Selective Glycosylations E-Book

• Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 605

Veröffentlichungsjahr: 2017

Beschreibung

A comprehensive summary of novel approaches to the stereoselective construction of glycosidic linkages, covering modern glycosylation methods and their use and application in natural product synthesis and drug discovery.
Clearly divided into five sections, the first describes recent advances in classical methodologies in carbohydrate chemistry, while the second goes on to deal with newer chemistries developed to control selectivity in glycosylation reactions. Section three is devoted to selective glycosylation reactions that rely on the use of catalytic promoters. Section four describes modern approaches for controlling regioselectivity in carbohydrate synthesis. The final section focuses on new developments in the construction of "unusual" sugars and is rounded off by a presentation of modern procedures for the construction of glycosylated natural products.
By providing the latest advances in glycosylation as well as information on mechanistic aspects of the reaction, this is an invaluable reference for both specialists and beginners in this booming interdisciplinary field that includes carbohydrate chemistry, organic synthesis, catalysis, and biochemistry.

Leseprobe

Table of Contents

Cover

Title Page

Copyright

List of Contributors

Preface

Part I: Introduction

Chapter 1: Stereoselective Glycosylations – Additions to Oxocarbenium Ions

1.1 Introduction

1.2 Stability, Reactivity, and Conformational Behavior of Glycosyl Oxocarbenium Ions

1.3 Computational Studies

1.4 Observation of Glycosyl Oxocarbenium Ions by NMR Spectroscopy

1.5 Oxocarbenium Ion(-like) Intermediates as Product-Forming Intermediates in Glycosylation Reactions

1.6 Conclusion

References

Chapter 2: Application of Armed, Disarmed, Superarmed, and Superdisarmed Building Blocks in Stereocontrolled Glycosylation and Expeditious Oligosaccharide Synthesis

2.1 Introduction: Chemical Synthesis of Glycosides and Oligosaccharides

2.2 Fraser-Reid's Armed–Disarmed Strategy for Oligosaccharide Synthesis

2.3 Many Reactivity Levels Exist between the Armed and Disarmed Building Blocks

2.4 Modes for Enhancing the Reactivity: Superarmed Building Blocks

2.5 Modes for Decreasing the Reactivity: Superdisarmed Building Blocks

2.6 Application of Armed and Disarmed Building Blocks in Stereocontrolled Glycosylation

2.7 Application of Armed/Superarmed and Disarmed Building Blocks in Chemoselective Oligosaccharide Synthesis

2.8 Conclusions and Outlook

References

Chapter 3: Solvent Effect on Glycosylation

3.1 Introduction

3.2 General Properties of Solvents Used in Glycosylation

3.3 Polar and Noncoordinating Solvents in Glycosylation

3.4 Weakly Polar and Noncoordinating Solvents in Glycosylation

3.5 Polar and Coordinating Solvents in Glycosylation

3.6 Weakly Polar and Coordinating Solvents in Glycosylation

3.7 Solvent Effect of Ionic Liquid on Glycosylation

3.8 Solvent Effect on Electrochemical Glycosylation

3.9 Molecular Dynamics Simulations Studies on Solvent Effect

3.10 Conclusions

References

Part II: Stereocontrolled Approaches to Glycan Synthesis

Chapter 4: Intramolecular Aglycon Delivery toward 1,2-cis Selective Glycosylation

4.1 Introduction

4.2 Ketal Type Tethers

4.3 Silicon Tethers

4.4 2-Iodoalkylidene Acetals as Tether

4.5 Benzylidene Acetals as Tether

4.6 IAD through Hemiaminal Ethers

4.7 Conclusions

References

Chapter 5: Chiral Auxiliaries in Stereoselective Glycosylation Reactions

5.1 Introduction

5.2 Neighboring Group Participation of O-2 Chiral Auxiliaries

5.3 Neighboring Group Participation of O-2 Achiral Auxiliaries

5.4 Preconfigured Chiral Auxiliaries

5.5 Conclusion

References

Chapter 6: Glycosylation with Glycosyl Sulfonates

6.1 Introduction

6.2 Formation of Glycosyl Sulfonates

6.3 Evidence for Glycosyl Sulfonates

6.4 Location of the Glycosyl Sulfonates in the General Glycosylation Mechanism

6.5 Applications in

O

-Glycoside Synthesis

6.6 Applications in

S

-Glycoside Synthesis

6.7 Applications in

C

-Glycoside Synthesis

6.8 Polymer-Supported Glycosylation with Sulfonates

6.9 Conclusion

References

Part III: Catalytic Activation of Glycosides

Chapter 7: Stereoselective C-Glycosylation from Glycal Scaffolds

7.1 Introduction

7.2 Classification of

C

-Glycosylation Reactions

7.3 Ferrier-Type Rearrangement

7.4 Pd-Catalyzed Heck-Type

7.5 Tsuji–Trost-Type

C

-Glycosylation

7.6 Sigmatropic Rearrangement

7.7 NHC-Catalyzed

C

-Glycosylations

7.8 Conclusion

References

Chapter 8: Brønsted- and Lewis-Acid-Catalyzed Glycosylation

8.1 Introduction

8.2 Chiral Brønsted Acids

8.3 Achiral Brønsted Acids

8.4 Lewis-Acid-Catalyzed Glycosylations

8.5 Metals as Lewis Acids

8.6 Synthesis of C-Glycosides

8.7 Conclusions and Outlook

References

Chapter 9: Nickel-Catalyzed Stereoselective Formation of 1,2-cis-2-Aminoglycosides

9.1 Introduction

9.2 Biological Importance of 1,2-

cis

-Aminoglycosides

9.3 Use of Nonparticipatory Groups to Form 1,2-

cis

-Aminoglycosides

9.4 Nickel-Catalyzed Formation of 1,2-

cis

-Aminoglycosides

9.5 C(2)-

N

-

Substituted Benzylidene Glycosyl Trichloroacetimidate Donors

9.6 Studies of C(2)-

N

-Substituted Benzylideneamino Glycosyl

N

-Phenyl Trifluoroacetimidate Donors

9.7 1,2-

cis

-Amino Glycosylation of Thioglycoside Acceptors

9.8 Application to the Synthesis of Biologically Active Glycans

9.9 Conclusion

References

Chapter 10: Photochemical Glycosylation

10.1 Introduction

10.2 Photochemistry Basics

10.3 Photosensitized O-Glycosylation with Chalcogenoglycoside Donors

10.4 Photochemical

O

-Glycosylation with Other Donors

10.5 Photosensitized C-Glycosylation

10.6 Conclusions

References

Part IV: Regioselective Functionalization of Monosaccharides

Chapter 11: Regioselective Glycosylation Methods

11.1 Introduction

11.2 Substrate Control: “Intrinsic” Differences in OH Group Reactivity of Glycosyl Acceptors

11.3 Substrate Control: Modulation of Acceptor OH Group Reactivity by Variation of Protective Groups

11.4 Substrate Control: Glycosyl Donor/Acceptor Matching in Regioselective Glycosylation

11.5 Reagent-Controlled, Regioselective Glycosylation

11.6 Enzyme-Catalyzed Regioselective Glycosylation

11.7 Synthetic Catalysts for Regioselective Glycosylation

11.8 Summary and Outlook

References

Chapter 12: Regioselective, One-Pot Functionalization of Carbohydrates

12.1 Introduction

12.2 Regioselective, Sequential Protection/Functionalization of Carbohydrate Polyols

12.3 Regioselective, One-Pot Protection of Sugars via TMS Protection of Polyols

12.4 Orthogonally Protected d-Glycosamine and Bacterial Rare Sugar Building Blocks via Sequential, One-Pot Nucleophilic Displacements of O-Triflates

12.5 Summary and Outlook

References

Part V: Stereoselective Synthesis of Deoxy Sugars, Furanosides, and Glycoconjugate Sugars

Chapter 13: Selective Glycosylations with Deoxy Sugars

13.1 Introduction

13.2 Challenges in 2-Deoxy-Sugar Synthesis

13.3 Protecting Group Strategies

13.4 Addition to Glycals

13.5 Additions to Glycosyl Halides

13.6 Latent Glycosyl Halides

13.7 Reagent-Controlled Approaches

13.8 Umpolung Reactivity

13.9 Conclusion

References

Chapter 14: Selective Glycosylations with Furanosides

14.1 Introduction

14.2 Construction of the Furanose Template

14.3 Stereoselective Glycosylation with Furanoside Donors

14.4 Reactivity Tuning of Furanosides for Oligosaccharide Synthesis

14.5 Conclusion

References

Chapter 15: De novo Asymmetric Synthesis of Carbohydrate Natural Products

15.1 Introduction

15.2 Danishefsky Hetero-Diels–Alder Approach

15.3 MacMillan Proline Aldol Approach

15.4 The O'Doherty Approaches

15.5 Conclusion

References

Chapter 16: Chemical Synthesis of Sialosides

16.1 Introduction

16.2 Chemical Synthesis of Sialosides

16.3 Conclusions

References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Introduction

Begin Reading

List of Tables

Chapter 1: Stereoselective Glycosylations – Additions to Oxocarbenium Ions

Table 1.1 Changing diastereoselectivity in the addition of

C

-nucleophiles of increasing reactivity.

Table 1.2 A selection of oxocarbenium ions and their calculated energies (determined by DFT calculations).

Chapter 2: Application of Armed, Disarmed, Superarmed, and Superdisarmed Building Blocks in Stereocontrolled Glycosylation and Expeditious Oligosaccharide Synthesis

Table 2.1 Survey of stereoselectivity in glycosylation with different donors.

Table 2.2 A survey of oligosaccharide sequences that can be obtained by chemoselective activation.

Chapter 3: Solvent Effect on Glycosylation

Table 3.1 mp, bp, dielectric constant, molecular dipole, donicity number, and Lewis basicity of several organic solvents that are used in various glycosylation contexts.

Table 3.2 Selectivity of glycosylations at different concentrations of 26 and 27.

Table 3.3 Ether solvent effect for glucosyl tosylates 37 and 38.

Table 3.4 Ether-containing binary solvent system in glycosylation.

Table 3.5 Use of ionic liquid as solvent in glycosylation.

Table 3.6 Population of glucosyl conformers in different solvent systems.

Chapter 4: Intramolecular Aglycon Delivery toward 1,2-cis Selective Glycosylation

Table 4.1 β-Mannosylation with chitobiose acceptors through IAD.

Chapter 5: Chiral Auxiliaries in Stereoselective Glycosylation Reactions

Table 5.1 Yields and anomeric stereoselectivity for glycosylations of donors 9-

R

/

S

with acceptor alcohols 10–14 using TMSOTf in DCM at −78 °C to form glycosides 15–19.

Table 5.2 Reaction conditions, yields, and anomeric ratios of glycosylations using donors 40a–c or 44 with acceptor 12.

Table 5.3 Yields and anomeric ratios of glycosides synthesized from

O

-2-(2-cyanobenzyl) glycosyl donor 57.

Table 5.4 Yields and anomeric ratios of products 75Ac/Bn and 76Ac/Bn synthesized using donors 73Ac/Bn and acceptors 12 and 59b, proceeding via activated aryl sulfonium ion intermediate 74.

Table 5.5 Yields and anomeric ratios of product glycosides 89–93 synthesized using oxathiane ether donor 83.

Chapter 7: Stereoselective C-Glycosylation from Glycal Scaffolds

Table 7.1 Lewis-acid-catalyzed Ferrier rearrangements with

C

-nucleophiles.

Table 7.2 Lewis-acid-catalyzed Ferrier rearrangements with pentopyranose glycal donors.

Table 7.3 Heck-type C-glycosylation with glycal donors.

Chapter 9: Nickel-Catalyzed Stereoselective Formation of 1,2-cis-2-Aminoglycosides

Table 9.1 Optimized conditions for selective formation of 1,2-

cis

-2-aminoglycosides.

Table 9.2 Substrate scope of nickel-catalyzed 1,2-

cis

-amino glycosylation.

Table 9.3 α-Selective coupling with D-galactosamine trichloroacetimidate.

Table 9.4 Initial studies of the formation of mycothiol with trichloroacetimidates.

Table 9.5 Study of

N

-phenyl trifluoroacetimidates donors.

Table 9.6 Optimization with various thiophenyl derivatives.

Table 9.7 Activation of

N

-Phenyl trifluoroacetimidate with various catalysts.

Table 9.8 Coupling of various thioglycosides with

N

-phenyl trifluoroacetimidate donors.

Table 9.9 Formation of mycothiol core pseudosaccharides.

Table 9.10 Coupling of disarmed glucuronic acid thioglycosides with disarmed and armed glucosamine donors.

Chapter 12: Regioselective, One-Pot Functionalization of Carbohydrates

Table 12.1 Kong's approach for one-pot protection of free sugars.

Selective Glycosylations

Synthetic Methods and Catalysts

Edited by Clay S. Bennett

Editor

Prof. Clay S. Bennett

Tufts University

Department of Chemistry

62 Talbot Ave.

Medford, MA 02155

United States

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List of Contributors

Mithila D. Bandara

University of Missouri - St. Louis

Department of Chemistry and Biochemistry

One University Blvd.

St. Louis, MO 63121

USA

David Benito-Alifonso

University of Bristol

School of Chemistry

Cantock's Close

Bristol BS8 1TS

UK

Clay S. Bennett

Tufts University

Department of Chemistry

62 Talbot Ave.

Medford, MA 02155

USA

Luis Bohé

Institut de Chimie des Substances Naturelles

CNRS-ICSN UPR2301

Université Paris-Sud

Avenue de la Terrasse

91198 Gif-sur-Yvette

France

Robin Brabham

York Structural Biology Laboratory

Department of Chemistry

University of York

Heslington, York

YO10 5DD

UK

Jeroen D.C. Codée

Leiden University

Leiden Institute of Chemistry

PO Box 9502

2300 RA Leiden

The Netherlands

David Crich

Wayne State University

Department of Chemistry

5101 Cass Ave.

Detroit, MI 48202

USA

Alexei V. Demchenko

University of Missouri - St. Louis

Department of Chemistry and Biochemistry

One University Blvd.

St. Louis, MO 63121

USA

Alisa E. R. Fairweather

University of Iowa

Department of Chemistry

E331 Chemistry Building

Iowa City, IA 52245

USA

Martin A. Fascione

York Structural Biology Laboratory

Department of Chemistry

University of York

Heslington, York

YO10 5DD

UK

M. Carmen Galan

University of Bristol

School of Chemistry

Cantock's Close

Bristol BS8 1TS

UK

Carola Gallo-Rodriguez

Universidad de Buenos Aires

CIHIDECAR Departamento de Química Orgánica

Ciudad Universitaria, Pabellón II

1428 Buenos Aires

Argentina

Bas Hagen

Leiden University

Leiden Institute of Chemistry

PO Box 9502

2300 RA Leiden

The Netherlands

Thomas Hansen

Leiden University

Leiden Institute of Chemistry

PO Box 9502

2300 RA Leiden

The Netherlands

Kim Le Mai Hoang

Nanyang Technological University

Division of Chemistry and Biological Chemistry

School of Physical and Mathematical Sciences

SPMS-CBC-02-01

21 Nanyang Link, 637371

Singapore

Akihiro Ishiwata

RIKEN

Synthetic Cellular Chemistry Laboratory

2-1 Hirosawa Wako

Saitama 351-0198

Japan

Yukishige Ito

RIKEN

Synthetic Cellular Chemistry Laboratory

2-1 Hirosawa Wako

Saitama 351-0198

Japan

Gustavo A. Kashiwagi

Universidad de Buenos Aires

CIHIDECAR Departamento de Química Orgánica

Ciudad Universitaria, Pabellón II

1428 Buenos Aires

Argentina

Suvarn S. Kulkarni

Indian Institute of Technology Bombay

Department of Chemistry

Powai

Mumbai 400076

India

Wei-Lin Leng

Nanyang Technological University

Division of Chemistry and Biological Chemistry

School of Physical and Mathematical Sciences

SPMS-CBC-02-01

21 Nanyang Link, 637371

Singapore

Yu-Hsuan Lih

Genomics Research Center, Academia Sinica

128 Academia Road, Section 2, Nankang

Taipei 115

Taiwan

Xue-Wei Liu

Nanyang Technological University

Division of Chemistry and Biological Chemistry

School of Physical and Mathematical Sciences

SPMS-CBC-02-01

21 Nanyang Link, 637371

Singapore

Ravi S. Loka

University of Iowa

Department of Chemistry

E331 Chemistry Building

Iowa City, IA 52245

USA

Gijs van der Marel

Leiden University

Leiden Institute of Chemistry

PO Box 9502

2300 RA Leiden

The Netherlands

KwoK-Kong Tony Mong

National Chiao Tung University

Applied Chemistry Department

1001 Ta Hsueh Road

Hsinchu 300

Taiwan ROC

Hien M. Nguyen

University of Iowa

Department of Chemistry

E331 Chemistry Building

Iowa City, IA 52245

USA

Pham Be Nhi

National Chiao Tung University

Applied Chemistry Department

1001 Ta Hsueh Road

Hsinchu 300

Taiwan ROC

Toshiki Nokami

Tottori University

Department of Chemistry and Biotechnology

4-101 Koyama-Minami

Tottori city

680-8552 Tottori

Japan

George A. O'Doherty

Northeastern University

Department of Chemistry and Chemical Biology

360 Huntington Ave.

Boston, MA 02115

USA

Justin Ragains

Louisiana State University

Department of Chemistry

232 Choppin Hall

Baton Rouge, LA 70803

USA

Pei Shi

Corden Pharma

1-B Gill Street

Woburn, MA 01801

USA

Eric T. Sletten

University of Iowa

Department of Chemistry

E331 Chemistry Building

Iowa City, IA 52245

USA

Yu-Jia Tan

Nanyang Technological University

Division of Chemistry and Biological Chemistry

School of Physical and Mathematical Sciences

SPMS-CBC-02-01

21 Nanyang Link, 637371

Singapore

Mark S. Taylor

University of Toronto

Department of Chemistry

80 St. George Street

Toronto, ON M5S 3H6

Canada

Nhut Thi Thanh Tran

National Chiao Tung University

Applied Chemistry Department

1001 Ta Hsueh Road

Hsinchu 300

Taiwan ROC

Stefan van der Vorm

University of Leiden

Leiden Institute of Chemistry

PO Box 9502

2300 RA Leiden

The Netherlands

Chung-Yi Wu

Genomics Research Center, Academia Sinica

128 Academia Road, Section 2, Nankang

Taipei 115

Taiwan

Jagodige P. Yasomanee

University of Missouri - St. Louis

Department of Chemistry and Biochemistry

One University Blvd.

St. Louis, MO 63121

USA

Preface

The past decade has seen increased recognition of the important roles oligosaccharides play in an array of biological process including (but not limited to) protein folding, pathogen invasion, cell adhesion, and immune response. As a consequence, the field of glycoscience is undergoing rapid growth, with an ever-increasing number of investigators turning their attention to it. Despite all of this, the field is still in its infancy, especially compared to other areas of biology such as genomics and proteomics. There are several reasons for this; chief among them is the fact that glycoscientists do not enjoy ready access to homogeneous material for study, an advantage that was critical for the advances in other areas of biomedical research. This is because, unlike the other major classes of biopolymers, cells produce carbohydrates as heterogeneous mixtures, which are often intractable. As a consequence, organic synthesis (including chemoenzymatic synthesis) remains the only avenue for the production of pure oligosaccharides for biomedical evaluation. The synthesis of most oligosaccharides is a nontrivial undertaking, however, owing to issues of regiochemistry and stereochemistry. Thus, while chemical glycosylation has been known for over a century, the construction of a new oligosaccharide can still be a research project in and of itself.

Among the challenges facing the chemist who wishes to synthesize oligosaccharides, one of the most significant is controlling selectivity in the glycosylation reaction. Typical glycosylation reactions proceed through a mechanism somewhere along the SN1–SN2 continuum, which renders controlling selectivity in the reaction immensely difficult. While several elegant solutions to this problem have been devised, a general approach to controlling selectivity in glycosylation reactions with a broad range of substrates remains to be developed. This has prompted calls for the development of new approaches to glycosylation from numerous sectors. Before embarking on developing a new approach to glycosylation, however, it is first necessary to understand the advances that currently constitute the state of the art. The purpose of this volume is to describe the principles of chemical glycosylation. Rather than break down the text into chapters focusing on activating different classes of leaving groups, the focus is instead largely on mechanistic aspects that are responsible for selectivity. Furthermore, technologies for automated and one-pot synthesis have been extensively reviewed elsewhere and will only be covered when relevant.

This volume is organized into five parts. The first part deals with an introduction to the basic principles or carbohydrate synthesis. In Chapter 1, Codeé et al. outline the factors responsible for controlling additions to oxocarbenium cations. Next, Demchenko and coworkers describe the roles protecting groups play in both attenuating glycan reactivity and controlling stereoselectivity in glycosylations in Chapter 2. This part concludes with Chapter 3 from Mong, Nokami, and coworkers, which details the roles solvents play in controlling the stereochemical outcome of glycosylation.

Part II describes ways in which electrophilic glycosyl donors can be modified to undergo selective reactions. In Chapter 4, Ishiwata and Ito provide a detailed introduction to the use of Intramolecular Aglycone Delivery (IAD) for the stereoselective synthesis of cis-1,2-glycans. This is followed by a discussion of the use of chiral auxiliaries in oligosaccharide synthesis by Brabham and Fascione in Chapter 5. Finally, Bohé and Crich describe how glycosyl sulfonates permit the construction of the so-called difficult linkages through SN2-like glycosylations in Chapter 6.

The development of methods for catalytic activation of glycosyl donors is the focus of Part III. This part begins with a description of methods for the construction C-glycans, often through transition-metal-mediated processes, by Liu et al. in Chapter 7. This is followed by a comprehensive overview of recent approaches for catalytic activation of donors for O-glycosylation by Benito-Alfonso and Galan in Chapter 8. In Chapter 9, Nguyen and coworkers provide a case study in catalytic activation, focusing on their Ni-catalyzed 1,2-cis-glycoside synthesis. This part concludes with an introduction to the increasingly popular field of photochemical glycosylation by Ragains in Chapter 10.

In addition to the challenges in controlling the stereochemical outcome of glycosylation reactions, regioselectivity is a problem the synthetic chemist must attend to when dealing with glycosides. Current state-of-the-art approaches to addressing this issue are outlined in Part IV of the volume. In Chapter 11, Taylor provides us with a discussion of methods for regioselectively glycosylating unprotected glycosyl acceptors. This is followed by a discussion of methods for one-pot protection and functionalization of unprotected glycans by Kulkarni in Chapter 12.

The final part of the volume provides the reader with examples of classes of glycans where standard approaches to glycosylation do not always apply. This begins with an overview of recent advances in 2-deoxy-sugar synthesis by Bennett in Chapter 13. Gallo-Rodriguez and Kashiwagi follow this up with an introduction to the challenging issue of controlling selectivity in glycosylations with furanoside donors (Chapter 14). Next, Shi and O'Doherty provide us with a description of how the de novo synthesis can permit the construction of a number of carbohydrate natural products in Chapter 15. Finally, Lih and Wu provide an overview of the state of the art in the synthesis of sialic acids in Chapter 16.

The goal of this volume is to try to provide a holistic view of chemical glycosylation. Our target audience is not limited to individuals who are currently engaged in carbohydrate chemistry but extends to the larger synthetic community, many of whom may be new to the field. Our hope is that this volume will inspire investigators to make new, and ideally unforeseen, contributions to the field. We do this because we believe that it will be necessary to engage as many investigators as possible if we are to achieve the long-term goal of developing technologies that will permit the routine and rapid construction of oligosaccharide libraries that are desperately needed for the study of glycobiology.

Medford, MA, USA

Clay S. Bennett

Tufts University

Part IIntroduction

Chapter 1Stereoselective Glycosylations – Additions to Oxocarbenium Ions

Bas Hagen, Stefan van der Vorm, Thomas Hansen, Gijs A. van der Marel, and Jeroen D.C. Codée

1.1 Introduction

Tremendous progress has been made in the construction of oligosaccharides, and many impressive examples of large and complex oligosaccharide total syntheses have appeared over the years [1]. At the same time, the exact mechanism underlying the union of two carbohydrate building blocks often remains obscure, and optimization of a glycosylation reaction can be a time- and labor-intensive process [2, 3]. This can be explained by the many variables that affect the outcome of a glycosylation reaction: the nature of both the donor and acceptor building blocks, solvent, activator and activation protocol, temperature, concentration, and even the presence and the type of molecular sieves. The large structural variety of carbohydrates leads to building blocks that differ significantly in reactivity, with respect to both the nucleophilicity of the acceptor molecule and the reactivity of the donor species. The reactivity of a donor is generally related to the capacity of the donor to accommodate developing positive charge at the anomeric center, upon expulsion of the anomeric leaving group. This also determines the amount of carbocation character in the transition state leading to the products. Most glycosylation reactions will feature characteristics of both SN1- and SN2-type pathways in the transition states leading to the products. It is now commonly accepted that the exact mechanism through which a glycosidic linkage is formed can be found somewhere in the continuum of reaction mechanisms that spans from a completely dissociative SN1 mechanism on one side to an associative SN2 pathway on the other side (Figure 1.1) [4–6]. On the SN1-side of the spectrum, glycosyl oxocarbenium ions are found as product-forming intermediates. On this outer limit of the reaction pathway continuum, the oxocarbenium ions will be separated from their counterions by solvent molecules (solvent-separated ion pairs, SSIPs), and there will be no influence of the counterion on the selectivity of the reaction. Moving toward the SN2 side of the spectrum contact (or close) ion pairs (CIPs) are encountered, and in reactions of these species, the counterion will have a role to play. Because glycosylation reactions generally occur in apolar solvents (dichloromethane is by far the most used one), ionic intermediates have very limited lifetimes, and activated donor species will primarily be present as a pool of covalent intermediates. The stability, lifetime, and reactivity of an oxocarbenium ion depend – besides the nature of the counterion – on the nature and orientation of the functional groups present on the carbohydrate ring. This chapter explores the role of oxocarbenium ions (and CIPs, featuring a glycosyl cation) in chemical glycosylation reactions. While it was previously often assumed that glycosylations, proceeding via an oxocarbenium ion intermediate, show poor stereoselectivity, it is now clear that oxocarbenium ions can be at the basis of stereoselective glycosylation events. The first part of this chapter deals with the stability, reactivity, and conformational behavior of glycosyl oxocarbenium ions, whereas the second part describes their intermediacy in the assembly of (complex) oligosaccharides.

Figure 1.1 Continuum of mechanisms to explain the stereochemical course of glycosylation reactions.

1.2 Stability, Reactivity, and Conformational Behavior of Glycosyl Oxocarbenium Ions

Amyes and Jencks have argued that glycosyl oxocarbenium ions have a short but significant lifetime in aqueous solution [7]. They further argued that in the presence of properly positioned counterions (such as those derived of expulsion of an aglycon), CIPs will rapidly collapse back to provide the covalent species and that the “first stable intermediate for a significant fraction of the reaction” should be the solvent-separated oxocarbenium ion. By extrapolation of these observations to apolar organic solvents, Sinnott reached the conclusion that intimate ion pairs have no real existence in an apolar environment, such as used for glycosylation reactions [8]. Hosoya et al. have studied CIPs by quantum mechanical calculations in dichloromethane as a solvent [9]. In these calculations, they have included four solvent molecules to accurately mimic the real-life situation. In many of the studied cases, CIPs turned out to be less stable than the corresponding solvent-separated ions, as will be described next [10]. Yoshida and coworkers have described that activation of thioglucoside 1 with a sulfonium salt activator, featuring the bulky nonnucleophilic tetrakis(pentafluorophenyl) borate counterion, in a continuous-flow microreactor, provides a reactive species (2) that has a lifetime on the order of a second (Scheme 1.1) [11]. They argued that this species was a glucosyl oxocarbenium ion, “somewhat stabilized” by the disulfide generated from the donor aglycon and the activator.

Scheme 1.1 Generation of glucosyl oxocarbenium ions in a continuous-flow microreactor.

The stability of a glycosyl oxocarbenium ion is largely influenced by the substituents on the carbohydrate ring. The electronegative substituents (primarily oxygen, but also nitrogen-based) have an overall destabilizing effect on the carbocation, and the destabilizing effect can be further enhanced by the presence of electron-withdrawing protecting groups, such as acyl functions. The exact position of the substituent on the ring and its orientation influence the stability of the anomeric cation. The combined influence of all substituents on the ring determines the reactivity of a glycosyl donor, and the extensive relative reactivity value (RRV) charts, drawn up by the Ley and Wong groups for a large panel of thioglycosides, clearly illustrate these functional group effects [12–14]. From these RRV tables, it is clear that the donor reactivity spectrum spans at least eight orders of magnitude. To investigate the influence of the carbohydrate ring substituents on the stereochemical outcome of a glycosylation reaction, Woerpel and coworkers have systematically studied C-glycosylation reactions of a set of furanosides and pyranosides, featuring a limited amount of ring substituents [15–20]. Their studies in the furanose series are summarized in Scheme 1.2a [15, 17]. As can be seen, the alkoxy groups at C2 and C3 have a strong influence on the stereochemical outcome of the reaction, where the alkoxy group at C5 appears to have less effect on the reaction. The presence of an alkoxy or alkyl group at C3 leads to the formation of the allylglycosides 11 and 12 with opposite stereoselectivity. Woerpel and coworkers have devised a model to account for these stereodirecting substituent effects that takes into account the equilibrium between two possible envelope oxocarbenium ion conformers (13 and 14, Scheme 1.2b) [17]. Attack on these oxocarbenium ion conformers by the nucleophile occurs from the “inside” of the envelopes, because this trajectory avoids unfavorable eclipsing interactions with the substituent at C2, and it leads, upon rehybridization of the anomeric carbon, to a fully staggered product (15 and 16), where attack on the “outside” would provide the furanose ring with an eclipsed C1–C2 constellation. The spatial orientation of the alkoxy groups influences the stability of the oxocarbenium ions. An alkoxy group at C3 can provide some stabilization of the carbocation when it takes up a pseudo-axial position. Stabilization of the oxocarbenium ion featuring a C2-alkoxy group is best achieved by placing the electronegative substituent in a pseudo-equatorial position to allow for the hyperconjugative stabilization by the properly oriented C2–H2 bond. Alkyl substituents at C3 prefer to adopt a pseudo-equatorial position because of steric reasons. With these spatial substituent preferences, the stereochemical outcome of the C-allylation reactions in Scheme 1.2 can be explained. Activation of the C3-benzyloxyfuranosyl acetate with SnBr4 can provide an oxocarbenium ion intermediate that preferentially adopts an E3 conformation, as in 14. Nucleophilic attack on this conformer takes place from the diastereotopic face that leads to the 1,3-cis product. In a similar vein, inside nucleophilic attack on the C2-benzyloxy furanosyl oxocarbenium ion E3 conformer, derived from furanosyl acetate 4, accounts for the stereochemical outcome of the C-allylation leading to product 9.

Scheme 1.2 (a) Diastereoselective C-allylations of furanosyl acetates. (b) “Inside” attack model.

To accurately gauge the combined effect of multiple substituents on a furanosyl ring, van Rijssel et al