrous conditions in the presence of excess arylboronic acid, stoichiometric copper(II) acetate, and diisopropylethylamine. The cross-coupling step was followed by a phase-switching workup (see section 4.3),142 which in this context facilitated the separation of the carbohydrate-derived product from both the boronic acid and the copper salt byproducts. The site of arylation appears to be dictated by the in situ formation of a substrate-derived boronic ester,142,316 followed by arylation of an adjacent OH group (Scheme 84). This pattern of selectivity generally enabled the selective modification of positions that display relatively low intrinsic reactivity (e.g., the 4-OH group of α-rhamnopyranoside

corresponding diphenylborinates, displayed improved activity in comparison to precatalyst 163 for representative alkylation reactions.303 Niu and co-workers have developed a dual catalysis approach to the site-selective propargylation of carbohydrate derivatives, using borinic acid activation of the diol nucleophile in concert with copper(I) activation of a propargylic carbonate electrophile.304 The borinic acid cocatalyst played an essential role in this transformation, as aliphatic alcohols otherwise displayed low reactivity toward the electrophilic copper complex.305 Oxaboraanthracene 215 (see the preceding paragraph) was found to be optimal in terms of reactivity and stereoselectivity in a simple model system. The use of a cationic copper complex was essential for high reactivity, perhaps due to acceleration of the C−C bond-forming step by ion-pairing with the anionic borinate nucleophile.241 Chiral ligand-controlled site-divergent functionalizations were demonstrated: for example, the complex derived from (R,R)-Me-pybox resulted in propargylation of the equatorial position of the proposed borinate intermediate 218, whereas the axial position was functionalized using (S,S)-Mepybox (Scheme 83). The protocol was applied to the modification of complex glycosides, including in the construction of 219, a derivative of the steroidal glycoside digitoxin bearing both a benzophenone photoaffinity label and a terminal alkyne suitable for conjugation to azide-containing molecules via the copper-catalyzed [3 + 2] cycloaddition.

Scheme 84. Selective, Copper-Mediated O-Arylation of Pyranosides Using Boronic Acidsa

8. O-ARYLATION The O-aryl glycoside motif is present in numerous natural products and is of utility as a protective group or leaving group in glycosylation reactions. In contrast, aryl ethers at other positions of the carbohydrate scaffold are essentially absent from nature and are considerably less well-explored in synthesis. Nonetheless, such compounds hold potential value for the discovery of novel medicinal agents306 and chiral ligands307 for catalysis. Methods allowing for the direct installation of the aryl ether functionality could additionally facilitate the development of carbohydrate protecting groups and metabolically stable tags for glycobiology research. Procedures to construct these compounds generally require protecting groups to facilitate arylation at the desired site, either via Caryl−O bond formation or

a

Structures of the proposed boronic ester intermediates are depicted in brackets.

AA


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Scheme 85. Mechanistic Proposals for Chan−Lam-Type O-Arylation of Methyl α-L-Rhamnopyranoside

and the ancillary ligand; depending on the configuration of the glycoside, either the (S,S) or (R,R) enantiomer was required to obtain high site-selectivity. Selective arylation of the 3-OH group was achieved for most of the monosaccharides investigated, with the exception of benzylidene-protected pyranosides, where the major product was the 2-O-arylated isomer (e.g., product 224). It was proposed that the selectivity resulted from intrinsic differences in reactivity between substrate OH groups, augmented by the matching effect with the appropriately configured chiral ligand, as discussed above. The authors noted that selective arylation of the most acidic OH group of the carbohydrate substrate could generally be achieved under these conditions.319 Competition experiments suggested that chelation of the catalyst to a substrate-derived vicinal diol motif was not required for reactivity or selectivity, in contrast to other copper-catalyzed monofunctionalizations (see sections 5.6.4 and 7.3). Using this protocol, both electron-rich and -deficient aryl groups having diverse substitution patterns, as well as 3pyridyl and 3-thienyl groups, were installed successfully. Steroidal glycoside mimetic 225 was constructed by the coupling of an estrone-derived diaryliodonium salt with galactopyranoside α-145.

L-77,

which is the least reactive under conditions of steric control). Chan−Lam couplings with functionalized arylboronic acids resulted in the selective installation of styryl and dansylamino moieties, as well as the para-methoxyphenyl (PMP) group, which has been used as a blocking group for the anomeric OH in carbohydrate chemistry but rarely for protection of other positions. A series of competition experiments suggested that the formation of the boronic ester intermediate not only acted to transiently protect a diol group but also accelerated the arylation of a proximal OH group. Two general mechanistic hypotheses were advanced: one involving an intramolecular transfer of an aryl group from boron to copper and the other postulating a boron-directed formation of a copper alkoxide (Scheme 85). Computational modeling was used to identify plausible transition states for these two scenarios, both characterized by boron−carboxylate interactions that have been implicated in previous mechanistic studies of the Chan−Lam O-arylation.317 Crossover experiments, which are often useful for distinguishing between intra- and intermolecular reactions, were thwarted by the relatively rapid transesterification of sugar-derived boronates under the reaction conditions. Niu and co-workers reported a copper-catalyzed O-arylation of carbohydrates that displays complementary site-selectivity to that of the Chan-Lam couplings discussed above.318 Diaryliodonium salts, arylating agents previously employed by Olofsson and co-workers for O-arylations of protected carbohydrate derivatives,311 were adopted in the presence of catalytic copper(II) triflate, a chiral bis(oxazoline) ligand and trimethylamine (Scheme 86). The authors observed a matching/mismatching effect between carbohydrate substrate

9. GLYCOSYLATION The displacement of a leaving group from the anomeric position of a sugar-based electrophile (glycosyl donor) by a nucleophilic glycosyl acceptor is the key bond construction mode in oligosaccharide synthesis. Site-selective glycosylation is of interest as a way to facilitate the laboratory synthesis of oligosaccharides by reducing the number of protective group manipulations.320−323 In the biosynthesis of oligosaccharides, site-selectivity is under the control of the glycosyltransferase enzymes that catalyze the formation of glycosidic bonds. Such enzymes are powerful tools in laboratory synthesis. In addition to glycosyltransferases, glycosyl hydrolases (enzymes that catalyze the hydrolysis of glycosidic bonds) and glycosynthases (engineered mutants of glycosyl hydrolases) have been employed in chemoenzymatic glycosylations. This topic has been discussed in several review articles16−20 and will not be covered here.

Scheme 86. Copper-Catalyzed Couplings of Glycosides with Diaryliodonium Reagentsa

9.1. Substrate Control in Site-Selective Glycosylation

Glycosylations of acceptors having multiple free OH groups often display some level of site-selectivity due to the types of steric and electronic effects discussed in section 2. Steric effects have been exploited productively in site-selective glycosylation.322 Gao and Guo’s synthesis of the repeating unit of the type V group B Streptococcus capsular polysaccharide illustrates the utility of this approach (Scheme 87).324 The coupling of

a

See Scheme 68 for the structure of the Ph-box ligand. AB


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Scheme 87. Regioselective Glycosylations in the Synthesis of a Group B Streptococcus Capsular Polysaccharide

trichloroacetimidate 226 with β-galactopyranoside 172 provides another example of the selective functionalization of an equatorial group having an adjacent axial substituent (see section 2.1). The resulting disaccharide 227 was elaborated further into tetrasaccharide 231. The trisaccharide component needed for this [4 + 3] approach was generated by 3-Oglycosylation of glucosamine-derived diol 229. The selectivity at play in the monoglycosylation of the “all-equatorial” array of 229 presumably results from the steric effect of the N-phthaloyl substituent. Without isolation, intermediate thioglycoside 230 was activated as a glycosyl donor for reaction with 231, taking advantage of the higher glycosyl acceptor reactivity of primary versus secondary OH groups. Inductive effects,325 intramolecular hydrogen bonding,326,327 and relative acidities of OH groups40 have all been invoked to account for the outcomes of site-selective glycosylation reactions. For example, Moitessier and co-workers explored the application of directing-protecting groups (see section 2.3) to selective glycosylations of pyranoside-derived triols.328 With the use of this approach, disarmed, per-benzoylated glycosyl trichloroacetimidate 233 was coupled with glucopyranoside derivative 22 at the 3-OH group (Scheme 88). The reaction of

the corresponding 6-O-TBDPS-protected glucopyranoside acceptor gave the β-1 → 2- and β-1 → 3-linked disaccharides in 18% and 20% yields, respectively, suggesting that the directing-protecting group had an appreciable effect on reactivity and site-selectivity. The issue of substrate control in glycosylation reactions is complex because the configuration, protective group substitution pattern and leaving group of the glycosyl donor, as well as the choice of activator and reaction conditions can have significant effects on selectivity.329 Differences in site-selectivity have been observed for couplings of armed (ether-protected) versus disarmed (ester-protected) glycosyl donors with acceptors having more than one free OH group.330−333 The studies of Fraser-Reid and co-workers have provided several illustrations of this effect, which they have termed “reciprocal donor− acceptor selectivity”.334 For example, a 1:1:1 mixture of disarmed pentenyl glycoside 235, armed 236, and diol acceptor 237 resulted in the formation of 238 in 50% yield as the only observable trisaccharide component of the product mixture (Scheme 89).335 In general, donors capable of the formation of trioxolenium or dioxolenium ion intermediates (n-pentenyl orthoesters and 2-O-acylated donors, respectively) favored glycosylation of the less sterically hindered group, whereas

Scheme 88. Selective Glycosylation of Glucopyranoside 22 Bearing a Directing-Protecting Group (DPG)

Scheme 89. Reciprocal Donor−Acceptor Selectivity in the Synthesis of Trisaccharide 238

AC


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broadly useful approach, enabling selective couplings of glycosyl halides or thioglycosides with a range of unprotected pyranoside substrates (Scheme 91).341−344 Whereas stannylene acetal-

donors incapable of the formation of such fused-ring intermediates (namely, armed donors) displayed lower selectivities. Thus, the example shown in Scheme 89 can be understood as arising from initial activation of the (more reactive) orthoester donor and selective coupling with the primary OH group as dictated by steric effects, followed by activation of donor 236 to generate a less discriminating electrophile capable of attack at the secondary OH group. Glycosylation of a carbohydrate acceptor is a coupling of two chiral partners, and thus the potential exists for relative configuration to have an influence on site-selectivity (as well as α/β selectivity).329 Because most commonly occurring sugars are not readily available in both D- and L-forms, it is often not straightforward to obtain unambiguous support for these types of matching/mismatching effects. One example is the coupling of the enantiomeric chiro-inositol-derived trans-1,2-diols L-239 and D-239 with donor 240 (Scheme 90).336 The 3-O-

Scheme 91. 6-O-Glycosylation of a GalactopyranosideDerived Stannylene Acetal

mediated alkylations often enable selective reactions of secondary over primary OH groups, the corresponding glycosylations generally occur at the 6-OH group, perhaps due to the higher steric demand of the glycosyl donor electrophile. Kaji and co-workers have shown that this preference can be reversed by the use of Bu4N+F− as an additive, causing 3-Oglycosylation of galactopyranoside β-53 to be favored over 6-Oglycosylation.345 O’Doherty and co-workers used stannylene acetal activation to achieve the site-selective, palladium-catalyzed coupling of allylic carbonate 246 with a rhamnopyranoside-derived diol (Scheme 92).346 Direct coupling of these two partners without

Scheme 90. Effect of Relative Configuration on SiteSelectivity in a Glycosylation Reaction

Scheme 92. Pd-Catalyzed Allylic Substitution Using a Rhamnopyranoside-Derived Stannylene Acetal

glycosylated product 241 was predominant for the D-donor/Lacceptor pair, whereas a modest level of selectivity for 2-Oglycosylation was observed using the D-configured acceptor. DFT modeling of putative oxocarbenium ion intermediates was used to identify intra- and intermolecular hydrogen-bonding interactions that may have contributed to this behavior. A matching/mismatching effect has also been encountered in an organoboron-catalyzed glycosylation (see section 9.3): the selectivity for arylborinic acid-catalyzed 3-O-glycosylation of an α-L-arabinopyranoside triol was significantly higher with an Lconfigured fucopyranosyl donor than with its D-antipode.337

stannylene acetal formation led primarily to the undesired product of allylic substitution at the 2-OH group. Product 247 was a key intermediate in the synthesis of cleistrioside and cleistetroside natural products. 9.2.2. Organoboron-Promoted Glycosylation. As discussed in section 4.3, boronic esters have been applied productively as transient protective groups in selective glycosylations, using thioglycosides,138,140,146 glycosyl bromides,139 and glycosyl trichloroacetimidates142 as donors. In a distinct approach that capitalizes on the nucleophilic reactivity of tetracoordinate organoboron complexes (see sections 5.6.2 and 7.4), researchers have developed boron-based promoters for activation of glycosyl acceptors toward site-selective glycosylation. Oshima and Aoyama used compound 249 in selective Koenigs−Knorr-type glycosylations of unprotected pyranosides (Scheme 93).347 The formation of a tetracoordinate complex via intramolecular B−O coordination was proposed to be crucial to the function of the organoboron promoter employed in this study. A survey of glycosyl acceptors showed that this reagent enabled glycosylation of the 6-OH group of pyranosides, or the 3-OH group of galacto- or mannopyranosides, consistent with the formation of complexes at 1,3- or cis-1,2-diol groups. Taylor and co-workers have employed combinations of boronic acids and trialkylamine bases to achieve selective

9.2. Reagent-Controlled Glycosylation

9.2.1. Organotin-Promoted Glycosylation. Approaches based on transient protection and complexation-induced activation have been used to achieve reagent-controlled glycosylations. Initial developments along this line relied on activation of glycosyl acceptor OH groups by organotin-based promoters (see section 5.6.1). Ogawa and Matsui showed that tributylstannyl ethers served as activated acceptors in reactions with glycosyl bromides,338 a result that was later extended to site-selective glycosylations of 1,6-anhydrogalactose and methyl β-lactoside.339 The use of stannylene acetals in glycosylation was pioneered by Augé and Veyrières, who employed Bu2SnO as a promoter for the site-selective coupling of a galactopyranosidederived diol with a glycosyl chloride.340 Glycosyl acceptor activation by stannylene acetal formation has proved to be a AD


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Scheme 95. Sequential, Selective Transformations of α-1 Using an Arylboronate As a Switchable Protective/Activating Groupa

Scheme 93. Glycosyl Acceptor Activation As a Tetracoordinate Boronate

glycosylations of pyranoside derivatives. This approach hinges on the formation of a tetracoordinate boronic ester−amine adduct, as first described by Aoyama and co-workers for selective alkylation reactions (see section 7.4).301 The ability to vary the structure of the boronic acid and amine components provides opportunities to optimize the system for a specific glycosyl donor−acceptor coupling of interest. For example, the combination of pentafluorophenylboronic acid and N-methylmorpholine was used to achieve the coupling of arabinopyranoside α-L-26 and D-fucopyranosyl bromide 252 in 74% yield (Scheme 94).337 This was a significant improvement over the

a

Ar denotes 4-trifluoromethylphenyl.

couplings of peracetylated glycosyl bromides in the presence of Ag2O. 9.2.3. Calcium(II)-Promoted Glycosylation. Selective glycosylations of sucrose (101) have been achieved using glycosyl fluoride donors in the presence of calcium(II) salts and trimethylamine.349 These reactions were conducted in water, using unprotected glycosyl fluorides, and led to installation of glycosyl groups at the 3′-position of sucrose and related fructofuranoside derivatives (Scheme 96). Acceptors having

Scheme 94. Glycosylation of a Tetracoordinate Boronic Ester/Trialkylamine Adduct

Scheme 96. Aqueous-Phase 3′-O-Glycosylation of Sucrose Promoted by Ca(OTf)2 and Trimethylamine

up to 14 distinct OH groups underwent selective glycosylation under these conditions. Comparable levels of activity and selectivity were observed for deoxy derivatives of sucrose at the 4-, 6-, 4′-, and 6′-positions, whereas 2-, 3-, 1′-, and 3′deoxysucrose derivatives were unreactive. The authors proposed that intramolecular hydrogen-bonding interactions involving the latter set of OH groups played a significant role in the glycosyl acceptor reactivity and/or Ca2+-complexing ability of sucrose. Nuclear magnetic resonance spectroscopy experiments using the secondary isotopic multiplets of partially labeled entities (SIMPLE) technique were consistent with this hypothesis.

17% yield obtained using diarylborinic acid catalysis (see section 9.3.1 below), apparently due to a mismatch between the desired site of reactivity and the relative stereochemical configuration of donor and acceptor. Disaccharide 253 was subjected to a substrate-controlled 2-O-glycosylation using a trisaccharidederived donor, thus enabling a convergent synthesis of the pentasaccharide moiety from a saponin-type natural product. The ability to “switch” the behavior of a boronic ester from protective group to activating group by addition of a Lewis base has been exploited to achieve multistep, site-selective transformations of carbohydrate derivatives.348 Scheme 95 depicts such a sequence, in which benzoylation and glycosylation of the free OH groups of 254 (in the absence of a strong Lewis base) were followed by activation of the boronic ester as the triethylamine adduct, leading to glycosylation at the 6-position. The 4-trifluoromethylphenylboronic ester, paired with triethylamine as the Lewis basic promoter, proved to be optimal for

9.3. Catalyst-Controlled Glycosylation

The possibility of using synthetic catalysts to influence the outcome of glycosylation reactions has attracted considerable interest. Several impressive demonstrations of catalyst-controlled, stereoselective glycosylation have been reported in AE


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recent years.350−353 Catalyst control of site selectivity in glycosylations will be the focus of the discussion below. 9.3.1. Organoboron-Catalyzed Glycosylation. Diarylborinic acid catalysis (see sections 5.6.2 and 7.4) has been used to achieve selective monoglycosylation of 1,3- or cis-1,2-diol groups in unprotected or minimally protected glycosyl acceptor substrates. The first-generation variant of this catalytic reaction involved Koenigs−Knorr-type conditions, using glycosyl halides activated by Ag2O under heterogeneous conditions (Scheme 97).354 This transformation displayed first-order kinetics in

Scheme 98. Site- and Stereoselective Couplings of Glycosyl Methanesulfonates

Scheme 97. Diphenylborinic Acid Catalyzed Couplings of Glycosyl Halides

β-glycosyl mesylate isomers. The isomerization displayed firstorder kinetics in the concentration of mesylate ion, consistent with a mechanism involving SN2-type displacement at the anomeric position. Both the uncatalyzed and the catalyzed glycosylation reactions displayed kinetic orders consistent with associative mechanisms, suggesting that the (major) α-anomer led to the β-product in the catalyzed pathway, whereas the uncatalyzed formation of α-glycoside occurred via the minor βglycosyl mesylate. Interactions between the sterically hindered diarylborinate nucleophile and the substituent at the 2-position of the glycosyl donor could be responsible for the α-selectivity of the catalytic pathway, a conclusion consistent with the scope and limitations of the methodology. Borinic acid catalyzed, βselective couplings of unprotected ceramides (e.g., 267) with glycosyl mesylates have been employed in a direct synthesis of glycosphingolipids.360 Borinic acid catalysis has proved to be useful for controlling site-selectivity in palladium-catalyzed substitutions of pyranonederived allylic carbonates.241 O’Doherty and co-workers developed this cocatalytic glycosylation protocol for use as a key step in the synthesis of the mezzettiasides, a family of oligorhamnopyranoside natural products. Building block 271 was generated in 74% yield and 7.5:1 site-selectivity using borinic ester precatalyst 163 and Pd(PPh3)2 (Scheme 99). In the

glycosyl donor, acceptor, and catalyst, and resulted in inversion of configuration using both ester- and ether-protected α-glycosyl halide donors, observations that are consistent with an associative, SN2-type mechanism. The method has been extended to couplings of α-configured 2-deoxyglycosyl chlorides (e.g., 259)355 and a perbenzoylated α-galactofuranosyl bromide (262).356 In the case of the 2-deoxy donors, the selective formation of the β-glycosidic linkage was again attributed to an SN2-type displacement with inversion of configuration. Net retention of configuration was observed for the coupling of galactofuranosyl bromide 262, in contrast to the behavior of other glycosyl halides using this catalyst system. Borinic acid catalyzed, site-selective reactions of glycosyl bromides have been employed to generate analogs of the steroidal glycoside digitoxin357 and in the total syntheses of naturally occurring oligosaccharides.337,358 Glycosyl methanesulfonates (mesylates), generated in situ from the corresponding hemiacetals, have been employed as donors in a second-generation variant of the diarylborinic acidcatalyzed glycosylation (Scheme 98).359 The diarylborinic acid was again found to have a significant influence on the stereochemical outcome of these reactions as well as their siteselectivity: 1,2-trans-configured glycosidic linkages were obtained from “armed” glucopyranosyl, galactopyranosyl, and arabinofuranosyl donors. Oxaboraanthracene-derived borinic acid 215303 displayed higher yield and β-selectivity than 163 or diphenylborinic anhydride for this transformation. A control experiment showed that the α-isomer of product 266 was favored in the absence of the organoboron catalyst. The ability to conduct these reactions under homogeneous conditions, and without a metal-based promoter, represents an advantage from a preparative standpoint, and has facilitated in-depth studies of the reaction mechanism. Exchange NMR spectroscopy (EXSY) was used to establish the rates of interconversion between the α- and

Scheme 99. Organoboron/Palladium Co-Catalysis in the Coupling of Rhamnopyranoside 270 with Allylic Carbonate 246

absence of the organoboron catalyst, the 2-OH group of 270 was the primary site of functionalization. The authors proposed that an ion-pairing interaction between the cationic π-allyl-palladium complex and the anionic borinate contributed to the effectiveness of the observed cocatalysis under these conditions. Site-selective construction of 1,2-cis-configured glycosidic linkages has been achieved using boronic acid catalysts in combination with glycal epoxide electrophiles.361,362 Under AF


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9.3.3. Organocatalyzed Acetalization and Glycosylation. Although research on organocatalyzed glycosylations has largely been focused on control of stereoselectivity, considerable potential exists for extending such investigations to address the issue of site selectivity. A step toward this goal was achieved by Nagorny and co-workers, who used chiral phosphoric acids to effect selective acetalization reactions of diol groups in partially protected pyranosides.364 Using catalyst (R)-278, a tetrahydropyranyl (THP) group was installed selectively at the 2position of glucopyranoside substrate 276 (Scheme 102).

these conditions, the key tetracoordinate organoboron nucleophile is proposed to arise from an interaction of the glycosyl acceptor-derived boronic ester with the glycal epoxide. This serves to activate the latter and triggers intramolecular delivery of the aglycon, consistent with the observed 1,2-cis stereoselectivity. For couplings of unprotected pyranosides, an electron-deficient arylboronic acid provided optimal results, with water used as an additive to promote catalyst turnover (Scheme 100). The heavy atom kinetic isotope effect at C-1 and Scheme 100. Boronic Acid Catalyzed 1,2-cis-Selective Glycosylation

Scheme 102. Chiral Phosphoric Acid Catalyzed Acetalization of Glucopyranoside-Derived Diol 276a

a

secondary kinetic isotope effect at H-1 suggested a highly dissociative SNi mechanism or an SN1 mechanism, while computational modeling provided a rationale for the regiochemical outcomes obtained using 1,2-anhydroglucose-, galactose-, and mannose-derived donors. 9.3.2. Organotin-Catalyzed Glycosylation. Catalytic activation of glycosyl acceptors as stannylene acetals was achieved by Muramatsu and Yoshimatsu, who employed diphenyltin dichloride (10 mol %) in site-selective Koenigs− Knorr glycosylations of unprotected pyranosides.363 A catalyst structure−activity relationship study showed that dialkyltin dichlorides gave significantly lower yields of disaccharide than Ph2SnCl2. This method enabled glycosylation of the 3-OH group of free galacto- and mannopyranosides, despite the presence of a free primary OH group (Scheme 101). This is a

1-Ad denotes the 1-adamantyl group.

Acetalization of the 3-OH group, albeit with lower siteselectivity and yield, could be achieved using the (S)-configured catalyst. The achiral phosphoric acid (PhO)2PO2H delivered a 1:1 mixture of the two isomers. Although this approach has not yet been extended to site-selective glycosylations of carbohydrate-derived acceptors, activation of glycosyl trichloroacetimidates by chiral phosphoric acids has been used in desymmetrizations of meso-diols365 and selective glycosylations of macrolide antibiotic derivatives.366

10. SILYLATION Silyl ethers are robust protecting groups that are frequently employed in carbohydrate chemistry. Initial reports of siteselective installation of silyl ethers took advantage of innate differences in OH group reactivity based on steric effects, maximized through the use of large silyl substituents (see section 2.1). Ogilvie and co-workers reported the protection of the primary OH group of carbohydrate derivatives with tbutyldimethylsilyl chloride (TBSCl) in the presence of silver nitrate in THF.25,367 Silylation of primary OH groups can alternatively be accomplished by treatment with bulky silyl chlorides and imidazole in DMF (279 → 280, Scheme 103).24,368 Other protocols that enable selective silylation of carbohydrates based on steric control include the use of silyl trifluoromethanesulfonates,369,370 silyl chlorides under solventfree conditions in the presence of tetrabutylammonium bromide as a catalyst,371 or trialkylsilyl methallylsulfinates in DMF.372 Selectivity between secondary OH groups according to the trends discussed in section 2.1 can often be achieved under such conditions (e.g., 281 → 282, Scheme 103). Selective cleavage of silylenes provides an alternative route to silyl ethers derived from secondary OH groups (see section 4.4).151

Scheme 101. Ph2SnCl2-Catalyzed Glycosylation of Methyl αGalactopyranosidea

a

DMBPY denotes 5,5′-dimethyl-2,2′-bipyridyl.

noteworthy result, considering that most reported stannylenepromoted transformations deliver the products of 6-Oglycosylation from such substrates (see section 9.2.1). In general, disarmed glycosyl bromides were employed as the electrophiles, although an example of a β-selective coupling of a perbenzylated glucopyranosyl halide donor was demonstrated. The authors achieved a selective glycosylation of the steroidal glycoside digoxin using this method. AG


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Scheme 103. Examples of Selective Silylation under Conditions of Steric Control

Scheme 105. Selective Silylations via Stannylene Acetals

pyranoside 141 by condensation with dibutyltin oxide, followed by treatment with TBSCl in DMF.377 Transient protection of carbohydrates as boronic esters (see section 4.3) has been used to achieve site-selective installation of silyl groups. Scheme 106 depicts the installation of a TBS group at the 4-position of rhamnopyranoside L-77 by formation of the 2,3-O-phenylboronate.142

10.1. Silyl Transfer Reactions

As mentioned in section 4.1, per-O-silylated carbohydrates participate in Lewis acid-catalyzed silyl transfer reactions that can enable selective installation of acetal, ether, and ester groups.127−129 Another useful method for the synthesis of differentially protected carbohydrates from per-O-silylated starting materials is the regioselective silyl exchange technology (ReSET) developed by Gervay-Hague and co-workers.373,374 In the presence of acetic anhydride, acetic acid, and pyridine, exchange of trimethylsilyl for acyl groups occurs in a selective fashion for a variety of mono- and disaccharide-derived substrates. Primary TMS ethers were found to be most reactive under these conditions, followed by TMS ethers at the anomeric position. Representative applications of this methodology to silylated derivatives of galactose and lactose are depicted in Scheme 104. Selective hydrolysis of the TMS groups, yielding

Scheme 106. Selective Silylation by Transient Protection As a Phenylboronic Ester

10.3. Catalysis of Silylation Reactions

Schlaf and co-workers have demonstrated that carbohydratederived silyl ethers can be accessed in a regioselective manner by transition metal-catalyzed alcoholysis of silanes.378,379 In the presence of palladium(II) chloride and tBuMe2SiH (3.3 equiv) in N,N-dimethylacetamide (DMA), gluco- and mannopyranoside substrates underwent preferential 3,6-bis-silylation, whereas galactopyranosides gave mixtures of 2,6- and 3,6-bis-silyl ether products (Scheme 107). The transformation likely occurs at the

Scheme 104. Regioselective Exchange of Silyl for Acyl Groups

Scheme 107. Palladium- and Iridium-Catalyzed Regioselective Silane Alcoholysis with Mannopyranoside α49

products of partial acetylation, was accomplished under acidic conditions (Dowex resin, MeOH). Lactose derivatives generated by this method were employed in syntheses of αlactosylceramide, globotriaose, and isoglobotriaose.375 10.2. Reagent-Controlled Silylation

surface of palladium(0) nanoparticle colloids generated in situ by reduction of the Pd(II) precatalyst. The product distributions are consistent with a sterically controlled reaction, perhaps reflecting the relative accessibility of the substrate OH groups to the heterogeneous catalyst surface. Later studies from the same group investigated the use of the iridium complex [Ir(COD)(PPh3)2]+SbF6− as a catalyst for the regioselective silylation of monosaccharides with tBuMe2SiH. While product distributions employing this homogeneous catalyst system paralleled those obtained with the palladium nanoparticles, in some cases improved yields of the 3,6-bis-silylated products could be obtained (Scheme 107). The iridium catalyst system also provided access to tris-silylated pyranoside derivatives that

Stannylene acetal methodology (see section 5.6.1) has been employed to achieve site-selective silylations of carbohydrate derivatives. Leigh and co-workers achieved selective silylations of lactose derivatives via dibutylstannylene acetals.376 In a similar way to the glycosylation reactions described in section 9.2.1, the use of a bulky silicon-based electrophile led to a selective reaction at the more sterically accessible 6’-OH group of 287, rather than the 3′-position, the preferred site of reaction with acyl and alkyl halides (Scheme 105). An example of selective silylation of the secondary position of a stannylene acetal was reported by Garegg and co-workers, who accomplished the TBS protection of benzylidene-protected mannoAH


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activation method reported previously by Aoyama (see section 7.4).301 For most of the substrates investigated, 3,5-bis(trifluoromethyl)phenylboronic acid (296) in combination with the Lewis base cocatalyst tri-n-butylphosphine oxide (20 mol % each) provided optimal activity and selectivity in reactions of carbohydrate derivatives with chlorosilanes (Scheme 109). An exception to this trend was the silylation of

would be difficult to obtain under conventional conditions using silyl chloride reagents. Selective silylation of carbohydrate OH groups has been achieved using the chiral scaffolding catalysts developed by Tan and co-workers, which are described in more detail in section 5.5.3.204 Pseudoenantiomers of the catalyst provided complementary outcomes, with the matched catalyst providing enhanced selectivity relative to the achiral model catalyst Nmethylimidazole, and the mismatched catalyst leading to the opposite sense of site-selectivity. For example, mannopyranoside 212 (Scheme 108) underwent selective silylation with

Scheme 109. Boronic Acid/Lewis Base Co-Catalyst Systems for Selective Silylation of Pyranoside Derivativesa

Scheme 108. Regioselective Silylation of Carbohydrate Derivatives with Scaffolding Catalysts

a

Results from uncatalyzed reactions are indicated in parentheses.

arabinopyranoside β-D-26 with TBSCl: a screen of commercially available boronic acids and Lewis bases revealed that the combination of 4-(dimethylamino)phenylboronic acid (298) and pyridine N-oxide provided optimal results for this transformation. Molecular sieves had an inhibitory effect, suggesting a role for water in catalyst turnover, but the addition of exogenous water (between 0.2 and 0.6 equiv relative to substrate) also resulted in diminished yields of silyl ether.

11. REACTIONS WITH PHOSPHORUS-CENTERED ELECTROPHILES Monosaccharide-derived phosphate esters play important roles in metabolism, signaling, and oligosaccharide biosynthesis. Phosphorylated oligosaccharides have been implicated as sorting signals and recognition markers for glycoproteins and are constituents of the cell walls of several types of pathogenic organisms. In addition, introduction of phosphoryl and related functional groups to the ribofuranosyl moiety of nucleosides and nucleoside analogs is often needed in the synthesis of medicinal agents or biological probe compounds. Thus, there is a need for methods that enable selective phosphorylation of carbohydrates and related polyols. Both phosphorus(V) and phosphorus(III)based electrophiles have been employed for this purpose, with the phosphatidylation products obtained from the latter class of reagents generally being subjected to oxidation prior to isolation.

chlorotriethylsilane (TESCl) at the intrinsically less reactive 2OH group when catalyst (+)-132 was employed and at the 3OH group in the presence of (−)-133. Use of oxazolidine catalyst (−)-133 allowed for the silylation of the 2-OH position of the all-cis-1,2,3-triol motif of 4-formylphenyl β-D-allopyranoside (Helicid). This chemistry could additionally be applied to the regioselective silylation of the 2’-OH group of DMTrprotected uridine (294). 2′-O-Silylated ribonucleotides of the type generated in this last transformation are common monomers in the automated synthesis of RNA and are challenging to synthesize selectively by direct silylation. Later studies demonstrated successful extensions of these scaffolding catalysts to the silylation of other natural and unnatural ribonucleosides as well as the synthesis of 3′-O-silylated ribonuclotides.380,381 Lee and Taylor investigated the use of organoboron catalysts for the regioselective silylation of cis-1,2-diol groups in pyranosides.382 The aminoethyl diphenylborinate catalyst previously employed by the Taylor group for other site-selective activations of carbohydrate OH groups (see section 5.6.2) did not provide useful levels of rate acceleration or enhanced regioselectivity relative to the uncatalyzed process. Combinations of boronic acids with Lewis bases were thus investigated as an alternative means of accessing tetracoordinate complexes that could serve as reactive nucleophiles, building on a stoichiometric

11.1. Phosphorylation of Mono- And Oligosaccharides

Matta and co-workers investigated the selective phosphorylation of primary OH groups of mannopyranosides to access recognition motifs involved in targeting of newly biosynthesized enzymes to lysozomes (Scheme 110).383,384 The use of partially protected dimannosides 301 and 303 enabled access to either the 6′- or 6-phosphate ester, while the bis-phosphate could be synthesized from unprotected dimannoside 305. Another example of sterically controlled phosphorylation of a primary OH group in the presence of secondary alcohols was reported by the group of Honek, who achieved a selective coupling of di-tertbutyl phosphorobromidate with L-rhamnulose (Scheme 111).385 In this last example, complex mixtures of products AI


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transformations employing glycosyltransferases. Nitz and coworkers developed a Cu(II)-promoted substitution reaction of glycosylsulfonohydrazides (see section 2.4) for the protectivegroup-free synthesis of glycosyl-1-phosphates (Scheme 113).387

Scheme 110. Selective Phosphorylations of Mannose Derivatives

Scheme 113. Protective-group-free phosphorylation of the anomeric OH group via a glycosylsulfonohydrazide

The use of 2-methyl-2-oxazoline as an additive resulted in improved yields by suppressing hydrolysis of the glycosyl donor. Hanessian and co-workers have employed substitutions of unprotected 3-methoxypyridyl glycosides to generate glycosyl 1phosphates.388 Kiessling developed selective phosphorylations of carbohydrate-derived stannylene acetals.389 After condensation with dibutyltin oxide, galactopyranoside-derived triol β-198b underwent selective 3-O-phosphorylation using dibenzyl phosphorochloridate (Scheme 114). This method was extended to the 3′O-phosphorylation of protected trisaccharide 314, a key step in the synthesis of a phosphate analog of 3′-O-sulfo Lewisa.

were obtained using diaryl phosphorochloridates as electrophiles in place of (t-BuO)2POBr. Scheme 111. Phosphorylation of L-Rhamnulose

Scheme 114. Organotin-Mediated Phosphorylation of Galactopyranoside β-198b and Trisaccharide Derivative 314 A protocol for selective exchange of silyl for phosphoryl groups has been developed, enabling the synthesis of 6-Ophosphorylated carbohydrate derivatives from per-O-TMSprotected substrates (see sections 4.1 and 10.1 for related reactivity of per-O-silylated sugars).386 This method was used to effect the 6′-O-phosphorylation of lactose, cellobiose, and fructose (e.g., 309, Scheme 112) and the desymmetrization of trehalose (310, Scheme 112). Phosphorylation of reducing sugars at the 1-OH group is of interest as a way of accessing donors for chemoenzymatic Scheme 112. Selective Phosphorylation via Silyl Exchange

Through a combination of catalyst design and screening, Han and Miller identified functionalized peptides (see section 5.5.3) capable of mediating the selective phosphorylation of the primary OH group of each of the three glycosyl residues of the glycopeptide antibiotic teicoplanin A2-2.390 A derivative of the natural product with protected amine, phenol, and carboxylic acid moieties was employed as the substrate for these reactions (316, Scheme 115). Capitalizing on the structurally characterized binding mode of teicoplananin to its biological target, the D-Ala-D-Ala motif of the growing bacterial peptidoglycan, catalyst 318 was designed to place a catalytically active πmethylhistidine group in proximity to the N-decanoylglucosamine moiety of compound 316. Consistent with this hypothesis, peptide 318 catalyzed the selective 6-O-phosphorylation of the N-decanoylglucosamine group (42% yield of 317a AJ


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Scheme 115. Site-Selective Phosphorylations of Teicoplanin Derivative 316

depicts the phosphorylation of guanosine under these conditions. Several other protocols for installation of phosphoryl or protected phosphoryl groups at the 5′-position of unprotected nucleosides or nucleoside derivatives have been developed (e.g., the phosphorylation of N6,N6-dimethyladenosine depicted in Scheme 116).395−400 Phosphoromorpholidate 322 was converted to the corresponding monophosphate by reductive cleavage of the tribromoethyl ether, followed by hydrolysis. It also served as a useful precursor to modified nucleoside di- and triphosphates through couplings with phosphate or pyrophosphate prior to hydrolysis. Selective phosphorylation of the secondary OH groups of ribonucleosides has been achieved using stannylene acetal methodology.220 The reaction of adenosine with tributyltin oxide in methanol, followed by treatment with phosphorus oxychloride, gave a roughly 9:1 selectivity for 3′- versus 2′-Ophosphorylation (Scheme 117). Base-mediated hydrolysis of the

after purification by reverse phase HPLC). A screen of 15 peptides revealed that phosphorylation of the mannosyl moetiy of 316 could be achieved using catalyst 319, which had previously been employed for the enantioselective desymmetrization of a myo-inositol derivative via O-phosphorylation.391 The results of this screen also informed the design of peptide 320, bearing a β-turn-inducing proline-2-aminoisobutyric acid motif as well as the glycopeptide-binding D-Ala-D-Ala moiety. With the use of 320 as the catalyst, selective phosphorylation of the N-acetylglucosamine motif was achieved, generating product 317c in 41% yield. 11.2. Phosphorylation and Related Transformations of Nucleosides

The selective installation of phosphoryl and related groups to nucleosides and nucleoside analogs has been pursued for decades and continues to be an important problem.392,393 A useful method for synthesis of 5′-nucleotides from nucleosides was reported by Yoshikawa and co-workers, who used POCl3 as the phosphorylating agent in trialkylphosphate solvents.394 The authors noted that addition of a controlled amount of water was useful for suppressing the formation of bis-phoshosphorylated side products from certain nucleoside substrates. Scheme 116

Scheme 117. Phosphorylation of an Adenosine-Derived Stannylene Acetal

Scheme 116. Phosphorylations of Nucleosides at the 5′-OH Group

initially formed dimethyl phosphate esters led to a mixture of 2′and 3′-phosphates due to participation by the neighboring OH group in the hydrolysis reaction. Amino acid derived aryloxy phosphoramidates (ProTides) have attracted significant interest due to their applications as pro-drugs for nucleotide analogues.393 Their synthesis poses interesting selectivity challenges, as it is often important to control both the site of phosphorylation and the configuration of the P-stereogenic phosphoramidate. Because these issues have been addressed in depth in a recent review article,401 only a few AK


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(NOESY) and diffusion-ordered spectroscopy (DOSY), led the authors to propose that deprotonation of the uracil base by DBU resulted in a complex having a relatively strong 5′−OH--O-2 uracil hydrogen bond. In this complex, the 5′-OH group was effectively blocked toward reaction with the electrophile. DFT calculations were used to model conformer distributions for other nucleoside substrates and their conjugate bases, providing further support for this mechanistic proposal. DiRocco and co-workers at Merck developed a catalystcontrolled stereo- and site-selective coupling of phosphoramidochloridates with nucleoside-derived diols (Scheme 120).405 In

illustrative examples will be described here. Couplings of nucleosides with enantiopure, phenol-derived phosphoramidates provide a flexible means of access to ProTides with control of the configuration of the P-stereogenic center.402 For example, Ross and co-workers achieved the site-selective and stereospecific coupling of electrophile (S,S P )-325 with the magnesium(II) alkoxide derived from nucleoside analog 324 as a key step in the synthesis of 326a (PS-7977, now called sofosbuvir, an approved drug for treatment of heptatis C virus infections, Scheme 118). The authors noted that achieving high Scheme 118. Protocols for 5′-Selective Coupling of a Nucleoside Derivative with an Enantiopure Aryl Phosphoramidate

Scheme 120. Catalyst-Controlled Stereo- And Site-Selective Coupling of Nucleoside Analog 327 with a Phosphoramidochloridate

conversion while minimizing the formation of the 3′,5′-bisphosphoramidate byproduct was a challenge, necessitating careful control of the reaction temperature and rate of addition of (S,SP)-325. An evaluation of Lewis acidic promoters by scientists from Merck’s process chemistry group revealed that 326a could be obtained in 84% yield in the presence of dimethylaluminum chloride and pyridine (conditions B, Scheme 118).403 This combination of reagents suppressed the formation of the undesired 3′,5′-bis-phosphoramidate and proceeded with strict inversion of stereochemistry at phosphorus. The authors proposed that a switch in activation mode, Lewis acid activation of the phosphoramidate electrophile with Me2AlCl, rather than alkoxide formation with t-BuMgCl, was responsible for the improvement in site-selectivity. This protocol was applied to the 5′-selective coupling of several nucleoside analogs with enantiopure aryl phosphoramidates. The 3′-selective phosphorylation of nucleoside analogs has been achieved using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a Brønsted base promoter.404 For example, a 98:2 3′:5′selectivity was obtained for the coupling of 324 and (R,RP)-325 (Scheme 119). Several nucleoside-derived diols underwent 3′phosphorylation under these conditions, which were also applicable to selective esterification with isobutyric anhydride. Studies of the 324−DBU interaction by 1H and 13C NMR spectroscopy, nuclear Overhauser effect spectroscopy

these reactions, the most profound effect of the chiral organocatalyst 329 was to influence the configuration of the P-stereogenic center through a dynamic kinetic resolution of phosphoramidochloridate 328, but the high levels of selectivity for 5′-O-phosphorylation obtained using this protocol are also noteworthy. The design of the linked dimeric catalyst was motivated by kinetic experiments that suggested a dual role for the dihydropyrroloimidazole moiety, involving Lewis base activation of the phosphoramidochloridate electrophile and Brønsted base activation of the nucleoside OH group. 11.3. Phosphorylation of Inositols

The importance of phosphorylated inositol derivatives as cellular signaling agents and components of lipids or glycolipids has motivated the development of new synthetic methods. Since inositols are not formally classified as carbohydrates, only a brief description of such methods will be provided below. Methods for selective transformations of OH groups in inositol derivatives have been the subject of a review article.406 Miller and co-workers have used functionalized peptide catalysts to achieve site-selective phosphorylations of inositol derivatives.407 A key initial result was the identification of peptides 319391 (see section 11.1 above) and 333,408 capable of delivery of phosphoryl groups to the enantiotopic 1- and 3-OH groups of myo-inositol-derived triol 331 (Scheme 121). Building on these methods, the Miller group has achieved the synthesis of inositol-derived phosphates409,410 and polyphosphates,411 as well as phosphatidylinositols,412−415 for use as biological probes. Enantio- and site-selective transfers of phosphorus(III)-based electrophiles to inositol derivatives have been achieved using peptide catalysts bearing a tetrazole moiety (Scheme 122).416 In the presence of peptide-derived catalyst 335, 6-O-phosphitylation of compound 334 was achieved in 71% yield and 70% ee, as judged after oxidation to the corresponding phosphate. The

Scheme 119. Base-Mediated, 3′-Selective Coupling of a Nucleoside Analog with an Aryl Phosphoramidate

AL


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Scheme 121. Site-Selective Phosphorylation of myo-InositolDerived Triol 331

Scheme 123. Phosphorylation of myo-Inositol Derivative 338 Using BINOL-Derived P(III) and P(V) Electrophiles

Scheme 122. Enantioselective Synthesis of D-myo-Inositol-6phosphate (337) via Catalyst-Controlled Phosphitylation

these studies: the products are relatively stable and in some cases crystalline compounds, facilitating isolation and characterization, while the low propensity of sulfonyl groups toward migration simplifies interpretation of product distributions. The utility of sugar-derived sulfonate esters, either as protected building blocks or as substrates for nucleophilic substitution or reduction reactions, has continued to motivate the development of methodology for site-selective sulfonylation. 12.1.1. Sulfonyl Halides in Pyridine. Reactions of carbohydrate derivatives with arenesulfonyl chlorides, usually para-toluenesulfonyl chloride, TsCl, in pyridine solvent generally yield the products of sulfonylation of the most sterically accessible OH group, in analogy to the esterification chemistry described in section 5.1. Thus, free hexopyranosides can be sulfonylated at the 6-OH group under such conditions,420,421 while equatorial groups having a flanking axial substituent are generally the most reactive of the secondary OH groups in pyranosides (Scheme 124).422,423 Robertson and

latter was resubjected to phosphitylation conditions using the catalyst 335, resulting an upgrading of the enantiomeric excess to >96% via kinetic resolution. After deprotection and ionexchange, myo-inositol-6-phosphate 337 was obtained in 95% yield. On the basis of mechanistic understanding of tetrazolemediated phosphoramidite transfers, the authors proposed that P(III) transfer was achieved via a catalyst-derived tetrazolylphosphonite electrophile, with the 10 Å molecular sieves enabling catalyst turnover by acting as a scavenger for the diethylamine byproduct. A BINOL-derived chiral phosphitylating agent has been used to achieve the desymmetrization of protected myo-inositol 338 (Scheme 123).417 An evaluation of related phosphorus(V)based electrophiles revealed that the highest selectivity (1-OH vs 3-OH) was obtained using phosphorochloridoselenoate 341.418 These methods were used to prepare inositol phospholipids from the protozoan parasite Entamoeba histolytica.

Scheme 124. Selective Sulfonylations with TsCl in Pyridine Solvent

Griffith noted that selective tosylation of benzylidene-protected glucopyranoside α-9 at the 2-OH group was more straightforward than benzoylation, perhaps reflecting the more sterically discriminating nature of the arenesulfonyl halide in comparison to benzoyl chloride. Sulfonylations of pyranosides with methanesulfonyl chloride (MsCl) have also been conducted and follow a similar trend in terms of the relative reactivity of OH groups (Scheme 125).424−426 However, due to the relatively low steric demand of MsCl, these reactions are generally conducted at lower

12. REACTIONS WITH SULFUR-CENTERED ELECTROPHILES 12.1. Sulfonylation

Along with acyl halides, sulfonyl halides were among the first electrophiles to be explored for selective reactions with unprotected or minimally protected carbohydrate derivatives.419 Reactions of arenesulfonyl chlorides figured prominently in AM


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Selective sulfonylation of the 2-OH group of sucrose has been achieved using TsIm and molecular sieves in DMF, in the absence of base (Scheme 128).434 This result stands in contrast

Scheme 125. Reactions of Carbohydrates with Methanesulfonyl Chloridea

Scheme 128. Selective Sulfonylations of Sucrose Using TsIm and TsCl

a

pNP denotes para-nitrophenyl.

temperatures (−20 to −40 °C) and nonetheless often result in mixtures of products. 12.1.2. Other Sulfonylation Reagents and Conditions. Other reagents that have been used to accomplish the sulfonylation of the most sterically accessible OH group of carbohydrate-derived substrates include sulfonyl chlorides with trialkylamine bases,427,428 or sulfonic anhydrides with pyridine.162,429−432 For example, L-fucose-derived diol 347 underwent monosulfonylation in the presence of trifluoromethanesulfonic anhydride (triflic anhydride, Tf2O) and pyridine (Scheme 126).432 The resulting triflate was subjected to a

to that obtained using TsCl in pyridine, in which the three primary OH groups underwent selective sulfonylation.435,436 Studies of the sulfonylation of β-cyclodextrin under the same conditions, another transformation that resulted in functionalization of the 2-OH group of a glucopyranoside in the presence of free primary OH groups, suggested that the molecular sieves did not act as a drying agent but rather served an active role in promoting the selective coupling reaction.437 N-Tosylimidazole has been employed in monofunctionalization reactions of cyclodextrins (CDs). 6A-O-p-Toluenesulfonylβ-cyclodextrin, a useful electrophilic building block for the synthesis of modified cyclodextrins,438 was prepared in 40−61% yield by treatment of β-CD with TsIm in water, followed by addition of sodium hydroxide (Scheme 129).439 The formation of a β-CD−TsIm complex was likely responsible for the siteselectivity and controlled monofunctionalization observed under these conditions.

Scheme 126. Synthesis of 4-Azido-4,6-dideoxy-L-glucose Derivative 348 by Selective Installation of a Triflate Group

nucleophilic substitution reaction to generate 4-azido-4,6dideoxy-L-glucose derivative 348. It is noteworthy that the axial 4-OH group was sulfonylated in preference to the 2-OH group, which is hindered by the equatorial substituents at the 1and 3-positions (see section 2.1). N-Tosylimidazole (TsIm) is a useful reagent in carbohydrate chemistry due to its distinct pattern of site-selectivity: under the strongly basic conditions needed for efficient reactions with this relatively poor electrophile, the regiochemical outcome may reflect the preferred site of alkoxide formation (see the discussion of N-benzoylimidazole, section 5.2). Hicks and Fraser-Reid showed that an efficient 2-O-sulfonylation of benzylidene α-9 could be achieved using TsIm in the presence of sodium methoxide (Scheme 127).433 When sodium hydride (2.1 equiv) was employed as a base in the DMF solvent, 2,3anhydrosugar 350 was obtained directly in 78% yield.

Scheme 129. Monofunctionalization of β-Cyclodextrin (βCD) with TsIm

Scheme 127. Sulfonylation and 2,3-Anhydrosugar Formation Using TsIm

12.1.3. Phase-Transfer Catalysis. Phase-transfer catalysis has been used to achieve site-selective sulfonylations of pyranosides.440 Under biphasic conditions, benzylidene-protected gluco- and mannopyranosides were converted to the 2-Otosylates in the presence of TsCl, NaOH, and Bu4N+HSO4− (Scheme 130). As was the case for benzylation reactions under similar conditions (see section 2.2), it was the most acidic OH group, rather than the most sterically accessible one, that underwent selective functionalization. 12.1.4. Organotin Promoters and Catalysts. Sulfonylation was among the selective transformations of nucleosideAN


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Scheme 130. Site-Selective Sulfonylation in the Presence of a Phase-Transfer Catalyst

Scheme 132. Organotin-Catalyzed Sulfonylations of Carbohydrate Derivatives

derived stannylene acetals investigated by Moffatt and coworkers in 1974.220 For example, 2′-O-tosyladenosine was prepared in 70% yield from the reaction of the adenosinederived dibutylstannylene acetal with TsCl and Et3N in methanol. Applications of the stannylene acetal method to sulfonylations of pyranosides were explored by the groups of Szmant222 and Tsuda.441 An example from the latter study is depicted in Scheme 131. For certain substrates, differences in pyranosides.445 Optimal results were obtained using electrondeficient arenesulfonyl chlorides such as 358, with Bu2SnCl2 as catalyst and PEMP as base. Under these conditions, pyranosides having a cis-1,2-diol group underwent sulfonylation at the equatorial position and not at the free 6-OH group, consistent with the results of other organotin-catalyzed functionalizations of carbohydrates (see section 5.6.1). This selectivity is evident in the selective monosulfonylation of lactose derivative 357 (Scheme 132). Xia and Lowary employed organotin catalysis to achieve siteselective, multiple sulfonylations of oligosaccharide derivatives.236 Tris-tosylation of trisaccharide 360 was accomplished in 69% yield using Bu2SnCl2 as catalyst (Scheme 133). As

Scheme 131. Tosylation of Methyl α-D-Galactopyranoside by the Stannylene Acetal Method

product distributions for tosylation (TsCl, catalytic DMAP, dioxane, room temperature) versus benzoylation (BzCl, dioxane, room temperature) were evident. Galactopyranoside α-53 was one such substrate; in contrast to the selective 3-Osulfonylation depicted in Scheme 131, benzoylation resulted in a mixture of 2-, 3-, and 6-O-functionalized products. It is unclear whether this difference reflects a kinetic issue (e.g., trapping of the initially formed distribution of stannylene acetal isomers with BzCl versus a Curtin−Hammett scenario for the less reactive TsCl) or whether acyl group migration occurred under the conditions of benzoylation. Trialkylstannyl ether intermediates (see section 5.6.1) have also been employed in selective sulfonylation reactions: Ogawa and Matsui reported selective 2,6-bis-sulfonylations of glucopyranoside α-1 by activation with (Bu3Sn)2O.227 Catalytic quantities of organotin compounds have been used in selective sulfonylations of carbohydrate derivatives. Martinelli and co-workers from the process chemistry group at Eli Lilly developed a protocol for monosulfonylation of 1,2-diols and related substrates capable of forming five-membered chelates, using dibutyltin oxide as catalyst and triethylamine base.442,443 This protocol enabled the 6-O-sulfonylation of a glucofuranoside derivative having a free exocyclic diol motif and was also applied to sulfonylations of methyl xylopyranosides α-92 and β92 (Scheme 132). For substrate α-92, the catalytic protocol resulted in a significantly different product distribution from that obtained by Tsuda and co-workers using stoichiometric stannylene acetal activation (primarily 2-O-sulfonylation with catalytic Bu2SnO versus 4-O-sulfonylation under the conditions depicted in Scheme 131). Another catalytic variant was developed by Kawana, Tsujimoto, and Takahashi, who employed Bu2SnCl2 (10−40 mol %), TsCl, and Et3N in acetonitrile to effect sulfonylations of adenosine and methyl αhexopyranosides.444 The 2′-O-tosylate was obtained from the former, whereas the latter class of substrates led to bissulfonylated products (e.g., α-53 → 356, Scheme 132). In 2012, Muramatsu reported the results of an extensive survey of conditions and substrates for selective sulfonylation of

Scheme 133. Organotin-Catalyzed Sulfonylations of Oligosaccharide Derivatives

discussed in section 5.6.1, the selectivity for functionalization of the axial groups stems from the presence of a sterically bulky substituent at the 4-position of each mannopyranosyl moiety. Product 361 was carried forward to a 3,3′,3′′-trimethylated derivative of the mannose trisaccharide. Under similar conditions, protected α-cyclodextrin derivative 362 underwent sulfonylation at the 2-OH group of each glucopyranosyl residue. 12.1.5. Transition Metal Promoters and Catalysts. Selective introduction of the tosyl group to a range of pyranoside derivatives has been accomplished using silver(I) oxide as promoter in the presence of catalytic potassium iodide.255 Thioglycosides generally underwent sulfonylation at the 3position, whereas glycopyranoside-derived diols were sulfonyAO


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lated at the 2-OH group (Scheme 134). As discussed in section 5.6.4, the relative acidities of OH groups likely play a role in

Scheme 137. Borinic Acid Catalyzed Monosulfonylation of Galactopyranoside α-145

Scheme 134. Sulfonylation of Pyranoside β-9 Promoted by Ag2O/KI

substrate cis-1,2-cyclohexanediol showed first-order kinetic dependence on the concentrations of Ph2BOH and TsCl and pseudo zero-order kinetics in diol and iPr2NEt. These observations suggest that sulfonylation of a borinic acid−diol adduct is the turnover-limiting step of the reaction. 12.1.7. Organocatalysts. Methanesulfonyl chloride is among the electrophiles that react selectively with carbohydrate derivatives in the presence of imidazole-functionalized scaffolding catalysts (see section 5.5.3).204 With the use of “matched” catalyst (+)-132, arabinopyranoside β-L-26 was sulfonylated at the 3-OH group in 91% yield, while the least reactive 4-OH group could be sulfonylated selectively using the mismatched catalyst (Scheme 138). The achiral reference catalyst Nmethylimidazole gave rise to a modest selectivity for mesylation of the 2-OH group.

determining the site-selectivity under the strongly basic conditions generated from the Ag2O/KI promoter system. In addition to acylation (see section 5.6.4), sulfonylation of carbohydrate derivatives can be conducted in a site-selective fashion using chiral copper(II) bis(oxazoline) or pyridinebis(oxazoline) catalysts.259,260 For example, protected disaccharide 364 underwent monotosylation at the 2’-OH group, providing 365 in 75% yield as the only observed regioisomer (Scheme 135). Scheme 135. Sulfonylation of a Disaccharide Using a Chiral Copper(II) Complex

Scheme 138. Selective Sulfonylations Using Scaffolding Catalysts (+)- and (−)-132

A protocol for monosulfonylation of β-cyclodextrin has been developed based on the complexation of diol groups by Cu(II) salts (Scheme 136).446 In contrast to the results described in the Scheme 136. Monosulfonylation of β-Cyclodextrin in the Presence of a Cu(II) Salt

Miller and co-workers discovered a tetrapeptide catalyst capable of mediating enantioselective sulfonylations of meso-1,3diols, including inositol derivatives (Scheme 139).448 Best Scheme 139. Selective Sulfonylation of myo-Inositol Derivative 331 Using a Functionalized Tetrapeptide Catalyst

preceding paragraph, the formation of cyclic Cu(II) complexes was proposed to result in deactivation, rather than activation, of the bound OH groups. In particular, a 2:3 aggregate of the cyclodextrin−TsCl inclusion complex and Cu(II), generated by metal coordination of the 2- and 3-OH groups of each glucopyranosyl moiety, was proposed to be the reactive species. In the absence of the Cu(II) salt, a mixture of isomers was obtained. 12.1.6. Organoboron Catalysts. Diarylborinic acid catalysis (see section 5.6.2) has been employed in site-selective tosylations of carbohydrates: pyranoside derivatives lacking a free primary OH group underwent selective sulfonylation at equatorial positions of cis-1,2-diol motifs (Scheme 137).447 Studies of the rates of sulfonylation of the simple model

results were obtained using an electron-deficient sulfonyl chloride such as para-nitrobenzenesulfonyl chloride (NsCl), while TsCl and PMPSO2Cl gave lower yields and inferior enantioselectivities. Intriguingly, the absolute sense of stereochemical induction for sulfonylation using catalyst 368 was opposite to that obtained upon phosphorylation of the same substrate using closely related catalyst 333 (see section 11.3 above). This observation suggests that different mechanisms operate, both in a highly enantioselective manner, for the two group transfer reactions, despite the close similarities between the substrate and catalyst structures. AP


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12.2. Sulfation

Scheme 140. Selective Sulfations of Partially Protected Carbohydrate Derivatives

Sulfation is an important “postglycosylation modification”, often playing a key role in mediating processes involving protein− carbohydrate recognition, with the anionic sulfate group providing a site of interaction with positively charged residues of the protein partner.449−451 Both the degree and the position(s) of sulfation are often important in promoting the interaction of the carbohydrate derivative with its intended protein target.452 Methods allowing for the reliable and siteselective introduction of sulfate groups to carbohydrate derivatives are thus of interest. The discussion below will focus primarily on reactions of mono- and oligosaccharides: readers interested in selective sulfations of polysaccharides are directed to a recent review article on this topic.453 Various reagents have been employed as sulfating agents for carbohydrates and oligosaccharides, including sulfuric acid (in combination with a dehydrating agent such as acetic anhydride or a carbodiimide), sulfamic acid, pyridine-N-sulfonic acid, chlorosulfonic acid, and sulfuryl chloride. Here, the focus will be on two strategies that are commonly employed for site-selective sulfation of carbohydrates: one involving direct installation of sulfate groups by reaction of carbohydrate OH groups with SO3 complexes and the other employing chlorosulfate esters or related electrophiles as “masked sulfating agents” to generate Oprotected variants. A brief description of chemoenzymatic sulfations mediated by sulfotransferases will also be provided. 12.2.1. Direct Sulfation with SO3 Complexes. A common approach to the synthesis of sulfated carbohydrates is by reaction of a protected carbohydrate derivative with a complex of SO3 such as SO3·trialkylamine, SO3·pyridine, or SO3· DMF, followed by cleavage of the O-protective groups. Reducing or eliminating the need for O-protective groups through the development of site-selective reactions of carbohydrate derivatives would simplify access to this class of targets. Accordingly, several investigations of the reactions of SO3 complexes with unprotected or partially protected glycosides have been undertaken. Sulfation of methyl gluco- and galactopyranosides with SO3·pyridine occurred primarily at the primary OH group, although an appreciable amount of bissulfate was obtained from the β-galactopyranoside.454 Protected trehalose derivative 370 underwent sulfation at the less sterically hindered 2-OH group, enabling the synthesis of a substructure of the sulfated glycolipids produced by Mycobacterium tuberculosis (Scheme 140).455 A similar level of selectivity was observed upon sulfation of benzylidene-protected glucopyranoside α-9,456,457 whereas β-9 led to a mixture of sulfates (3:2 2sulfate:3-sulfate). In the course of a study of the sulfation of heparin derivatives and analogs, Perlin and co-workers carried out reactions of idopyranoside 372 and altropyranoside 374 with SO3·trimethylamine.458 Substantial levels of bis-sulfation were observed in both cases, but a single monosulfate was obtained from 374 versus a 1:1 mixture from 372. Again, this is consistent with a sterically controlled reaction, as the 2-OH group of 374 is less hindered due to the equatorial orientation of the substituent at C-4 of the altropyranoside. An unusual outcome was observed by the group of Kondo upon sulfation of the Lewisx analog 376: contrary to the authors’ expectations, monosulfation occurred exclusively at the axial 4′-OH group.459 Protection of the 4′-OH group as an ester, via ring-opening of an orthoester, was needed to access the desired 3′-sulfate. Reactions of stannylene acetals (see section 5.6.1) with SO3 complexes provide direct access to sulfated carbohydrates and have been employed in the synthesis of several biologically

relevant targets. Couplings of dibutylstannylene acetals with SO3·NMe3 were reported by Flitsch and co-workers in 1994.460,461 Sulfatide 379 was prepared in 97% yield from βgalactosylceramide 378 by this method, which also enabled the sulfation of several disaccharide derivatives, including Nacetyllactosamine 380 (Scheme 141). In the same year, Scheme 141. Selective Sulfations of Stannylene Acetals

Lubineau and Lemoine reported the dibutyltin oxide-mediated 3-sulfations of several β-galactopyranosides, including Lewisa derivative 382,462 while the group of Vasella disclosed organotin-mediated sulfations of a range of gluco-, galacto-, and mannopyranoside derivatives.463 Scheme 142 depicts an interesting transformation achieved in the latter study, in which transient protection of a 4,6-diol group as a phenylboronic ester was combined with organotin-mediated activation in the synthesis of glucopyranoside-2-sulfate 385. Hydrolysis of the boronic ester group occurred during purification of the sulfate derivative by silica gel chromatography. Stannylene acetal activation has also been employed in the preparation of a AQ


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Scheme 142. Transient Protection and Stannylene Acetal Activation in the Synthesis of a Glucopyranoside-2-Sulfatea

Scheme 144. Ring Opening of Cyclic Sulfates

a

DMI denotes 1,3-dimethylimidazolidin-2-one.

synthetic substrate for the iduronate-2-sulfatase enzyme implicated in Hunter’s syndrome464 and in the selective sulfation of xylopyranose-containing di- and trisaccharides.465 12.2.2. Installation of Masked Sulfate Groups. Introduction of one or more charged sulfate groups to a carbohydrate derivative can create challenges for purification and lead to potential incompatibilities with certain reagents or conditions. The use of chlorosulfate esters or related reagents enables the installation of masked sulfate groups that can be deprotected at a later stage. This tactic has been employed in the synthesis of a number of complex, carbohydrate-derived sulfates, including a heparin oligosaccharide.466 Early efforts to incorporate masked sulfate groups in a regioselective fashion were carried out by the group of Perlin, who investigated the reactions of phenyl chlorosulfate with partially protected pyranoside derivatives.467,468 Substrates having free OH groups at the 4- and 6-positions reacted selectively at the primary OH group (e.g., 260 → 386, Scheme 143). Formation of the 4,6-

chloride followed by periodate-mediated oxidation of the resulting cyclic sulfites. Ring opening of cyclic sulfate 389 with benzoate occurred selectively at the primary position, yielding the protected 4-sulfate product 390, whereas a mixture of isomers was obtained upon hydrolysis of 2,3-cyclic sulfate 391. Taylor and co-workers have pioneered the use of 2,2,2trichloroethyl-protected sulfuryl imidazolium salts as reagents for the synthesis of complex, carbohydrate-derived sulfates.470 The trichloroethyl protective group proved to be stable to a range of reaction conditions but could be removed cleanly by reduction in the presence of ammonium formate and zinc or palladium(0) on carbon. The use of a sulfuryl imidazolium salt rather than a chlorosulfate ester prevented the formation of chlorodeoxy sugar byproducts by nucleophilic substitution. When pyranoside-derived diols were treated with reagent 78, the products of sulfation of the less sterically hindered OH group were formed selectively.471 For example, glucopyranoside 393 underwent sulfation at the primary OH group, whereas benzylidene galactopyranose 395 reacted primarily at the 3position (Scheme 145). Transient protection via boronic ester

Scheme 143. Reactions of Pyranoside-Derived Diols with Phenyl Chlorosulfate

Scheme 145. Selective Introduction of Masked Sulfate Groups Using Sulfuryl Imidazolium Salt 78

cyclic sulfate was observed when the reactions were conducted at room temperature rather than −30 °C. In a similar way, the reaction of α-9 led to monosulfate 387 at −25 °C and to the 2,3cyclic sulfate (79% yield) at room temperature. 2,3-Anhydrosugars 350 and 388 were obtained from altropyranoside 374 due to a facile intramolecular nucleophilic displacement reaction. Flitsch and co-workers evaluated phenyl chlorosulfate as a reaction partner for sulfations of stannylene acetals but found that it provided inferior results to those obtained using SO3· trimethylamine.460 A variant of the masked sulfate strategy involves the regioselective ring opening of cyclic sulfates. Dagron and Lubineau explored this strategy for the preparation of βgalactopyranoside-derived sulfates from the 2,3- and 4,6-cyclic congeners (Scheme 144).469 The requisite substrates were prepared from galactopyranoside diols by reaction with thionyl

formation has been used to achieve selective monofunctionalizations of pyranoside substrates using reagent 78 (see Scheme 28, section 4.3). Related masked sulfating agents have been employed in selective functionalizations of carbohydrate derivatives.472,473 Trehalose derivative 397 reacted with trifluoroethyl-protected sulfuryl imidazolium salt 398 at the 2’OH group, which is both the most acidic and the least hindered of the three OH groups in this substrate (Scheme 146). Deprotection of the trifluoroethyl sulfate ester in product 399 was accomplished by treatment with sodium azide in DMF at 65 °C. AR


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Scheme 146. Reaction of Masked Sulfating Reagent 398 with Trehalose-Derived Triol 397

Scheme 147. Chemoenzymatic Sulfations in the Synthesis of a Heparin Oligosaccharide

groups or at C-1 of aldoses or aldonic acids,479−481 is also of considerable utility in carbohydrate chemistry, but here the focus will be on oxidations of OH groups. Enzymes have long offered ways to achieve such transformations in a site-selective fashion. While nonenzymatic, site-selective oxidations of carbohydrate primary OH groups are well documented at this stage, methods for the oxidation of secondary OH groups have only recently been developed.

12.2.3. Chemoenzymatic Sulfation with Sulfotransferases. Carbohydrate sulfotransferases catalyze the delivery of a sulfate group from an activated electrophile (in eukaryotic cells, 3′-phosphoadenosine-5′-phosphosulfonate, or PAPS) to a hydroxyl or amino group of a sugar-derived substrate.474 Members of this family of enyzmes have been found to display distinct selectivity patterns: examples include N-acetylglucosamine-6-O-sulfotransferase, galactosylceramide-3-O-sulfotransferase, and various heparan sulfate O-sulfotransferases. Latestage sulfations using this last class of enzymes have been employed in chemoenzymatic syntheses of heparin polysaccharides and heparan sulfate oligosaccharides.475−478 Scheme 147 depicts successive chemoenzymatic sulfations employed by Linhardt, Liu, and co-workers in the synthesis of an analog of Arixtra, a synthetic heparin oligosaccharide that is employed clinically as an anticoagulant. The two steps shown were part of a four-step sequence (of which three steps employed enzyme catalysts) that took place with an overall yield of 90%.

13.1. Enzyme-Catalyzed Oxidation

The utility of enzymes in the site-selective oxidations of carbohydrates has been discussed in recent review articles.6,21 Glucose oxidase, which catalyzes the conversion of D-glucose to gluconolactone, is the most well-studied of these enzymes. It employs molecular oxygen as the stoichiometric oxidant and relies on flavin adenine dinucleotide (FAD) as a cofactor. Applications of this enzyme are widespread and diverse, ranging from diagnostics and biosensors to additives in the food and beverage industry. The ability to generate gluconolactone on a large scale from glucose makes it an appealing bioderived feedstock for applications in polymer chemistry and other areas. Oxidation of the primary OH group of D-galactose and related substrates (e.g., N-acetylgalactosamine, galactopyranosides, and terminal galactopyranosyl moieties in di- and oligosaccharides) to the corresponding aldehyde has been achieved using galactose oxidase.482−484 This copper-containing enzyme operates by a free radical mechanism, also employing oxygen as the oxidant with generation of H2O2. In addition to providing

13. OXIDATION Direct differentiation of carbohydrate OH groups through selective oxidation is a useful transformation. The subsequent manipulation of the oxidized site, via reductive amination, nucleophilic addition, deoxygenation, or reduction, can potentially allow rapid access to valuable carbohydrate derivatives that would be otherwise difficult to obtain. Oxidative carbon−carbon bond cleavage, either at exocyclic 1,2-diol AS


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pyranosides or furanosides. One of the first reported methods involved the use of stoichiometric (Bu3Sn)2O and molecular bromine, proceeding through a stannyl ether intermediate (see section 5.6.1).511,512 Substrates having a cis-1,2-diol group were selectively oxidized at the axial position, presumably a result of selective abstraction of the more accessible, equatorial hydrogen. The authors also noted that the configuration of the anomeric substituent influenced the site-selectivity of oxidation, with pyranosides having an axial anomeric substituent undergoing oxidation at the 4-position and those having an equatorial anomeric substituent generating the 3-keto products. For example, oxidation of α-1 generated product α-404b, the same keto sugar that was generated from the galactopyranoside α-53, in 65% yield, whereas β-1 was oxidized at the 3-position (Scheme 149).

valuable products, for applications as cross-linking reagents in protein chemistry, for example, the galactose oxidase-catalyzed formation of aldehydes has been used in the modification and labeling of complex glycoconjugates.485 Imperiali and Whitworth recently developed a method for labeling of cell-surface glycans of Campylobacter jejuni by oxidation of terminal GalNAc moieties with galactose oxidase, followed by conjugation of the resulting aldehyde to a hydroxylamine-functionalized tag or fluorophore.486 Through a series of saturation mutagenesis experiments, Arnold and co-workers were able to identify a galactose oxidase variant capable of oxidation of glucopyranosyl moieties, which are not processed by the wild-type enzyme.487 Such variants have been employed in modification and labeling of complex glycans that do not contain terminal galactose moieties.488 Pyranose oxidases can be used in the selective oxidations of the secondary positions of monosaccharides to generate either 2- or 3-ketoses.489−491 Dehydrogenases can also be used in siteselective oxidations of various positions.492−495

Scheme 149. Trialkylstannyl Ether-Mediated Selective Oxidations of Pyranosides

13.2. Oxidation Using Synthetic Reagents or Catalysts

Primary OH groups of carbohydrates can be selectively oxidized to either the corresponding aldehyde or carboxylic acid in the presence of catalytic amounts of a nitroxyl radical and a stoichiometric secondary oxidant (Scheme 148). The selectivity Scheme 148. Oxidations of Methyl Glucopyranoside α-1 at the Primary OH Group Organotin-catalyzed, site-selective oxidations at secondary positions of carbohydrate derivatives have been developed, using stannylene acetals as key intermediates (see section 5 . 6. 1 ). 5 1 3 T r i m e t h y l p h e n y l a m m o n i u m t r i b r o m i d e ([TMPhA]+Br3−) was employed as the oxidant, with di-noctyltin dichloride being the optimal catalyst. As was the case for the stannyl ether-mediated methodology discussed in the preceding paragraph, the diorganotin-catalyzed variant resulted in the selective oxidation of the axial position of cis-1,2-diol groups (Scheme 150). In general, galacto-configured substrates Scheme 150. Organotin-Catalyzed Oxidations of Pyranosides obtained under these conditions has been attributed to the higher steric accessibility of primary OH groups relative to secondary ones. 2,2,6,6-Tetramethyl-1-piperidinyloxyl (TEMPO) and related compounds can be used in conjunction with sodium hypobromite,496,497 sodium hypochlorite,498−502 or a peracid503,504 to obtain uronic acid derivatives. Alternatively, primary OH groups can be oxidized to carboxylic acids in the presence of platinum(0) on carbon or Al2O3 under an oxygen atmosphere,505−507 or by employment of a rhodium(I) complex.508 Through proper selection of reaction conditions, oxidation at primary positions of carbohydrates can be conducted in a controlled fashion to generate the corresponding aldehyde products. Trichloroisocyanuric acid has been used at low temperature as a mild, secondary oxidant in TEMPO-catalyzed oxidations of primary OH groups to aldehydes.509 The reactivity of TEMPO derivatives can similarly be controlled under electrochemical conditions.510 The site-selective oxidation of carbohydrate secondary OH groups is generally challenging, and few nonenzymatic methods exist for the direct synthesis of keto sugar derivatives from

reacted more efficiently than those of manno configuration, possibly because the electron-withdrawing effect of the anomeric center hampered the oxidation of the latter at the 2OH group. Substrates lacking a cis-1,2-diol group also underwent selective oxidation, albeit with a higher loading of the organotin catalyst. The effect of the configuration of the anomeric substituent on the site-selectivity of oxidation (formation of the 3-keto sugar from a β-glucopyranoside vs the 4-keto sugar from an α-glucopyranoside) was also consistent with the results of the earlier work of Tsuda and coworkers.511,512 AT


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Transition metal catalysis has been employed productively in the selective oxidation of carbohydrate secondary OH groups. Seminal reports from Waymouth disclosed a cationic 2,9dimethylphenanthroline (neocuproine) palladium catalyst ([(neocuproine)PdOAc]2(OTf)2, 406) which, in the presence of stoichiometric benzoquinone as terminal oxidant, allowed for the selective oxidation of the secondary over the primary OH groups of glycerol.514,515 It was proposed that the ability of vicinal diols to chelate to the metal center enhanced the reactivity of these substrates relative to 1,3-diols and other primary or secondary alcohols. This catalytic system was adopted by Minnaard and co-workers for selective oxidation of the C-3 position of glucopyranoside derivatives, using dichlorobenzoquinone (DCBQ) as oxidant (Scheme 151).516−518 Free glucose and galactosamine, as well as

Scheme 152. Proposed Mechanism for Selective Oxidation of β-1, and Applications of Pd Catalyst 406 to Oxidations of Other Carbohydrate-Derived Substrates

Scheme 151. Selective Oxidations of Glucopyranosides

possess an axially configured 3-OH group (e.g., Scheme 152, product 410). When reactions were performed in 2,2,2trifluoroethanol, oxidation at C-3 was accompanied by epimerization of axial OH groups. This oxidation-epimerization pathway provided a rapid route to a 3-keto derivative of the rare sugar L-quinovose, starting from fucopyranoside α-L-187 (product 411).520 N-Acetylneuraminic acid methyl ester 412 underwent selective oxidation at the 8-OH group under these conditions. Minnaard and co-workers employed NMR spectroscopy to determine relative rates and product distributions for Pdcatalyzed oxidations of carbohydrate derivatives.521 Competition experiments showed that glucopyranoside derivatives reacted more rapidly than manno- or galacto-configured substrates. Under the conditions employed, oxidations of the latter two classes were complicated by further downstream reactions of the C-3 oxidized product; initially formed 3-ketose sugars were prone to hemiacetal formation, followed by further oxidation and rearrangement (Scheme 153). Yields of 3-ketose products from manno- and galactopyranosides could be improved by using substrates with protecting groups at the 6position and by lowering the quantity of terminal oxidant

glucopyranosyl moieties in oligosaccharides, were also subject to oxidation at the 3-OH group under these conditions, whereas methyl α-galacto- and -mannopyranoside did not undergo selective oxidation. Deuteration of the methyl groups of the neocuproine ligand was found to increase the stability of the Pd catalyst, thus enabling aerobic oxidation of methyl αglucopyranoside.519 Waymouth and co-workers also conducted a detailed study of the Pd-catalyzed oxidation of carbohydrates, including refinements and modifications of the catalytic protocol as well as applications to a wide range of sugar-derived substrates.520 Changes to the initially reported catalytic conditions included the use of molecular oxygen as the stoichiometric oxidant (in the presence of 2,6-diisopropylphenol as a sacrificial reductant) and the application of fluorinated alcohol solvents. In agreement with the work of Minnaard’s group, selective oxidation at the 3position was observed for carbohydrates containing all equatorial OH groups; the minor products in these cases were C-4 keto sugar derivatives. The authors proposed that chelation of the palladium catalyst to the 3-OH and 4-OH groups, followed by preferential β-hydride elimination from C-3, could account for the observed selectivity in such cases (Scheme 152).515,520 Oxidations of galacto- or manno-configured substrates lacking a 6-OH group (methyl α-rhamnopyranoside, α-fucopyranoside, or β-arabinopyranoside) occurred in good yields, but with relatively low selectivities for oxidation of the 3versus the 4-OH group. A mismatch between the effects of OH group configuration (preference for oxidation of axial OH groups)515 and position (intrinsically favored oxidation at the 3position) was proposed to account for the latter observation. Consistent with this idea, exclusive oxidation of the 3-OH group was observed upon oxidation of 1,6-anhydrogalactose and -mannose, which are locked in the 1C4 conformation and thus

Scheme 153. Rearranged Products Obtained upon Oxidation of Mannopyranoside α-49 and Suppression of Rearrangement Using a 6-O-Silylated Derivative

AU


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employed (Scheme 153). Studies of the reactions of deoxygenated substrates suggested that the observed C-3 selectivity did not depend on substitution pattern; chelation of the palladium catalyst to the 3-OH and either the 4-OH or 2-OH was sufficient for oxidation. Substrates without substitution at the 4-OH group reacted faster than substituted derivatives, thus accounting for the selectivity for oxidation at the terminal sugar moiety of di- and oligosaccharides.

ASSOCIATED CONTENT

14. CONCLUSIONS Although site-selective transformations of OH groups in sugars have been pursued for more than a century, this problem continues to attract broad interest and to inspire new ideas and approaches. In particular, advances in organocatalysis and transition metal catalysis have had a significant impact on carbohydrate chemistry in recent years, and further exciting advances are to be expected given the increasing number of catalysis researchers who are active in this area. The propargylation and O-arylation reactions discussed in this review are examples of new types of bond constructions on carbohydrates made possible through the use of transition metal catalysts or promoters. Such transformations could be of particular value for the development of carbohydrate mimetics or analogs or for selective labeling of oligosaccharides. The use of chiral catalysts to achieve site-selectivity in reactions of carbohydrates is another development that has been highlighted in this review: the ability to overcome intrinsic differences in the reactivity of OH groups using catalyst chirality clearly offers new levels of flexibility in synthetic planning. Control of glycosylation reactions by synthetic catalysts is a third area that shows considerable promise: several of the cases discussed in section 9.3 illustrate how synthetic catalysts can influence both regioand stereocontrol in such transformations. Opportunities exist to further build upon these advances in selective glycosylation, for instance, by developing methods for the construction of challenging linkages or by targeting the synthesis of complex oligosaccharides relevant to glycobiology research. The substrates used in the development of the methods described in this review have generally been monosaccharides, occasionally with extensions to disaccharides or other glycosides. However, several of the most interesting opportunities in site-selective functionalization of sugars hinge of the ability to discriminate between OH groups in more complex oligosaccharides or polysaccharides: the chemoenzymatic sulfations shown in Scheme 147 exemplify the level of substrate complexity that chemists may face in such efforts. At present, transformations of this type are generally out of the reach of synthetic catalysts and reagents and remain the exclusive domain of enzyme catalysis. Extending synthetic methods for site-selective transformations of OH groups to oligosaccharides will likely be a considerable challenge, not only in terms of recognition and activation but also because of the high polarity and low solubility of these substrates in organic solvents. However, such extensions could provide powerful tools for the preparation of well-defined oligosasccharides and glycoconjugates or for the labeling or tagging of glycosylated biomolecules. The progress that has been made in site-selective catalysis using functionalized peptides, from inositol-based triols to substrates as complex as the teicoplanin derivative shown in Scheme 115, provides an inspiring illustration of what is possible in this regard. It can be anticipated that advances in synthesis will continue to provide new tools for probing and perturbing the complex functions of carbohydrates and oligosaccharides in biological systems.

ORCID

Special Issue Paper

This paper is an additional review for Chem. Rev. 2018, Volume 118, Issue 17, “Carbohydrate Chemistry”.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

Mark S. Taylor: 0000-0003-3424-4380 Notes

The authors declare no competing financial interest. Biographies Victoria Dimakos was born in Toronto, Ontario, Canada. In 2015, she received her undergraduate degree in Chemistry and Art History at the University of Toronto. As an undergraduate student, she was introduced to carbohydrate chemistry in the laboratories of both Prof. Mark Nitz and Prof. Mark S. Taylor. She began her graduate studies in 2015 at the University of Toronto in the Taylor group, where her research has focused on the development of new site-selective functionalizations of carbohydrate derivatives using organoboron reagents. Mark S. Taylor was born in Oxford, England, and grew up in Toronto. He received his B.Sc. in chemistry in 2000 from the University of Toronto, where he conducted research in the laboratory of Prof. Mark Lautens on transition metal catalysis. After graduate studies at Harvard University from 2000−2005 under the supervision of Prof. Eric Jacobsen, he took up a postdoctoral fellowship at the Massachusetts Institute of Technology, working in the research group of Prof. Tim Swager. In 2007, he returned to the Department of Chemistry at the University of Toronto, where he is Professor and Canada Research Chair in Molecular Recognition and Catalysis. His research interests span the areas of organic synthesis, catalysis, molecular recognition, and polymer chemistry. The development of organoboron catalysts and reagents for selective transformations of sugars is an ongoing project in his laboratory.

ACKNOWLEDGMENTS M.S.T. acknowledges NSERC for support of his group’s research on selective reactions of carbohydrate derivatives. V.D. acknowledges NSERC for a PGS-D3 doctoral scholarship. REFERENCES (1) Sugihara, J. M. Relative reactivities of hydroxyl groups of carbohydrates. Adv. Carbohydr. Chem. 1953, 8, 1−44. (2) Haines, A. H. Relative reactivities of hydroxyl groups in carbohydrates. Adv. Carbohydr. Chem. Biochem. 1976, 33, 11−109. (3) Miljković, M. Relative reactivity of hydroxyl groups in monosaccharides. In Carbohydrates; Springer: New York, 2010. (4) Lee, D.; Taylor, M. S. Catalyst-controlled regioselective reactions of carbohydrate derivatives. Synthesis 2012, 44, 3421−3431. (5) Taylor, M. S. Catalyst-controlled, regioselective reactions of carbohydrate derivatives. Top. Curr. Chem. 2015, 372, 125−155. (6) Jäger, M.; Minnaard, A. J. Regioselective modification of unprotected glycosides. Chem. Commun. 2016, 52, 656−664. (7) Muramatsu, W. Recent advances in the regioselective functionalization of carbohydrates using non-enzymatic catalysts. Trends Glycosci. Glycotechnol. 2016, 28, J1−J11. (8) Lawandi, J.; Rocheleau, S.; Moitessier, N. Regioselective acylation, alkylation, silylation and glycosylation of monosaccharides. Tetrahedron 2016, 72, 6283−6319. AV


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