The Experimental Evidence in Support of Glycosylation Mechanisms at the SN1-SN2 Interface

Abstract

A critical review of the state-of-the-art evidence in support of the mechanisms of glycosylation reactions is provided. Factors affecting the stability of putative oxocarbenium ions as intermediates at the S_N1 end of the mechanistic continuum are first surveyed before the evidence, spectroscopic and indirect, for the existence of such species on the time scale of glycosylation reactions is presented. Current models for diastereoselectivity in nucleophilic attack on oxocarbenium ions are then described. Evidence in support of the intermediacy of activated covalent glycosyl donors is reviewed, before the influences of the structure of the nucleophile, of the solvent, of temperature, and of donor-acceptor hydrogen bonding on the mechanism of glycosylation reactions are surveyed. Studies on the kinetics of glycosylation reactions and the use of kinetic isotope effects for the determination of transition-state structure are presented, before computational models are finally surveyed. The review concludes with a critical appraisal of the state of the art.

Figure 1

Carbenium and Resonance Stabilized Oxocarbenium Ions

Figure 2

The σ-π and τ Bond Models for Oxocarbenium Ions

Figure 3

Relative Rates of Solvolysis of 1-Adamantanyl Tosylate and 2-Oxa-1-adamantanyl Tosylate

Figure 4

Stable α-Oxa Triflates

Figure 5

Retardation of Relative Rates of Solvolysis by β-C-O Bonds

Figure 6

Structure and Preferred Conformations of 1-Alkoxyoxocarbenium Ions as a Function of the Substituent

Figure 7

Plot of the Negative Logarithm of the Rate Constant for Spontaneous Hydrolysis of 2,4-Dinitrophenyl Glycosides versus the Sum of Stereoelectronic Constants for the Substrate

Figure 8

Comparison of the Relative Reactivity of Glycosyl Donors with the pK_a of the Corresponding Piperidinium Ions

Figure 9

Dominant Solution Conformations of the 2,3-Dideoxy-4,6-di-O-benzyl-1-ethoxy, 2-Deoxy-3,4,6-tri-O-benzyl-1-ethoxy glucopyranosyl, and 1-Ethoxy-5-Benzyloxymethyltetrahydropyranosyl Oxocarbenium Ions with Emphasis on the Side Chain Conformation

Figure 10

Influence of C7 Configuration on Reactivity and Selectivity in the Sialic Acids

Figure 11

Enforced gg Conformation Reduces Equatorial Selectivity in Mannopyranosylation

Figure 12

Crystallographically Established Structures of Bicyclic Glycosyl Sulfonium Ions

Figure 13

Reactivity Sequence of a Series of Thioglycosides Toward Activation by N-Iodosuccinimide and Trimethylsilyl Triflate

Figure 14

Relative Reactivity Order of Two NMR Characterized Glycosyl Sulfonium Ions

Figure 15

Glycosyl Nitrilium Ions Characterized by NMR Spectroscopy

Figure 16

Three Component Transition State with Dual Function of the Phosphoric Acid

Figure 17

Hypothetical Four-component Transition State Accounting for the Roles of a Thiourea and a Phosphoric Acid in Organocatalyzed Glycosylation with a Trichloroacetiomidate Donor

Figure 18

Computationally Derived Transition State for Macrocyclic Bisthiourea Promoted S_N2-Like Galactosylation^,

Figure 19

Correlation of Anomeric Selectivity and Specific Rotation of the Solution in an Arabinofuranosylation Reaction

Figure 20

Computed Methanol Adducts with the 4,6-O-Benzylidene Protected Manno- and Glucopyranosyl Oxocarbenium Ions Including Donor-Acceptor Hydrogen Bonds

Figure 21

Computationally-Located Transition State for the S_N2-Like Opening of a Bicyclic Sulfonium Ion Reveals a Key Hydrogen Bond to the O3 Carboxylate

Figure 22

Kinetics-Derived Associative Transition State for the Reaction of Acetobromoglucose with Alcohols and an Insoluble Silver Salt.

Figure 23

Experimental and Computed ¹³C Primary Kinetic Isotope Effects for the 4,6-O-Benzylidene Directed Manno- and Glucopyranosylation and an Experimental and Computed Secondary Deuterium KIE for β-Mannoside Formation

Figure 24

Plot of Mannoside to Cyclization Ratio vs Acceptor Concentration for Mannosylation Following Scheme 64.

Figure 25

Schematic Representation of the Change in the Per-O-methylmannopyranosyl Oxocarbenium Ion Conformation and Counterion Location with Solvent Dielectric Constant When ion Pair Collapse is Prevented

Figure 26

Computed Per-O-Methyl Glucopyranosyl Oxocarbenium Ion Pairs with Explicit Dichloromethane-Solvation

Scheme 1

The Glycosylation Reaction

Scheme 2

The Glycosylation Reaction with the Two Limiting Associative Mechanisms and the Central Dissociative Limiting Mechanism

Scheme 3

Barrier to Rotation about the C-O π Bond in the 7-Methoxy-7-norbornyl Carbenium Ion Determined by VT NMR

Scheme 4

Substitution of a Phenylthiomethyl Glycoside without Fragmentation

Scheme 5

Hydrolysis of Isopropenyl Glycosides Does not Involve Glycosyl Oxocarbenium Ions

Scheme 6

Generation of Glycosyl Oxocarbenium Ions in Superacidic Media

Scheme 7

Preferential Loss of Protium over Deuterium from Two Diastereomeric Sialyl Thioglycosides Suggestive of Equilibrating Oxocarbenium Ions

Scheme 8

Loss of the Pseudoaxial Deuterium from a Conformationally Locked System

Scheme 9

Equilibration and Cyclization of a Transient Mannopyranosyl Oxocarbenium Ion in CH₂Cl₂ at −20 °C

Scheme 10

Formation and Cyclization of a Transient Glucopyranosyl Oxocarbenium Ion in CH₂Cl₂ at −20 °C

Scheme 11

trans-Selective Formation of a Bicyclic Acetal Indicative of Direct Displacement of an α-Triflate

Scheme 12

Intramolecular Sialidation Reactions

Scheme 13

Threshold ESI Cone Voltages for the Fragmentation of Sialyl Phosphates as a Function of O4 and N5 Protecting Groups and Their Dipoles

Scheme 14

Formation of an Oxocarbenium Ion by Protonation of a Glycosylidene Carbene

Scheme 15

Facial Selectivity in the Reaction of Allylsilane with Per-O-benzyl Lyxopyranosyl Acetate

Scheme 16

Operation of Curtin Hammett-Type Kinetics in Nucleophilic Attack on the Gluco- and Mannopyranosyl Oxocarbenium Ions

Scheme 17

Woerpel’s Inside Attack Model for the Reactions of Furanosyl Oxocarbenium Ions

Scheme 18

1,2-cis-Selective Attack on the Lyxofuranosyl Oxocarbenium Ion^{a a}Experimental work employed benzyl ethers while computations were conducted with methyl ethers

Scheme 19

tau-Bond Model for Nucleophilic Attack on the 4,6-O-Benzylidene-Protected Gluco and Mannopyranosyl Oxocarbenium Ions with Preferential Attack Antiperiplanar to the Lower Energy tau Bond (in Red)

Scheme 20

Formation of 2-Chloro-2-deoxy-gluco- and Mannopyranosyl Perchlorates from the Corresponding Chlorides

Scheme 21

Formation of a Glycosyl Toluenesulfonate by Metathesis with the Corresponding Bromide

Scheme 22

Identification and Characterization of Glycosyl Triflates in the Mannopyranosyl Series

Scheme 23

Formation and Characterization of Glycosyl Mesitylenesulfonates from Thioglycosides with Mesitylenesulfonyl Hydroxylamine

Scheme 24

Formation and Characterization of Glycosyloxyphosphonium Salts

Scheme 25

NMR Characterization of a cis-Fused Bicyclic Sulfonium Ion

Scheme 26

Observation of a trans-Fused Bicyclic Sulfonium Ion as a Possible but not Necessary Intermediate in β-Selective Mannosylation with a 3,6-Mannuronolactone-Based Donor

Scheme 27

Alternative Intermediates Tentatively Identified by NMR Spectroscopy in β-Selective Mannosylation with a 3,6-Mannuronolactone-Based Donor

Scheme 28

Formation, Characterization and Displacement of a Glycosyl Isouronium Salt

Scheme 29

The Lemieux Bromide Ion Catalysis Concept for the Synthesis of α-Glycosides

Scheme 30

Equilibrating Furanosyl Bromides Identified by NMR Spectroscopy in the Synthesis of Nucleosides

Scheme 31

Rates of In Situ Anomerization of Glycosyl Mesylates Determined by EXSY

Scheme 32

Intermolecular Trapping of a Glycosyl Nitrilium Ion

Scheme 33

Intramolecular Trapping of a Glycosyl Nitrilium Ion

Scheme 34

Isolation of an N-Acetyl Sialyl N-glycoside Indicative of Intermediate Nitrilium Ion Formation

Scheme 35

Hypothesis for the Selectivity of 4,6-O-Benzylidene-Directed Mannosylation Based on the Order of Mixing

Scheme 36

β-Mannoside Formation in the Absence of Triflate with Trimethylsilyl Tetrakis(pentafluorophenyl)borate as Promotor

Scheme 37

β-Mannoside Formation in the Presence of Only Catalytic Triflate or in the Presence of Perchlorate

Scheme 38

Role of Lithium Triflate in Overcoming Fluoride Abstraction on Activation of a Mannosyl Trichloroacetimidate in the Presence of the Acceptor by Boron Trifluoride Etherate

Scheme 39

Counterion Sensitive Outcome of a Gold-Catalyzed β-Mannosylation Reaction

Scheme 40

Counterion Sensitive Outcome of a β-Mannosylation Reaction Employing β-Mannosyl Trichloroacetimidates as Donors

Scheme 41

Identification of Counter-ion Dependent Divergent Mechanistic Pathways by Diffusion Ordered NMR Spectroscopy

Scheme 42

Donor Configuration Dependent Selectivity in Glycosylation Reactions of 2,6-Mannuronolactone Based Donors

Scheme 43

Counterion Dependent Selectivity in Glucosylation Reactions

Scheme 44

Dependence of Reaction Time on the Concentration of the Nucleophilic 3,3-Difluoro-2-oxindole Additive Suggestive of the Formation of a Covalent Intermediate

Scheme 45

Dependence of Selectivity on the Absolute Configuration of an Added Phosphoric Acid

Scheme 46

Regioselective Polyol Glycosylation with Formation of an Intermediate Glycosyl Phosphate

Scheme 47

Concerted Cyclization of a Tethered Alcohol onto a Glycal in the Presence of a Chiral Phosphoric Acid

Scheme 48

Use of a 2-Deuteriogalactal to Probe the Selectivity of Addition and a Hypothetical Four-Component Transition State

Scheme 49

Double Diastereodifferentiation in Glycosylation

Scheme 50

Complete Kinetic Analysis of a Borinate-Catalyzed Heterogeneous Glycosylation Indicating an Associative Mechanism

Scheme 51

Complete Kinetic Analysis of a Borinate-Catalyzed Homogeneous Glycosylation Indicating an Associative Mechanism (PMP = pentamethylpiperidine)

Scheme 52

Boronic Acid Catalyzed β-Mannosylation of with a 1,2-Anhydromannopyranose Derivative

Scheme 53

Influence of Solvent in the Formation of a Mannosyl Phosphate

Scheme 54

Use of VT NMR Spectroscopy to Identify the Minimum Temperature for Clean Activation

Scheme 55

Stereodirecting Donor-Acceptor Hydrogen Bonding Aided by the Presence of a Picolyl Group in the Donor

Scheme 56

Kinetics Derived Early Depiction of the Application of Winstein’s Ion Pair Theory to Glycosylation

Scheme 57

Bimolecular Displacement of Chloride from Acetochloroglucose by Chloride as Revealed by Isotopic Labelling and Kinetics

Scheme 58

Early Ion Pair Mechanism for the Reactions of Glycosyl Sulfonates

Scheme 59

Associative Mechanism for Cyclization of a 1-(2-Hydroxymethylphenyl)-1,2-Anhydro Sugar Requires Assistance from Two Molecules of Methanol as Revealed by Kinetic Analyses

Scheme 60

Secondary Deuterium KIEs Reveal Associative Mechanisms for the Formation of α- and β-Mannosides from Mannosyl Iodides

Scheme 61

DKIE-Supported Transition State for the Formation of a β-Mannoside from the Corresponding α-Mannosyl Chloride on Promotion by a Macrocyclic Bisthiourea

Scheme 62

Experimental and Computational Primary and Secondary KIEs Supporting an Exploded S_Ni Mechanism for the Boronic Acid-Catalyzed Glycosylation of a Polyol by a 1,2-Anhydroglucopyranose

Scheme 63

Deuterium Kinetic Isotope Effects Support the Intermediacy of an Oxocarbenium Ion in Furanosylation with a 2,3-Anhydro Furanosyl Thioglycoside

Scheme 64

The Cation Clock Concept

Scheme 65

Dependence of Selectivity in an Arabinofuranosylation on Donor Concentration