Regioselective Functionalization of Polyols via Organoboron

Regioselective Functionalization of Polyols via

Organoboron Catalysis

by

Lina Chan

A thesis submitted in conformity with the requirements for the degree of Masters of Science Graduate Department of Chemistry

University of Toronto

© Copyright by Lina Chan, 2011

ii

Regioselective Functionalization of Polyols via Organoboron

Catalysis

Lina Chan

Masters of Science

Department of Chemistry

University of Toronto

2011

Abstract

With the increasing realization of their involvement in numerous biological processes, synthetic

oligosaccharides present promising potential in drug and vaccine discovery. Selective

functionalization of hydroxy groups in polyols represent a long-standing goal in chemistry since

the chemical synthesis of O-glycosides often requires extensive protecting group manipulation.

Organoboron catalysis is a recent strategy for regioselective activation of the equatorial hydroxy

group of cis-vicinal diols. Following the initial findings that diarylborinic acid catalyzes the

regioselective acylation of carbohydrate derivatives, kinetic studies were conducted to obtain

better insight on the mechanism. Thereafter, the ability of diarylborinic acid to catalyze the

regioselective alkylation of carbohydrates was demonstrated. Finally, investigations in the

capability of diarylborinic acid to influence regiochemical outcome of glycosylation reactions

were explored. Similarly, kinetic experiments were devised to shed light on the mechanism of

the reaction.

iii

Dedication:

This dissertation is dedicated to Keith Fagnou.

Being the best is nothing. Being the best and being modest is everything.

iv

Acknowledgments

First and foremost, I am thankful to my family. Without their encouragement and belief in me, I

would have not been able to come this far. While everyone else’s kid went to medical or law

school, my parents didn’t force that on me. They let me pick my own path and supported it no

matter what, and that is something I greatly admire about them.

I am eternally grateful to Dr. Keith Fagnou. He has changed my life and everyone who has been

part of the Fagnou lab understands where I am coming from when I say he was a great mentor

and friend. I am glad I got the chance to join his lab and if it weren’t for him, all the

opportunities I’ve been given since then would have never happened.

I can’t say that without mentioning Malcolm Huestis and David Stuart. Most of the success I

have achieved was guided by their chemistry advice, and now I am especially thankful to

Malcolm as he is always looking out for me. I would like to thank Ho-yan Sun and David

Lapointe for always having time to help me out again and again. It was awesome being able to

work with such a great people and I’m definitely proud to be a Fagnou girl.

Over my time at the University of Toronto, Dr. Mark S. Taylor has given me guidance, support,

and the opportunity of a lifetime, and I truly thank him. Working in his lab, I experienced a lot

and did some ‘sweet’ chemistry! I hope to take all that I have learned and continue to grow.

A big thank you to the Taylor gang! I am especially thankful to Corey McClary and Alice Wei.

When I first joined the Taylor lab, Corey and Alice were the people who made me feel truly

welcome. I also want to thank Christina Gouliaras, as she has been with me through all the harsh

times in Ottawa and Toronto.

A special thank you goes to Kevin Kou for helping me waste the evenings on endless

conversations, and for truly believing in me. I hope we’ll be friends for a lifetime.

Lastly, I want to thank my very awesome supervisor at Genentech, Mike Siu. Thanks Mike! For

giving me a chance that literally changed my life.

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Table of Contents

Abstract ................................................................................................................... ii

Acknowledgments ...................................................................................................vi

Table of Contents.....................................................................................................v

List of Abbreviations ........................................................................................... viii

List of Tables ......................................................................................................... xii

List of Figures .......................................................................................................xiv

List of Schemes.................................................................................................... xvii

Chapter 1: Mechanistic Studies on the Monofunctionalization of Polyols by

Boron Catalysis ...................................................................................................... 1 1.0 Introduction...................................................................................................................... 1

1.1 Mechanistic Proposal of Borinic Acid-Catalyzed Functionalization of Diols ............ 6

1.2 Kinetic Studies on the Mechanism ................................................................................. 7 1.2.1 Pseudo First-order Kinetics in cis-1,2-Cyclohexanediol .........................................................9 1.2.2 Dependence of the Initial Rate on the Concentration of 4-Toluenesulfonyl Chloride ..........10 1.2.3 Dependence of the Initial Rate on the Concentration of N,N-Diisopropylethylamine ..........12 1.2.4 Dependence of the Initial Rate on the Concentration of 2-Aminoethyl Diphenylborinate

…………………...………………………………………………………………….……...…………13 1.2.5 Effect of 2-Aminoethanol ......................................................................................................15 1.2.6 Electronic and Steric Effects on Reactivity ...........................................................................18

1.3 Conclusion ...................................................................................................................... 24

Chapter 2: Regioselective Alkylation of Carbohydrate Derivatives Catalyzed

by a Diarylborinic Acid Derivative ..................................................................... 26 2.0 Introduction.................................................................................................................... 26

2.1 Reactivity of the Hydroxy Group................................................................................. 27

2.2 Reductive Cleavage of Benzylidene Acetals ................................................................ 29

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2.3 Organotin-Mediated Regioselective Alkylation .......................................................... 31 2.3.1 Stannyl Ethers ........................................................................................................................32 2.3.2 Stannylene Acetals .................................................................................................................36

2.4 Other Transition Metal Promoted Alkylations........................................................... 39

2.5 Boron Activation of Hydroxy Groups for Regioselective Alkylation ....................... 41

2.6 Diarylborinic Acid Catalyzed Regioselective Alkylation ........................................... 43 2.6.1 Synthesis of the Carbohydrate Substrates ..............................................................................44 2.6.2 Reaction Development and Extension of Scope ....................................................................45

2.7 Monoalkylation via Halide Catalysis ........................................................................... 54

2.8 DFT Calculations ........................................................................................................... 58

2.9 Conclusion ...................................................................................................................... 59

Chapter 3: Regioselective Glycosylation by a Diarylborinic Acid Derivative 61 3.0 Introduction.................................................................................................................... 61

3.1 Inherent Reactivity of Hydroxy Groups in Glycosylations........................................ 62

3.2 Regioselective Glycosylations of Carbohydrate Derivatives via Activating Agents 64 3.2.1 Activation via Organotin Reagents ........................................................................................65 3.2.2 Activation via Arylboronic Acids ..........................................................................................69

3.3 Regioselective Activation of Glycosyl Acceptors by a Diarylborinic Acid Catalyst 72 3.3.1 Synthesis of Glucosamine Derived Donors ...........................................................................74 3.3.2 Regioselective Glycosylations with Nitrogen-Containing Glycosyl Donors.........................76 3.3.3 Regioselective Glycosylations to Form β-Mannoside Linkages............................................80 3.3.4 Regioselective Glycosylations with Halide Ion Catalysis .....................................................83 3.3.5 Regioselective Glycosylations with Stoichiometric Boronic Acid ........................................86

3.4 Kinetic Studies: Reagent Order ................................................................................... 88 3.4.1 Pseudo First-order Kinetics in Glycosyl Donor .....................................................................88 3.4.2 Dependence of the Initial Rate on the Concentration of Glycosyl Donor .............................89 3.4.3 Dependence of the Initial Rate on the Concentration of Glycosyl Acceptor .........................91 3.4.4 Dependence of the Initial Rate on the Concentration of Borinic Acid-Catalyst....................92 3.4.5 Dependence of the Initial Rate on the Concentration of Promoter ........................................94 3.4.6 Dependence of Rate on the Nature of the Catalyst Used .......................................................95 3.4.7 Effect of 2-Aminoethanol ......................................................................................................96

3.5 Conclusion ...................................................................................................................... 97

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Chapter 4: Final Conclusion................................................................................ 98

Chapter 5: Experimental Procedures ............................................................... 101 5.0 General Information.................................................................................................... 101

5.1 Experimental and Characterization Data ................................................................. 102 5.1.1 General Procedure A: Tosylation Kinetic Experiments.......................................................102 5.1.2 General Procedure B: Hydrolysis of Diarylboronic Esters ..................................................103 5.1.3 General Procedure C: Borinic Acid-Catalyzed Alkylation ..................................................103 5.1.4 General Procedure D: Borinic Acid-Catalyzed Alkylation with Halide Salts .....................103 5.1.5 General Procedure E: Borinic Acid-Catalyzed Glycosylation.............................................131 5.1.6 General Procedure F: Borinic Acid-Catalyzed Synthesis of Sugar Substrates Bearing a

Carbonate at O-2 and O-3 ....................................................................................................131 5.1.7 General Procedure G: Borinic Acid-Catalyzed Glycosylation with Halide Catalysis .........134 5.1.8 General Procedure H: Borinic Acid-Mediated Glycosylation .............................................135 5.1.9 General Procedure I: Glycosylation Kinetic Experiments ...................................................136

Appendix A: NMR Spectra................................................................................ 137

Appendix B: DFT Calculations ......................................................................... 195

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List of Abbreviations

1H proton NMR

13C carbon 13 NMR

°C degrees Celcius

aq. aqueous

Ac acetyl

Bn benzyl

BOM benzyloxymethyl

Bu butyl

Bz benzoyl

CDI N,N’-carbonyldiimidazole

d doublet

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DCE dichloroethane

DCM dichloromethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

EI electron impact

Et ethyl

ix

equiv equivalents

ESI electron spray ionization

fk Fukui index

FTIR fourier-transform infrared spectrometry

HMPA hexamethylphosphoramide

HPLC high-performance liquid chromatography

HRMS high-resolution mass spectrometry

hr hour

IR infrared spectrometry

kobs observed rate constant

M molar

m multiplet

M+ parent molecular ion

Me methyl

mg milligram

MHz megahertz

mL milliliters

mmol millimoles

MS molecular sieves

Nap naphthyl

x

NIS N-iodosuccinimide

NMR nuclear magnetic resonance

NOESY nuclear overhauser enhancement spectroscopy

n.r. no reaction

Oct octyl

OH hydroxy

Ph phenyl

Piv pivaloyl

PMB p-methoxybenzyl

ppm parts per million

rpm revolutions per minute

rt room temperature

s singlet

t tert

t triplet

TBAB tetrabutylammonium bromide

TBAF tetrabutylammonium fluoride

TBAI tetrabutylammonium iodide

TBMDSOTf tert-butyldimethylsilyl trifluoromethane sulfonate

TBSCl tert-butyldimethylsilyl chloride

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TCP tetrachlorophthaloyl

TCT 2,4,6-trichloro[1,3,5]triazine

TESCl triethylchlorosilane

THF tetrahydrofuran

TLC thin layer chromatography

Tr trityl

Troc 2,2,2-trichloroethyl chloroformate

µL microliter

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List of Tables

Table 1.1 – Synthesis of Diarylborinate Catalysts ....................................................................... 19

Table 1.2 – Synthesis of Borinate Esters Containing Other Ligands........................................... 20

Table 1.3 – Synthesis of 8-Hydroxyquinoline Diarylborinate Ester Catalysts ............................ 21

Table 1.4 – Sulfonylation of cis-1,2-Cyclohexanediol Using 8-Hydroxyquinoline Diarylborinate

Esters as Catalysts......................................................................................................................... 22

Table 2.1 – Solvent Screen for Alkylation of Carbohydrate Derivatives .................................... 46

Table 2.2 – Optimization for Alkylation of Carbohydrate Derivatives ....................................... 47

Table 2.3 – Further Optimization for Alkylation of Carbohydrate Derivatives........................... 48

Table 2.4 – Further Optimization for Alkylation of Carbohydrate Derivatives........................... 49

Table 2.5 – Optimization of Silver(I) Salt.................................................................................... 50

Table 2.6 – Scope of Regioselective Alkylation of Monosaccharides......................................... 51

Table 2.7 – Scope of Regioselective Allylation of Monosaccharides.......................................... 52

Table 2.8 – Scope of Regioselective p-Methoxybenzylation of Monosaccharides ..................... 53

Table 2.9 – Alkylation of Using Sodium Iodide and Brønsted bases .......................................... 55

Table 2.10 – Optimization of Iodide Salts ................................................................................... 55

Table 2.11 – Glycosylation of Thiogalactosides Using TBAI in Halide Catalysis...................... 57

Table 2.12 – Glycosylation of Thiogalactosides Using KI in Halide Catalysis........................... 58

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Table 3.1 – Scope of Optimized Reaction Conditions for Glycosylation.................................... 73

Table 3.2 – Glycosylation Screen with 2-Phthalimido-β-D-Glucopyranosyl Bromide ............... 76

Table 3.3 – Optimization of Reaction Conditions........................................................................ 77

Table 3.4 – Glycosylation Screen with 2-[(2,2,2-Trichloroethoxy)carbonylamino]α-D-

Glucopyranosyl Bromide .............................................................................................................. 78

Table 3.5 – Glycosylation Screen with 2-Azido-α-D-Galactopyranosyl Chloride ...................... 79

Table 3.6 – Synthesis of 2,3-O-Carbonyl-α-L-Rhamnopyranoside ............................................. 81

Table 3.7 – Screening Conditions for Desilylation ...................................................................... 82

Table 3.8 – Glycosylation with 4-Benzoyl-2,3-O-Carbonyl-α-L-Rhamnopyranosyl Bromide... 83

Table 3.9 – Glycosylation of Methyl-6-(tert-Butyldimethylsilyloxy)-α-D-Mannopyranoside via

Organoboron and Halide Ion Catalysis......................................................................................... 84

Table 3.10 – Glycosylation of Methyl-6-(tert-Butyldimethylsilyloxy)-α-D-Galactopyranoside

via Organoboron and Halide Ion Catalysis ................................................................................... 85

Table 3.11 – Glycosylation Using 2,3,4,6-Tetra-O-Benzyl-α-D-Mannopyranosyl Chloride ...... 86

Table 3.12 – Boronic Acid-Activated Glycosylation of Rhamnose Derivative........................... 87

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List of Figures

Figure 1.1 – D-Glucose Selective Molecular Fluorescence Sensor............................................... 4

Figure 1.2 – Boronic Acid-Based Chiral Saccharide Sensor ......................................................... 4

Figure 1.3 – Proposed Catalytic Cycle for Regioselective Monofunctionalization of Diols......... 7

Figure 1.4 – Formation of 2-Hydroxycyclohexyl 4-Methylbenzenesulfonate Over Time ............ 8

Figure 1.5 – Plot of cis-1,2-Cyclohexanediol Concentration Versus Time Under Pseudo First-

order Reaction Conditions ............................................................................................................ 10

Figure 1.6 – Formation of Product Over Time With Variation in the Concentration of 4-

Toluenesulfonyl Chloride ............................................................................................................. 11

Figure 1.7 – Initial Rate Dependence on the Concentration of 4-Toluenesulfonyl Chloride ...... 11

Figure 1.8 – Formation of Product Over Time With Variation in the Concentration of N,N-

Diisopropylethylamine.................................................................................................................. 12

Figure 1.9 – Initial Rate Dependence on the Concentration of N,N-Diisopropylethylamine ...... 13


Aminoethyl Diphenylborinate ...................................................................................................... 14

Figure 1.11 – Initial Rate Dependence on the Concentration of 2-Aminoethyl Diphenylborinate

....................................................................................................................................................... 14

Figure 1.12 – Consumption of cis-1,2-Cyclohexanediol Over Time Using 2-Aminoethyl

Diphenylborinate (A) or Diphenylborinic Acid (B) as the Catalyst ............................................. 16

Figure 1.13 – Rate of Consumption of cis-1,2-Cyclohexanediol Using 2-Aminoethyl

Diphenylborinate (A) or Diphenylborinic Acid (B) as the Catalyst ............................................. 16

xv

Figure 1.14 – Consumption of cis-1,2-Cyclohexanediol Over Time in the Absence (A) and

Presence (B) of Excess 2-Aminoethanol ...................................................................................... 17

Figure 1.15 – Rate of Consumption of cis-1,2-Cyclohexanediol Over Time in the Absence (A)

and Presence (B) of Excess 2-Aminoethanol................................................................................ 18

Figure 1.16 – Consumption of cis-1,2-Cyclohexanediol Over Time Using Different Catalysts. 23

Figure 1.17 – Rate of Consumption of cis-1,2-Cyclohexanediol Over Time Using Different

Catalysts ........................................................................................................................................ 23

Figure 2.1 – Incompatible Monosaccharide Derivatives ............................................................. 54

Figure 2.2 – Calculated Structures and Condensed Fukui Indices (B3LYP/6-311+G(d,p)) ....... 60

Figure 3.1 – Plot of 2,3,4,6-Tetra-O-Acetyl-α-D-Glucopyranosyl Bromide Concentration Versus

Time Under Pseudo First-order Reaction Conditions................................................................... 89

Figure 3.2 – Formation of Product Over Time With Variation in the Concentration of Glycosyl

Donor ............................................................................................................................................ 90

Figure 3.3 – Initial Rate Dependence on the Concentration of Glycosyl Donor ......................... 90

Figure 3.4 – Formation of Product Over Time With Variation in the Concentration of Glycosyl

Acceptor ........................................................................................................................................ 91

Figure 3.5 – Initial Rate Dependence on the Concentration of Glycosyl Acceptor..................... 92


Aminoethyl Diphenylborinate ...................................................................................................... 93

Figure 3.7 – Initial Rate Dependence on the Concentration of 2-Aminoethyl Diphenylborinate 93

Figure 3.8 – Formation of Product Over Time With Variation in the Concentration of Silver

Oxide............................................................................................................................................. 94

xvi

Figure 3.9 – Initial Rate Dependence on the Concentration of Silver Oxide .............................. 95

Figure 3.10 – Formation of Product Over Time Using Diphenylborinic Acid (A) or 2-

Aminoethyl Diphenylborinate (B) as the Catalyst........................................................................ 96

Figure 3.11 – Formation of Product Over Time in the Absence (A) and Presence (B) of Excess

2-Aminoethanol ............................................................................................................................ 97

xvii

List of Schemes

Scheme 1.1 – Boronic Acid–Diol Complexation Equilibria .......................................................... 3

Scheme 1.2 – Boron Containing Fluorescent Chemosensors for Polyols ...................................... 3

Scheme 1.3 – Diphenylborinic Acid-Catalyzed Aldol Reaction of Pyruvic Acids........................ 5

Scheme 1.4 – Borinic Ester-Catalyzed Regioselective Acylation of Carbohydrate Derivatives ... 6

Scheme 1.5 – Regioselective Sulfonylation of Carbohydrate Derivatives..................................... 6

Scheme 1.6 – Regioselective Tosylation of cis-1,2-Cyclohexanediol ........................................... 8

Scheme 1.7 – Tosylation of cis-1,2-Cyclohexanediol Under Pseudo First-order Reaction

Conditions ....................................................................................................................................... 9

Scheme 1.8 – Reaction Order in 4-Toluenesulfonyl Chloride ..................................................... 10

Scheme 1.9 – Reaction Order in N,N-Diisopropylethylamine ..................................................... 12

Scheme 1.10 – Reaction Order in 2-Aminoethyl Diphenylborinate ............................................ 13

Scheme 1.11 – Effect of 2-Aminoethanol .................................................................................... 15

Scheme 1.12 – Cleavage of 2-Aminoethanol by Acid Catalysis.................................................. 15

Scheme 1.13 – Effect of Excess 2-Aminoethanol ........................................................................ 17

Scheme 1.14 – Schaab’s Synthesis of Borinic Acids ................................................................... 19

Scheme 1.15 – Tavassoli’s Synthesis of Borinic Acids ............................................................... 19

Scheme 1.16 – Electronic and Steric Effects on Reactivity ......................................................... 22

Scheme 2.1 – Selective Alkylation of O-2 Over O-3 Using Phase Transfer Catalysis................ 28

xviii

Scheme 2.2 – Selective Alkylation of O-6 Over O-4 Using Phase Transfer Catalysis................ 28

Scheme 2.3 – Regioselective Alkylation of the Anomeric Position by Alkyl Triflates............... 29

Scheme 2.4 – Preferential Reactivity of Hydroxy Groups in D-Glucal ....................................... 29

Scheme 2.5 – Bhattacharjee and Gorin’s Reductive Cleavage of Benzylidene Acetals .............. 30

Scheme 2.6 – Nánási and Lipták’s Reductive Cleavage of Benzylidene Acetals........................ 30

Scheme 2.7 – Garegg’s Reductive Cleavage of Benzylidene Acetals ......................................... 30

Scheme 2.8 – Solvent Effect on Reductive Cleavage of Benzylidene Acetals ............................ 31

Scheme 2.9 – Stannyl Ethers and Stannylene Acetals ................................................................. 31

Scheme 2.10 – Organotin-Mediated Sulfamoylation of Adenosine Derivative........................... 32

Scheme 2.11 – Regioselective O-Stannylation ............................................................................ 33

Scheme 2.12 – Ogawa and Matsui’s Benzoylation of Polyols..................................................... 33

Scheme 2.13 – Ogawa’s Benzylation of Alkyl β-D-Glucopyranoside Derivatives ..................... 34

Scheme 2.14 – Ogawa’s Benzylation of Methyl β-D-Galactopyranoside ................................... 34

Scheme 2.15 – Ogawa’s Benzylation of Methyl α-D-Glucopyranoside ...................................... 35

Scheme 2.16 – Veyrières’ Benzylation of α-D-Mannopyranoside Derivatives ........................... 35

Scheme 2.17 – Effect of Halide Salts on Trialkyltin Species....................................................... 35

Scheme 2.18 – Veyrières’ Benzylation of α-D-Glucopyranoside Derivatives ............................ 36

Scheme 2.19 – Moffatt’s Benzylation of β-D-Ribofuranosyl Nucleosides.................................. 36

Scheme 2.20 – David’s Benzylation of α-D-Galactopyranoside Derivatives .............................. 37

Scheme 2.21 – Nashed and Anderson’s Benzylation of α-D-Galactopyranoside Derivatives .... 37

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Scheme 2.22 – David and Thieffry’s Benzylation of D-Galactopyranoside Derivatives ............ 38

Scheme 2.23 – Ley’s Selective Alkylation of Diols Using Dibutyltin Dimethoxide................... 38

Scheme 2.24 – Tin(II) Catalyzed Benzylation of α-L-Rhamnopyranoside Derivatives .............. 39

Scheme 2.25 – Schuerch’s Alkylation of α-D-Mannopyranoside Derivatives ............................ 40

Scheme 2.26 – Gridley’s Methylation of β-D-Glucopyranoside Derivatives .............................. 40

Scheme 2.27 – Demchenko’s Alkylation of Carbohydrate Derivatives....................................... 40

Scheme 2.28 – Kartha’s Alkylation of Carbohydrate Derivatives ............................................... 41

Scheme 2.29 – Aoyama’s Alkylation of Fucose and Arabinose Derivatives............................... 42

Scheme 2.30 – Onomura’s Monoalkylation of 1,2-Diols............................................................. 42

Scheme 2.31 – Evtushenko’s Methylation of Methyl Glucopyranosides .................................... 42

Scheme 2.32 – Borinic Acid-Catalyzed Monoacylation of cis-1,2-Diols .................................... 43

Scheme 2.33 – Proposal for Regioselective Alkylation of Polyols.............................................. 43

Scheme 2.34 – TBS-Protection of the Primary Hydroxy Group.................................................. 44

Scheme 2.35 – Synthesis of 3,4,6-Tri-O-Benzyl-D-Mannopyranoside ....................................... 45

Scheme 2.36 – Extension of Halide Catalysis Method to Other Substrates................................. 56

Scheme 3.1 – Selective Glycosylation Due to Steric Effects ....................................................... 62

Scheme 3.2 – Regiodifferentiation in Glycosylation Reactions................................................... 63

Scheme 3.3 – Glycosylations of n-Pentenyl Glycosides and n-Pentenyl Ortho Esters................ 64

Scheme 3.4 – Ogawa’s Regioselective Glycosylation of Carbohydrate Derivatives................... 65

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Scheme 3.5 – Augé and Veyrières’ Regioselective Glycosylation Method................................. 66

Scheme 3.6 – Regioselective Glycosylation of 1,6-Anhydro-β-D-Galactopyranose................... 67

Scheme 3.7 – Regioselective Glycosylation of Methyl β-Lactoside............................................ 67

Scheme 3.8 – Regioselective Glycosylation of Methyl β-D-Galactopyranoside ......................... 68

Scheme 3.9 – Regioselective Glycosylation of Methyl β-D-Galactopyranoside With Silver Silica

Alumina as a Promoter.................................................................................................................. 68

Scheme 3.10 – Protection of Carbohydrate Derivatives by Boronic Acids ................................. 69

Scheme 3.11 – Regioselective Glycosylation Using Boronic Acids as a Protecting Group........ 69

Scheme 3.12 – Boronic Acids as a Transient Masking Agent ..................................................... 70

Scheme 3.13 – Tetracoordinated Arylboronate Complex ............................................................ 71

Scheme 3.14 – Regioselective Glycosylation Activated by Arylboronic Acids .......................... 71

Scheme 3.15 – Synthesis of 2-Phthalimido-β-D-Glucopyranosyl Bromide ................................ 74

Scheme 3.16 – Synthesis of 2-Phthalimido-α-D-Glucopyranosyl Chloride ................................ 74

Scheme 3.17 – Synthesis of 2-[(2,2,2-Trichloroethoxy)carbonylamino]-α-D-Glucopyranosyl

Bromide......................................................................................................................................... 75

Scheme 3.18 – Synthesis of 2-Azido-α-D-Galactopyranosyl Chloride ....................................... 75

Scheme 3.19 – Unsuccessful Glycosylation of 2-Phthalimido-β-D-Glucopyranosyl Chloride ... 78

Scheme 3.20 – Formation of β-Mannoside Linkages................................................................... 80

Scheme 3.21 – Synthesis of 4-Benzoyl-2,3-O-Carbonyl-α-L-Rhamnopyranosyl Bromide ........ 82

Scheme 3.22 – Synthesis of Methyl-6-(tert-Butyldimethylsilyloxy)-2,3-O-Carbonyl-α-D-

Mannopyranoside.......................................................................................................................... 82

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Scheme 3.23 – Glycosylation Under Pseudo First-order Reaction Conditions............................ 89

Scheme 3.24 – Reaction Order in Glycosyl Donor ...................................................................... 90

Scheme 3.25 – Reaction Order in Glycosyl Acceptor.................................................................. 91

Scheme 3.26 – Reaction Order in 2-Aminoethyl Diphenylborinate ............................................ 92

Scheme 3.27 – Reaction Order in Silver Oxide ........................................................................... 94

Scheme 3.28 – Effect of the Nature of Catalyst Used.................................................................. 95

Scheme 3.29 – Effect of 2-Aminoethanol .................................................................................... 96

1

1 Mechanistic Studies on the Monofunctionalization of Polyols

by Boron Catalysis

1.0 Introduction

Direct, regioselective protection of hydroxy groups in diols and polyols represents an important

and long-standing goal in chemistry. The selective functionalization of carbohydrates is an

increasingly active area of research due to its broad potential in synthesis. In addition, this

strategy enables readily available starting materials such as sugar feedstocks to be converted into

value-added intermediates that are otherwise difficult to prepare in short reaction sequences. The

development of regioselective methods has undergone significant advances in recent years with

efforts focused towards strategies based on catalysis, which include enzyme-catalyzed1 methods,

organocatalytic methods2, Lewis acid-promoted processes3, and tandem catalytic reactions of

1 (a) Therisod, M.; Klibanov, A. M. J. Am. Chem. Soc. 1987, 109, 3977–3981. (b) Wang, Y.-F.; Lalonde, J. J.; Momongan, M.; Bergbreiter, D. E.; Wong, C.-H. J. Am. Chem. Soc. 1988, 110, 7200–7205. 2 (a) Griswold, K. S.; Miller, S. J. Tetrahedron 2003, 59, 8869–8875. (b) Kawabata, T.; Muramatsu, W.; Nishio, T.; Shibata, T.; Schedel, H. J. Am. Chem. Soc.2007, 129, 12890–12895.

2

persilyated sugar derivatives4. In light of these studies, organoboron reagents are emerging as an

attractive alternative in comparison to organometallic reagents. The ability for organoboron

compounds to form reversible covalent interactions with diols has been employed extensively in

the design of receptors and sensors for carbohydrates in aqueous media.5

In aqueous solutions, an equilibria boronic acid–diol complexation exists between the boronic

acid and boronate ester (Scheme 1.1).5b These species also undergo acid-base equilibria to form

anionic tetracoordinated species, where the acidity of the boronate ester is generally higher than

the boronic acid. It is postulated that this effect is due to the relative lower angle strain present in

the tetracoordinate boronate ester in comparison to the tricoordinate conjugate acid. Lorand and

Edwards exploited this phenomenon by measuring the pH depression to determine the

association constants between phenylboronic acid and various polyols (including carbohydrate

derivatives) in water.6 For more than four decades, these studies remained the dominant source

of quantitative data in regards to phenylboronic acid–diol complex.

More recently, Wang and co-workers reported quantitative studies of arylboronic acid–diol

equilibria using indicator–displacement assays to investigate pH and substitution effects on

binding affinity.7

3 Sn(IV) derivatives: (a) Iwasaki, F.; Maki, T.; Onomura, O.; Nakashima, W.; Matsumura, Y. J. Org. Chem. 2000, 65, 996–1002. (b) Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.; Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Van Khau, V.; Kosmrjl, B. J. Am. Chem. Soc. 2002, 124, 3578–3585. (c) Demizu, Y.; Kubo, Y.; Miyoshi, H.; Maki, T.; Matsumura, Y.; Moriyama, N.; Onomura, O. Org. Lett. 2008, 10, 5075–5077. La(III) salts: Dhiman, R. S.; Kluger, R. Org. Biomol. Chem. 2010, 8, 2006–2008. 4 (a) Wang, C.-C.; Lee, J.-C.; Luo, S.-Y.; Kulkami, S. S.; Huang, Y.-W.; Lee, C.-C.; Chang, K.-L.; Hung, S.-C. Nature 2007, 446, 896–899. (b) Français, A.; Urban, D.; Beau, J.-M. Angew. Chem., Int. Ed. 2007, 46, 8662–8665. 5 (a) Nishiyabu, R.; Kubo, Y.; James, T. D.; Fossey, J. S. Chem. Commun. 2011, 47, 1106–1123. (b) James, T. D. Boronic Acids (Ed. D. G. Hall) 2005, pp. 441–479. 6 Lorand, J. P.; Edwards, J. O. J. Org. Chem. 1959, 24, 769–774. 7 (a) Springsteen, G.; Wang, B. Tetrahedron 2002, 58, 5291–5300; (b) Yan, J.; Springsteen, G.; Deeter, S.; Wang, B. Tetrahedron 2004, 60, 11205–11209.

3

Scheme 1.1 – Boronic Acid–Diol Complexation Equilibria

In the intervening years, several reports demonstrated the ability of boronic acid-based receptors

to relay the reversible, covalent binding of polyols into colorimetric or fluorescence-based

signals.

In a report by Czarnik, it was found that pKa modulation of anthrylboronic acid serves as a

useful fluorescent chemosensor for carbohydrates (Scheme 1.2).8

Scheme 1.2 – Boron Containing Fluorescent Chemosensors for Polyols

8 Yoon, J.; Czarnik, A. W. J. Am. Chem. Soc. 1992, 114, 5874–5875.

HO OH

R1 R2

HO OH

R1 R2

-2 H2O

Keq-trig

Keq-tet

-2 H2O

+ H2O- H+

+ H2O- H+

Ka2Ka1

BHO OH

BOO

R2R1

B O

OR2

R1

HOB OHOH

HO

B(OH)2

OOH

HOOH

OH

OHOH+

H2O

OOH

OO

OH

OH

BOH

4

Later, James and Shinkai reported a boronic acid based photoinduced electron transfer sensor

designed to selectively bind D-glucose (Figure 1.1).9 This was followed up by a chiral variant

that could detect one enantiomer in the presence of the other (Figure 1.2).10

Figure 1.1 – D-Glucose Selective Molecular Fluorescence Sensor

Figure 1.2 – Boronic Acid-Based Chiral Saccharide Sensor

More recent developments in this field have led to the synthesis of sensors that incorporate

boronic acid functional groups into three-dimensional scaffolds with spacings and orientations

complementary to the carbohydrate of interest.11

In contrast to the vast literature on the properties and applications boronic acids as receptors and

sensors, only one quantitative study on the application of borinic acids has been reported. In the

study conducted by Smith and co-workers, diphenylborinic acid and phenylboronic acid were

investigated as a glycoside transporter for aqueous/organic interfaces.12 It was revealed that the

two boron acids differ in their extraction efficiency and transport rate.

9 James, T. D.; Sandanayake, K. R. A. S.; Shinkai, S. Angew. Chem., Int. Ed. 1994, 33, 2207–2209. 10 James, T. D.; Sandanayake, K. R. A. S.; Shinkai, S. Nature 1995, 374, 345–347. 11 Shan, J.; Cheng, Y.; Reid, S.; Li, M.; Wang, B. Med. Res. Rev. 2010, 30, 171–257. 12 Morin, G. T.; Hughes, M. P.; Paugam, M.-F.; Smith, B. D. J. Am. Chem. Soc. 1994, 116, 8895–8901.

N

N

B BHO

OHOH

HO

OMe

N

OMe

N

B

B

OHHO

OHHO

Me

Me

5

Several studies on related compounds bearing two hydroxy groups such as catechols, α-

hydroxycarboxylic acids13, and the enol tautomers of pyruvic acids14, have also demonstrated the

ability to interact with boronic acids in a two-point fashion. They have also been exploited in

organoboron-based recognition assays.

Previously, our group has demonstrated the ability of catalytic boron to direct aldol reactions of

pyruvic acids in aqueous conditions where stabilization of the enol tautomer of pyruvic acids

underlies the process (Scheme 1.3).15 The studies revealed that borinic acids displayed far

superior catalytic activity and selectivity in comparison to boronic acids.

Scheme 1.3 – Diphenylborinic Acid-Catalyzed Aldol Reaction of Pyruvic Acids

Such interactions may become an area of interest for reaction development due to key features;

these include their tolerance of aqueous medium, favourable kinetics, and selectivity for cis-

vicinal diol moieties.16 Inspired by this reactivity, our group has developed methods for selective

acylation17 and sulfonylation18 of vicinal cis-diol moieties in carbohydrates catalyzed by 2-

aminoethyl diphenylborinate ester 1.01 (Scheme 1.4 and 1.5). These methods have been shown

to provide reliable selectivity for a given regiochemical outcome and generality for a wide range

of sugar substrate and protecting group combinations.

13 Wang, W.; Gao, X. Curr. Org. Chem. 2002, 6, 1285–1317. 14 Zhu, L.; Zhong, Z.; Anslyn, E. V. J. Am. Chem. Soc. 2005, 127, 4260–4269. 15 Lee, D.; Newman, S. G.; Taylor, M. S. Org. Lett. 2009, 11, 5486–5489. 16 (a) James, T. D.; Sandanayake, K. R. A. S.; Shinkai, S. Angew. Chem., Int. Ed. 1996, 35, 1910–1922.(b) Davis, A. P.; James, T. D. In Functional Synthetic Receptors; Schrader, T., Hamilton, A. D., Eds.; Wiley: Weinheim, 2005; pp 45-109. 17 Lee, D.; Taylor, M. S. J. Am. Chem. Soc. 2011, 133, 3724–3727. 18 Lee, D.; Williamson, C.; Chan, L.; Taylor, M. S. Unpublished results.

R OH

O

O

R' H

O

O

O

HO

R R'

(1.0–5.0 equiv)

Ph2BOH (0.5–20 mol %)H2O, rt

56–90% (13 examples)

6

Scheme 1.4 – Borinic Ester-Catalyzed Regioselective Acylation of Carbohydrate

Derivatives

While these methods are synthetically useful, the development of novel catalysts that show

increased reactivity and that can be applied to asymmetric catalysis still remains a challenge. In

order to develop new catalysts, a better mechanistic understanding of the reaction is crucial since

this mode of catalytic reactivity is not well precedented. As well, such studies would allow for

improvements to be made on existing reaction conditions and be useful in developing new

reactions. Herein a detailed investigation on the mechanism of the diarylborinic acid-catalyzed

regioselective monosulfonylation of cis-1,2-cyclohexanediol is described.

Scheme 1.5 – Regioselective Sulfonylation of Carbohydrate Derivatives

1.1 Mechanistic Proposal of Borinic Acid-Catalyzed Functionalization

of Diols

A proposed mechanism for the diarylborinic acid-catalyzed monofunctionalization reaction is

schematically depicted in the diagram below (Figure 1.3). In the sequence of steps postulated to

occur, 2-aminoethyl diphenylborinate 1.01 serves as a precatalyst from which under the reaction

conditions, the ethanolamine ligand is functionalized prior to displacement by the diol substrate.

Upon substrate binding, the organoboron catalyst and diol generate a cyclic ‘ate’ complex. Such

substrate-catalyst binding selectively activates one B-O bond over the other towards reactivity

PhB

Ph NH2

O

(5-10 mol %)

RCl (1.2–2.0 equiv)iPr2NEt (1.2–2.0 equiv)

MeCN, rt

R2R1

HO

HO R2R1

HO

RO

17 examples69–99%

1.01

OOTBSHO

HOOH

SiPr

PhB

Ph NH2

O

(10 mol %)

TsCl (1.2 equiv)iPr2NEt (1.2 equiv)

MeCN, rt

OOTBSHO

TsOOH

SiPr

97%

1.01

7

with the electrophile. Displacement of the bound, monofunctionalized product by another diol

would then be favourable as to regenerate the active catalyst.

Figure 1.3 – Proposed Catalytic Cycle for Regioselective Monofunctionalization of Diols

1.2 Kinetic Studies on the Mechanism

A preliminary screening of vicinal cis-diol substrates and electrophiles was carried out to identify

a suitable pair for kinetic studies. Our substrate selection consisted of cis-1,2-cyclopentanediol,

meso-hydrobenzoin and cis-1,2-cyclohexanediol. Ideal reactions for kinetic studies would be

relatively slow since the faster the reaction proceeds, the larger the range of uncertainty is in the

measured rates. Acylation and sulfonylation of cis-1,2-cyclopentanediol was found unsuitable for

kinetic studies as the reaction was complete within the first 30 minutes. In comparison, acylation

of meso-hydrobenzoin consistently gave maximum yields of 60% after 7 hours, and tosylation

reactions generated epoxide side-products. Ultimately, the diarylborinic acid-catalyzed tosylation

PhB

Ph NH2

O

HO OH

PhB

Ph O

O

PhB

Ph O

O

R

RXiPr2NEt

-iPr2NEt-HX

PhB

Ph HN

O

R

R1 R2iPr2NEt

HONHR

R1

R2

iPr2NHEt

R2

R1

RX

iPr2NEt-HX

RO OH

R1 R2

HO OH

R1 R2iPr2NEt +

+

8

reaction of cis-1,2-cyclohexanediol afforded the desired product in >99% yield after 4 hours

(Scheme 1.6, Figure 1.4).

Scheme 1.6 – Regioselective Tosylation of cis-1,2-Cyclohexanediol

Figure 1.4 – Formation of 2-Hydroxycyclohexyl 4-Methylbenzenesulfonate Over Time

With the goal of obtaining a more detailed understanding of the catalytic cycle, and more

specifically the intimate role of each of the reaction components, the order for each reagent in the

sulfonylation of cis-1,2-cyclohexanediol was obtained using the method of initial rates.

Employing 2-aminoethyl diphenylborinate 1.01 as the catalyst, the concentration of each reaction

component was varied and the progression of the reaction over 4 hours at room temperature was

monitored. The initial time of each kinetic run corresponded to the time at which N,N-

diisopropylethylamine was added to the reaction vial. During the course of the reaction, aliquots

of the reaction mixture were removed and quenched with methanol, thus stopping the reaction.

OH

OH

OTs

OHTsCl (1.1 equiv)iPr2NEt (1.1 equiv)MeCN, 0.2 M4 hr, rt

PhB

Ph NH2

O

(1 mol %)

100%

1.01

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The solvent was then removed and the resulting samples were analyzed by 1H-NMR

spectroscopy for the formation of product with mesitylene as an internal standard. Integrations

for the internal standard peak and an isolated proton peak of the product were used to calculate

moles of product formed and therefore % conversion in each of the aliquots. For each of the

reagents, the concentration of product formed was calculated and values not exceeding 10%

conversion were plotted against time. The slope was extrapolated to determine the initial rate of

the reaction, which was then plotted against concentration of the reagent to establish its order in

the reaction.

1.2.1 Pseudo First-order Kinetics in cis-1,2-Cyclohexanediol

The reaction was carried out under pseudo first-order conditions where cis-1,2-cyclohexanediol

was a limiting reagent and all other reagents were in excess in order to maintain a constant

concentration (Scheme 1.7). A plot of cis-1,2-cyclohexanediol concentration over time fit to the

exponential function:

[cis-1,2-cyclohexanediol](t) = [cis-1,2-cyclohexanediol]0e–kt

indicating the reaction is first-order in substrate (Figure 1.5).

Scheme 1.7 – Tosylation of cis-1,2-Cyclohexanediol Under Pseudo First-order Reaction

Conditions

OH

OH

OTs

OHTsCl (5 equiv)iPr2NEt (5 equiv)MeCN, 0.1 M

PhB

Ph NH2

O

(1 mol %)

0.2 mmol

1.01

10

Figure 1.5 – Plot of cis-1,2-Cyclohexanediol Concentration Versus Time Under Pseudo

First-order Reaction Conditions

1.2.2 Dependence of the Initial Rate on the Concentration of 4-Toluenesulfonyl

Chloride

Reactions were carried out where the concentration of 4-toluenesulfonyl chloride was varied

from 1 to 5 equivalents (Scheme 1.8). A plot of the initial rates versus the concentration of 4-

toluenesulfonyl chloride gave a slope of 0.0049 M.s-1. The linear relationship between the initial

kobs and the initial concentration of 4-toluenesulfonyl chloride indicates first-order kinetics in

sulfonylating agent. (Figure 1.7).

Scheme 1.8 – Reaction Order in 4-Toluenesulfonyl Chloride

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OHTsCl (1–5 equiv)iPr2NEt (5 equiv)MeCN, 0.1 M

PhB

Ph NH2

O

(1 mol %)

0.2 mmol

11


Toluenesulfonyl Chloride

Figure 1.7 – Initial Rate Dependence on the Concentration of 4-Toluenesulfonyl Chloride

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1.2.3 Dependence of the Initial Rate on the Concentration of N,N-

Diisopropylethylamine

The order in N,N-diisopropylethylamine was established in a similar manner by varying its

concentration from 1 to 11 equivalents (Scheme 1.10). Plotting the initial rates against

concentration of N,N-diisopropylethylamine gave a slope of -0.0003 M.s-1. The invariant values

of the initial kobs as a function of N,N-diisopropylethylamine concentration indicate zero-order

behaviour in base (Figure 1.9).

Scheme 1.9 – Reaction Order in N,N-Diisopropylethylamine

Figure 1.8 – Formation of Product Over Time With Variation in the Concentration of N,N-

Diisopropylethylamine

OH

OH

OTs

OHTsCl (1 equiv)iPr2NEt (1–11 equiv)MeCN, 0.1 M

PhB

Ph NH2

O

(1 mol %)

0.2 mmol

1.01

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Figure 1.9 – Initial Rate Dependence on the Concentration of N,N-Diisopropylethylamine

1.2.4 Dependence of the Initial Rate on the Concentration of 2-Aminoethyl

Diphenylborinate

The reactions were carried out using a range of catalyst loadings from 0.5 to 2.0 mol % (Scheme

1.10). The order in 2-aminoethyl diphenylborinate 1.01 was then determined by plotting the

initial rates against the concentration of catalyst (Figure 1.11). A slope of 0.419 M.s-1 was

obtained from the plot. The linear relationship between the initial kobs and the catalyst

concentration indicates first-order kinetics in catalyst.

Scheme 1.10 – Reaction Order in 2-Aminoethyl Diphenylborinate

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OHTsCl (1.1 equiv)iPr2NEt (1.1 equiv)MeCN, 0.1 M

PhB

Ph NH2

O

(0.5–2 mol %)

0.2 mmol

1.01

14


Aminoethyl Diphenylborinate

Figure 1.11 – Initial Rate Dependence on the Concentration of 2-Aminoethyl

Diphenylborinate

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1.2.5 Effect of 2-Aminoethanol

Experiments were performed to examine the effect the nature of the borinic acid catalyst had on

the reaction rate. Reactions were carried out using 1 mol % of either 2-aminoethyl

diphenylborinate 1.01 (Condition A) or diphenylborinic acid (Condition B) as the catalyst

(Scheme 1.12). Diphenylborinic acid 1.02 can be furnished by treatment of 2-aminoethyl

diphenylborinate 1.01 with 1 M hydrochloric acid in a 1:1 mixture of methanol:acetone (Scheme

1.13).15 The results showed that the rate of the reaction with diphenylborinic acid was faster in

comparison to 2-aminoethyl diphenylborinate 1.01 (Figure 1.12 and 1.13). This outcome is

consistent with our hypothesis that diphenylborinic acid 1.02 serves as a catalyst and that 2-

aminoethyl diphenylborinate 1.01 is a precatalyst for the reaction.

• Condition A: 2-Aminoethyl Diphenylborinate 1.01

• Condition B: Diphenylborinic Acid 1.02

Scheme 1.11 – Effect of 2-Aminoethanol

Scheme 1.12 – Cleavage of 2-Aminoethanol by Acid Catalysis

OH

OH

OTs

OHTsCl (5 equiv)iPr2NEt (5 equiv)

MeCN, 0.1 M0.2 mmol

Catalyst (1 mol %)

BNH2

O HCl, 1M

MeOH:Acetone (1:1)B OH

1.01 1.02, 96%

16

Figure 1.12 – Consumption of cis-1,2-Cyclohexanediol Over Time Using 2-Aminoethyl

Diphenylborinate (A) or Diphenylborinic Acid (B) as the Catalyst

Figure 1.13 – Rate of Consumption of cis-1,2-Cyclohexanediol Using 2-Aminoethyl

Diphenylborinate (A) or Diphenylborinic Acid (B) as the Catalyst

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The effect of excess 2-aminoethanol on the rate was also examined. The reactions were carried

out in the absence (Condition A) or presence (Condition B) of 1 mol % 2-aminoethanol (Scheme

1.14). The concentration of cis-1,2-cyclohexanediol was monitored and plotted against time

(Figure 1.14). Comparing the rate of consumption of starting material over time revealed that

excess 2-aminoethanol inhibited the reaction (Figure 1.15). This can be due to competitive

binding between 2-aminoethanol and cis-1,2-cyclohexanediol onto the organoboron catalyst

indicative a reversible process.

• Condition A: No Added 2-Aminoethanol

• Condition B: 1 mol % 2-Aminoethanol

Scheme 1.13 – Effect of Excess 2-Aminoethanol

Figure 1.14 – Consumption of cis-1,2-Cyclohexanediol Over Time in the Absence (A) and

Presence (B) of Excess 2-Aminoethanol

OH

OH

OTs


MeCN, 0.1 MCondition A or B

PhB

Ph NH2

O

(1 mol %)

0.2 mmol

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Figure 1.15 – Rate of Consumption of cis-1,2-Cyclohexanediol Over Time in the Absence

(A) and Presence (B) of Excess 2-Aminoethanol

1.2.6 Electronic and Steric Effects on Reactivity

The relative catalytic activities of commercially available 2-aminoethyl diphenylborinate 1.01

and three other diarylborinate catalysts were evaluated. The various diarylborinate esters

investigated were synthesized as depicted below (Table 1.1). Following the method of

Kobayashi19, the aryl halide underwent lithium-halogen exchange to form the organolithium

species in situ and addition of tributyl borate furnished the borinic acid after acidic work-up. The

borinic acid was then heated in toluene, and treatment with a slight excess of ethanolamine

precipitated out the borinate ester product. The overall reaction was found to be low yielding for

all borinate products (24–34% yield). Procedures by Schaab20 (Scheme 1.14) and Tavassoli21

(Scheme 1.15) which employ organomagnesium derivatives to synthesize borinic acids were also

attempted, however, in our hands no product was observed.

19 Mori, Y.; Kobayashi, J.; Manabe, K.; Kobayashi, S. Tetrahedron 2002, 58, 8263–8268. 20 Winkle, D. D.; Schaab, K. M. Org. Process Res. Dev. 2001, 5, 450–451. 21 Tavassoli, A. et al. US Patent No.: 7405304 B2. July 29, 2008.

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Table 1.1 – Synthesis of Diarylborinate Catalysts

Scheme 1.14 – Schaab’s Synthesis of Borinic Acids

Scheme 1.15 – Tavassoli’s Synthesis of Borinic Acids

MeO

CF3

F3C

Me

R

i. B(OBu)3 (1 equiv)ii. sec-BuLi (2.94 equiv)

2.94 equiv

Br

R

B OH

R

Et2O, 0.2 M-78 °C – rt, 16 hr

HO(CH2)2NH2 (1.2 equiv)toluene, 0.2 M

50 °C, 12 hr

R

B

R

NH2

O

entry yield (%)aryl

1

2

3

34

27

24

1.02

1.03

1.04

B(OiPr)3 (0.6 equiv)-5 °C, 1hr

Br HCl, 1 M

MeO

1) Mg, THF2)

3)n.r.

B(OMe)3 (0.95 equiv)-78 °C – rt

Br

MeO

1) Mg, THF2)

3) MeOHn.r.

20

Switching the 2-aminoethanol group on the borinate ester to other ligands was also investigated

to evaluate whether it would facilitate isolation of the product (Table 1.2). No product was

observed using L-glycine or L-proline, however, 8-hydroxyquinoline afforded the target borinate

ester 1.05 in 89% yield.

Table 1.2 – Synthesis of Borinate Esters Containing Other Ligands

Electron rich and electron deficient diarylborinate esters containing 8-hydroxyquinoline as a

ligand were also synthesized in a similar manner (Table 1.3). Although reaction with 8-

hydroxyquinoline gave cleaner diarylborinate products by 1H-NMR, the yields were lower than

those with 2-aminoethanol.

entry yield (%)conditions

1

2

3

n.r.

n.r.

1.05, 89

ligand

B OH

NH O

H2NOH

O

NOH

BNR

O R'

OH

EtOH:H2O (1:1), rt, 16 hr

toluene, 50 °C, 16 hr

1 equiv

EtOH:H2O (1:1), rt, 16 hr

RHN R'

OH (1 equiv)

BN

O

BNH2

O O

BHN

O O

product

Conditions

21

Table 1.3 – Synthesis of 8-Hydroxyquinoline Diarylborinate Ester Catalysts

Subsequently, the catalysts were tested out in sulfonylation reactions with cis-1,2-

cyclohexanediol (Table 1.4). The 8-hydroxyquinoline diarylborinate derivatives were observed

to give the desired product in comparable yields to their corresponding 2-aminoethyl

diarylborinate catalysts. For ease of synthesis, kinetic studies were then carried out using the 2-

aminoethyl diarylborinate esters as catalysts.

The reactions were carried out with 1 mol % of a diarylborinate ester catalyst and the

disappearance of cis-1,2-cyclohexanediol was monitored over time (Scheme 1.16). A plot of the

initial rates revealed that 2-aminoethyl diphenylborinate 1.01 was the fastest, followed by the

bis(4-methoxyphenyl) catalyst 1.02 and the bis(3,5-bis(trifluoromethyl)phenyl) catalyst 1.03

(Figure 1.16). The more sterically demanding di-o-tolyl catalyst 1.04 gave the slowest rate. After

4 hours, the reaction showed less than 10% product formation.

MeO

CF3

F3C

R

i. B(OBu)3 (1 equiv)ii. sec-BuLi (2.94 equiv)

2.94 equiv

Br

R

B OH

R

Et2O, 0.2 M-78 °C – rt, 16 hr

entry yield (%)aryl

1

2

22

19

1.06

1.07

NOH

BN

O

toluene50 °C, 16 hr

(1 equiv)R

R

22

Table 1.4 – Sulfonylation of cis-1,2-Cyclohexanediol Using 8-Hydroxyquinoline

Diarylborinate Esters as Catalysts

Scheme 1.16 – Electronic and Steric Effects on Reactivity

Catalyst (5 mol %)TsCl (1.1 equiv)

iPrNEt (1.1 equiv)MeCN, 0.2 M

rt, 4 hr

OH

OH

OTs

OH

>99%

>99% 97%

81%

BN

O

BNH2

O

42%

36%

CF3

F3CF3C

CF3

CF3

F3CF3C

CF3

BN

OB

N

O

MeO

MeO

MeO

B

MeO

NH2

OB

NH2

O

Yields determined by 1H NMR with mesitylene as a quantitative internal standard.

OH

OH

OTs


MeCN, 0.1 M

Catalyst (1 mol%)

0.2 mmol

BNH2

O

1.01 1.02 1.03 1.04

BNH2

OB

NH2

OB

NH2

O

MeO

MeO

CF3

F3C

F3C

CF3

Catalyst:

23

Figure 1.16 – Consumption of cis-1,2-Cyclohexanediol Over Time Using Different Catalysts

Figure 1.17 – Rate of Consumption of cis-1,2-Cyclohexanediol Over Time Using Different

Catalysts

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24

The fact that both electron-rich and electron-deficient diarylborinic acids displayed lower

catalyst activity than diphenylborinic acid was unexpected. It can be reasoned that the electron

rich bis(4-methoxyphenyl) catalyst 1.02 decreases the Lewis acidity of boron causing the B-O

bonds to be weaker. This would then negatively affect diol binding, however, should speed up

reactivity with the electrophile. In the case of the electron deficient bis(3,5-

bis(trifluoromethyl)phenyl) catalyst 1.03, the Lewis acidity of boron is increased which

strengthens the B-O bonds. A tighter binding between the catalyst and substrate would then

inhibit the release of product or decrease reactivity of the bound diol. The reactivity of di-o-tolyl

catalyst 1.04 can be attributed to the bulky methyl group on the arenes. The binding of the diol is

an unfavourable process as boron is more sterically congested, thus very low reactivity is

observed. We have observed steric effects on equilibrium constants for boric acid-diol

interactions.22

1.3 Conclusion

The mechanistic insight we obtained from the results of the various experiments performed have

been consistent with the proposed catalytic cycle. The initial rate kinetic studies showed:

• first-order kinetics in substrate, electrophile, and catalyst

• zero-order kinetics in base

The zero-order kinetics in base signifies that this component is not involved in the rate-

determining step. The first-order dependence on the substrate, electrophile and catalyst may

reflect that attack of the electrophile by the bound cyclic ‘ate’ complex is the rate-limiting step.

The fact that we observe higher initial rates for the reaction catalyzed by the diphenylborinic acid

in comparison to its ethanolamine derivative is consistent with our proposal that the latter acts as

a precatalyst under the reaction conditions. Inhibition by 2-aminoethanol indicates that the

disassociation of the ligand is a reversible process and is also consistent with the proposal that 2-

aminoethyl diphenylborinate is a precatalyst. Variation in the electronic and steric properties of

22 Chudzinski, M. G.; Chi, Y.; Taylor, M. S. Manuscript submitted (July 15, 2011).

25

the borinic acid catalyst did not show any improvements on the reaction rate, however, it was

revealed that electron rich catalysts undergo faster reactions than electron poor catalysts.

26

2 Regioselective Alkylation of Carbohydrate Derivatives

Catalyzed by a Diarylborinic Acid Derivative23

2.0 Introduction

Complex oligosaccharides and glycoconjugates display prevalent roles in a diverse range of

biological processes including cell-cell signaling, immune response, and the development of

human diseases and cancer.24 With the increasing realization of their potential in drug and

vaccine discovery, chemical methods for their preparation have been sought after.25 However,

the synthesis of carbohydrate derivatives is a synthetic challenge due to their complex structures

requiring extensive protecting group manipulations.26 For decades, selective protection of

carbohydrates for applications in glycosylations has been pursued intensively. Monoalkylation,

in particular benzylation, represents one of the main strategies used in the preparation of

23 A significant portion of the work described in this chapter has been published: Chan, L.; Taylor, M. S. Org. Lett. 2011, 13, 3090–3093. 24 Boltje, T. J.; Buskas, T.; Boons, G.-J. Nature Chem. 2009, 1, 611–622. 25 Seeberger, P. H.; Werz, D. B. Nature 2007, 446, 1046–1051. 26 Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2007.

27

carbohydrates as alkyl ether groups are relatively stable and have low propensities to migrate.27

In recent years, transition metal-mediated approaches for the monofunctionalization of

carbohydrates have introduced new possibilities, with tin playing a central role. This section will

present a survey of the developments in this area of research with an emphasis on methods

involving regioselective installation of benzyl and related groups. Later, the development of a

regioselective diarylborinic acid-catalyzed preparation of monoalkylated carbohydrates will be

described.

2.1 Reactivity of the Hydroxy Group

In certain cases, selective protection of the most acidic hydroxy group, usually C-2, may be

achieved with varying degrees of efficiency.28 Generally in a 6-membered ring, it is well known

that an equatorial hydroxy group is functionalized preferentially in the presence of an axial

hydroxy group. In a study by Williams and Richardson, it was found that acylation of mannose,

glucose and galactose derivatives all showed that the reactivity of the equatorial hydroxy groups

were greater than the axial hydroxy groups.29 Likewise, a primary hydroxy group may be

protected selectively with a bulky substituent in the presence of several other secondary hydroxy

groups.30 For example, the primary hydroxy group can be selectively silylated in the presence of

free secondary hydroxy groups using tert-butyldimethylsilyl chloride.26 However, applications of

this method generally are not efficient as they may require several steps to occur prior to the

desired transformation. Thus, a more direct approach would avoid the tedious and costly steps.

In 1976, Garegg and co-workers reported the use of phase transfer catalysis to carry out

monobenzylation of carbohydrate derivatives.31 In phase transfer catalysis, the reaction is

heterogeneous where at least one of the reagents exist in a different phase. Reactions are able to

occur due to the use of a catalyst to increase the concentration of the insoluble reagent in the

reaction phase. It was observed that methyl 4,6-O-benzylidene-α-D-glucopyranoside could be

27 Gómez, A. M. In Glycoscience; Fraser-Reid, B., Tatsuka, K., Thiem, J., Eds.; Springer-Verlag: Berlin, 2008; pp 103–177. 28 Garegg, P. J. Pure Appl. Chem. 1984, 56, 845–858. 29 Williams, J. M.; Richardson, A. C. Tetrahedron 1967, 23, 1369–1378. 30 David, S.; Hanessian, S. Tetrahedron 1985, 41, 643–663. 31 Garegg, P. J.; Iversen, T.; Oscarson, S. Carbohydr. Res. 1976, 50, C12–C14.

28

selectively alkylated at the O-2 position over O-3 using benzyl bromide, tetrabutylammonium

hydrogen sulfate, aqueous sodium hydroxide in dichloromethane under refluxing conditions

(Scheme 2.1).

Scheme 2.1 – Selective Alkylation of O-2 Over O-3 Using Phase Transfer Catalysis

With methyl 2,3-O-benzyl-α-D-glucopyranoside, base catalyzed phase transfer conditions

selectively benzylated the O-6 position over the O-4 position to give 68% and 18% yields

respectively (Scheme 2.2).28

Scheme 2.2 – Selective Alkylation of O-6 Over O-4 Using Phase Transfer Catalysis

In a report by Schmidt, it was demonstrated that the anomeric position of partially unprotected

carbohydrate derivatives could undergo regioselective alkylation using sodium hydride and alkyl

triflates (Scheme 2.3).32 The regioselectivity arises from the higher acidity of the anomeric

32 Schmidt, R. R.; Klotz, W. Synlett 1991, 168–169.

OOHO

OMe

O

HO

PhBnBr (1.7 equiv)

TBAHS (0.2 equiv)

R1 = H, R2 = Bn, 54%R1 = Bn, R2 = H, 20%R1 = Bn, R2 = Bn, 6%

OOR1O

OMe

O

R2O

Ph

5% NaOHCH2Cl2, 0.06 Mreflux, 2 days

OOHO OMeO

HO

PhBnBr (1.7 equiv)

TBAHS (0.2 equiv)

R1 = H, R2 = Bn, 50%R1 = Bn, R2 = H, 20%R1 = Bn, R2 = Bn, 7%

OOR1O OMe

O

R2O

Ph

5% NaOHCH2Cl2, 0.06 Mreflux, 2 days

OOH

BnO

OMe

HO

BnO

BnBr (1.7 equiv)TBAHS (0.2 equiv)

R1 = H, R2 = Bn, 68%R1 = Bn, R2 = H, 18%

OOR2

BnO

OMe

R1O

BnO5% NaOHCH2Cl2, 0.06 Mreflux, 2 days

29

hydroxy group in comparison to other unprotected hydroxy groups that results from indirect

stabilization by the ring oxygen atom.

Scheme 2.3 – Regioselective Alkylation of the Anomeric Position by Alkyl Triflates

In the total synthesis the KH-1 adenocarcinoma antigen by Danishefsky, the preferential

reactivity of the hydroxy groups in D-glucal, C-6 > C-3 > C-4, were exploited to generate the

desired product for glycosylation (Scheme 2.4).33

Scheme 2.4 – Preferential Reactivity of Hydroxy Groups in D-Glucal

2.2 Reductive Cleavage of Benzylidene Acetals

In 1968, Bhattacharjee and Gorin introduced an efficient method for regioselective ring-opening

of cyclic benzylidene acetals on hexafuranose and hexopyranose compounds (Scheme 2.5).34 An

aluminum dihydride chloride reactive species generated from an equimolar mixture of lithium

aluminum hydride and aluminum chloride complexes to the acetal, promoting ring-opening to

the corresponding ether. Reductive cleavage of the methyl 4,6-O-benzylidene derivative of α-D-

galactopyranoside gave preferentially the 6-O-benzyl derivative, whereas preferential formation

of the 4-O-benzyl derivative was observed for α-D-glucopyranoside and α-D-mannopyranoside.

33 Deshpande, P. P.; Danishefsky, S. J. Nature 1997, 387, 164–166. 34 Bhattacharjee, S. S.; Gorin, P. A. J. Can. J. Chem. 1968, 47, 1195–1206.

OOH

BnOOH

BnO

BnO

OOH

BnO OdecylBnO

BnOCH2Cl2, NaH

rt, 2hr

decyl triflate

64%

OOH

HOHO

NaH, BnBr

TESCl, pyrii.i.

OOBn

HOTESO

30

Scheme 2.5 – Bhattacharjee and Gorin’s Reductive Cleavage of Benzylidene Acetals

Shortly thereafter, Nánási, Lipták and coworkers reported that under similar reaction conditions,

dibenzylidene isomers of α-D-mannopyranosides and α-L-rhamnopyranosides could be

selectively cleaved (Scheme 2.6).35

Scheme 2.6 – Nánási and Lipták’s Reductive Cleavage of Benzylidene Acetals

A related strategy for reductive ring opening of 4,6-O-benzylidene acetals was introduced by

Garegg (Scheme 2.7).28 Previously, Horne and Jordan had demonstrated that the use of sodium

cyanoborohydride and hydrogen chloride in methanol could reductively open the

phenylethylidene acetal of ethylene glycol.36 Under slightly modified reaction conditions, excess

sodium cyanoborohydride and hydrogen chloride in tetrahydrofuran delivered the major product

with the benzyl group at the O-6 position in good to high yields.

Scheme 2.7 – Garegg’s Reductive Cleavage of Benzylidene Acetals

35 Lipták, A.; Imre, J.; Harangi, J.; Nánási, P. Tetrahedron 1982, 38, 3721–3727. 36 Horne, D. A.; Jordan, A. Tetrahedron Lett. 1978, 16, 1357–1358.

OO

BnO OBn

O

OBn

Ph

OOBn

BnO OBn

HO

OBn

AlCl3, LiAlH4

29%

CH2Cl2:Et2O (1:3)40 °C

OOO OBn

OOPh

AlCl3, LiAlH4

81%

CH2Cl2:Et2O (1:1)

PhH

OOBnO OBn

OOHPh

OO

BnOOMe

O

BnO

Ph

OOBn

BnOOMe

HO

BnO93%

HCl, THFNaCNBH3

31

It was also found that when borane-trimethylamine was employed as a reducing agent with

aluminum chloride as the acid, the regioselectivity of the opening of 4,6-O-benzylidene acetals

could be controlled by the choice of the solvent (Scheme 2.8).37 Using tetrahydrofuran as the

solvent, the benzyl group was installed at the O-6 position, whereas toluene led to the benzyl

group at the O-4 position of the pyranoside.

Scheme 2.8 – Solvent Effect on Reductive Cleavage of Benzylidene Acetals

2.3 Organotin-Mediated Regioselective Alkylation

Since their introduction in the 1970s, trialkylstannyl ethers and dialkylstannylene acetals have

become widely applied in the synthesis of carbohydrate derivatives (Scheme 2.9).38 Although

stoichiometric amounts of potentially toxic di- or trialkyltin (IV) byproducts are generated, these

intermediates have been extensively used since they provide a reliable, high-yielding route to

generate monosubstituted products with high regioselectivity.

Scheme 2.9 – Stannyl Ethers and Stannylene Acetals

37 Ek, M.; Garegg, P. J.; Hultberg, H.; Oscarson, S. J. Carbohydrate Chem. 1983, 2, 305–311. 38 Grindley, T. B. Adv. Carbohydr. Chem. Biochem. 1998, 53, 17–142.

OOBnO OBn

O

OBn

Ph Me3N.BH3, AlCl3

toluene: R = Bn, R' = H, 52%THF: R = H, R' = Bn, 72%

solventO

OR'

BnO OBnRO

OBn

OOH

HO OMe

OH

OH

OOH

BnO OMe

OH

OH

BnBr, DMF

95%

OOH

O OMe

O

OH

Bu2SnBu2SnO

100 °CMeOH

OOHO

OMe

O

HO

Ph OOHO

OMe

O

BnO

Ph

89%

(Bu3Sn)2O

MeOH

OOHO

OMe

O

O

Ph

Bu3Sn

BnBr, DMF

90 °C

32

These methods involve a two-step procedure whereby the sugar substrate is initially heated with

the tin reagent to form one or two Sn-O bonds. In the case of stannyl ethers, the tin forms a

coordination bond with a neighbouring oxygen atom.39 The formation of such intermediates

enhances the nucleophilicity of the oxygen atoms in the stannyl ether or stannylene acetal.

Subsequent treatment with the appropriate electrophile yields the corresponding

monofunctionalized product. The outcome of the reaction is dependant on several parameters

such as substrate, electrophile, additives, etc., however, generally the primary hydroxy group and

the equatorial hydroxy group in a vicinal cis-diol configuration are functionalized preferentially.

2.3.1 Stannyl Ethers

In 1971, Moffatt reported one of the first examples of the utility of alkoxy trialkyltin ethers in

carbohydrate chemistry (Scheme 2.10)40. The 5’-hydroxy group of 4’-fluoro-2’,3’-O-

isopropylidene adenosine was converted to the tributylstannyl ether using bis(tributyltin) oxide.

Subsequent sulfamoylation with sulfamoyl chloride yielded the desired sulfamate product in high

yield.

Scheme 2.10 – Organotin-Mediated Sulfamoylation of Adenosine Derivative

Investigations by Smith revealed that the hydroxy groups at the 1, 4 and 6 positions of

unsubstituted carbohydrates preferentially undergo O-stannylation with bis(tributyltin) oxide to

form the corresponding ethers (Scheme 2.11).41

39 Smith, P. J.; White, R. F. M.; Smith, L. J. Organomet. Chem. 1972, 40, 341–343. 40 Jenkins, I. D.; Verheyden, J. P. H.; Moffatt, J. G. J. Am. Chem. Soc. 1971, 93, 4323–4324. 41 Crowe, A. J.; Smith, P. J. J. Organomet. Chem. 1976, 110, C57–C59.

N

NN

N

NH2

O

OO

HO

Me Me

F

N

NN

N

NH2

O

OO

H2NO2S

Me Me

F

i. (Bu3Sn)2O, benzene

ii. ClSO2NH2, 5 °C

87%

33

Scheme 2.11 – Regioselective O-Stannylation

Ogawa and Matsui subsequently made several contributions to this area.42 In 1977, they reported

a novel approach to regioselectively acylate polyols using trialkylstannyl alkoxides (Scheme

2.12). Treatment of methyl α-D-glucopyranoside with bis(tributylstannyl)oxide in refluxing

toluene followed by the addition of benzoyl chloride at room temperature afforded methyl 2,6-di-

O-benzoyl-α-D-glucopyranoside and methyl 2,3,6-tri-O-benzoyl-α-D-glucopyranoside in 82%

and 15% yields respectively. Likewise, reactivity with methyl α-D-mannopyranoside and methyl

β-D-galactopyranoside were also shown to give high yields (90% and 92% respectively). The

results of the study also revealed that the stereochemistry of the diols in the five-membered

coordination ring is crucial for regioselectivity as cis-vicinal diols are expected to be much

favoured than trans-vicinal diols.

Scheme 2.12 – Ogawa and Matsui’s Benzoylation of Polyols

Building on the preceding results, Ogawa and co-workers reported a stannylation-alkylation

sequence to obtain monoalkylated carbohydrate derivatives (Scheme 2.13).43 Compared to

acylation, however, alkylation presented to be far more challenging. Stannylation of 2,2,2-

trichloroethyl 2-deoxyl-2-phthalimido-β-D-glucopyranoside using bis(tributylstannyl)oxide

followed by reaction with benzyl bromide for 4 days at 75 to 80 °C afforded the monobenzylated

product at the primary position in 60% yield. However, leaving the reaction to proceed for 8.5

42 (a) Ogawa, T.; Matsui, M. Carbohydr. Res. 1977, 56, C1–C6. (b) Ogawa, T.; Matsui, M. Tetrahedron 1981, 37, 2363–2369. 43 Ogawa, T.; Nakabayashi, S.; Sasajima, K. Carbohydr. Res. 1981, 96, 29–39.

OOH

HOOH

HO

OHtoluene

OOSnBu3

HO OSnBu3Bu3SnO

OH

(Bu3Sn)2O

OOH

HO

OMe

HO

HO

OOBz

HO

OMe

R'O

RO

R = Bz, R' = H, 82%R = R' = Bz, 15%

i. (Bu3Sn)2O, toluene 140 °C

ii. BzCl

34

days at 100 to 105 °C gave the 3,6-dibenzyl ether, 4,6-dibenzyl ether and monobenzyl ether in

9%, 4% and 14% yields respectively.

Scheme 2.13 – Ogawa’s Benzylation of Alkyl β-D-Glucopyranoside Derivatives

Shortly thereafter, a regioselective approach to the alkylation of alkyl β-D-galactopyranosides

using trialkylstannyl ethers was disclosed (Scheme 2.14).44 Reaction of methyl β-D-

galactopyranoside with bis(tributylstannyl)oxide, followed by alkylation with benzyl bromide

for 3 days at 85 °C resulted in the 3,6-dibenzyl ether in 48% yield and the 6-monobenzyl ether in

24% yield.

Scheme 2.14 – Ogawa’s Benzylation of Methyl β-D-Galactopyranoside

Extension of the stannylation-alkylation method to regioselective alkylation of methyl α-D-

glucopyranoside was demonstrated thereafter (Scheme 2.15).45 Methyl α-D-glucopyranoside was

condensed with bis(tributylstannyl)oxide and subsequent reaction with benzyl bromide at 80 to

90 °C for 2 days gave the 3,6-dibenzyl ether, 2,6-dibenzyl ether, 4,6-dibenzyl ether and 6-

monobenzyl ether in 4%, 30%, 6% and 48% yields respectively.

44 Ogawa, T.; Nukada, T.; Matsui, M. Carbohydr. Res. 1982, 101, 263–270. 45 Ogawa, T.; Takahashi, Y.; Matsui, M. Carbohydr. Res. 1982, 102, 207–215.

OOH

HO OCH2CCl3HO

NPhth

OOBn

HO OCH2CCl3HO

NPhth60%


ii. BnBr, 4 days 75–80 °C

OOBn

RO OCH2CCl3R'O

NPhth


ii. BnBr, 8.5 days 100–105 °C

R = R' = H, 14%R = Bn, R' = H, 9%R = H, R' = Bn, 4%

OOH

HO OMe

HO

OH


ii. BnBr, 3 days 85 °C

R = H, 24%R = Bn, 48%

OOBn

RO OMe

HO

OH

35

Scheme 2.15 – Ogawa’s Benzylation of Methyl α-D-Glucopyranoside

In a report by Veyrières, the addition of tetrabutylammonium bromide as an additive was found

to strongly accelerate the alkylation step (Scheme 2.16).46 The reaction of allyl bromide and the

stannylated derivative of benzyl 6-O-trityl-α-D-mannopyranoside with tetrabutylammonium

bromide at 80 °C for 2 days was found to give 62% of the 3-O-allyl ether and 15% of the 2-O-

allyl ether.

Scheme 2.16 – Veyrières’ Benzylation of α-D-Mannopyranoside Derivatives

It is postulated that the addition of halide salts forms an anionic pentacoordinate tin species that

reversibly dissociates into a highly reactive quaternary ammonium alkoxides and tributyltin

halide adduct (Scheme 2.17).47 The large separation in the cation-anion pair of the newly formed

quaternary ammonium alkoxide attributes to the enhanced reactivity of the alkoxides.

Scheme 2.17 – Effect of Halide Salts on Trialkyltin Species

46 Alais, J.; Veyrières, A. J. Chem. Soc., Perkin Trans. I 1981, 377–381. 47 Tagliavini, G.; Zanella, P. Anal. Chim. Acta. 1968, 40, 33–39.

OOH

HOOMe

HO

HO


ii. BnBr, 2 days 80–90 °C

R = R" = H, R' = Bn, 4%R = Bn, R' = R" = H, 30%R = R' = H, R" = Bn, 6%R = R' = R" = H, 48%

OOBn

R'OOMe

R''O

RO

OOTr

HOOBn

HOOH


ii. AllylBr, TBAB 2 days, 80 °C

R = H, R' = Allyl, 62%R = Allyl, R' = H, 15%

OOTr

R'OOBn

HOOR

Bu3SnORBr

Bu3SnBrOR ROBu3SnBr +

36

Similarily, it was shown that the benzyl 2-acetamido-3-O-benzyl-2-deoxy-α-D-glucopyranoside

stannyl derivative could be benzylated at the 6-position in 86% yield (Scheme 2.18).48

Scheme 2.18 – Veyrières’ Benzylation of α-D-Glucopyranoside Derivatives

2.3.2 Stannylene Acetals

After demonstrating the viability of using stannyl ether intermediates to carry out regioselective

stannylation and subsequent alkylation reactions, Moffatt and co-workers disclosed the utility of

O-stannylene acetals in regioselective acylation and alkylation of nucleosides (Scheme 2.19).49

Upon treatment of β-D-ribofuranosyl uridine with equimolar equivalents of dibutyltin oxide to

afford the corresponding 2’,3’-O-stannylene acetal, reaction with benzyl bromide at 100 °C for 1

hour gave a 1:1 mixture of the 2’-O-benzyluridine and 3’-O-benzyluridine products in a

combined yield of 65% with no indication of other benzylated products.

Scheme 2.19 – Moffatt’s Benzylation of β-D-Ribofuranosyl Nucleosides

Later, David and co-workers reported the utility of stannylene acetals for regioselective

monobenzylation of cis-vicinal diols of carbohydrate derivatives (Scheme 2.20).50 Reaction of

48 Veyrières, A. J. Chem. Soc., Perkin Trans. I 1981, 1626–1629. 49 Wagner, D.; Verheyden, J. P. H.; Moffatt, J. G. J. Org. Chem. 1974, 39, 24–30. 50 Augé, C.; David, S.; Veyrières, A. J. Chem. Soc. Chem. Comm. 1976, 375–376.

OOH

BnOOBn

HO

AcHN

i. (Bu3Sn)2O, toluene reflux

ii. BnBr, TBAB 3 days, 80 °C

86%

OOBn

BnOOBn

HO

AcHN

NO

OHHO

HOi. (Bu2SnO)n, MeOH

ii. BnBr, DMF, 100 °C

NH

O

O NO

ORR'O

HO

NH

O

O

R = Bn, R' = HR = H, R' = Bn

37

the 3,4-O-stannylene derived from benzyl α-D-galactopyranoside with benzyl bromide at 100 °C

for 2 hours resulted in exclusive benzylation at the O-3 position with 66% yield. It is noteworthy

that benzylation of the same carbohydrate substrate using sodium hydride was found to give a

mixture of four products, and in other cases, preferential attack occurs at the O-4 position51.

Scheme 2.20 – David’s Benzylation of α-D-Galactopyranoside Derivatives

Likewise, independent studies by Nashed and Anderson reported the use of dibutyltin oxide to

mediate regioselective alkylation of allyl 2,6-di-O-benzyl-α-D-galactopyranoside to afford the

corresponding 3-O-allylated product in 79% yield (Scheme 2.21).52 The practicality of this

method was subsequently demonstrated in a series of reports for the syntheses of

oligosaccharides.53 Furthermore, extension of the regioselective alkylation to benzylation of

1,2:5,6-di-O-isopropylidene-L-inositol was found to give 95% yield of the 3-O-benzylated

derivative using benzyl bromide in a 1:1 mixture of benzene and dimethylformamide.30

Scheme 2.21 – Nashed and Anderson’s Benzylation of α-D-Galactopyranoside Derivatives

David and Thieffry subsequently developed milder reaction conditions in which the alkylation

step is carried out with an equimolar quantity of tetrabutylammonium iodide (Scheme 2.22).54

An improvement of this method was developed where the reaction takes place in non-polar

solvents such as toluene or benzene rather than the traditional polar solvents. Treatment of the

51 Flowers, H. M. Carbohydr. Res. 1975, 39, 245–251. 52 Nashed, M. A.; Anderson, L. Tetrahedron Lett. 1976, 39, 3503–3506. 53 (a) Nashed, M. A.; Anderson, L. Carbohydr. Res. 1977, 56, 419–422. (b) Slife, C. W.; Nashed, M. A.; Anderson, L. Carbohydr. Res. 1981, 93, 219–230. (c) Nashed, M. A.; Chowdhary, M. S.; Anderson, L. Carbohydr. Res. 1982, 102, 99–110. 54 David, S.; Thieffry, A.; Veyrières, A. J. Chem. Soc., Perkin Trans 1 1981, 1796–1801.

OOAllyl

HOOBn

HO

BnO

i. (Bu2SnO)n, benzene

ii. BnBr, DMF 2 hr, 100 °C

66%

OOAllyl

BnO

OBn

HO

BnO

OOBn

HOOAllyl

HO

BnO

i. (Bu2SnO)n, MeOH

ii. AllylI, DMF 1 hr, 100 °C

79%

OOBn

AllylO

OAllyl

HO

BnO

38

benzyl 2,3-di-O-benzyl-α-D-glucopyranoside stannylene derivative with benzyl bromide under

the reaction conditions was found to give the 6-O-benzylated product in 80% yield. Application

of the reaction conditions to carbohydrate derivatives bearing three free hydroxy groups was also

successful. Benzyl 2-O-benzyl-β-D-galactopyranoside afforded the 3-O-benzyl ether product in

68% yield, whereas benzyl 3-O-benzyl-β-D-galactopyranoside gave preferentially the 6-O-benzyl

ether product in 72% yield. Interestingly, reaction using benzyl β-D-galactopyranoside resulted in

exclusively the 3-O-benzylated product in 67% yield.

Scheme 2.22 – David and Thieffry’s Benzylation of D-Galactopyranoside Derivatives

A much more recent report by Ley and co-workers revealed the use of dibutyltin dimethoxide to

effect selective alkylation of varying diols in benzene or toluene (Scheme 2.23).55 Under Dean-

Stark conditions, the corresponding stannylene acetal is generated in situ and treated with the

alkylating reagent to afford the selectively substituted product. This contrasts with the dibutyltin

oxide method as it is not necessary to remove and replace the solvent prior to the addition of the

alkylating agent.

Scheme 2.23 – Ley’s Selective Alkylation of Diols Using Dibutyltin Dimethoxide

55 Boons, G.-J.; Castle, G. H.; Clase, J. A.; Grice, P.; Ley, S. V.; Pinel, C. Synlett 1993, 913–914.

OOH

HO OBn

HO

OBn


ii. BnBr, TBAI, benzene

68%

OOH

BnO OBn

HO

OBn

OOH

HO OBn

HO

OH


ii. BnBr, TBAI, benzene

67%

OOH

BnO OBn

HO

OH

OOHO OBnO

OH

PhBu2Sn(OMe)2BenzeneDean-Stark OO

BnO OBnO

OH

Ph

BnBr

i.

ii.

83%

39

Selective monobenzylation of alkyl α-L-rhamnopyranoside derivatives in the presence of

catalytic tin(II) chloride has also been reported by Toman et al. (Scheme 2.24).56 Treatment of

methyl α-L-rhamnopyranoside with excess benzyl bromide and triethylamine in acetonitrile

afforded a mixture of the 3-O-benzylated and 2-O-benzylated products in 52% and 5% yields

respectively.

Scheme 2.24 – Tin(II) Catalyzed Benzylation of α-L-Rhamnopyranoside Derivatives

2.4 Other Transition Metal Promoted Alkylations

Further developments in the area of carbohydrate chemistry have revealed a variety of other

transition metals capable of promoting regioselective alkylation. Several examples have

demonstrated the capability of metal chelation to impart regioselective alkylation of diols. Earlier

work by Avela showed that copper chelates of the dianions of methy 4,6-O-benzylidene-α- and -

β-D-glucopyranoside react with methyl iodide to give preferential substitution at the 3-O

position57. It is postulated that the formation of the copper(II) salts deactivate the carbohydrate

dianions, and as a result invokes the reaction to occur at the C-3 hydroxy group. Dialkylation is

also suppressed under these conditions.58 With methyl 2,3-di-O-benzyl-D-glucopyranoside,

differences in the reaction stoichiometry were also found to affect the selectivity of the reaction

either at the 4-O versus 6-O position.

An extension of this work was reported by Schuerch and co-workers, in which conditions to

form benzyl and allyl ethers regioselectively on carbohydrate derivatives were developed

56 Toman, R.; Rosík, J.; Zikmund, M. Carbohydr. Res. 1982, 103, 165–169. 57 Gridley, J. J.; Osborn, H. M. I.; Suthers, W. G. Tetrahedron Lett. 1999, 40, 6991–6994. 58 Osborn, H. M. I.; Brome, V. A.; Harwood, L. M.; Suthers, W. G. Carbohydr. Res. 2001, 332, 157–166.

O

OMeMe

HOHO OH

O

OMeMe

HOR'O OR

SnCl2 (10 mol %)

BnBr, NEt3MeCN, 110 °C

R = H, R' = Bn, 52%R = Bn, R' = H, 5%

40

(Scheme 2.25).59 Reaction of methyl 2,3-O-isopropylidene-α-D-mannopyranoside and benzyl

iodide with copper(II) chloride gave only the 4-O-benzylated product in >99% yield.

Scheme 2.25 – Schuerch’s Alkylation of α-D-Mannopyranoside Derivatives

In addition, Gridley et al. have developed a method for regioselective alkylation of various alkyl

1-O/S/Se-4,6-benzylidene-β-D-glucopyranoside using copper(II) chloride activation (Scheme

2.26).57 Treatment of the phenyl 4,6-O-benzylidene-β-D-glucopyranoside dianion, generated

from two equivalents of sodium hydride, with copper(II) chloride and methyl iodide afforded the

corresponding 3-O-methyl ether product in 64% yield.

Scheme 2.26 – Gridley’s Methylation of β-D-Glucopyranoside Derivatives

Demchenko and co-workers have also reported the use of nickel chelates to mediate

regioselective alkylation of carbohydrate derivatives (Scheme 2.27).60 Several 4,6-O-

benzylidene derivatives of D-glucopyranosides and D-galacopyranosides have been shown to

undergo regioselective alkylation using nickel(II) chloride in the presence of NaH in good yields.

Scheme 2.27 – Demchenko’s Alkylation of Carbohydrate Derivatives

59 Eby, R.; Webster, K. T.; Schuerch, C. Carbohydr. Res. 1984, 129, 111–120. 60 Gangadharmath, U. B.; Demchenko, A. V. Synlett 2004, 12, 2191–2193.

OOH

O

OMe

HOO

>99%

i.ii.

NaH, THFCuCl2BnIiii.

OOH

O

OMe

BnOO

OOHO OPhO

OH

Ph OOMeO OPh

O

OH

Phi.ii.

64%

NaH, THFCuCl2MeIiii.

OOHO

OMe

O

HO

Ph OOHO

OMe

O

BnO

Phi.ii.

61%

NaH, THF/DMFNiCl2BnBr, 16 hriii.

41

Very recently, a mild and regioselective method for benzylation of carbohydrate derivatives has

appeared where silver carbonate acts as a promoter (Scheme 2.28).61 Kartha et al. reported that

using p-methoxybenzyl chloride, octyl β-D-galactosidepyranoside could be selectively alkylated

at the 6-O position in 91% yield. Silver carbonate has also been proven to be highly efficient in

regioselective glycosylation of ‘naked’ galactosides using glycosyl halides.62

Scheme 2.28 – Kartha’s Alkylation of Carbohydrate Derivatives

2.5 Boron Activation of Hydroxy Groups for Regioselective

Alkylation

The selective formation of cyclic boronates between arylboronic acids and vicinal 1,2-diols or

1,3-diols with the exocyclic CH2OH moiety of carbohydrate derivatives has been well known in

the area of carbohydrate chemistry.63 Although the majority of these studies disclose the use of

boronate esters as protecting agents, several studies have emerged demonstrating their ability as

activating agents for diols.

Aoyama and co-workers reported that 3,4-boronate esters generated from phenylboronic acid and

either methyl α-L-fucopyranoside or methyl α-L-arabinopyranoside could be alkylated selectively

at the O-3 position by 1-iodobutane in the presence of triethylamine and silver oxide (Scheme

2.29).64 They proposed that the ‘ate’ complex formed from the amine and boronate ester promote

regioselective alkylation at the equatorial B-O bond.

61 Malik, S.; Dixit, V. A.; Bharatam, P. V.; Kartha, K. P. R. Carbohydr. Res. 2010, 345, 559–564. 62 Kartha, K. P. R.; Kiso, M.; Hasegawa, A.; Jennings, H. J. J. Chem. Soc., Perkin Trans. 1 1995, 3023–3026. 63 Duggan, P. J.; Tyndall, E. M. J. Chem. Soc., Perkin Trans. 1 2002, 1325–1339. 64 Oshima, K.; Kitazono, E. -i.; Aoyama, Y. Tetrahedron Lett. 1997, 38, 5001–5004.

OOH

HO OOct

HO

OH

pMBnCl, Ag2CO3

toluene, dark, 60 °C

91%

OOpMBn

HO OOct

HO

OH

42

Scheme 2.29 – Aoyama’s Alkylation of Fucose and Arabinose Derivatives

More recently, Onomura demonstrated an approach to monoalkylate 1,2-diols using catalytic

quantities of boronic acids in the presence of potassium carbonate (Scheme 2.30).65 They

reported that the efficiency of the reaction was controlled by the acidity of the diol and catalyst.

Less acidic diols required strong Lewis acids, whereas more acidic diols needed weak Lewis

acids.

Scheme 2.30 – Onomura’s Monoalkylation of 1,2-Diols

Studies by Evtushenko have also found that boric acid in catalytic quantities can help influence

regioselective methylation of methyl glycopyranosides with diazomethane (Scheme 2.31).66 The

reaction, however, results in variable yields and in some cases a mixture of products may be

observed.

Scheme 2.31 – Evtushenko’s Methylation of Methyl Glucopyranosides

65 Maki, T.; Ushijima, N.; Matsumura, Y.; Onomura, O. Tetrahedron Lett. 2009, 50, 1466–1468. 66 Evtushenko, E. V. Carbohydr. Res. 1999, 316, 187–200.

O

OMeMe

OHOH

OHPhB(OH)2

O

OMeMe

OO

OH

B

Ph

O

OMeMe

OHOBu

OH

O

OMeMe

OO

OH

B

Ph

NEt3

NEt3

nBuIAg2O

50%

OH

OH

B(OH)2

FBnBr, K2CO3, DMF

OBn

OH

99%

(0.1 equiv)

O

OMeMe

HOHO

OH

O

OMeMe

R''OR'O

OR

B(OH)3 (0.04 equiv)

R = R" = H, R' = Me, 48%R = R' = H, R" = Me, 47%R' = H, R = R" = Me, 2%

MeOH, CH2N2

43

2.6 Diarylborinic Acid Catalyzed Regioselective Alkylation

As described above, the use of organotin reagents is the most current state-of-the-art method for

regioselective monoalkylation of carbohydrates. However, these processes generate

stoichiometric quantities of tin byproducts. The report of Aoyama indicates that organoboron

reagents are capable of regioselective monoalkylations, although the process requires the use of

equimolar quantities of the organoboron reagent. Development of a catalytic variant of these

reactions would thus be an attractive improvement. Very recently our group reported that

derivatives of diphenylborinic acid are capable of catalyzing the selective monoacylation of the

equatorial hydroxy groups of cis-vicinal diol motifs in a wide range of carbohydrate derivatives

(Scheme 2.32).17

Scheme 2.32 – Borinic Acid-Catalyzed Monoacylation of cis-1,2-Diols

Building on our previous results, we sought to determine whether a similar mode of reactivity

could be employed to achieve catalyst-controlled, regioselective monoalkylation of carbohydrate

derivatives bearing multiple secondary hydroxy groups (Scheme 2.33). Described herein are the

studies that led to the successful realization of such an approach. These studies point to new

opportunities for the regioselective functionalization of carbohydrate derivatives and may find

application in the preparation of complex oligosaccharide compounds.

Scheme 2.33 – Proposal for Regioselective Alkylation of Polyols

O

OMeMe

HOHO

OH

PhB

Ph NH2

O

(10 mol %)PhCOCl, iPr2NEt

MeCN

O

OMeMe

HOPhOCO

OH94%

HO OH

R1 R2

RO OH

R1 R2

RXLnBOH (cat.)

LnBOH

LnB

O O

R1 R2

44

2.6.1 Synthesis of the Carbohydrate Substrates

Methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside 2.01 was synthesized for method

development since it was readily prepared on gram-scale from methyl α-D-mannopyranoside.

Following a procedure reported by our group17, commercially avaliable methyl-α-D-

mannopyranoside was silylated using tert-butyldimethyl silyl chloride under basic conditions to

deliver the substrate in 89% yield (Scheme 2.34). Subsequently, methyl α-D-galactopyranoside

and methyl β-D-galactopyranoside were silylated in a similar fashion to afford 2.05 and 2.06 in

46% and 91% yields respectively.

Scheme 2.34 – TBS-Protection of the Primary Hydroxy Group

The 3,4,6-tri-O-benzyl-D-mannopyranoside 2.03 was synthesized in six steps using a literature

procedure reported by Namme (Scheme 2.35).67 Commercial 1,2,3,4,6-penta-O-acetyl-D-

galactopyranose was first converted to the orthoester product via bromination at the anomeric

position, followed by cyclization upon treatment with 2,6-lutidine in methanol. Deacetylation

was then carried out followed by alkylation with benzyl bromide to afford a tribenzylated

galactopyranoside. Treatment with acetic acid cleaved the orthoester and subsequent

deacetylation delivered the target sugar in 29% yield overall.

67 Namme, R.; Mitsugi, T.; Takahashi, H.; Shiro, M.; Ikegami, S. Tetrahedron 2006, 62, 9183–9192.

OOH

HOHO

OH

OMe

TBSCl (1.2 equiv)pyridine, 0.7 M

OOTBS

HOHO

OH

OMe2.01, 89%

45

Scheme 2.35 – Synthesis of 3,4,6-Tri-O-Benzyl-D-Mannopyranoside

2.6.2 Reaction Development and Extension of Scope

Preliminary studies were conducted with methyl-6-(tert-butyldimethylsilyloxy)-α-D-

mannopyranoside 2.01, benzyl bromide, silver oxide and the commercially available

diphenylborinate ester as a catalyst. Protection of the 6-hydroxy group in α-D-mannopyranoside

was necessary to achieve efficient catalyst-controlled alkylation as a complex mixture of

products were formed when unprotected α-D-mannopyranoside was employed. This is

presumably due to competitive binding of the boron catalyst to the 4,6- and 3,4-diol groups.

The results of a solvent screen are summarized in Table 2.1. It was found that acetonitrile

afforded the product with the highest yield of 35%.

K2CO3 (2.2 equiv)

O

OAc

AcOAcO

OAc

OAc

i. 33% HBr in AcOHi. K2CO3 (2.1 equiv) MeOH, 0.2 M

34% over 4 steps

O

OBn

BnOBnO

OAc

OAc

O

OAc

AcOAcO

OO

OMeO

OBn

BnOBnO

OO

OMe

ii. 2,6-lutidine (2 equiv) MeOH, 0.4 M

ii. BnBr (3.2 equiv) NaH (3.2 equiv) DMF, 0.3 M 0 °C – rt

AcOH, 0.3 M

MeOH, 0.5 M0 °C – rt

O

OBn

BnOBnO

OH

OH2.03, 95% 89%

46

Table 2.1 – Solvent Screen for Alkylation of Carbohydrate Derivatives

Optimization of other reaction parameters such as catalyst loading, equivalents of benzyl

bromide and temperature was then carried out (Table 2.2). When elevated temperatures were

employed, the yield increased to 65% (entry 4), however, a decrease in yield was observed when

the reaction was heated to higher temperatures (entry 5). Increasing the stoichiometry of the

alkylating agent was also found to have a positive effect on the reaction (entry 8). No

improvement was observed when additional silver oxide was used (entry 11). Finally, doubling

the catalyst loading delivered the target molecule in 80% (entry 10). As a control, carrying out

the reaction with no catalyst was found to give traces of product (entry 1) and using more forcing

conditions resulted in no regioselectivity (entry 2).

entry yielda

15%19%

a Yield of 2.11 determined by 1H NMR with mesitylene as a quantitative internal standard.

solvent

123456

35%21%19%13%

7

7%

O

OTBS

HOHO

OH

OMeBnBr (1.1 equiv)Ag2O (1.1 equiv)solvent, 0.2 M

rt

PhB

Ph NH2

O

(10 mol %)O

OTBS

HOBnO

OH

OMe

dichloromethane

1,4-dioxane

diethyl etherdimethoxyether

toluene

acetonitrile

tetrahydrofuran

2.01 2.11

47

Table 2.2 – Optimization for Alkylation of Carbohydrate Derivatives

A further optimization was carried out to ascertain whether longer reaction times using lower

catalyst loadings could give the desired product with higher yields (Table 2.3). Carrying out the

reaction for two days at lower temperatures with the same amount of catalyst was found to give

similar yields (entries 1 and 2). As well, a lower catalyst loading and decrease in the equivalents

of alkylating agent also gave the desired product in 80% yield (entry 3). Switching the base from

silver oxide to silver carbonate had a negative effect as only 52% of product was observed (entry

5). Furthermore, diluting the reaction from 0.2 M to 0.1 M increased the yield to 91% (entry 6).

Ultimately, it was observed that using 10 mol % of the catalyst could afford the target compound

in 91% yield (entry 9).

entry NMR yield (isolated)

8910

11

12

49%

72% (70%)47%

59% (57%)

a Yield of 2.11 determined by 1H NMR with mesitylene as a quantitative internal standard and isolated yield in parentheses.b 1.5 equiv of Ag2O was employed.

15

x mol % y equiv

1.1

1.51.1

1.5

temperature (°C)

60

6080

8083% (80%)20 1.5 60

123456

4%complex mixture

35%63% (65%)

0

10

1.1

1.1

rt60rt60

7

49%80

O

OTBS

HOHO

OH

OMeBnBr (y equiv)

Ag2O (1.1 equiv)MeCN, 0.2 M

16 hr

PhB

Ph NH2

O

(x mol %) O

OTBS

HOBnO

OH

OMe

63%b (66%)60

66% (62%)70

0

1010

1.1

1.11.1

151515

20

20

1.5

1.5

2.01 2.11

48

Table 2.3 – Further Optimization for Alkylation of Carbohydrate Derivatives

A representative list of organoboron species were then evaluated as catalysts (Table 2.4). In the

absence of catalyst, only trace amounts of the target product 2.11 were observed (entry 1). Boric

acid and phenylboronic acid showed some activity and afforded the corresponding product in

moderate yields (entries 2 and 3). Modification of the electronic properties of the arylboronic

acid did not show any improvements in yield (entries 5 and 7). The electron deficient 3,5-

bis(trifluoromethyl)phenylboronic acid gave the product in 57% yield, whereas the electron rich

4-methoxyphenylboronic acid delivered the product in 56% yield. In contrast with the

observations disclosed by Aoyama and co-workers, the addition of triethylamine gave only trace

amounts of product (entries 4, 6 and 8). Although triphenylborane 2.60 displayed modest activity

(50%, entry 11), it is possible that under the reaction conditions, a C–B bond in the boron reagent

was oxidized to generate a borinic acid derivative.68 In contrast, the ethanolamine ester of

diphenylborinic acid 2.58 promoted alkylation of 2.01 with high conversion (91%, entry 10).

Similar results were obtained when diphenylborinic acid 2.56 was used (95%, entry 10),

68 Domaille, P. J.; Druliner, J. D.; Gosser, L. W.; Read, J. M.; Schmelzer, E. R.; Stevens, W. R. J. Org. Chem. 1985, 50, 189–194.

entry isolated yieldy equiv

80%1.5

x mol %

20

temp. (oC)

60

time

16 hr

52%a

86%

91%

1.5

1.5

1.5

15

10

10

40

40

40

2 d

2 d

2 d

z M

0.2

0.2

0.2

0.1

O

OTBS

HOHO

OH

OMeBnBr (y equiv)

Ag2O (1.1 equiv)MeCN, z M

PhB

Ph NH2

O

(x mol %) O

OTBS

HOBnO

OH

OMe

78%1.215 50 2 d0.280%1.215 40 2 d0.2

91%1.515 40 2 d0.1

79%2.010 40 2 d0.2

a 1.1 equiv of Ag2CO3 was used in place of Ag2O.

79%1.520 40 2 d0.2

9

21

43

5

6

78

2.01 2.11

49

suggesting that 2.55 serves as a precatalyst from which the ethanolamine ligand is alkylated prior

to displacement by the carbohydrate substrate.

Table 2.4 – Further Optimization for Alkylation of Carbohydrate Derivatives

Experimentation with silver(I) salts was also conducted, however, all provided inferior results in

comparison to silver oxide (Table 2.5). Silver acetate gave the lowest yield with 37% product

(entry 1), whereas silver carbonate and silver triflate, with 1.1 equivalents of N,N-

diisopropylethylamine to sequester generated triflic acid, provided the product with moderate

yields of 42% and 57% respectively (entries 2 and 3). The addition of stoichiometric or catalytic

(20 mol %) amounts of tetrabutylammonium iodide or tetrabutylammonium bromide salts to the

reaction conditions led to the formation of complex mixtures.

entry NMR yielda

89

10

11

<5%

<5%56%

91%

a Yield of 2.11 determined by 1H NMR with mesitylene as a quantitative internal standard and isolated yield in parentheses.b Reaction carried out in the presence of 1.1 equiv NEt3

2.56b

catalyst

95%2.59

123456

<5%52%54%<5%

None

7

57%

O

OTBS

HOHO

OH

OMecatalyst (10 mol %)

Ag2O (1.1 equiv)MeCN, 0.2 M40 °C, 2 days

O

OTBS

HOBnO

OH

OMe

50%

PhB(OH)2b

2.56

2.572.57b

2.58

2.60

2.01 2.11

B(OH)3

PhB(OH)2

BnBr (1.5 equiv)

Catalysts:F3C

B(OH)2

CF3

BX

OMe

B(OH)2

2.56 2.572.58: X = OCH2CH2NH22.59: X = OH2.60: X = Ph

50

Table 2.5 – Optimization of Silver(I) Salt

With the optimal conditions in hand, we then proceeded to evaluate the scope of the reaction

using a variety of carbohydrate derivatives and alkylating agents. Illustrative examples of the

scope for selective installation of benzyl, naphthylmethyl, 4-bromobenzyl and benzyloxymethyl

protecting groups on ten carbohydrate substrates derived from mannose 2.01–2.03, rhamnose

2.04, galactose 2.05–2.07, 2.10, fucose 2.08 and arabinose 2.09 are included in Table 2.6. As

demonstrated therein, the reaction conditions enables reliable and high-yielding alkylation of the

equatorial hydroxy group of cis-vicinal diol pairs. The transformation is equally compatible with

variation in the stereochemistry of the anomeric position (2.05 vs 2.06). In the galacto series, a

sterically hindered substituent at C-5 was found to be not essential for obtaining high

regioselectivity (galactose 2.05 vs fucose 2.08 and arabinose 2.09). As exemplified by the 1,6-

anhydro derivatives of mannose 2.02 and galactose 2.07, where the pyranose ring adopts a 1C4

conformation instead of a 4C1, complementary regiochemical outcomes to those obtained for

mannose 2.01 and galactose 2.05 was obtained respectively. Selective alkylation of tribenzylated

mannose 2.03 delivered the benzyl ether at the O-1 position to afford the challenging β-mannosyl

stereochemical outcome at the anomeric position (entry 9). Using a slight excess of 4-

bromobenzyl bromide and silver oxide, D-Galactal 2.10 was found to undergo selective

dialkylation at the O-3 and O-6 positions (entry 34).

entry isolated yield

1234

42%37%57%91%

OOTBS

HOHO

OH

OMeBnBr (1.5 equiv)Ag(I) (1.1 equiv)

MeCN, 0.2 M40 °C, 2 days

PhB

Ph NH2

O

(10 mol %) OOTBS

HOBnO

OH

OMe

AgOTf + i-Pr2NEt (1.1 equiv)

Ag2CO3

Ag(I)

AgOAc

Ag2O

2.01 2.11

51

Table 2.6 – Scope of Regioselective Alkylation of Monosaccharides

R2R1 R!X (1.5 equiv)

Ag2O (1.1 equiv)MeCN, 40 oC, 2 days

PhB

Ph NH2

O

(10 mol %)OH

HO R2R1

OH

RO

entry yielda

8

9

101112

2.15

2.172.16

2.18

substrate

2.19

1234

56

2.112.122.13

7

2.14

2.202.21

O

OTBS

HO

OMe

OH

HO

O

O

ROOH

OH

O

OOH

OH

OH

O

OTBS

HO OMe

OH

OH

O

OMeMe

OHOH

OH

O

OMeMe

HOHO

OH

O

OTBS

RO

OMe

OH

HO

O

O

HOOH

OH

O

OOH

OH

OR

O

OMeMe

OHOR

OH

O

OMeMe

HORO

OH

O

OBn

BnOBnO

OH

OH

O

OBn

BnOBnO

OH

OBn

O

OTBS

HOHO

OH

OMe

O

OTBS

HORO

OH

OMe

O

OTBS

RO OMe

OH

OH

2.01

2.02

2.03

2.04

2.05

2.06

2.07

2.08

91%(R = Bn)(R = 4-BrBn) 99%

2.26

2.28

2.27

2.292.30

2.222.23

2.242.25

2.31

2.322.332.342.35

2.362.372.382.39

2021

222324

13

14151617

1819

25

26272829

(R = Nap)(R = BOM)

(R = Bn)(R = 4-BrBn)(R = Nap)(R = BOM)

(R = Bn)






63%

72%

83%73%99%

89%84%

73%73%71%

99%88%

76%72%74%

83%

77%95%82%90%

74%91%

66%

94%89%86%98%

product

52

Selective protection using allyl bromide with mannose 2.01, galactose 2.05 and fucose 2.08 was

also carried out, however, under the optimized reaction conditions poor yields were obtained

(Table 2.7). It can be rationalized that the low yields arise from the ability of allyl bromide to

undergo SN2 and SN2’reactions, and is less sterically hindered.

Table 2.7 – Scope of Regioselective Allylation of Monosaccharides

a Isolated yield on 0.2-1.0 mmol scale. X = Br for the installation of the Bn, 4-BrBn, and Nap groups; X = Cl for installation of the BOM group.b 2.5 equiv of 4-BrBnBr and 2.1 equiv of Ag2O were employed.

O

OHHO

HOO

ORHO

RO

OHO OMe

OH

OH

ORO OMe

OH

OH2.09

2.10

2.402.412.42

2.44

2.433233

34

3031


(R = 4-BrBn)

71%82%

77%b

74%84%

R2R1 AllylBr (1.5 equiv)


PhB

Ph NH2

O

(10 mol %)OH

HO R2R1

OH

RO

entry isolated yieldsubstrate

1

2

3

53%

17%

56%

product

O

OMeMe

OHOH

OH

2.08

O

OMeMe

OHOAllyl

OH

O

OTBS

HO

OMe

OH

HO

O

OTBS

AllylO

OMe

OH

HO2.05

O

OTBS

HOHO

OH

OMe

O

OTBS

HOAllylO

OH

OMe2.01 2.45

2.46

2.47

53

Alkylation using p-methoxybenzyl chloride was found to be less selective in comparison as

mixtures of regioisomers were obtained (Table 2.8). In all cases, functionalization at the other

boron-bound hydroxy group was observed. The poor selectivity is presumably due to the weaker

chloride leaving group or possibly p-methoxybenzyl chloride is more prone to SN1 reactions.

Table 2.8 – Scope of Regioselective p-Methoxybenzylation of Monosaccharides

R2R1 PMBCl (1.5 equiv)


PhB

Ph NH2

O

(10 mol %)OH

HO R2R1

OH

RO

entry isolated yieldasubstrate

1

2

3

42% (33%)

61% (33%)

37% (15%)

product

O

OTBS

HOHO

OH

OMe

O

OTBS

HOPMBO

OH

OMe2.01 2.48

4

5

6

59% (20%)

62% (7%)

42% (29%)

O

OTBS

HO OMe

OH

OH

O

OTBS

PMBO OMe

OH

OH2.06

O

OMeMe

OHOH

OH O

OMeMe

OHOPMB

OH

2.08

O

OOH

OH

OH O

OOH

OH

OPMB

2.02

O

O

PMBOOH

OH

O

O

HOOH

OH2.07

OHO OMe

OH

OH

OPMBO OMe

OH

OH2.09

2.49

2.50

2.51

2.52

2.53a Yield in parentheses represent the isolated regioisomer.

54

Current limitations of the reaction condition include sugars that do not contain a cis-vicinal diol

motif such as glucose or xylose derivatives, thiogalactose derivatives and mannose derivatives

presented in Figure 2.1. Neither iodomethane or bromobutane was found to afford regioselective

alkylation under the optimized conditions indicating that it may be essential to use activated

(benzylic or alkoxymethyl) halides for high reactivity.

Figure 2.1 – Incompatible Monosaccharide Derivatives

2.7 Monoalkylation via Halide Catalysis

Several reports have described the use of tetrabutylammonium iodide as a key additive for

promoting increased product yields in alkylation reactions.69 It is postulated that in these

reactions, halide exchange occurs to generate the more reactive alkyl halide.

In an extension of this work, it was found that halide catalysis is also compatible with the

diphenylborinate ester catalyst to carry out regioselective alkylation. Activation of the alkyl

halide by the addition of iodide salts in conjunction with Brønsted bases rather than silver(I) salts

was evaluated. With sodium iodide as the halide salt, benzylation of 2.01 was carried out using

the optimized reaction conditions for silver oxide with potassium carbonate, N,N-

diisopropylethylamine or 1,2,2,6,6-pentamethylpiperidine as the Brønsted base (Table 2.9). N,N-

Diisopropylethylamine and 1,2,2,6,6-pentamethylpiperidine both gave only starting material

(entries 2 and 3), whereas potassium carbonate afforded the target sugar in 14% isolated yield

(entry 1).

The reaction outcome was significantly influenced by further experimentation as shown in Table

2.10. Elevating the reaction temperature to 60 °C and a shorter reaction time improved the yield

to 85% (entry 1). This yield was further increased to 89% when potassium iodide was employed

69 (a) Fox, D. L.; Whitely, N. R.; Cohen, R. J.; Salvatore, R. N. Synlett 2003, 13, 2037–2041; (b) Salvalore, R. N.; Smith, R. A.; Nischwitz, A. K.; Gavin, T. Tetrahedron Lett. 2005, 46, 8931–8935.

OOO

MeHO

OHHOO

OTBSHO

HOOH

SiPrO

OH

HO

OMe

HO

HO

OHO

OMe

HO

HO O

OH

HOHO

55

and the reaction temperature was increased to 80 °C (entry 5). Finally, tetra-n-butylammonium

iodide delivered the monoalkylated product 2.11 in >99% isolated yield (entry 8).

Table 2.9 – Alkylation of Using Sodium Iodide and Brønsted bases

Table 2.10 – Optimization of Iodide Salts

entry isolated yieldbase

BnBr (1.5 equiv)NaI (1.1 equiv)base (1.1 equiv)

MeCN, 0.2 M40 °C, 2 days

PhB

Ph NH2

O

(10 mol %)

1

2

3

K2CO3

DIPEA

N

nr

nr

14%

O

OTBS

HOHO

OH

OMe

O

OTBS

HOBnO

OH

OMe

2.01 2.11

BnBr (1.5 equiv)halide salt (1.0 equiv)

K2CO3 (1.1 equiv)MeCN, 0.2 M

PhB

Ph NH2

O

(10 mol %)

entry isolated yieldhalide salt time temperature (°C)

3

4

5

6

7

8

KI

KI

KI

TBAI

TBAI

TBAI

NaI

NaI

1

2

40

60

80

40

60

80

60

80

2 days

1 day

2 days

1 day

1 day

1 day

1 day

1 day

72%

61%

77%

76%

85%

73%

89%

>99%

O

OTBS

HOHO

OH

OMe

O

OTBS

HOBnO

OH

OMe

2.01 2.11

56

Further studies on the compatibility of the reaction conditions with other carbohydrate substrates

were tested (Scheme 2.31). Using 1,6-anhydro-β-D-galactopyranoside 2.07, the alkylation with

benzyl bromide and tetra-n-butylammonium iodide as an additive gave 78% yield of the

corresponding product 2.32. Switching the halide salt to potassium iodide surprisingly gave

>99% yield which is significantly greater than the amount furnished when silver oxide was

employed (76% yield, Table 2.6, entry 22). Alkylation of methyl-β-L-arabinopyranoside 2.09

using benzyl bromide and tetra-n-butylammonium iodide gave 52% yield of 2.40. Similar results

were obtained when potassium iodide was utilized (50% yield). In comparison, silver oxide

afforded benzylated arabinose 2.40 in 74% yield (Table 2.6, entry 30).

Scheme 2.36 – Extension of Halide Catalysis Method to Other Substrates

In efforts towards transferring this reactivity to thiogalactose derivatives, a screen of different

conditions with changes in stoichiometry of halide salt, temperature and reaction time was

carried out in the presence of tetra-n-butylammonium iodide (Table 2.11). Although no

reactivity was observed after one day even with heat (entry 1 to 3), low conversion to 2.55 was

observed after two days at room temperature (20% yield, entry 4). Increasing the temperature to

40 °C improved the yield to 32% (entry 5), however, excess halide salt resulted in no reactivity

(entry 6).

2.40, 52%

OO

HOOH

OH

OO

BnOOH

OH

O

OMeHOBnO

HOO

OMeHOHO

HO

BnBr (1.5 equiv)KI (1.0 equiv)

K2CO3 (1.1 equiv)MeCN, 0.2 M1 day, 80 °C

PhB

Ph NH2

O

(10 mol %)

2.32, >99%

BnBr (1.5 equiv)TBAI (1.0 equiv)

K2CO3 (1.1 equiv)MeCN, 0.2 M1 day, 80 °C

PhB

Ph NH2

O

(10 mol %)

2.07

2.09

57

Table 2.11 – Glycosylation of Thiogalactosides Using TBAI in Halide Catalysis

In order to test whether the low yields were associated with the halide salt, further studies were

carried out employing potassium iodide (Table 2.12). Similar results to those using tetra-n-

butylammonium iodide were obtained. Reactions after one day were found to give no reactivity

(entry 1 to 3), whereas low yields were observed after two days (entry 4 and 5). Higher

equivalents of potassium iodide were found to be less effective (entry 6).

The poor reactivity of the thiogalactose substrate is possibly attributed to the reactive thio group,

which was revealed to be incompatible in reactions using silver oxide. Further studies

investigating the effects of other functional groups on sulfur should be explored in the future.

OOTBSHO

HOHO

SiPrO

OTBSHO

BnOHO

SiPrBnBr (1.5 equiv)TBAI (1.0 equiv)


PhB

Ph NH2

O

(10 mol %)

entry yieldtime temperature (°C)

3

4

5

6a

1

2

rt

40

1 day

1 day

n.r.

n.r.

rt

40

40

80

2 days

1 day

2 days

2 days

20%

32%

n.r.

n.r.

2.54 2.55

a Reaction carried out using 3.0 equivalents of TBAI.

58

Table 2.12 – Glycosylation of Thiogalactosides Using KI in Halide Catalysis

2.8 DFT Calculations

Our mechanistic model for the regioselective alkylation reaction involves the formation of a

tetracoordinate borinate complex with a cis-vicinal diol motif (Figure 2.2). The B-O bonds of the

tetracoordinate adduct reacts preferentially with electrophiles to deliver the product of mono-

alkylation or acylation. Computational studies were performed to calculate Fukui indices. The

Fukui index takes into account the change in electron density of valence electrons when forming

molecules and relatively predicts which atom will have a higher tendency to either lose or accept

an electron for nucleophilic attack or electrophilic attack respectively.70 Previously, Fukui index

calculations of borinate esters derived from rhamnose 2.04 and fucose 2.08 demonstrated that

nucleophilic activity was found to be the highest at O-3, which was consistent with the observed

reactivity and also suggests an electronic basis for the observed selectivity.17 The boron-bound

oxygen atoms in the tetracoordinate complex have increased electron density in comparison to

non-bonded oxygen groups and the relative reactivity seems to reflect dipole–dipole interactions.

70 Yang, W.; Mortier, W. J. J. Am. Chem. Soc. 1986, 108, 5708–5711.

OOTBSHO

HOHO

SiPrO

OTBSHO

BnOHO

SiPrBnBr (1.5 equiv)KI (1.0 equiv)


PhB

Ph NH2

O

(10 mol %)

entry yieldtime temperature (°C)

3

4

5

6a

1

2

80

rt

40

40

rt

40

1 day

2 days

1 day

1 day

2 days

2 days

n.r.

16%

17%

24%

n.r.

n.r.

2.54 2.55

a Reaction carried out using 3.0 equivalents of KI.

59

For rhamnose 2.04 and fucose 2.08, the C3–O bond is in opposition of the C4–O and C5–O

bonds, and of the C2–O and C1–O bonds respectively.

Similar calculations modeling the adducts of anhydro[1,6]mannose 2.02 and

anhydro[1,6]galactose 2.07 provided additional support for this proposal. The Fukui indices were

found to give the highest nucleophilicity at O-2 for anhydro[1,6]mannose 2.02 and at O-4 for

anhydro[1,6]galactose 2.07, which is consistent with the observed data. For the tribenzylated

mannose 2.03, the Fukui index indicated the highest nucleophilicity at the O-2 position since the

C1 position in comparison is more electron deficient. However, selective alkylation at the O-1

position is observed under the reaction conditions. This may be indicative of a proton transfer

equilibria playing a role in the regiochemical outcome.32

2.9 Conclusion

In conclusion, we have demonstrated that borinic acid catalysts represent an efficient and broadly

applicable method for the regioselective alkylation of carbohydrate derivatives bearing multiple

secondary hydroxy groups. Attractive features of this new mode of catalytic reactivity include its

operational simplicity and avoidance of using stoichiometric quantities of organotin-based

reagents.

60

Figure 2.2 – Calculated Structures and Condensed Fukui Indices (B3LYP/6-311+G(d,p))

61

3 Regioselective Glycosylation by a Diarylborinic Acid

Derivative

3.0 Introduction

The stereo and regioselective formation of O-glycosidic bonds represents the key process in

oligosaccharide syntheses.71 Since the first introduction of glycoside synthesis by Michael72 and

Fischer73, and the seminal studies of Koenigs and Knorr74, the development of selective

glycosidation methods using readily available carbohydrate derivatives have been pursued for

more than a century. Regioselectivity in oligosaccharide synthesis, however, is a fundamental

challenge that arises from the fact that the glycosyl acceptor bears multiple, potentially reactive

hydroxy groups. Generally, this problem has been addressed through the use of protecting groups

to suppress glycosylations at undesired sites. As addressed earlier, the disadvantage of this

71 Zhu, X.; Schmidt, R. R. Angew. Chem. Int. Ed. 2009, 48, 1900–1934. 72 Michael, A. Am. Chem. J. 1879, 1, 305–312. 73 Fischer, E. Ber. Dtsch. Chem. Ges. 1893, 26, 2400–2412. 74 Koenigs, W.; Knorr, E. Ber. Dtsch. Chem. Ges. 1901, 34, 957–981.

62

strategy is that multiple inefficient steps are required to install and remove protecting groups,

generating chemical waste in the process.

Among other approaches towards addressing this issue, several are outlined below including

exploiting the inherent reactivity differences of the hydroxy groups and employing activating

agents such as organotin and organoboron reagents. Although there have been numerous

developments, none of these strategies rival the capabilities of enzymes.75

3.1 Inherent Reactivity of Hydroxy Groups in Glycosylations

Several reports of regioselective glycosylations have been achieved by exploiting inherent

differences in the steric and electronic properties of hydroxy groups for a limited group of

glycosyl substrates. These reactions, however, are generally optimized on a case-by-case basis

depending on the glycosyl donor and acceptor substrates employed, as outlined below. As well,

the regiochemical outcome of these processes may depend on the structure of the glycosyl donor

substrate. Various studies have reported the regioselective β-galactosylation of N-protected

glucosamine derivatives. In the synthesis of Lewis X pentasaccharide by Schmidt, glycosylation

of a 3-O,4-O-unprotected acceptor derived from N-TCP protected glucosamine using boron

trifluoride diethyl etherate as an activator was found to take place selectively at the 4-hydroxy

over the 3-hydroxy group (Scheme 3.1).76 It was proposed that the steric demand of the TCP

group suppressed reaction at the 3-hydroxy group.

Scheme 3.1 – Selective Glycosylation Due to Steric Effects

75 (a) Bennett, C. S.; Wong, C.-H. Chem. Soc. Rev. 2007, 36, 1227–1238; Hancock, S. M.; Vaughan, M. D.; Withers, S. G. Curr. Opin. Chem. Biol. 2006, 10, 509–519; (c) Gamblin, D. P.; Scanlan, E. M.; Davis, B. G. Chem. Rev. 2009, 109, 131–163. 76 Lay, L.; Manzoni, L.; Schmidt, R. R. Carbohydr. Res. 1998, 310, 157–171.

OO SPhHONTCP

OBn

O

OAc

OAcAcO

AcOOHO SPhHONTCP

OBnO

OAcAcO

AcOAcO

O NH

CCl3

BF3.OEt2 (0.05 equiv)

87%

–30 °C+

63

Similarily, work by the group of Magnusson reported that a N-TCP protected glucosamine

derivative could be selectively glycosylated to afford the 1→4 linked lactosamine product in the

presence of a free 3-hydroxy group using methylsulfenyl bromide and silver

trifluoromethanesulfonate as activators (Scheme 3.2).77 Glycosylation using a perbenzylated

fucosyl donor under the same reaction conditions was found to give a 3.6:1 mixture of the 1→3

and 1→4 linked disaccharides in 84% yield. In comparison, glycosylation using the

peracetylated fucosyl donor gave a 2.2:1 β:α mixture of the 4-O linked disaccharide in 58%

yield. The differences in the observed regioselectivities were attributed to several factors,

including the nature of the various protecting groups, and the nature and mode of activation of

the donor.

Scheme 3.2 – Regiodifferentiation in Glycosylation Reactions

77 Ellervik, U.; Magnusson, G. J. Org. Chem. 1998, 63, 9314–9322.

OO OPMBHONTCP

OBn

O

OAc

OBnAcO

AcOOHO OPMBHONTCP

OBnO

OBnAcO

AcOAcO

SPh

i. AgOTf, MeCN

84%

+ii. MeSBr, DCE –70 °C

OHO OPMBHONTCP

OBni. AgOTf, MeCN


SEtO

OBnBnO

MeOBn

OO OPMBHONTCP

OBn

OOBnBnO

MeOBn

3.6:1, 84%

OHO OPMBHONTCP

OBni. AgOTf, MeCN


SEtO

OAcAcO

MeOAc

OO OPMBHONTCP

OBn

O

OAcAcO

MeOAc

OO OPMBHONTCP

OBn

OOAcAcO

MeOAc

2.2:1, 58%

OHO OPMBONTCP

OBn

OOBnBnO

MeOBn

+

+

64

In a report by Fraser-Reid, glycosylations employing n-pentenyl ortho esters or n-pentenyl

glycosides as glycosyl donors were achieved with selectivity for the equatorial hydroxy group

and predominantly the axial hydroxy group respectively (Scheme 3.3).78 Reaction of the

mannose derived n-pentenyl glycoside with a mannoside diol afforded the disaccharide product

glycosylated at the axial hydroxy group as the major product, whereas with the mannose derived

n-pentenyl ortho ester only the equatorial glycosylated disaccharide was isolated. They

rationalize that the selectivity may arise from the distinct nature of the electrophilic species

involved (a trioxolenium ion versus oxocarbenium ion).

Scheme 3.3 – Glycosylations of n-Pentenyl Glycosides and n-Pentenyl Ortho Esters

3.2 Regioselective Glycosylations of Carbohydrate Derivatives via

Activating Agents

Regioselective reactions of carbohydrate derivatives have also been achieved by utilizing

activating agents to enhance the reactivity of specific hydroxy groups towards glycosyl donors.

In particular, organotin reagents have been widely applied; however, these protocols generally

require an additional synthetic step to incorporate the activating agent. As well, stoichiometric

quantities of toxic, lipophilic organotin species are generated in the process. More recently, an

78 Anilkumar, G.; Nair, L. G.; Fraser-Reid, B. Org. Lett. 2000, 2, 2587–2589.

NIS (1.3 equiv)

TBDMSOTf (cat.)CH2Cl2

OHO

OMe

AllylO

OHAllylOOBnO

O

BnO

OBnOBn

OBnO OBnO

OOBn

PhO

+

+NIS (1.3 equiv)

TBDMSOTf (cat.)CH2Cl2

OBnOBnO

OBnOBn

OHO

OMe

AllylO

OHAllylO

OHO

OMe

AllylO

OAllylO

OBnOBnO

OHOBn

OOAllylO

OHOAllyl

OMe69%

66%

65

alternative approach has been developed using arylboronic acids, in which a tetracoordinate

boronate complex of a cis-1,2-diol group undergoes selective reactions with electrophiles.

3.2.1 Activation via Organotin Reagents

The use of organotin reagents to control the activation of a specific hydroxy group for

glycosylation was first reported by Ogawa (Scheme 3.4).79 In these processes, participating

groups in the 2-position generated orthoesters which were then transformed with Lewis acids

into the corresponding disaccharides in moderate yields. Treatment of 2-O-acetyl-3,4,6-tri-O-

benzyl-α-D-mannopyranosyl chloride with stannylated methyl α-D-mannopyranoside, prepared

from bis(tributyltin) oxide, afforded a trimer derived from orthoester formation at the 3-O and 6-

O positions of methyl α-D-mannopyranoside in 34% yield. A minor amount (2% yield) of a

regioisomer in which orthoesters were generated at the 4-O and 6-O positions of methyl α-D-

mannopyranoside was also observed. The formation of the orthoesters is due to the participation

of the acetyl group at the 2-position of the glycosyl donor, generating a trioxolenium ion.

Scheme 3.4 – Ogawa’s Regioselective Glycosylation of Carbohydrate Derivatives

Augé and Veyrières demonstrated that glycosylation of the dibutylstannylene derivative of a

galactose-derived 3,4-cis-diol with glycosyl halides bearing no participating groups at the 2-

position gave good regio- and stereoselectivity when the reaction was carried out in a dipolar

aprotic solvent with lithium bromide or iodide salts as additives.80 Reaction of 2,3,4,6-tetra-O-

benzyl-α-D-galactopyranosyl chloride with an α-D-galactopyranoside stannylene derivative with

79 Ogawa, T.; Katano, K.; Matsui, M. Carbohydr. Res. 1978, 64, C3–C9. 80 Augé, C.; Veyrières, A. J. Chem. Soc. Perkin Trans. I 1979, 1825–1832.

OOBn

BnOBnO

OAc

Cl

OOH

HOHO

OH

OMe

i. (Bu3Sn)2O (1.5 equiv)

ii.O

O

HOO

OH

OMe

OOBn

BnOBnO

OO

Me

OOBn

BnOBnO

OO

Me

34%

66

lithium iodide in dry hexamethylphosphoroamide gave the desired α–linked disaccharide in 74%

yield and minor amounts of the β-linked isomer in 8% yield (Scheme 3.5).

The addition of lithium halide salts was inspired by a report by Gent and Gigg where they

demonstrated that tetrabutylammonium bromide helps avoid problems associated with the

instability of benzylated glycosyl bromides by converting 1,2-cis-glycosyl chloride into a 1,2-

trans-glycosyl bromide in 1,2-cis-glycoside synthesis.81 In later reports, it was found that the

same regioselectivity was observed in the absence of stannylene activation.80,82

Scheme 3.5 – Augé and Veyrières’ Regioselective Glycosylation Method

Martin-Lomas later reported the tributyltin ether-mediated regioselective glycosylations of 1,6-

anhydro-β-D-galactopyranose and methyl β-lactoside.83 Reaction of the stannylated 1,6-anhydro-

β-D-galactopyranose derivative with 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide in the

presence of tetraethylammonium bromide in toluene gave a 4:1 mixture of the 1,6-anhydro-4-O-

(2,3,4,6-tetra-O-benzyl-β- and -α-D-galactopyranosyl)-β-D-galactopyranose in 79% yield with

1,6-anhydro-3-O-(2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl)-β-D-galactopyranose as a minor

product in 14% yield (Scheme 3.6). Glycosylation of methyl β-lactoside occurred

regioselectively at the primary positions with complete α-stereoselectivity (Scheme 3.7). This

result contrasts with their previous findings of tributyltin ether-mediated benzylation of methyl

β-lactoside, in which the 3’-O position was the most reactive hydroxy group.83

81 Gent, P. A.; Gigg, R.; J. Chem. Soc. Perkin Trans. I 1975, 1521–1524. 82 Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am. Chem. Soc. 1975, 97, 4056–4062. 83 Cruzado, C.; Bernabe, M.; Martin-Lomas, M. Carbohydr. Res. 1990, 203, 296–301.

OBnO

BnOBnO

OBn

Cl

OBnO

BnOBnO

OBn

OHO

OAllylO

OBn

OBn

OHO

AllylO

OBn

OBn

HOi. (Bu2SnO)n, benzene

ii.

LiI (5 equiv)HMPA, 0.35 M

(2 equiv)

OBnO

BnOBnO

OBn

OHO

OAllylO

OBn

OBn

+

74%:8%

67

Scheme 3.6 – Regioselective Glycosylation of 1,6-Anhydro-β-D-Galactopyranose

Scheme 3.7 – Regioselective Glycosylation of Methyl β-Lactoside

More recently, Oscarson and co-workers reported the regioselective glycosidation at the primary

position of galactopyranosides bearing no protecting groups at the 2-,3-,4-,6-positions.84 The

dibutylstannylene derivative of β-D-galactopyranoside underwent regioselective glycosylation

with 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside in the presence of tetrabutylammonium iodide

to afford the α-linked disaccharide in 78% yield (Scheme 3.8).

84 Garegg, P. J.; Maloisel, J.-L.; Oscarson, S. Synthesis 1995, 409–414.

OBzO

BzOBzO

OBz

Br

i. (Bu3Sn)2O, toluene

ii.

Et4NBr (6 equiv)CH2Cl2, 0.04 M

(2 equiv)

OO

HOOH

OH

OO

OOH

OH

OBzO

BzOBzO

OBz

OO

OOH

OH

OBzO

BzOBzO

OBz

OO

HOO

OH

OBzO

BzOBzO

OBz

4:1, 79%+

14%

HO OMeOO

HO

HOHO

OH

OH

OH

HO OMeOO

HO

HOHO

OH

O

OH

OBzO

BzOBzO

OBz

Br

i. (Bu3Sn)2O, toluene

ii.

Et4NBr (6 equiv)CH2Cl2, 0.04 M

(2 equiv)

OBzO

BzOBzO

OBz

HO OMeOO

HO

HOHO

O

OH

OH

OBzO

BzOBzO

OBz 16%

58%

+

68

Scheme 3.8 – Regioselective Glycosylation of Methyl β-D-Galactopyranoside

In 2000, Kaji reported an alternative stannylene acetal-mediated regioselective glycosylation

strategy for methyl β-D-galactopyranoside and methyl α-L-rhamnopyranoside using silver silica

alumina as an effective promoter to access β(1→6)- and β(1→3)-linked disaccharides.

Treatment of the stannylene-acetal derivative of methyl β-D-galactopyranoside with per-O-

pivaloylglucosyl bromide afforded the disaccharide in 72% yield as the sole product (Scheme

3.9).

Scheme 3.9 – Regioselective Glycosylation of Methyl β-D-Galactopyranoside With Silver

Silica Alumina as a Promoter

OMeO

HO

HOHO

OH

OBnOBnO

BnO

OBn

Br

i. (Bu3Sn)2O, MeOH

ii.

Bu4NI (1.2 equiv)CH2Cl2

(1.2 equiv) OMeO

HO

HOHO

O

OBnOBnO

BnO

OBn

78%

OMeO

HO

HOHO

OH

OPivOPivO

PivO

OPiv

Br

i. (Bu2SnO)n, MeOH

ii.

Ag-silica aluminaCH2Cl2

(2 equiv)OMe

OHO

HOHO

OOBnOBnO

BnO

OBn

72%

69

3.2.2 Activation via Arylboronic Acids

Generally, the formation of boronic esters with cis-vicinal diols or 1,3-diols involving an

exocyclic 6-hydroxy group of carbohydrate derivatives has been employed as a strategy for OH

protection. A series of reports by Fréchet and co-workers demonstrated the ability of

polystyrylboronic acids to act as protective agents for cis-diols. In their studies, protection of

methyl α-D-xylopyranoside with polystyrylboronic acid, followed by treatment with acetic

anhydride afforded the 3-O monoacetylated product in 87% yield (Scheme 3.10).85

Scheme 3.10 – Protection of Carbohydrate Derivatives by Boronic Acids

Boons and co-workers reported an extension of this method where they demonstrated the use of

polystyrylboronic acid in the synthesis of di- and trisaccharides.86 Methyl 3-O-benzyl-

galactoside was immobilized on polystyrylboronic acid, and treated with an N-phthalimido

thioglucopyranoside derivative, N-iodosuccinimide and trimethylsilyl trifluoromethanesulfonate

in dichloromethane to obtain the β-disaccharide in 95% yield (Scheme 3.11).

Scheme 3.11 – Regioselective Glycosylation Using Boronic Acids as a Protecting Group

85 Fréchet, J. M. J.; Seymour, E. Tetrahedron Lett. 1976, 41, 3669–3672. 86 (a) Belogi, G.; Zhu, T.; Boons, G.-J. Tetrahedron Lett. 2000, 41, 6965–6968; (b) Belogi, G.; Zhu, T.; Boons, G.-J. Tetrahedron Lett. 2000, 41, 6969–6972.

OHO

OMeOH

HOi. pyridine, !

ii. Ac2O, pyridine

B(OH)2

O

OAc

OO B

OMe

87%

OMeO

HO

BnOHO

OH

pyridine, !

B(OH)2

OMeO

O

BnOHO

OB SEt

OBnOBnO

NPhth

OBni.

NIS, TMSOTf, CH2Cl2ii. acetone-H2O 60 °C

OMeO

HO

BnOO

OH

OBnOBnO

NPhth

OBn

95%

70

More recently, the group of Kaji has reported an alternative procedure where boronic acids act as

transient masking agents for hydroxy groups to carry out regioselective glycosylation of fully

unprotected methyl hexopyranosides in one-pot.87 In these reactions, the boronic acid forms

cyclic boronates with the 1,2-cis-diol or 4,6-diols of carbohydrate derivatives, thus allowing the

glycosyl donor to attack a free hydroxy group other than the masked hydroxy groups. Exposure

to aqueous sodium perborate after the glycosylation step easily cleaves the boronic acid and

affords the desired product. Treatment of methyl β-D-galactopyranoside with per-O-

pivaloylglucosyl bromide, phenylboronic acid, and silver silica alumina in dichloroethane

afforded the β(1→3)- and β(1→2)-linked disaccharides in a 92:8 mixture in 78% yield (Scheme

3.12).

Scheme 3.12 – Boronic Acids as a Transient Masking Agent

In contrast, studies by Aoyama and Oshima have demonstrated the ability of boronate esters to

activate hydroxy groups towards regioselective glycosylation. Previously, it was demonstrated

that triethylamine activated boronic esters generated from phenylboronic acid and a fucose

derivative undergo highly regioselective alkylations.88 Initial attempts to extend such studies to

the synthesis of di- and trisaccharides using the same conditions were futile, however, it was

found that intramolecular oxygen coordination to activate the boronate oxygen atom towards

glycosylation allowed such reactions to occur regioselectively with unprotected sugars (Scheme

87 Kaji, E.; Nishino, T.; Ishige, K.; Ohya, Y.; Shirai, Y. Tetrahedron Lett. 2010, 51, 1570–1573. 88 Oshima, K.; Kitazono, E.-I.; Aoyama, Y. Tetrahedron Lett. 1997, 38, 5001–5004.

OMeO

HO

HOOH

OH

Br

OPivOPivO

PivO

OPiv

1,2-DCE, 0.05 M3Å MS

Ag-silica alumina

+

BHO OH

(1 equiv)

(1 equiv)

(2 equiv)

OMeO

HO

OOH

OHOPivO

PivOPivO

OPiv

OMeO

HO

HOO

OH

OPivOPivO

PivO

OPiv

+

92:8, 78%

71

3.13).89 The two vicinal methyl groups on the boronate ester were proposed to block the benzylic

oxygen atom, preventing undesired glycosylation reactions at that site.

Scheme 3.13 – Tetracoordinated Arylboronate Complex

Treatment of the methyl-α-L-fucoside 3,4-boronate ester with 2,3,4,6-tetra-O-acetyl-α-D-

glucopyranosyl bromide, tetraethylammonium iodide, silver carbonate and molecular sieves in

tetrahydrofuran gave glycosylation exclusively at the 3-O position to afford a disaccharide in

74% yield. Increasing the equivalents of the glycosyl donor to 3.5 equivalents improved the yield

to 93% (Scheme 3.14). Following a similar procedure, other carbohydrate substrates bearing four

hydroxy groups were converted to trisaccharides with yields up to 84%. The regioselectivity for

glycosylation was rationalized as occurring at the least hindered oxygen atom of the boronate

ester.

Scheme 3.14 – Regioselective Glycosylation Activated by Arylboronic Acids

89 Oshima, K.; Aoyama, Y. J. Am. Chem. Soc., 1999, 121, 2315–2316.

O

OH

OHOH

OMeMe

O B O

MeMe

HMe

Me

Ag2CO3 O B O

MeMe

MeMe

Et4NI4Å MS

O

O

OHO

OMeMe

B O

Me

MeEt4N

OAcOAcO

AcO

OAcO

OH

OHO

OMeMeO

OH

OHOH

OMeMe

i. promoter, Ag2CO3 Et4NI, 4Å MS

ii.

Ag2CO3, THF

OAcOAcO

AcO

OAc

Br74%

O B O

MeMe

MeMe

promoter:

72

3.3 Regioselective Activation of Glycosyl Acceptors by a

Diarylborinic Acid Catalyst

Following our investigations of the diarylborinic acid-catalyzed regioselective functionalization

of carbohydrate derivatives containing cis-vicinal diol moieties, we sought to determine whether

we could achieve regioselective activation of glycosyl acceptors for glycosylation reactions.

Extensive investigations by other members of our laboratory90 resulted in the discovery of

reaction conditions suitable for the glycosylation of several derivatives of mannose, galactose,

fucose and arabinose to access 1,2-trans linkages from donors of gluco or galacto

configuration.91 In contrast to other protocols, this method is operationally simple and avoids the

use of stoichiometric quantities of organotin or organoboron reagents. In addition, this new mode

of reactivity displayed remarkable compatibility towards the synthesis of disaccharides and

trisaccharides.

Reaction development was carried out on methyl-6-(tert-butyldimethylsilyloxy)-α-D-

mannopyranoside and the optimal conditions were found to utilize the diphenylborinic acid

derivative as a catalyst, silver oxide as a promoter and base, and acetonitrile as a solvent. The

versatility of this method was illustrated by the variety of glycosyl donors and acceptors that are

tolerated (Table 3.1).

90 This work was done by Christina Gouliaras and Doris Lee. 91 Gouliaras, C.; Lee, D.; Chan, L.; Taylor, M. S. J. Am. Chem. Soc. DOI: 10.1021/ja2062715.

73

Table 3.1 – Scope of Optimized Reaction Conditions for Glycosylation

Given the success of the aforementioned reaction, subsequent investigations were carried out to

further expand the scope of the organo-boron catalyzed glycosylations. These include

glycosylations using glucosamine derived donors, the formation of β-mannoside linkages,

reactivity in conjunction with halide ion catalysis, and boronic acid-mediated glycosylations.

OOAc

AcOAcO

AcO OOOH

OOH

O

OAc

AcOAcO

AcO OO

OTBS

HO

HO

OMe

OOPiv

PivOPivO

PivOOMe

O

OMe

OH

OHO

OAc

AcOAcO

AcO OOTBS

HOO

OH

OMe

OOAc

AcOAcO

AcOO

OHO

O

OH

OMe

OOAc

AcOAcO

AcO

OAcO

OAc

AcO

OAc

OAcO

OAc

OO

OTBSOH

HO

OMeOAc

AcO

OAcO

OBn

OO

OTBSOH

HO

OMeOAc

AcO

OAcO O

O

OTBSOH

HO

OMeOAc

AcO

OMe

OAcOAc

OAcO

OHOMe

OH

OMe

OBnO

OBn

OO

OTBSOH

HO

OCH3OBn

BnO

OOAc

AcOAcO

AcO OO

OTBS

HO

HO

OMe

R3R4 Ag2O (1.1 equiv)

MeCN, 23–60 °C

PhB

Ph NH2

O

(10 mol %)HO

HO R3R4

HO

O

OR1R2

X

OR1R2

+

OO

HO

HOOMe

99%

94%

73%

81%

73%

68%a

86%a

71%a

80%

75%88%

74%

a Reaction was carried out using the glycosyl chloride

74

3.3.1 Synthesis of Glucosamine Derived Donors

Various glucosamine donors investigated for use in the glycosylation reactions were synthesized

by literature methods as depicted below.

3,4,6-Tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranosyl bromide 3.01 was synthesized in

73% yield by treating commercially available 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-

glucopyranoside with hydrogen bromide (33% in acetic acid) (Scheme 3.15).92

Scheme 3.15 – Synthesis of 2-Phthalimido-β-D-Glucopyranosyl Bromide

The α-D-glucopyranosyl chloride version was also synthesized in order to compare their

reactivity. 1,3,4,6-Tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranoside was deacetylated

at the anomeric position using imidazole and methanol to afford 3.02 in 72% yield.93

Chlorination was carried out following a protocol by Mong94 using trichlorotriazine,

dimethylformamide and diazabicyclo-[5.4.0]-undec-7-ene to afford the product in a 3:1 α:β

mixture in 46% yield. Recrystallization in cold (–20 °C) diethyl ether gave pure 3,4,6-tri-O-

acetyl-2-deoxy-2-phthalimido-α-D-glucopyranosyl chloride 3.03 in 39% yield (Scheme 3.16).

Scheme 3.16 – Synthesis of 2-Phthalimido-α-D-Glucopyranosyl Chloride

92 Ruttens, B.; Blom, P.; Van Hoof, S.; Hubrecht, I.; Van der Eycken, J. V. J. Org. Chem. 2007, 72, 5514–5522. 93 Brain n’ Beyond. Biotech. Pvt. Ltd. 2007. Patent W02007/52308 A2. 94 Chang, C.-W.; Chang, S.-S.; Chao, C.-S.; Mong, K.-K. T. Tetrahedron Lett. 2009, 50, 4536–4540.

OOAc

AcOAcO

PhthNOAc

i. 33% HBr in AcOH

ii. recrystallization in Et2O

OOAc

AcOAcO

PhthNBr

3.01, 73%

OOAc

AcOAcO

PhthNOAc

OOAc

AcOAcO

PhthN OHMeOH, 0.2 M

40 °C

3.02, 72%

Imidazole (1 equiv)

DBU (1.1 equiv)DCM, 0.3 M

60 °C

TCT (1.1 equiv)DMF (4 equiv)

OOAc

AcOAcO

PhthNCl

3.03, 39%

75

The synthesis of 3,4,6-tetra-O-acetyl-2-deoxy-2-[(2,2,2-trichloroethoxy)carbonylamino]α-D-

glucopyranosyl bromide 3.06 was carried out following the procedure by Herdewijn (Scheme

3.17).95 Beginning with D-glucosamine hydrochloride, protection of the amine with

(trichloroethoxy)carbonyl chloride, followed by peracetylation of the hydroxy groups and

bromination of the anomeric position furnished the desired α-product in 45% yield overall.

Scheme 3.17 – Synthesis of 2-[(2,2,2-Trichloroethoxy)carbonylamino]-α-D-Glucopyranosyl

Bromide

Following the procedure by Sewald96, 3,4,6-tri-O-acetyl-D-glucal 3.07 was treated with ferric

chloride hexahydrate, sodium azide and hydrogen peroxide in acetonitrile at -20 °C for 7 hours to

afford 3,4,6-tri-O-acetyl-2-deoxy-2-azido-α-D-galactopyranosyl chloride 3.08 in 76% yield as a

6:1 mixture of α:β products (Scheme 3.18). Attempts to obtain only the α-anomer through

recrystallization were unsuccessful.

Scheme 3.18 – Synthesis of 2-Azido-α-D-Galactopyranosyl Chloride

95 Lioux, T.; Busson, R.; Rozenski, J.; Nguyen-Distèche, M.; Frére, J.-M. Herdewijn, P. Collect. Czech. Chem. Commun. 2005, 70, 1615–1641. 96 Plattner, C.; Hofener, M.; Sewald, N. Org. Lett. 2011, 13, 545–547.

OOH

HOHO

NH2 OH

HCl

NaHCO3 (1.7 equiv)TrocCl (1.5 equiv)

H2O, 1.2 MO

OH

HOHO

TrocHN OH

3.04, 53%

OOAc

AcOAcO

TrocHN OAc

3.05, >99%

Ac2O (4.5 equiv)

pyridine, 0.5 M

33% HBrin AcOH

OOAc

AcOAcO

TrocHNBr3.06, 86%

OOAc

AcOAcO

OOAc

AcOCl

AcO

N3

NaN3 (1.1 equiv)FeCl3.6H2O (0.8 equiv)

H2O2 (1.1 equiv)MeCN, 0.12 M–20 °C, 7 hr 6:1 alpha:beta

3.08, 76%

OOH

HOHO

Ac2O (3.5 equiv)

pyridine, 0.5 M

3.07, 92%

76

3.3.2 Regioselective Glycosylations with Nitrogen-Containing Glycosyl Donors

The optimal reaction conditions for glycosylations using the diarylborinic acid were tested with

the glucosamine derived donors. Initial screening of 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-

D-glucopyranosyl bromide 3.01 with mannose 3.09, galactose 3.10, fucose 3.11 or arabinose 3.12

was carried out to determine ideal coupling partners for optimization studies (Table 3.2). Results

showed that only galactose 3.10 delivered the desired disaccharide in 42% isolated yield.

Reaction with mannose 3.09 and arabinose 3.12 gave no reactivity, whereas fucose 3.11 gave no

selectivity and resulted in a complex mixture of products.

Table 3.2 – Glycosylation Screen with 2-Phthalimido-β-D-Glucopyranosyl Bromide

OOAc

AcOAcO

PhthNBr

3.01

entry yieldacceptor

1

2

3

4

O

OTBS

HO OMe

HO

OH

O

OTBS

HOHO

OH

OMe

n.r.

3.13, 42%

n.r.

complex mixture

product

O

OMeMe

OHOH

OH

OHO OMe

HO

OH

OOAc

AcOAcO

PhthN

O

OTBS

HOO

OH

OMe

OOAc

AcOAcO

PhthN

OOAc

AcOAcO

PhthN

OOAc

AcOAcO

PhthN

O

OTBS

O OMe

HO

OH

O

OMeMe

OHO

OH

OO OMe

HO

OH


16 hr, rt

PhB

Ph NH2

O

(10 mol %)

R2R1

HO

O+ O

OAc

AcOAcO

PhthNR2R1

HO

HO

3.09

3.10

3.11

3.12

77

Optimization studies were then carried out with 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-

glucopyranosyl bromide 3.01 and galactose 3.10. Extensive experimentation of all reaction

parameters such as the stoichiometry of the donor, acceptor and catalyst, and temperature was

found only to provide low conversions (Table 3.3). Visualization by TLC revealed that minor

amounts of other regioisomers were also being formed under the reaction conditions. Although

all starting material was consumed, it is postulated that the glycosyl donor was unstable and

decomposed in the reaction.

Table 3.3 – Optimization of Reaction Conditions

It is proposed that the configuration of the glycosyl halide plays a part in the success of the

transformation. The kinetic anomeric effect97 explains that hyperconjugation or anti-periplanar

lone pairs gives rise to greater lability of axial glycosides.98 Thus, axial anomeric halides

experience greater weakening between the C-X bond and upon activation with silver salts, are

more susceptible to nucleophilic attack. Thus 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-α-D-

glucopyranosyl chloride 3.03 was then tested under the reaction conditions with galactose 3.10,

however, no reactivity was observed (Scheme 3.19).

97 Deslongchamps, P. Tetrahedron 1975, 31, 2463–2490. 98 Mydock, L. K.; Demchenko, A. V. Org. Biomol. Chem. 2010, 8, 497–510.

OOAc

AcOAcO

NPhthBr Ag2O (1.1 equiv)

MeCN, 0.13 M16 hr

PhB

Ph NH2

O

(z mol %)OOTBSHO

HOOH

OMe+ O

OAc

AcOAcO

NPhth

OOTBSHO

OOH

OMe

3.10, y equiv.3.01, x equiv.

temperature (°C) isolated yield

26%

35%

39%37%

35%

33%

y equiv.

1.0

1.5

1.51.5

1.1

1.5

404040rt

rtrt

x equiv.

1.01.51.01.0

1.01.0

z mol %

10101010

2015

entry

2345

76

45%1.1 rt1.0 101

3.13

78

Scheme 3.19 – Unsuccessful Glycosylation of 2-Phthalimido-β-D-Glucopyranosyl Chloride

To test whether the glycosylation was unsuccessful due to incompatibility with the phthalimido

protecting group, 3,4,6-tetra-O-acetyl-2-deoxy-2-[(2,2,2-trichloroethoxy)carbonylamino]α-D-

glucopyranosyl bromide 3.06 was evaluated under the reaction conditions (Table 3.4). The

reaction gave higher conversions for mannose 3.09 (entry 2) in comparison to that of galactose

3.10 (entry 1), however, the yield was still modest. Furthermore, heating the reaction had a

negative effect (entry 3) and increasing stoichiometry of acceptor (entry 4) or donor (entry 5) still

gave no significant improvements.

Table 3.4 – Glycosylation Screen with 2-[(2,2,2-Trichloroethoxy)carbonylamino]α-D-

Glucopyranosyl Bromide


16 hr, rt

PhB

Ph NH2

O

(10 mol%)O

OTBSHO

HOHO

OMen.r.+O

OAc

AcOAcO

PhthNCl

3.03 3.10

OOAc

AcOAcO

TrocHNBr

3.06

entry yieldacceptor

1

234

29%

45%

49%a38%

product

OOAc

AcOAcO

TrocHN

O

OTBS

HOO

OH

OMe

OOAc

AcOAcO

TrocHN

O

OTBS

O OMe

HO

OH


16 hr

PhB

Ph NH2

O

(10 mol %)

R2R1

OH

O+ O

OAc

AcOAcO

TrocHNR2R1

OH

HO

5 46%b

O

OTBS

HO OMe

HO

OH

O

OTBS

HOHO

OH

OMe3.09

3.10

temperature (°C)

rt

rt40rtrt

3.14

3.15

a Reaction carried out with 1.5 equivalent of glycosyl acceptorb Reaction carried out with 1.5 equivalent of glycosyl donor

79

The final nitrogen-containing glycosyl donor studied was the 3,4,6-tri-O-acetyl-2-deoxy-2-azido-

α-D-galactopyranosyl chloride 3.08 (Table 3.5). The glycosyl donor was screened with mannose

3.09 and galactose 3.10, and reaction parameters such as stoichiometry of reagents, temperature

and time were carried. However, conditions providing successful glycosylations could not be

identified.

Overall, the attempted glycosylation reactions with nitrogen-containing glycosyl donors were

unsuccessful as only up to modest yields were obtained.

Table 3.5 – Glycosylation Screen with 2-Azido-α-D-Galactopyranosyl Chloride

entry yieldacceptor

123a

4b

n.r.n.r.

n.r.n.r.

product

OOAc

AcOAcO

N3

O

OTBS

HOO

OH

OMe

OOAc

AcOAcO

N3

O

OTBS

O OMe

HO

OH


16 hr

PhB

Ph NH2

O

(10 mol %)

R2R1

OH

O

+ OOAc

AcOAcO

N3R2

R1

OH

HO

O

OTBS

HO OMe

HO

OH

O

OTBS

HOHO

OH

OMe3.09

3.10

temperature (°C)

rt40rtrt

OOAc

AcOCl

AcO

N36:1 alpha:beta

3.08

567a

8b

n.r.n.r.

n.r.n.r.

rt40rtrt

a Reaction carried out with 1.5 equivalent of glycosyl acceptorb Reaction carried out with 1.5 equivalent of glycosyl donorc Reaction was left stirring for 2 days

80

3.3.3 Regioselective Glycosylations to Form β-Mannoside Linkages

Of the glycosidic linkages possible, the β-mannoside link is one of the most difficult to form due

to both anomeric effect and neighbouring group participation effect favouring the formation of α-

mannosides. A strategy developed by Gorin and co-workers exploited the use of a cyclic

carbonate at the 2-O and 3-O positions of mannose to block neighbouring group participation

allowing the formation of β-linkages (Scheme 3.20).99

Scheme 3.20 – Formation of β-Mannoside Linkages

We envisioned that a diarylborinic acid variant of that reaction would offer a major improvement

since minimally protected carbohydrate derivatives bearing cis-1,2-diols could potentially act as

glycosyl acceptors (the β-mannosylation often works best when the nucleophile is unhindered).

To test the hypothesis, the mannose and rhamnose derivatives bearing a cyclic carbonate at the 2-

O and 3-O positions were required to be synthesized.

In initial efforts to form the cyclic carbonate on rhamnose, methyl α-L-rhamnopyranoside was

treated with phenyl chloroformate and N,N-diisopropylethylamine in dichloromethane, however,

no reactivity was observed (Table 3.6, entry 1). It was proposed that perhaps a diarylborinic acid

could help activate the hydroxy groups and impart regioselectivity. With the addition of 10 mol

% of diarylborinic acid derivative and the use of acetonitrile as the solvent, only starting material

was observed (entry 2). Switching the electrophile to bis(4-nitrophenyl) carbonate afforded a

complex mixture of products (entry 3). Ultimately, it was found that using

N,N’carbonyldiimidazole as the electrophile gave the desired cyclic carbonate 3.16 in 72% yield

(entry 4). Protection of the free hydroxy group with benzoyl chloride followed by treatment with

99 (a) Gorin, P. A. J.; Perlin, A. S. Can. J. Chem. 1961, 39, 2474–2485; (b) Bebault, G. M.; Dutton, G. G. S. Carbohydr. Res. 1974, 37, 309–319; (c) Backinowsky, L. V.; Balan, N. F.; Shashkov, A. S.; Kochetkov, N. K. Carbohydr. Res. 1980, 84, 225–235.

O

OAc

AcOOO

Br

O

O

OHOMe

O

OMe

MeMe

Ag2O, CHCl3 O

OAc

AcOOO

O

O

OO

Me

O

OMe

MeMe

82%

+

81

hydrogen bromide (33% in acetic acid) afforded the desired glycosyl bromide 3.18 in 30% yield

(Scheme 3.21).

Synthesis of the mannose donor was attempted under a similar protocol. Treatment of methyl-6-

(tert-butyldimethylsilyloxy)-α-D-mannopyranoside 3.09 with catalytic 2-aminoethyl

diphenylborinic ester, N,N’carbonyldiimidazole and N,N-diisopropylethylamine in acetonitrile

delivered the desired cyclic carbonate 3.19 in >99% yield (Scheme 3.22). In order to install the

bromide at the anomeric position, steps for desilylation followed by peracetylation were

necessary. However, attempts to desilylate 3.19 were futile as either only starting material or a

complex mixture of products were obtained (Table 3.7). Thus, glycosylation reactions were

investigated using the rhamnose donor 3.18.

Table 3.6 – Synthesis of 2,3-O-Carbonyl-α-L-Rhamnopyranoside

entry yieldelectrophile

1a

2

3

4

n.r.

n.r.

72%

complex mixture

electrophileiPr2NEt (1.1 equiv)

MeCN, 0.2 M40 °C, 16 hr

PhB

Ph NH2

O

(10 mol %)O

OMeMe

HOHO

OH

O

OMeMe

HOO O

O3.16

O Cl

O

O O

OO2N NO2

O Cl

O

N N

O

NN

a Reaction without catalyst in dichloromethane

82

Scheme 3.21 – Synthesis of 4-Benzoyl-2,3-O-Carbonyl-α-L-Rhamnopyranosyl Bromide

Scheme 3.22 – Synthesis of Methyl-6-(tert-Butyldimethylsilyloxy)-2,3-O-Carbonyl-α-D-

Mannopyranoside

Table 3.7 – Screening Conditions for Desilylation

With the desired rhamnosyl donor in hand, glycosylation reactions were executed using methyl-

6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside 3.09 as the glycosyl acceptor (Table 3.8).

Disappointingly, under the optimal reaction conditions, it was found that the reaction gave no

O

OMeMe

HOO O

O

BzCl (1.1 equiv) O

OMeMe

BzOO O

O

33% HBr in AcOH O

BrMe

BzOO O

O3.18, 45%3.17, >99%

pyridine, 0.5 M

3.16

O

OTBS

HO OO

OMe

O

OOTBS

HOHO

OH

OMeCDI (1.1 equiv)

iPr2NEt (1.1 equiv)MeCN, 0.2 M40 °C, 16 hr

PhB

Ph NH2

O

(10 mol %)

3.19, >99%3.09

entry yieldconditions

1

2

3

n.r.

complex mixture

complex mixture

O

OH

HO OO

OMe

O

conditions

3.203.19

O

OTBS

HO OO

OMe

O

80% AcOH, MeCN, 40 °C, 18 hr

TBAF (3 equiv), THF, rt, 2 hr

2 M H2SO4, Ac2O, 90 °C, 16 hr

83

desired product, and only starting material was isolated (entry 1). Additionally, longer reaction

times and higher temperatures lead to complex mixtures of product (entry 2 and 3).

Due to time constraints, further experimentation could not be carried out. Future work would

involve extensive optimization of all reaction parameters such as stoichiometry, reagents,

temperature and time. Furthermore, we also envision employing such donors for glycosylation at

the 6-O position.

Table 3.8 – Glycosylation with 4-Benzoyl-2,3-O-Carbonyl-α-L-Rhamnopyranosyl Bromide

3.3.4 Regioselective Glycosylations with Halide Ion Catalysis

Halide ion-catalyzed glycosylation reactions established by Lemieux and co-workers

demonstrate that halide salts such as tetraethylammonium chloride can be exploited to rapidly

anomerize glycosyl halides to form the less thermodynamically stable anomer in low

concentrations and which react readily.100 Studies were then carried out to examine whether the

halide ion-catalyzed glycosylation method would be compatible with borinic acid catalysis.

Preliminary tests to screen the glycosylation reaction between 2,3,4,6-tetra-O-acetyl-α-D-

glucopyranosyl bromide and methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside 3.09

were carried out with 2-aminoethyl diphenylborinic ester, potassium carbonate and a halide salt

100 Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. J. Am. Chem. Soc. 1975, 97, 4056–4062.


PhB

Ph NH2

O

(10 mol %) OOTBS

HOOH

OMeO+ OMe

BzOO O

O

O

BrMe

BzOO O

O3.18

OOTBS

HOHO

OH

OMe

3.09

entry yieldtime (hr)

1

2

n.r.

complex mixture

temperature (°C)

16

48

rt

40

3 complex mixture48 80

84

in dry acetonitrile (Table 3.9). Employing either potassium iodide or tetrabutylammonium iodide

as the halide source, no reactivity was observed at room temperature (entry 1 and 6) and with

heating to 40 °C (entry 2 and 7). Longer reaction times at the same temperature led to complex

mixtures of products (entry 4, 5, 9 and 10). Modest yields were achieved for both halide salts

when reactions were heated to 80 °C and only allowed to stir for 1 day (entry 3 and 8).

Table 3.9 – Glycosylation of Methyl-6-(tert-Butyldimethylsilyloxy)-α-D-Mannopyranoside

via Organoboron and Halide Ion Catalysis

Experimentation with methyl-6-(tert-butyldimethylsilyloxy)-α-D-galactopyranoside 3.10 was

also investigated, however, similar results were obtained (Table 3.10). In the case of potassium

iodide as a halide salt, shorter reaction times with higher temperatures gave better results that

longer reaction times with lower temperatures (entry 1 versus 3). In comparison,

tetrabutylammonium iodide showed no reactivity a lower temperatures and longer reaction times

(entry 4 versus 6). In both cases, using 3 equivalents of the halide salt was found to be

marginally better (entry 1 versus 2 and entry 4 versus 5).

halide salt (1 equiv)K2CO3 (1.1 equiv)

MeCN, 0.2 M

PhB

Ph NH2

O

(10 mol %)O

OTBS

HOHO

OH

OMe

OOTBS

HOOH

OMe

O

OAc

AcOAcO

BrAcO

+ O

OAc

AcOAcO AcO

O

3.09 (1.1 equiv)(1 equiv)

rt

40

80

rt

40

rt

40

80

rt

40

n.r.

n.r.

25%

complex mixture

complex mixture

n.r.

n.r.

38%

complex mixture

complex mixture

entry yieldtemperature (°C)

1

2

3

4

5

6

7

8

9

10

1

1

1

2

2

1

1

1

2

2

time (d)

KI

KI

KI

KI

KI

TBAI

TBAI

TBAI

TBAI

TBAI

halide salt

3.21

85

Table 3.10 – Glycosylation of Methyl-6-(tert-Butyldimethylsilyloxy)-α-D-Galactopyranoside

via Organoboron and Halide Ion Catalysis

It could be rationalized that the poor reactivity stems from using 2,3,4,6-tetra-O-acetyl-α-D-

glucopyranosyl bromide as a glycosyl donor since it is uncommon in halide catalysis. Electron-

withdrawing groups such as acetyl are considered ‘disarming’ given that they decrease the

reactivity of the glycosyl donor. Generally, electron-donating groups are incorporated on the

glycosyl donor in halide catalysis as they are found to increase the reactivity of the glycosyl

donor.

Doris Lee, another graduate student in the Taylor group, investigated the reactivity of

perbenzylated mannosyl chloride with methyl-6-(tert-butyldimethylsilyloxy)-α-D-

mannopyranoside 3.09 in halide catalysis, however, was unsuccessful (Table 3.11). Reactions

with potassium iodide or tetraethylammonium chloride at room temperature gave no reactivity

(entry 1 and 3), whereas heating to 40 °C led to complex mixtures containing starting material,

the desired product and its isomers, and byproducts.

These studies have shown that organoboron-catalysis in conjunction with halide ion catalysis is

possible, however, extensive investigation is requried as only moderate to low conversions are

obtained.

OOTBSHO

HOOMe

O

OAc

AcOAcO AcO

O

a Reaction was carried out with 3 equivalents of halide salt

halide salt (1 equiv)K2CO3 (1.1 equiv)

MeCN, 0.2 M

PhB

Ph NH2

O

(10 mol %)O

OAc

AcOAcO

BrAcO

+


80

80

40

80

80

40

27%

29%a

complex mixture

14%

18%a

n.r.


1

2

3

4

5

6

1

1

2

1

1

2

time (d)

KI

KI

KI

TBAI

TBAI

TBAI

halide salt

3.22

OOTBSHO

HOHOOMe

86

Table 3.11 – Glycosylation Using 2,3,4,6-Tetra-O-Benzyl-α-D-Mannopyranosyl Chloride

3.3.5 Regioselective Glycosylations with Stoichiometric Boronic Acid

Previous studies by Aoyama and co-workers demonstrated the ability of boronic acids bearing 2-

hydroxy-2-propyl groups at the ortho position capable of regioselective glycosylation of

unprotected sugars. Further work in this area has not been reported which inspired us to expand

on this methodology especially since the organoboron reagent is not commercially available and

the scope is narrow in terms of glycosyl donors. Extensive investigation on the ability of

stoichiometric quantities of organoboron reagents to activate the cis-1,2-diol in rhamnose and

galactose derivatives towards regioselective glycosylation were carried out.

Starting with methyl α-L-rhamnopyranoside, several different boronic esters were synthesized by

condensation with arylboronic acids in refluxing toluene. The boronic esters were then exposed

to glycosylation conditions by treatment with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide

in the presence of silver oxide and an activator in dry acetonitrile. Six different boronic acids

were tested with four different activators (Table 3.12). In the screen, it was found that all

reactions with quinuclidine as a promoter gave no reactivity, whereas tributylphosphine oxide

and dimethyl sulfoxide generally gave complex mixtures of product. Triethylamine was

identified to be the optimal promoter as it afforded only the desired disaccharide product. In

terms of the boronic acid, the more sterically demanding 8-quinolinyl-boronic acid delivered the

product in 82% yield (entry 21). p-Methoxyboronic acid, biphenyl-2-boronic acid and

conditions

PhB

Ph NH2

O

(10 mol %)O

OTBS

HOHO

OH

OMe

OOTBS

HOOH

OMe

O

OBn

BnOBnO

Cl

OBn+ O

OBn

BnOBnO

OBnO


rt

40

rt

40

n.r.

complex mixture

n.r.

complex mixture


1

2

3

4

conditions

KI (1 equiv), K2CO3 (1.1 equiv)MeCN, 0.2 M

Et4NCl (1 equiv), iPr2NEt (1 equiv)DCM, 0.33 M

87

bis(trifluoromethyl)boronic acid gave good yields of 76% (entry 9), 69% (entry 17) and 58%

(entry 5) yields respectively. Low conversions of 39% (entry 1) and 27% (entry 13) yields were

obtained with phenylboronic acid and ferroceneboronic acid respectively.

Table 3.12 – Boronic Acid-Activated Glycosylation of Rhamnose Derivative

O

OMeMe

HOHO

OH

boronic acid (1 equiv)

toluene, 0.2 M100 °C

O

OMeMe

HOO

OB

R

OOAc

AcOAcO

BrAcO

Ag2O (1 equiv)Activator (1 equiv)

MeCN, 0.2 M

O

OAc

AcOAcO

AcO

O

OMeMeHO

OOH

(1 equiv)

(1 equiv)

3.23

NEt3quinuclidine

tributylphosphine oxideDMSO

NEt3quinuclidine


NEt3quinuclidine


NEt3quinuclidine


NEt3quinuclidine


NEt3quinuclidine


complex mixture

39%n.r.

complex mixturecomplex mixture

58%n.r.


76%n.r.


69%n.r.


82%n.r.


entry yieldboronic acid activator

1234

5678

9101112

13141516

17181920

21222324

27%n.r.

complex mixture

F3C

CF3

B(OH)2

B(OH)2

MeO

B(OH)2

PhB(OH)2

NB(OH)2

Fe

B(OH)2

88

This is a promising initial result as it employs commercially available boronic acids and occurs

under operationally simple reaction conditions. With the optimized reaction conditions, future

work would require extension of this method to other unprotected carbohydrate substrates such

as thiogalactose derivatives.

3.4 Kinetic Studies: Reagent Order

Efforts in future reaction and catalyst design are best focused on accelerating the rate limiting

step of a reaction. To establish this, initial rate kinetic studies were performed to determine the

order in each component of the reaction of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide

and methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside following the methods

described in Chapter 1. Initial rates were determined for reactions where the concentration in

glycosyl donor, glycosyl acceptor, borinic acid-catalyst, and silver oxide were modified

independently.

3.4.1 Pseudo First-order Kinetics in Glycosyl Donor

Under pseudo first-order conditions, the conversion of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl

bromide to product was monitored over a period of 10 hours (Scheme 3.23). A plot of the

concentration of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide over time was found to fit

the exponential function:

[glycosyl donor](t) = [glycosyl donor]0e–kt

indicating that the reaction follows pseudo-first-order kinetics under the reaction conditions

(Figure 3.1).

89

Scheme 3.23 – Glycosylation Under Pseudo First-order Reaction Conditions

Figure 3.1 – Plot of 2,3,4,6-Tetra-O-Acetyl-α-D-Glucopyranosyl Bromide Concentration

Versus Time Under Pseudo First-order Reaction Conditions

3.4.2 Dependence of the Initial Rate on the Concentration of Glycosyl Donor

Reactions were then carried out where the concentration of 2,3,4,6-tetra-O-acetyl-α-D-

glucopyranosyl bromide was varied from 0.75 to 5.0 equivalents (Scheme 3.24). Plotting the

initial rate against the concentration of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide

revealed a slope of 0.0051 M.s-1 indicating first-order kinetics in glycosyl donor. (Figure 3.3).

OOTBS

HOHO

OH

OMeAg2O (3 equiv)MeCN, 0.13 M

OOTBS

HOOH

OMe

O

OAc

AcOAcO

BrAcO

+ O

OAc

AcOAcO AcO

O

0.6 mmol0.2 mmol

PhB

Ph NH2

O

(10 mol %)

!"

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!#!&"

!#!'"

!#("

!#($"

!" (!!" $!!" )!!" %!!" *!!" &!!"

!"#$%&'(#)*

&+&,-)./0)

1234).32+0)

90

Scheme 3.24 – Reaction Order in Glycosyl Donor

Figure 3.2 – Formation of Product Over Time With Variation in the Concentration of

Glycosyl Donor

Figure 3.3 – Initial Rate Dependence on the Concentration of Glycosyl Donor

OOTBS

HOHO

OH


OOTBS

HOOH

OMe

O

OAc

AcOAcO

BrAcO

+ O

OAc

AcOAcO AcO

O

0.22 mmol0.75–5.0 equiv

PhB

Ph NH2

O

(10 mol %)

!"

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91

3.4.3 Dependence of the Initial Rate on the Concentration of Glycosyl Acceptor

The order in methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside was established by

varying its concentration from 1.0 to 6.0 equivalents (Scheme 3.25). Plotting the initial rates

against concentration of glycosyl acceptor gave a slope of 0.001 M.s-1. The linear relationship

between the initial kobs and the initial concentration of glycosyl acceptor indicates first-order

kinetics in glycosyl acceptor (Figure 3.5).

Scheme 3.25 – Reaction Order in Glycosyl Acceptor


Glycosyl Acceptor

OOTBS

HOHO

OH


OOTBS

HOOH

OMe

O

OAc

AcOAcO

BrAcO

+ O

OAc

AcOAcO AcO

O

1.0–6.0 equiv0.2 mmol

PhB

Ph NH2

O

(10 mol %)

!"

!#!!$"

!#!%"

!#!%$"

!#!&"

!#!&$"

!#!'"

!#!'$"

!#!("

!" %!" &!" '!" (!" $!" )!"

!"#$%&

'()*+,-*

./01*+0/2-*

)#!"*+,-."

$#!"*+,-."

(#!"*+,-."

'#!"*+,-."

&#!"*+,-."

%#!"*+,-."

92

Figure 3.5 – Initial Rate Dependence on the Concentration of Glycosyl Acceptor

3.4.4 Dependence of the Initial Rate on the Concentration of Borinic Acid-

Catalyst

A plot of the initial rates versus the concentration of 2-aminoethyl diphenylborinic acid revealed

a slope of 0.0299 M.s-1 for catalyst loadings of 7.0 to 13.0 mol % (Figure 3.7). The slope is

indicative of a first-order rate dependence in catalyst.

Scheme 3.26 – Reaction Order in 2-Aminoethyl Diphenylborinate

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$%$$$+"

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)*+,-!#,+$.--/01!23$%4($

OOTBS

HOHO

OH


OOTBS

HOOH

OMe

O

OAc

AcOAcO

BrAcO

+ O

OAc

AcOAcO AcO

O

0.6 mmol0.2 mmol

PhB

Ph NH2

O

(7–10 mol %)

93


Aminoethyl Diphenylborinate

Figure 3.7 – Initial Rate Dependence on the Concentration of 2-Aminoethyl

Diphenylborinate

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94

3.4.5 Dependence of the Initial Rate on the Concentration of Promoter

The reactions were carried out using varying concentrations of silver oxide from 0.5 to 5.0

equivalents (Scheme 3.27). A plot of the initial rates against the concentration of promoter gave a

slope of 0.00002 M.s-1 (Figure 3.9). The invariant values of the initial kobs as a function of silver

oxide concentration indicate zero-order behaviour in promoter. It is postulated that the zero-order

kinetics may reflect saturation-type behaviour of the reactive sites on the silver oxide surface.

Scheme 3.27 – Reaction Order in Silver Oxide


Silver Oxide

OOTBS

HOHO

OH

OMeAg2O (0.5–5.0 equiv)

MeCN, 0.13 M

OOTBS

HOOH

OMe

O

OAc

AcOAcO

BrAcO

+ O

OAc

AcOAcO AcO

O

0.22 mmol0.2 mmol

PhB

Ph NH2

O

(10 mol %)

!"

!#!!$"

!#!%"

!#!%$"

!#!&"

!#!&$"

!#!'"

!" %!" &!" '!" (!" $!"

!"#$%&

'()*+,-*

./01*+0/2-*

$#!")*+,-"

(#!")*+,-"

'#!")*+,-"

&#!")*+,-"

%#!")*+,-"

!#$")*+,-"

95

Figure 3.9 – Initial Rate Dependence on the Concentration of Silver Oxide

3.4.6 Dependence of Rate on the Nature of the Catalyst Used

Experiments were performed to examine the effect the nature of the borinic acid catalyst has on

the reaction rate. The reactions were carried out using 10 mol % of either diphenyl borinic acid

or 2-aminoethyl diphenylborinate (Scheme 3.28). A plot of the concentration of product versus

time indicated that the reaction rate is slower with 2-aminoethyl diphenylborinate (A) compared

to diphenyl borinic acid (B), (Figure 3.10). This is consistent with our hypothesis that 2-

aminoethyl diphenylborinate acts as a pre-catalyst under the reaction conditions.

• Catalyst A: Diphenylborinic Acid

• Catalyst B: 2-Aminoethyl Diphenylborinate

Scheme 3.28 – Effect of the Nature of Catalyst Used

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)*+,-.$%/($

OOTBS

HOHO

OH

OMeAg2O (0.2 mmol)MeCN, 0.13 M

OOTBS

HOOH

OMe

O

OAc

AcOAcO

BrAcO

+ O

OAc

AcOAcO AcO

O

0.22 mmol0.2 mmol

catalyst A or B

96

Figure 3.10 – Formation of Product Over Time Using Diphenylborinic Acid (A) or 2-

Aminoethyl Diphenylborinate (B) as the Catalyst

3.4.7 Effect of 2-Aminoethanol

Further experiments were performed to examine the effect of excess 2-aminoethanol on the rate.

The reactions were carried out in the absence (Condition A) or presence (Condition B) of 1 mol

% 2-aminoethanol (Scheme 3.29). Comparing the rate of formation of product over time

indicated that excess 2-aminoethanol did not impede the reaction (Figure 3.11). This suggests

that although 2-aminoethanol can bind back onto the borinic acid, it is displaced at a rate faster

than the limiting step.

• Condition A: No Added 2-Aminoethanol

• Condition B: 1 mol % 2-Aminoethanol

Scheme 3.29 – Effect of 2-Aminoethanol

!"#"$%$$$&'"("$%$$))"

!"#"$%$$$)'"("$%$$*+"

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$%$+"

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./01*+0/2-*

01213!42"5"

01213!42"6"

OOTBS

HOHO

OH

OMeAg2O (0.2 mmol)MeCN, 0.13 M

Condition A or B

OOTBS

HOOH

OMe

O

OAc

AcOAcO

BrAcO

+ O

OAc

AcOAcO AcO

O

0.22 mmol0.2 mmol

PhB

Ph NH2

O

(10 mol %)

97

Figure 3.11 – Formation of Product Over Time in the Absence (A) and Presence (B) of

Excess 2-Aminoethanol

3.5 Conclusion

In conclusion, these studies have illustrated the potential of organoboron reagents in the

development of new reactivity for regioselective glycosylation reactions with minimally

protected glycosyl acceptors bearing cis-vicinal diols. Kinetic studies using the method of initial

rates were also undertaken which found that the reaction shows:

• first-order kinetics in glycosyl donor, glycosyl acceptor and catalyst

• zero-order in silver oxide

This is consistent with the mechanistic proposal of an SN2-type inversion rather than through the

formation of an oxonium ion intermediate. Similarly to previous findings, higher initial rates

were observed for reactions promoted by diphenylborinic acid in comparison to its ethanolamine

ester, suggesting the latter serves as a precatalyst under the reaction conditions.

!"

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98

4

Final Conclusion

The ability to selectively functionalize a hydroxy group on carbohydrate derivatives is

challenging due to their complex structure, which require extensive protecting group

manipulation. With the inspiration of using boron–diol interactions that are widely known in the

chemical sensing literature, our group has demonstrated the catalytic ability of organoboron

reagents to carry out acylation and sulfonylation reactions of carbohydrate derivatives

regioselectively. This led us to further explore and expand on the capability of the organoboron

catalyst.

In the first chapter, the mechanism for the sulfonylation of cis-1,2-cyclohexanediol was studied

by carrying out kinetic studies by the method of initial rates. The proposed mechanism follows

that the 2-aminoethyl diphenylborinate is converted to the active catalyst by functionalization of

the ethanolamine ligand. The diol substrate then binds to the catalyst forming a cyclic ‘ate’

complex which activates one of the two B–O bonds towards nucleophilic attack. Displacement of

the product is then achieved by attack of another diol substrate.

99

The various experiments performed revealed that the reaction follows first-order kinetics in

substrate, electrophile and catalyst, and zero-order kinetics in base. This reveals that attack of the

electrophile by the bound cyclic ‘ate’ complex is possibly part of the rate-determining step. As

well, the zero-order in base is indicative that the base does not have a significant part in the rate-

determining step. The observation that the 2-aminoethyl diphenylborinate catalyst shows a

slower reaction rate in comparison to the diphenylborinic acid suggests that the former is a

precatalyst under the reaction conditions. Slower rates were also observed upon the addition of 2-

aminoethanol revealing that the dissociation of the ligand is a reversible process. All these were

found to be consistent with our proposed catalytic cycle.

In the second chapter, the development of a regioselective method for the monoalkylation of

carbohydrate derivatives was explored. With having recently developed a method for

regioselective acylation of cis-diols by boron-catalysis, we sought to determine whether a similar

mode of reactivity could be employed. With extensive optimization of all reaction parameters

such as catalyst, base, solvent, concentration, stoichiometry and temperature, a set of conditions

were discovered which gave high-yielding results. This method was carried out on ten

carbohydrate substrates employing four alkylating agents to generate a scope table with thirty-

four entries. Thereafter, further studies revealed that the alkylation by diphenylborinic acid-

catalysis could also be achieved in combination with halide catalysis. Current limitations of this

protocol include the use of thiogalactosides and carbohydrate derivatives not bearing the cis-1,2-

diol moiety.

In the third chapter, we explore the ability of the diphenylborinic acid to catalyze regioselective

glycosylation reactions. Previously, extensive investigations carried out by other members in our

group have discovered suitable reaction conditions that were compatible for glycosylation

reactions using several derivatives of mannose, galactose, fucose and arabinose to access 1,2-

trans linkages from donors of glucose or galactose configuration. Building on these results,

further investigations were carried out to expand the scope of this method which included

glycosylations with glucosamine derived donors, the formation of β-mannoside linkages,

reactivity in halide ion catalysis, and boronic acid-mediated glycosylations.

100

In the study of glucosamine derived donors, several substrates were synthesized and tested,

however, all attempts to optimize the reaction conditions were found to only give modest yields.

In examining the ability to form β-mannoside linkages, a rhamnose derivative containing a cyclic

carbonate at the 2-O and 3-O positions was synthesized and investigated. Disappointingly, it was

found that either no reactivity or complex mixtures were obtained under tested reaction

conditions. Glycosylation using halide catalysis was also found to be futile as optimization of the

reaction conditions using a variety of iodide salts only gave low conversions. When exploring the

use of stoichiometric amounts of organoboron catalyst to carry out glycosylations, it was found

that 8-quinolinyl-boronic acid with triethylamine as an activator promoted the coupling of a

rhamnose acceptor and glucose derived donor with high yields.

Kinetic studies on the glycosylation reaction were then carried out which revealed the reaction is

first-order in glycosyl donor, glycosyl acceptor and catalyst, and zero-order in silver oxide. It

was also found that the reaction carried out using diphenylborinic acid was faster in comparison

to 2-aminoethyl diphenylborinate which is consistent with the proposal that the latter is a

precatalyst in the reaction. In contrast to previous findings, the presence of excess 2-

aminoethanol does not inhibit the reaction.

101

5

Experimental Procedures

5.0 General Information

General: Reactions were carried out without effort to exclude air or moisture, unless otherwise

indicated. Stainless steel syringes were used to transfer air- and moisture-sensitive liquids. Flash

chromatography was carried out using silica gel (Silicycle).

Materials: HPLC grade acetonitrile was dried and purified using a solvent purification system

equipped with columns of activated alumina, under argon (Innovative Technology, Inc.).

Deionized water was obtained from an in-house supply. All other reagents and solvents were

purchased from Sigma-Aldrich, Caledon, Carbosynth or Alfa Aesar, and used without further

purification. Diphenylborinic acid was prepared from 2-aminoethyl diphenylborinate according

to a reported procedure.Error! Bookmark not defined.

Instrumentation: 1H and 13C NMR spectra were recorded in CDCl3 using a Bruker Avance III

400 MHz or Varian Mercury 400 MHz spectrometer, referenced to residual protium in the

102

solvent. Spectral features are tabulated in the following order: chemical shift (δ, ppm);

multiplicity (s-singlet, d-doublet, t-triplet, q-quartet, m-complex multiplet); coupling constants

(J, Hz); number of protons; assignment. Assignments are based on analysis of coupling constants

and COSY spectra. In cases of uncertain assignments, structural confirmation was secured

through NOESY experiments. High-resolution mass spectra (HRMS) were obtained on a VS 70-

250S (double focusing) mass spectrometer at 70 eV. Infrared (IR) spectra were obtained on a

Perkin-Elmer Spectrum 100 instrument equipped with a single-reflection diamond / ZnSe ATR

accessory, either in the solid state or as neat liquids, as indicated. Spectral features are tabulated

as follows: wavenumber (cm–1); intensity (s-strong, m-medium, w-weak, br-broad).

5.1 Experimental and Characterization Data

5.1.1 General Procedure A: Tosylation Kinetic Experiments

Into an oven-dried 1 dram vial were added cis-1,2-cyclohexanediol, 4-toluenesulfonyl chloride,

and 2-aminoethyl diphenylborinate. The reaction vial was capped with a septum and purged with

argon. Dry acetonitrile (0.1 M) was added followed by N,N-diisopropylethylamine and the

resulting mixture was stirred vigorously (750 rpm) at room temperature. During the course of the

reaction, aliquots of the reaction mixture were removed and quenched with methanol. The

solvent was then removed and the resulting samples were analyzed by 1H-NMR spectroscopy for

the formation of product with mesitylene as an internal standard. Integrations for the internal

standard peak and an isolated proton peak of the product were used to calculate moles of product

formed and therefore % conversion.

OH

OH

OTs

OHTsCl, iPr2NEtMeCN

PhB

Ph NH2

O

103

5.1.2 General Procedure B: Hydrolysis of Diarylboronic Esters

In a 2-dram vial equipped with a stir bar was added diethylamino diphenylborinate ester (0.8

mmol, 180 mg), acetone (0.4 mL) and methanol (0.4 mL). To the resulting solution was added

HCl(aq) (1 M, 1 mL). The vial was capped in ambient atmosphere and stirred at 500 rpm at room

temperature. After 1 hour, the mixture was diluted with diethyl ether, washed with water, and

extracted several times with diethyl ether. The combined organic extracts were dried over

MgSO4, filtered, and concentrated in vacuo to afford 128 mg of 2a as a colourless oil (88%

yield). Spectral data were in agreement with previous reports.101

5.1.3 General Procedure C: Borinic Acid-Catalyzed Alkylation

The carbohydrate substrate (1 equiv), 2-aminoethyl diphenylborinate (10 mol %) and Ag2O (1.1

equiv) were weighed into a 1-dram vial, and dissolved in dry acetonitrile (0.1–0.2 M, see below).

The alkyl halide (1.5 equiv) was then added, and the reaction vessel was capped with a septum

and purged with argon. The mixture was stirred vigorously (750-1000 rpm) for 48 hr at 40 °C.

The resulting mixture was diluted with CH2Cl2, filtered through Celite® and concentrated to

dryness. The resulting crude material was purified by flash chromatography on silica gel using

the stated eluent system.

5.1.4 General Procedure D: Borinic Acid-Catalyzed Alkylation with Halide Salts

The carbohydrate substrate (1 equiv), 2-aminoethyl diphenylborinate (10 mol %), halide salt (1.0

equiv), potassium carbonate (1.1 equiv) were weighed into a 1-dram vial, and dissolved in dry

acetonitrile (0.1–0.2 M, see below). The alkyl halide (1.5 equiv) was then added, and the reaction

vessel was capped with a septum and purged with argon. The mixture was stirred vigorously

(750-1000 rpm) for 48 hr at 40 °C. The resulting mixture was diluted with MeOH, filtered

101 White, D. A. J. Inorg. Nucl. Chem. 1971, 33, 691–696.

PhB

Ph NH2

O HCl(aq), 1M

MeOH:Acetone (1:1)

PhB

PhOH

104

through Celite® and concentrated to dryness. The resulting crude material was purified by flash

chromatography on silica gel using the stated eluent system.

Carbohydrate substrates 2.01102, 2.03103, 2.05102, 2.06102 and 2.54102 were prepared following

literature methods. Spectral data were consistent with those presented in the literature.102,103

Substrates 2.02, 2.04 and 2.07–2.10 were purchased (Carbosynth, Alfa Aesar) and used as

received.

Benzyloxymethyl chloride was purchased at ~60% purity (technical grade) from Sigma-Aldrich

and was purified by flash chromatography prior to use.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-benzyl-α-D-mannopyranoside (2.11)

Methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside 2.01 (61.7 mg, 0.200 mmol),

benzyl bromide (35.6 µL, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and

Ag2O (50.9 mg, 0.220 mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon atmosphere

at 40 °C for 48 hr. Flash chromatographic purification (pentanes/EtOAc, 85:25) afforded the title

compound as a colourless oil (72.4 mg, 91%); Rf = 0.32 (pentanes/EtOAc, 70:30); FTIR (νmax)

3482 (br), 2927 (m), 1462 (w), 1361 (w), 1251 (m), 1106 (s), 1052 (s), 967 (m), 835 (s), 777 (m)

cm-1; 1H NMR (400 MHz, CDCl3): δ 7.40–7.29 (m, 5H, ArH), 4.73 (d, J = 1.6 Hz, 1H, H-1),

4.71 (s, 2H, ArCH2), 3.97 (dd, J = 3.2, 1.6 Hz, 1H, H-2), 3.91–3.84 (m, 3H, H-4, H-6a and H-

6b), 3.68 (dd, J = 9.2, 3.6 Hz, 1H, H-3), 3.60 (apparent dt, J = 9.2, 4.8 Hz, 1H, H-5), 3.36 (s, 3H,

OCH3), 2.97 (d, J = 1.6 Hz, 1H, C4-OH), 2.40 (d, J = 2.4 Hz, 1H, C2-OH), 0.91 (s, 9H,

Si(C(CH3)3)(CH3)2), 0.10 (s, 6H, Si(C(CH3)3)(CH3)2); 13C NMR (100 MHz, CDCl3): δ 138.0,

128.6, 128.0, 127.9, 100.4, 79.5, 72.2, 70.9, 69.2, 67.9, 64.8, 54.9, 25.9, 18.3, –5.4; HRMS m/z

calcd for C20H35O6Si [M+H]+: 399.2203. Found 399.2215.

102 Lee, D.; Taylor, M. S. J. Am. Chem. Soc. 2011, 133, 3724–3727. 103 Namme, R.; Mitsugi, T.; Takahashi, H.; Shiro, M.; Ikegami, S. Tetrahedron. 2006, 62, 9183–9192.

O

OMe

OTBSOH

BnOHO

105

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(4-bromobenzyl)-α-D-mannopyranoside (2.12)

Methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside 2.01 (61.7 mg, 0.200 mmol), 4-

bromobenzyl bromide (75.0 mg, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol

%) and Ag2O (50.9 mg, 0.220 mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon

atmosphere at 40 °C for 48 hr. Flash chromatographic purification (pentanes/EtOAc, 85:15)

afforded the title compound as a colourless oil (95.2 mg, >99%); Rf = 0.49 (pentanes/EtOAc,

70:30); FTIR (νmax) 3509 (br), 2927 (m), 1593 (w), 1488 (m), 1389 (m), 1251 (m), 1108 (s), 968

(s), 836 (s), 741 (s) cm-1; 1H NMR (400 MHz, CDCl3): δ 7.46 (apparent dt, J = 9.2, 2.8 Hz, 2H,

ArH), 7.25 (apparent dt, J = 9.2, 2.8 Hz, 2H, ArH), 4.72 (d, J = 1.6 Hz, 1H, H-1), 4.66 (s, 2H,

ArCH2), 3.95–3.93 (m, 1H, H-2), 3.92–3.82 (m, 3H, H-4, H-6a and H-6b), 3.65 (dd, J = 8.8, 3.6

Hz, 1H, H-3), 3.58 (apparent dt, J = 9.6, 5.6 Hz, 1H, H-5), 3.35 (s, 3H, OCH3), 3.12 (d, J = 1.6

Hz, 1H, C4-OH), 2.41 (d, J = 2.8 Hz, 1H, C2-OH), 0.90 (s, 9H, Si(C(CH3)3)(CH3)2), 0.09 (s, 6H,

Si(C(CH3)3)(CH3)2); 13C NMR (100 MHz, CDCl3): δ 137.0, 131.6, 129.5, 121.8, 100.3, 79.2,

71.3, 70.5, 69.6, 67.9, 64.9, 54.9, 25.9, 18.2, –5.4; HRMS m/z calcd for C20H34BrO6Si

[M+H]+: 477.1308. Found 477.1299.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(2-methylnaphthalenyl)-α-D-mannopyranoside

(2.13)


(bromomethyl)naphthalene (66.3 mg, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10

mol %) and Ag2O (50.9 mg, 0.220 mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon


afforded the title compound as a colourless oil (79.9 mg, 89.1%); Rf = 0.54 (pentanes/EtOAc,

O

OMe

OTBSOH

OHOBr

O

OMe

OTBSOH

OHO

106

70:30); FTIR (νmax) 3511 (br), 2927 (m), 1462 (m), 1334 (w), 1250 (m), 1106 (s), 1051 (s), 967

(m), 868 (w), 834 (s) cm-1; 1H NMR (400 MHz, CDCl3): δ 7.86–7.81 (m, 4H, ArH), 7.52–7.45

(m, 3H, ArH), 4.87 (s, 2H, ArCH2), 4.74 (d, J = 1.6 Hz, 1H, H-1), 4.01–3.99 (m, 1H, H-2), 3.96–

3.88 (m, 3H, H-4, H-6a and H-6b), 3.74 (dd, J = 9.2, 3.6 Hz, 1H, H-3), 3.61 (apparent dt,

J = 10.0, 5.2 Hz, 1H, H-5), 3.36 (s, 3H, OCH3), 3.04 (d, J = 1.6 Hz, 1H, C4-OH), 2.46 (d, J = 2.4

Hz, 1H, C2-OH), 0.90 (s, 9H, Si(C(CH3)3)(CH3)2), 0.09 (s, 6H, Si(C(CH3)3)(CH3)2); 13C NMR

(100 MHz, CDCl3): δ 135.5, 133.3, 133.1, 128.5, 127.9, 127.8, 126.7, 126.2, 126.0, 125.8,

100.4, 79.4, 72.2, 70.9, 69.4, 67.9, 64.8, 54.8, 25.9, 18.3, –5.4; HRMS m/z calcd for

C24H37O6Si [M+H]+: 449.2359. Found 449.2350.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-benzyloxymethyl-α-D-mannopyranoside (2.14)

Methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside 2.01 (61.7 mg, 0.200 mmol),

benzyloxymethyl chloride (41.7 µL, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10

mol %) and Ag2O (50.9 mg, 0.220 mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon


afforded the title compound as a pale yellow oil (71.9 mg, 84%); Rf = 0.40 (pentanes/EtOAc,

70:30); FTIR (νmax) 3510 (br), 2928 (m), 1388 (m), 1251 (m), 1106 (s), 1024 (s), 968 (s), 834

(s), 801 (m), 734 (s) cm-1; 1H NMR (400 MHz, CDCl3): δ 7.38–7.28 (m, 5H, ArH), 4.96 (d, J =

6.8 Hz, 1H, OCH2O), 4.91 (d, J = 6.8 Hz, 1H, OCH2O), 4.74 (d, J =11.6 Hz, 1H, ArCH2O), 4.72

(d, J = 2.4 Hz, 1H, H-1), 4.67 (d, J =11.6 Hz, 1H, ArCH2O), 3.90–3.86 (m, 1H, H-2), 3.94–3.79

(m, 4H, H-3, H-4, H-6a and H-6b), 3.60 (apparent dt, J = 9.2, 4.8 Hz, 1H, H-5), 2.89 (d, J = 1.2

Hz, 1H, C4-OH), 3.37 (s, 3H, OCH3), 2.33 (d, J = 2.8 Hz, 1H, C2-OH), 0.90 (s, 9H,


128.6, 128.0, 127.9, 100.4, 95.3, 80.1, 71.2, 70.4, 69.8, 68.4, 64.4, 54.8, 25.9, 18.3, –5.4; HRMS

m/z calcd for C21H37O7Si [M+H]+: 429.2308. Found 429.2297.

O

OMe

OTBSOH

BOMOHO

107

1,6-Anhydro-2-O-benzyl-β-D-mannopyranoside (2.15)

1,6-Anhydro-β-D-mannopyranoside 2.02 (32.4 mg, 0.200 mmol), benzyl bromide (35.6 µL,

0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O (50.9 mg, 0.220

mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon atmosphere at 40 °C for 48 hr.

Flash chromatographic purification (pentanes/EtOAc, 30:70) afforded the title compound as a

pale yellow oil (36.8 mg, 73%); Rf = 0.22 (pentanes/EtOAc, 30:70); FTIR (νmax) 3414 (br), 2901

(w), 1640 (w), 1496 (w), 1454 (w), 1395 (w), 1209 (w), 1076 (s), 1047 (s), 900 (s), 678 (s) cm-1; 1H NMR (400 MHz, CDCl3): δ 7.31–7.22 (m, 5H, ArH), 5.33 (apparent t, J = 1.6 Hz, 1H, H-1),

4.64 (d, J = 12.0 Hz, 1H, ArCH2), 4.52 (d, J = 12.0 Hz, 1H, ArCH2), 4.42–4.40 (m, 1H, H-5),

4.22 (dd, J = 7.2, 0.8 Hz, 1H, H-6a), 3.99–3.96 (m, 1H, H-3), 3.85–3.82 (m, 1H, H-4), 3.67 (dd,

J = 7.2, 6.0 Hz, 1H, H-6b), 3.48 (dd, J = 4.8, 2.0 Hz, 1H, H-2), 3.02 (d, J = 2.4 Hz, 1H, C3-OH),

2.28 (d, J = 8.8 Hz, 1H, C4-OH); 13C NMR (100 MHz, CDCl3): δ 137.0, 128.6, 128.3, 128.0,

100.3, 76.4, 72.6, 71.4, 71.1, 69.5, 64.9; HRMS m/z calcd for C13H20NO5 [M+NH4]+:

270.1342. Found 270.1344.

1,6-Anhydro-2-O-(4-bromobenzyl)-β-D-mannopyranoside (2.16)

1,6-Anhydro-β-D-mannopyranoside 2.02 (162.1 mg, 1.000 mmol), 4-bromobenzyl bromide

(374.9 mg, 1.500 mmol), 2-aminoethyl diphenylborinate (22.5 mg, 10 mol %) and Ag2O (254.9

mg, 1.100 mmol) were stirred in acetonitrile (5 mL, 0.2 M) under argon atmosphere at 40 °C for

48 hr. Flash chromatographic purification (pentanes/EtOAc, 40:60) afforded the title compound

as a colourless oil (252.8 mg, 96 % pure by 1H NMR: 73% yield). The contaminant is the 3-O-

(4-bromobenzyl) regioisomer. Rf = 0.25 (pentanes/EtOAc, 30:70); FTIR (νmax) 3479 (br), 2902

(m), 1488 (m), 1340 (m), 1101 (s), 1068 (s), 1049 (s), 969 (m), 817 (s), 681 (m) cm-1; 1H NMR

OOOH

OH

OBn

OOOH

OH

OBr

108

(400 MHz, CDCl3): δ 7.52 (apparent dt, J = 9.2, 2.4 Hz, 2H, ArH), 7.26 (apparent dt, J = 9.2, 2.4

Hz, 2H, ArH), 5.44 (apparent t, J = 1.6 Hz, 1H, H-1), 4.68 (d, J = 12.0 Hz, 1H, ArCH2), 4.56 (d,

J = 12.0 Hz, 1H, ArCH2), 4.54–4.50 (m, 1H, H-5), 4.31 (dd, J = 7.6, 1.2 Hz, 1H, H-6a), 4.09–

4.06 (m, 1H, H-3), 3.94–3.92 (m, 1H, H-4), 3.77 (dd, J = 7.2, 5.6 Hz, 1H, H-6b), 3.56 (dd,

J = 5.2, 2.0 Hz, 1H, H-2), 3.06 (d, J = 2.8 Hz, 1H, C3-OH), 2.35 (d, J = 8.0 Hz, 1H, C4-OH); 13C

NMR (100 MHz, CDCl3): δ 136.1, 131.7, 129.4, 122.2, 100.2, 76.5, 73.2, 71.6, 70.3, 69.7, 64.9;

HRMS m/z calcd for C13H19BrNO5 [M+NH4]+: 348.0454. Found 348.0447.

Major peaks from 3-O-(4-bromobenzyl) regioisomer: 5.37–5.35 (m, 1H, H-1), 4.68 (d,

J = 12.0 Hz, 1H, ArCH2), 4.56 (d, J = 12.0 Hz, 1H, ArCH2), 4.83–4.49 (m, 1H, H-5), 4.18 (dd,

J = 7.2, 0.8 Hz, 1H, H-6a), 2.44 (d, J = 9.6 Hz, 1H, C2-OH).

1,6-Anhydro-2-O-(2-methylnaphthalenyl)-β-D-mannopyranoside (2.17)

1,6-Anhydro-β-D-mannopyranoside 2.02 (32.4 mg, 0.200 mmol), 2-(bromomethyl)naphthalene

(66.3 mg, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O (50.9 mg,

0.220 mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon atmosphere at 40 °C for 48

hr. Flash chromatographic purification (pentanes/EtOAc, 50:50) afforded the title compound as a

colourless oil (42.9 mg, 71%). Rf = 0.26 (pentanes/EtOAc, 30:70); FTIR (νmax) 3464 (br), 2941

(m), 1508 (w), 1396 (m), 1251 (m), 1123 (s), 1048 (s), 992 (s), 896 (s), 802 (s) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.86–7.76 (m, 4H, ArH), 7.52–7.47 (m, 3H, ArH), 5.42 (apparent t,

J = 2.0 Hz, 1H, H-1), 4.87 (d, J = 12.0 Hz, 1H, ArCH2), 4.74 (d, J = 12.0 Hz, 1H, ArCH2), 4.48–

4.44 (m, 1H, H-5), 4.30 (dd, J = 7.2, 0.8 Hz, 1H, H-6a), 4.10–4.06 (m, 1H, H-3), 3.92–3.89 (m,

1H, H-4), 3.73 (dd, J = 7.2, 6.0 Hz, 1H, H-6b), 3.58 (dd, J = 5.2, 2.0 Hz, 1H, H-2), 3.12 (d, J =

2.4 Hz, 1H, C3-OH), 2.26 (d, J = 8.8 Hz, 1H, C4-OH); 13C NMR (100 MHz, CDCl3): δ 134.5,

133.3, 128.5, 128.0, 127.9, 127.7, 126.9, 126.3, 126.1, 125.5, 100.3, 76.5, 72.9, 71.6, 71.2, 69.7,

64.9; HRMS m/z calcd for C17H22NO5 [M+NH4]+: 320.1498. Found 320.1487.

OOOH

OH

O

109

1.6-Anhydro-2-O-benzyloxymethyl-β-D-mannopyranoside (2.18)

1,6-Anhydro-β-D-mannopyranoside 2.02 (32.4 mg, 0.200 mmol), benzyloxymethyl chloride

(41.7 µL, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O (50.9 mg,



pale yellow oil (37.1 mg, 97% pure by 1H NMR: 63% yield. The contaminant is the 3-O-

benzyloxymethyl regioisomer. Rf = 0.23 (pentanes/EtOAc, 30:70); FTIR (νmax) 3447 (br), 2898

(m), 1656 (w), 1406 (w), 1105 (s), 1047 (s), 973 (s), 902 (m), 820 (m), 699 (m) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.31–7.21 (m, 5H, ArH), 5.36 (apparent t, J = 1.6 Hz, 1H, H-1), 4.82 (s,

2H, OCH2O), 4.64 (d, J =12.0 Hz, 1H, ArCH2O), 4.57 (d, J =12.0 Hz, 1H, ArCH2O), 4.45–4.40

(m, 1H, H-5), 4.25 (dd, J = 7.6, 0.8 Hz, 1H, H-6a), 3.99–3.96 (m, 1H, H-3), 3.85–3.80 (m, 1H,

H-4), 3.73–3.67 (m, 2H, H-2 and H-6b), 2.88 (d, J = 2.0 Hz, 1H, C3-OH), 2.36 (d, J = 8.8 Hz,

1H, C4-OH); 13C NMR (100 MHz, CDCl3): δ 137.1, 128.6, 128.1, 128.0, 100.7, 93.9, 76.3, 72.1,

71.5, 70.4, 70.3, 65.0; HRMS m/z calcd for C14H19O6 [M+H]+: 283.1182. Found 283.1195.

Major peaks from 3-O-benzyloxymethyl regioisomer: 5.28–5.30 (m, 1H, H-1), 4.83 (d, J =12.0

Hz, 1H, ArCH2O), 4.75 (d, J =12.0 Hz, 1H, ArCH2O), 4.42–4.38 (m, 1H, H-5), 4.11 (dd, J = 7.6,

1.2 Hz, 1H, H-6a), 2.98 (d, J = 2.4 Hz, 1H, C2-OH).

1,3,4,6-Tetra-O-benzyl-β-D-mannopyranose (2.19)

3,4,6-Tri-O-benzyl-D-mannopyranoside 2.03 (81.0 mg, 0.200 mmol), benzyl bromide (35.6 µL,



OOOH

OH

OBOM

OOBn

OBnOH

BnOBnO

110


colourless oil (77.8 mg, 72%); Rf = 0.42 (pentanes/EtOAc, 70:30). Spectral data were in accord

with those presented in the literature.104

Methyl-3-O-benzyl-α-L-rhamnopyranoside (2.20)

Methyl-α-L-rhamnopyranoside 2.04 (35.6 mg, 0.200 mmol), benzyl bromide (35.6 µL, 0.300

mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O (50.9 mg, 0.220 mmol)

were stirred in acetonitrile (2 mL, 0.1 M) under argon atmosphere at 40 °C for 48 hr. Flash

chromatographic purification (pentanes/EtOAc, 60:40) afforded the title compound as a

colourless oil (44.6 mg, 83%); Rf = 0.56 (pentanes/EtOAc, 30:70); FTIR (νmax) 3430 (br), 2909

(m), 1497 (w), 1453 (m), 1197 (w), 1104 (s), 1053 (s), 985 (s), 905 (m), 740 (m) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.39–7.29 (m, 5H, ArH), 4.71 (d, J = 1.6 Hz, 1H, H-1), 4.70 (d,

J = 11.6 Hz, 1H, ArCH2), 4.55 (d, J = 11.6 Hz, 1H, ArCH2), 4.02–4.00 (m, 1H, H-2), 3.68–3.59

(m, 2H, H-3 and H-5), 3.54 (apparent td, J = 9.2, 2.4 Hz, 1H, H-4), 3.36 (s, 3H, OCH3), 2.40 (d,

J = 2.4 Hz, 1H, C2-OH), 2.22 (d, J = 2.8 Hz, 1H, C4-OH), 1.31 (d, J = 6.4 Hz, 3H, CHCH3); 13C

NMR (100 MHz, CDCl3): δ 137.7, 128.7, 128.2, 127.9, 100.4, 79.8, 71.6, 71.5, 67.7, 67.5, 54.8,

17.6; HRMS m/z calcd for C14H24NO5 [M+NH4]+: 286.1654. Found 286.1650.

Methyl-3-O-(4-bromobenzyl)-α-L-rhamnopyranoside (2.21)

104 Cumpstey, I.; Chayajarus, K.; Fairbanks, A. J.; Redgrave, A. J.; Seward, C. M. P. Tetrahedron: Asymmetry. 2004, 15, 3207–3222

O

OMeMeHOBnO

OH

O

OMeMeHO

OOH

Br

111

Methyl-α-L-rhamnopyranoside 2.04 (35.6 mg, 0.200 mmol), 4-bromobenzyl bromide (75.0 mg,




colourless oil (69.1 mg, >99%); Rf = 0.54 (pentanes/EtOAc, 30:70); FTIR (νmax) 3447 (br), 2910

(m), 1593 (w), 1488 (m), 1366 (w), 1265 (w), 1053 (s), 985 (s), 905 (w), 737 (m) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.48 (apparent dt, J = 8.8, 2.4 Hz, 2H, ArH), 7.22 (dt, J = 8.8, 2.4 Hz, 2H,

ArH), 4.68 (d, J = 2.0 Hz, 1H, H-1), 4.64 (d, J = 12.0 Hz, 1H, ArCH2), 4.52 (d, J = 12.0 Hz, 1H,

ArCH2), 3.99–3.97 (m, 1H, H-2), 3.66–3.51 (m, 3H, H-3, H-4 and H-5), 3.35 (s, 3H, OCH3),

2.37 (d, J = 2.8 Hz, 1H, C2-OH), 2.24 (d, J = 2.8 Hz, 1H, C4-OH), 1.31 (d, J = 6.0 Hz, 3H,

CHCH3); 13C NMR (100 MHz, CDCl3): δ 136.7, 131.8, 129.5, 122.1, 100.3, 79.8, 71.7, 70.8,

67.8, 67.5, 54.9, 17.6; HRMS m/z calcd for C14H23BrNO5 [M+NH4]+: 364.0750. Found

364.0759.

Methyl-3-O-(2-naphthyl)methyl-α-L-rhamnopyranoside (2.22)

Methyl-α-L-rhamnopyranoside 2.04 (35.6 mg, 0.200 mmol), 2-(bromomethyl)naphthalene (66.3

mg, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O (50.9 mg, 0.220



pale yellow oil (52.7 mg, 83%); Rf = 0.55 (pentanes/EtOAc, 30:70). Spectral data were in accord


105 Borbás, A.; Szabó, Z. B.; Szilágyi, L.; Bényei, A.; Lipták, A. Carbohydr. Res. 2002, 337, 1941–1951.

O

OMeMeHO

OOH

112

Methyl-3-O-benzyloxymethyl-α-L-rhamnopyranoside (2.23)

Methyl-α-L-rhamnopyranoside 2.04 (35.6 mg, 0.200 mmol), benzyloxymethyl chloride (41.7 µL,





(m), 1497 (w), 1454 (m), 1381 (m), 1053 (s), 982 (s), 905 (m), 802 (m), 740 (m) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.38–7.28 (m, 5H, ArH), 4.92 (d, J = 6.8 Hz, 1H, OCH2O), 4.86 (d, J =

6.8 Hz, 1H, OCH2O), 4.75 (d, J = 12.0 Hz, 1H, ArCH2O), 4.67 (d, J = 1.6 Hz, 1H, H-1), 4.65 (d,

J = 12.0 Hz, 1H, ArCH2O), 3.99–3.97 (m, 1H, H-2), 3.69–3.61 (m, 2H, H-3 and H-5), 3.52

(apparent td, J = 9.2, 2.0 Hz, 1H, H-4), 3.36 (s, 3H, OCH3), 3.24 (d, J = 2.4 Hz, 1H, C4-OH),

2.35 (d, J = 3.2 Hz, 1H, C2-OH), 1.34 (d, J = 6.4 Hz, 3H, CHCH3); 13C NMR (100 MHz,

CDCl3): δ 136.8, 128.6, 128.1, 127.9, 100.3, 95.3, 81.4, 71.4, 70.5, 70.1, 67.6, 54.8, 17.7;

HRMS m/z calcd for C15H26NO6 [M+NH4]+: 316.1760. Found 316.1753.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-benzyl-α-D-galactopyranoside (2.24)

Methyl-α-D-galactopyranoside 2.05 (61.7 mg, 0.200 mmol), benzyl bromide (35.6 µL, 0.300




O

OMeMeHOBOMO

OH

O

OMe

OTBS

HOBnO

HO

113



Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(4-bromobenzyl)-α-D-galactopyranoside (2.25)

Methyl-α-D-galactopyranoside 2.05 (61.7 mg, 0.200 mmol), 4-bromobenzyl bromide (75.0 mg,





(m), 1517 (w), 1487 (m), 1389 (m), 1250 (m), 1148 (m), 1083 (s), 963 (m), 836 (s) cm-1; 1H

NMR (400 MHz, CDCl3): δ 7.49 (apparent dt, J = 8.8, 2.4 Hz, 2H, ArH), 7.25 (apparent dt,

J = 8.8, 2.4 Hz, 2H, ArH), 4.81 (d, J = 4.0 Hz, 1H, H-1), 4.69 (s, 2H, ArCH2), 4.07–4.06 (m, 1H,

H-4), 4.01 (ddd, J = 9.6, 8.4, 4.0 Hz, 1H, H-2), 3.87 (dd, J = 10.4, 6.0 Hz, 1H, H-6a), 3.80 (dd,

J = 10.4, 5.6 Hz, 1H, H-6b), 3.69 (apparent t, J = 5.6 Hz, 1H, H-5), 3.56 (dd, J = 9.6, 3.2 Hz, 1H,

H-3), 3.40 (s, 3H, OCH3), 2.67 (s, 1H, C4-OH), 2.10 (d, J = 8.4 Hz, 1H, C2-OH), 0.89 (s, 9H,


131.6, 129.4, 121.8, 99.5, 78.6, 71.2, 69.9, 68.7, 67.1, 62.7, 55.2, 25.8, 18.3, –5.4; HRMS m/z

calcd for C20H34BrO6Si [M+H]+: 477.1308. Found 477.1292.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(2-methylnaphthalenyl)-α-D-galactopyranoside

(2.26)

106 Aurrecoechea, J. M.; Gil, J. H.; López, B. Tetrahedron. 2003, 59, 7111–7122.

O

OMe

OTBS

HOO

HO

Br

O

OMe

OTBS

HOO

HO

114

Methyl-α-D-galactopyranoside 2.05 (61.7 mg, 0.200 mmol), 2-(bromomethyl)naphthalene (66.3





(m), 1462 (m), 1360 (w), 1250 (s), 1084 (s), 1051 (s), 963 (m), 836 (s), 773 (m) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.85–7.82 (m, 4H, ArH), 7.54–7.45 (m, 3H, ArH), 4.90 (s, 2H, ArCH2),

4.81 (d, J = 4.0 Hz, 1H, H-1), 4.10–4.07 (m, 1H, H-4), 4.06–4.02 (m, 1H, H-2), 3.87 (dd,

J = 10.4, 6.0 Hz, 1H, H-6a), 3.79 (dd, J = 10.4, 5.6 Hz, 1H, H-6b), 3.77 (apparent t, J = 5.6 Hz,

1H, H-5), 3.64 (dd, J = 9.6, 3.2 Hz, 1H, H-3), 3.40 (s, 3H, OCH3), 2.70 (s, 1H, C4-OH), 2.23 (d,

J = 6.0 Hz, 1H, C2-OH), 0.89 (s, 9H, Si(C(CH3)3)(CH3)2), 0.07 (s, 6H, Si(C(CH3)3)(CH3)2); 13C

NMR (100 MHz, CDCl3): δ 135.4, 133.2, 133.1, 128.5, 127.9, 127.7, 126.7, 126.2, 126.1, 125.7,

99.5, 78.5, 72.1, 70.7, 68.7, 67.0, 62.7, 55.2, 25.8, 18.3, –5.4; HRMS m/z calcd for C24H37O6Si

[M+H]+: 449.2359. Found 449.2341.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-benzyloxymethyl-α-D-galactopyranoside (2.27)

Methyl-α-D-galactopyranoside 2.05 (61.7 mg, 0.200 mmol), benzyloxymethyl chloride (41.7 µL,





(m), 1518 (w), 1462 (m), 1388 (m), 1251 (m), 1083 (s), 1036 (s), 963 (m), 836 (s) cm-1; 1H

NMR (400 MHz, CDCl3): δ 7.36–7.28 (m, ArH), 4.96 (d, J = 7.2 Hz, 1H, OCH2O), 4.91 (d, J =

7.2 Hz, 1H, OCH2O), 4.83 (d, J = 4.0 Hz, 1H, H-1), 4.72 (d, J =12.0 Hz, 1H, ArCH2O), 4.70 (d,

J =12.0 Hz, 1H, ArCH2O), 4.14–4.12 (m, 1H, H-4), 4.00 (ddd, J = 9.6, 8.0, 4.0 Hz, 1H, H-2),

3.89 (dd, J = 10.4, 5.6 Hz, 1H, H-6a), 3.82 (dd, J = 10.4, 5.2 Hz, 1H, H-6b), 3.78 (dd, J = 10.0,

3.2 Hz, 1H, H-3), 3.74 (apparent t, J = 5.2 Hz, 1H, H-5), 3.42 (s, 3H, OCH3), 2.80 (s, 1H, C4-

O

OMe

OTBS

HOBOMO

HO

115

OH), 2.51 (d, J = 8.0 Hz, 1H, C2-OH), 0.89 (s, 9H, Si(C(CH3)3)(CH3)2), 0.07 (s, 6H,


78.2, 77.4, 77.1, 76.8, 70.1, 63.0, 55.2, 25.8, 18.3, –5.4; HRMS m/z calcd for C21H37O7Si

[M+H]+: 429.2308. Found 429.2290.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-benzyl-β-D-galactopyranoside (2.28)

Methyl-β-D-galactopyranoside 2.06 (308.4 mg, 1.000 mmol), benzyl bromide (178.2 µL, 1.500






Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(4-bromobenzyl)-β-D-galactopyranoside (2.29)

Methyl-β-D-galactopyranoside 2.06 (308.4 mg, 1.000 mmol), 4-bromobenzyl bromide (374.9

mg, 1.500 mmol), 2-aminoethyl diphenylborinate (22.5 mg, 10 mol%) and Ag2O (247.6 mg,




(m), 2856 (m), 1592 (w), 1462 (m), 1254 (s), 1070 (s), 1011 (m), 837 (s), 778 (m) cm-1; 1H

NMR (400 MHz, CDCl3): δ 7.45 (apparent dt, J = 9.2, 2.4 Hz, 2H, ArH), 7.26 (apparent dt,

107 Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1990, 55, 2776–2786.

OOMe

OTBS

HOBnO

HO

OOMe

OTBS

HOO

HO

Br

116

J = 9.2, 2.4 Hz, 2H, ArH), 4.69 (s, 2H, ArCH2), 4.14 (d, J = 7.6 Hz, 1H, H-1), 4.03–3.99 (m, 1H,

H-4), 3.90 (dd, J = 10.0, 6.4 Hz, 1H, H-6a), 3.81 (dd, J = 10.0, 5.6 Hz, 1H, H-6b), 3.77 (dd,

J = 9.6, 8.0 Hz, 1H, H-2), 3.52 (s, 3H, OCH3), 3.42–3.40 (m, 1H, H-5), 3.37 (dd, J = 9.2, 3.2 Hz,

1H, H-3), 2.55–2.58 (m, 2H, C2-OH and C4-OH), 0.89 (s, 9H, Si(C(CH3)3)(CH3)2), 0.07 (s, 6H,


74.6, 71.2, 71.1, 66.2, 62.1, 56.9, 25.8, 18.3, –5.4; HRMS m/z calcd for C20H34BrO6Si

[M+H]+: 477.1309. Found 477.1294.

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(2-methylnaphthalenyl)-β-D-galactopyranoside

(2.30)

Methyl-β-D-galactopyranoside 2.06 (308.4 mg, 1.000 mmol), 2-(bromomethyl)naphthalene




as a pale yellow oil (443.7 mg, >99%); Rf = 0.28 (pentanes/EtOAc, 70:30); FTIR (νmax) 3557

(br), 2928 (m), 1462 (w), 1389 (w), 1252 (m), 1154 (m), 1072 (s), 836 (s), 733 (s), 702 (m) cm-1; 1H NMR (400 MHz, CDCl3): δ 7.84–7.80 (m, 4H, ArH), 7.54–7.45 (m, 3H, ArH), 4.91 (s, 2H,

ArCH2), 4.14 (d, J = 8.0 Hz, 1H, H-1), 4.02–4.05 (m, 1H, H-4), 3.92 (dd, J = 10.4, 6.8 Hz, 1H,

H-6a), 3.87–3.81 (m, 2H, H-2 and H-6b), 3.54 (s, 3H, OCH3), 3.45 (dd, J = 9.6, 3.2 Hz, 1H, H-

3), 3.40 (apparent t, J = 6.0 Hz, 1H, H-5), 2.78 (s, 1H, C4-OH), 2.66 (d, J = 2.0 Hz, 1H, C2-OH),

0.89 (s, 9H, Si(C(CH3)3)(CH3)2), 0.07 (s, 6H, Si(C(CH3)3)(CH3)2); 13C NMR (100 MHz,

CDCl3): δ 135.3, 133.3, 133.1, 128.5, 127.9, 127.7, 126.8, 126.2, 126.1, 125.7, 104.0, 80.5, 74.7,

72.1, 71.1, 66.2, 62.1, 56.8, 25.8, 18.3, –5.4; HRMS m/z calcd for C24H37O6Si [M+H]+:

449.2359. Found 449.2346.

OOMe

OTBS

HOO

HO

117

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-benzyloxymethyl-β-D-galactopyranoside (2.31)

Methyl-β-D-galactopyranoside 2.06 (61.7 mg, 0.200 mmol), benzyloxymethyl chloride (41.7 µL,





(m), 1471 (w), 1387 (w), 1254 (m), 1206 (w), 1102 (s), 1041 (s), 837 (s), 736 (m) cm-1; 1H NMR


7.2 Hz, 1H, OCH2O), 4.73 (d, J =11.6 Hz, 1H, ArCH2O), 4.68 (d, J =11.6 Hz, 1H, ArCH2O),

4.20 (d, J = 7.6 Hz, 1H, H-1), 4.10–4.08 (m, 1H, H-4), 3.92 (dd, J = 10.4, 6.4 Hz, 1H, H-6a),

3.85 (dd, J = 10.4, 5.2 Hz, 1H, H-6b), 3.76 (apparent dt, J = 9.2, 1.2 Hz, 1H, H-2), 3.58 (dd, J =

9.2, 3.2 Hz, 1H, H-3), 3.55 (s, 3H, OCH3), 3.47 (apparent t, J = 5.6 Hz, 1H, H-5), 2.89 (d, J = 1.2

Hz, 1H, C2-OH), 2.66 (d, J = 3.2 Hz, 1H, C4-OH), 0.89 (s, 9H, Si(C(CH3)3)(CH3)2), 0.08 (s, 6H,


80.6, 74.4, 70.5, 70.2, 67.7, 62.4, 56.9, 25.8, 18.3, –5.4; HRMS m/z calcd for C21H37O7Si

[M+H]+: 429.2308. Found 429.2294.

1,6-Anhydro-4-O-benzyl-β-D-galactopyranoside (2.32)

1,6-Anhydro-β-D-galactopyranoside 2.07 (32.4 mg, 0.200 mmol), benzyl bromide (35.6 µL,




yellow oil (38.4 mg, 96% pure by 1H NMR: 73% yield). The contaminant is the 3-O-benzyl

OOMe

OTBS

HOBOMO

HO

OOOH

BnO

OH

118

regioisomer. Rf = 0.24 (pentanes/EtOAc, 30:70); FTIR (νmax) 3428 (br), 2902 (m), 1454 (m),

1333 (m), 1210 (m), 1133 (s), 1050 (s), 932 (s), 852 (m), 738 (m) cm-1; 1H NMR (400 MHz,

CDCl3): δ 7.39–7.30 (m, 5H, ArH), 5.35–5.38 (m, 1H, H-1), 4.69 (d, J = 12.0 Hz, 1H, ArCH2),

4.64 (d, J = 12.0 Hz, 1H, ArCH2), 4.40 (apparent t, J = 4.4 Hz, 1H, H-5), 4.29 (d, J = 7.6 Hz, 1H,

H-6a), 4.42–3.91 (m, 1H, H-3), 3.84–3.77 (m, 2H, H-2 and H-4), 3.63 (dd, J = 7.2, 5.6 Hz, 1H,

H-6b), 2.76 (d, J = 2.4 Hz, 1H, C3-OH), 2.34 (d, J = 8.0 Hz, 1H, C2-OH); 13C NMR (100 MHz,

CDCl3): δ 137.3, 128.6, 128.3, 127.8, 101.6, 72.7, 71.8, 71.7, 71.6, 69.9, 64.1; HRMS m/z calcd

for C13H20NO5 [M+NH4]+: 270.1341. Found 270.1338. Major peaks from 3-O-benzyl

regioisomer: 4.78 (d, J = 11.6 Hz, 1H, ArCH2), 4.46 (d, J = 11.6 Hz, 1H, ArCH2), 4.19 (d,

J = 7.6 Hz, 1H, H-6a), 3.12 (d, J = 6.0 Hz, 1H, C4-OH).

1,6-Anhydro-4-O-(4-bromobenzyl)-β-D-galactopyranoside (2.33)

1,6-Anhydro-β-D-galactopyranoside 2.07 (162.1 mg, 1.000 mmol), 4-bromobenzyl bromide




as a yellow oil (126.7 mg, 92% pure by 1H NMR: 72% yield). The contaminant is the 3-O-(4-

bromobenzyl) regioisomer. Rf = 0.23 (pentanes/EtOAc, 30:70); FTIR (νmax) 3424 (br), 2900

(m), 1592 (w), 1487 (m) 1333 (m), 1247 (m), 1132 (s), 1050 (s), 1011 (s), 931 (s) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.47 (apparent dt, J = 9.2, 2.4 Hz, 2H, ArH), 7.20 (apparent dt, J = 9.2, 2.4

Hz, 2H, ArH), 5.35–5.33 (m, 1H, H-1), 4.61 (d, J = 12.0 Hz, 1H, ArCH2), 4.54 (d, J = 12.0 Hz,

1H, ArCH2), 4.39 (apparent t, J = 4.4 Hz, 1H, H-5), 4.26 (d, J = 7.6 Hz, 1H, H-6a), 4.02–3.98

(m, 1H, H-3), 3.81–3.77 (m, 2H, H-2 and H-4), 3.61 (dd, J = 7.2, 5.6 Hz, 1H, H-6b), 2.76 (d, J =

2.8 Hz, 1H, C3-OH), 2.67 (d, J = 8.0 Hz, 1H, C2-OH); 13C NMR (100 MHz, CDCl3): δ 136.3,

131.8, 129.3, 122.3, 101.6, 72.7, 71.9, 71.6, 70.8, 69.8, 64.2; HRMS m/z calcd for

C13H19BrNO5 [M+NH4]+: 348.0446. Found 348.0456. Major peaks from 3-O-(4-bromobenzyl)

OOOH

O

OH

Br

119

regioisomer: 4.71 (d, J = 11.6 Hz, 1H, ArCH2), 4.16 (d, J = 7.6 Hz, 1H, H-6a), 3.03 (d, J = 9.6

Hz, 1H, C4-OH).

1,6-Anhydro-4-O-(2-methylnaphthalenyl)-β-D-galactopyranoside (2.34)

1,6-Anhydro-β-D-galactopyranoside 2.07 (32.4 mg, 0.200 mmol), 2-(bromomethyl)naphthalene

(66.3 mg, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O (50.9 mg,



yellow oil (46.1 mg, 97% pure by 1H NMR: 74% yield). The contaminant is the 3-O-(2-

methylnaphthalenyl) regioisomer. Rf = 0.23 (pentanes/EtOAc, 30:70); FTIR (νmax) 3433 (br),

2960 (w), 1509 (w), 1341 (m), 1238 (m), 1127 (s), 1018 (s), 923 (m), 824 (s), 751 (m) cm-1; 1H

NMR (400 MHz, CDCl3): δ 7.87–7.77 (m, 4H, ArH), 7.54–7.45 (m, 3H, ArH), 5.37 (apparent t,

J = 1.2 Hz, 1H, H-1), 4.86 (d, J = 11.6 Hz, 1H, ArCH2), 4.78 (d, J = 11.6 Hz, 1H, ArCH2), 4.43

(apparent t, J = 4.4 Hz, 1H, H-5), 4.34 (d, J = 7.6 Hz, 1H, H-6a), 4.06–4.04 (m, 1H, H-3), 3.88–

3.82 (m, 2H, H-2 and H-4), 3.67 (dd, J = 7.2, 5.2 Hz, 1H, H-6b), 2.70 (d, J = 0.8 Hz, 1H, C3-

OH), 2.25 (d, J = 7.6 Hz, 1H, C2-OH); 13C NMR (100 MHz, CDCl3): δ 134.6, 133.2, 133.1,

128.7, 127.9, 127.8, 127.0, 126.5, 126.4, 125.5, 101.5, 72.7, 71.9, 71.5, 71.4, 69.8, 64.3; HRMS

m/z calcd for C17H22NO5 [M+NH4]+: 320.1498. Found 320.1486.

Major peaks from 3-O-(2-methylnaphthalenyl) regioisomer: 4.93 (d, J = 12.0 Hz, 1H, ArCH2),

4.64 (d, J = 12.0 Hz, 1H, ArCH2), 4.23 (d, J = 8.0 Hz, 1H, H-6a), 3.12 (d, J = 9.6 Hz, 1H, C4-

OH).

1.6-Anhydro-4-O-benzyloxymethyl-β-D-galactopyranoside (2.35)

OOOH

O

OH

OOOH

BOMO

OH

120

1,6-Anhydro-β-D-galactopyranoside 2.07 (32.4 mg, 0.200 mmol), benzyloxymethyl chloride




yellow oil (37.0 mg, 96% pure by 1H NMR: 63% yield). The contaminant is the 3-O-

benzyloxymethyl regioisomer. Rf = 0.22 (pentanes/EtOAc, 30:70); FTIR (νmax) 3436 (br), 2895

(m), 1454 (w), 1266 (w), 1132 (s), 1107 (m), 1025 (s), 930 (s), 850 (m), 734 (s) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.39–7.30 (m, 5H, ArH), 5.39–5.40 (m, 1H, H-1), 4.91 (d, J = 10.8 Hz,

1H, OCH2O), 4.80 (d, J = 10.8 Hz, 1H, OCH2O), 4.64 (s, 2H, ArCH2O), 4.48 (apparent t,

J = 4.8 Hz, 1H, H-5), 4.32 (d, J = 7.2 Hz, 1H, H-6a), 4.05–3.99 (m, 2H, H-3 and H-4), 3.83 (d,

J = 9.6 Hz, 1H, H-2), 3.67 (dd, J = 6.8, 6.0 Hz, 1H, H-6b), 2.64 (d, J = 2.8 Hz, 1H, C3-OH), 1.95

(d, J = 9.6 Hz, 1H, C2-OH); 13C NMR (100 MHz, CDCl3): δ 137.1, 128.5, 128.0, 127.7, 101.5,

94.6, 73.4, 71.7, 71.6, 70.7, 70.6, 64.2; HRMS m/z calcd for C14H22NO6 [M+NH4]+: 300.1447.

Found 300.1459.

Major peaks from 3-O-benzyloxymethyl regioisomer: 5.38–5.36 (m, 1H, H-1), 4.22 (d,

J = 7.6 Hz, 1H, H-6a), 2.89 (d, J = 2.8 Hz, 1H, C4-OH).

Methyl-3-O-benzyl-α-L-fucopyranoside (2.36)

Methyl-α-L-fucopyranoside 2.08 (35.6 mg, 0.200 mmol), benzyl bromide (35.6 µL, 0.300 mmol),

2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O (50.9 mg, 0.220 mmol) were

stirred in acetonitrile (1 mL, 0.2 M) under argon atmosphere at 40 °C for 48 hr. Flash

chromatographic purification (pentanes/EtOAc, 60:40) afforded the title compound as a pale

yellow oil (50.4 mg, 94%); Rf = 0.26 (pentanes/EtOAc, 60:40); FTIR (νmax) 3445 (br), 2898 (m),

1497 (w), 1360 (m), 1191 (m), 1079 (s), 1049 (s), 956 (s), 875 (w), 749 (m) cm-1; 1H NMR (400

MHz, CDCl3): δ 7.39–7.28 (m, 5H, ArH), 4.76 (d, J = 4.0 Hz, 1H, H-1), 4.72 (s, 2H, ArCH2),

3.45 (ddd, J = 9.6, 8.0, 4.0 Hz, 1H, H-2), 3.86 (apparent q, J = 6.8 Hz, 1H, H-5), 3.82–3.80 (m,

1H, H-4), 3.61 (dd, J = 9.6, 3.2 Hz, 1H, H-3), 3.40 (s, 3H, OCH3), 2.40 (s, 1H, C4-OH), 2.17 (d,

O

OMeMe

HOOBnOH

121

J = 8.0 Hz, 1H, C2-OH), 1.29 (d, J = 6.8 Hz, 3H, CHCH3); 13C NMR (100 MHz, CDCl3): δ

137.9, 128.6, 128.0, 127.8, 99.5, 78.7, 72.0, 69.5, 68.4, 65.4, 55.3, 16.2; HRMS m/z calcd for

C14H24NO5 [M+NH4]+: 286.1654. Found 286.1658.

Methyl-3-O-(4-bromobenzyl)-α-L-fucopyranoside (2.37)

Methyl-α-L-fucopyranoside 2.08 (35.6 mg, 0.200 mmol), 4-bromobenzyl bromide (75.0 mg,




pale yellow oil (61.9 mg, 89%); Rf = 0.31 (pentanes/EtOAc, 30:70); FTIR (νmax) 3534 (m), 3463

(m), 2906 (m), 1593 (w), 1491 (m), 1135 (s), 1067 (s), 1023 (s), 805 (s) cm-1; 1H NMR (400

MHz, CDCl3): δ 7.44 (apparent dt, J = 8.8, 2.4 Hz, 2H, ArH), 7.22 (apparent dt, J = 8.8, 2.4 Hz,

2H, ArH), 4.72 (d, J = 4.0 Hz, 1H, H-1), 4.64 (s, 2H, ArCH2), 3.92 (ddd, J = 9.6, 8.0, 4.0 Hz, 1H,

H-2), 3.82 (apparent q, J = 6.4 Hz, 1H, H-5), 3.78–3.76 (m, 1H, H-4), 3.54 (dd, J = 9.6, 3.2 Hz,

1H, H-3), 3.37 (s, 3H, OCH3), 2.46 (s, 1H, C4-OH), 2.28 (d, J = 8.4 Hz, 1H, C2-OH), 1.26 (d, J =

6.4 Hz, 3H, CHCH3); 13C NMR (100 MHz, CDCl3): δ 137.0, 131.6, 129.4, 121.8, 99.6, 78.7,

71.2, 69.6, 68.4, 65.5, 55.3, 16.2; HRMS m/z calcd for C14H23BrNO5 [M+NH4]+: 364.0760.

Found 364.0764.

Methyl-3-O-(2-naphthyl)methyl-α-L-fucopyranoside (2.38)

O

OMeMe

HOOOH

Br

O

OMeMe

HOOOH

122

Methyl-α-L-fucopyranoside 2.08 (35.6 mg, 0.200 mmol), 2-(bromomethyl)naphthalene (66.3 mg,





(m), 1602 (w), 1447 (w), 1265 (m), 1124 (m), 1083 (s), 1049 (s), 857 (m), 735 (s) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.84–7.46 (m, 4H, ArH), 7.52–7.46 (m, 3H, ArH), 4.87 (s, 2H, ArCH2),

4.92–4.77 (d, J = 3.6 Hz, 1H, H-1), 4.00 (ddd, J = 9.6, 8.0, 4.0 Hz, 1H, H-2), 3.86–3.81 (m, 2H,

H-5 and H-4), 3.64 (dd, J = 9.6, 3.2 Hz, 1H, H-3), 3.38 (s, 3H, OCH3), 2.55 (s, 1H, C4-OH), 2.32

(d, J = 8.4 Hz, 1H, C2-OH), 1.29 (d, J = 6.8 Hz, 3H, CHCH3); 13C NMR (100 MHz, CDCl3): δ

135.4, 133.2, 133.1, 128.4, 127.9, 127.7, 126.7, 126.2, 126.1, 125.7, 99.6, 78.6, 72.1, 69.6, 68.4,

65.5, 55.3, 16.2; HRMS m/z calcd for C18H26NO5 [M+NH4]+: 336.1810. Found 336.1811.

Methyl-3-O-benzyloxymethyl-α-L-fucopyranoside (2.39)

Methyl-α-L-fucopyranoside 2.08 (35.6 mg, 0.200 mmol), benzyloxymethyl chloride (41.7 µL,





(m), 1454 (w), 1361 (w), 1266 (m), 1191 (m), 1065 (s), 958 (s), 801 (w), 735 (s) cm-1; 1H NMR


7.2 Hz, 1H, OCH2O), 4.78 (d, J = 3.8 Hz, 1H, H-1), 4.72 (d, J = 12.0 Hz, 1H, ArCH2O), 4.66 (d,

J = 12.0 Hz, 1H, ArCH2O), 3.96–3.88 (m, 2H, H-2 and H-5), 3.81–3.78 (m, 2H, H-3 and H-4),

3.41 (s, 3H, OCH3), 2.49 (d, J = 8.0 Hz, 1H, C2-OH), 2.34 (s, 1H, C4-OH), 1.29 (d, J = 6.8 Hz,

3H, CHCH3); 13C NMR (100 MHz, CDCl3): δ 137.3, 128.5, 128.0, 127.9, 99.6, 94.7, 78.3, 71.0,

70.2, 68.0, 65.4, 55.3, 16.1; HRMS m/z calcd for C15H26NO6 [M+NH4]+: 316.1760. Found

316.1752.

O

OMeMe

HOOBOMOH

123

Methyl-3-O-benzyl-β-L-arabinopyranoside (2.40)

Methyl-β-L-arabinopyranoside 2.09 (164.1 mg, 1.000 mmol), benzyl bromide (178.2 µL, 1.500




colourless oil (188.8 mg, 74%); Rf = 0.19 (pentanes/EtOAc, 30:70); FTIR (νmax) 3463 (m), 2922

(w), 2835 (w), 1450 (w), 1350 (m), 1136 (s), 1060 (s), 998 (s), 925 (w), 855 (m), 747 (s) cm-1; 1H NMR (400 MHz, CDCl3): δ 7.39–7.28 (m, 5H, ArH), 4.76 (d, J = 3.6 Hz, 1H, H-1), 4.72 (d,

J = 11.6 Hz, 1H, ArCH2), 4.68 (d, J = 11.6 Hz, 1H, ArCH2), 4.01–3.93 (m, 2H, H-2 and H-4),

3.73–3.68 (m, 2H, H-6a and H-6b), 3.65 (dd, J = 9.6, 3.2 Hz, 1H, H-3), 3.39 (s, 3H, OCH3), 2.84

(br s, 1H, C4-OH), 2.61 (d, J = 7.6 Hz, 1H, C2-OH); 13C NMR (100 MHz, CDCl3): δ 137.8,

128.6, 128.1, 127.8, 99.9, 77.9, 72.2, 68.6, 66.9, 61.7, 55.5; HRMS m/z calcd for C13H22NO5

[M+NH4]+: 272.1152. Found 272.1154.

Methyl-3-O-(4-bromobenzyl)-β-L-arabinopyranoside (2.41)

Methyl-β-L-arabinopyranoside 2.09 (32.8 mg, 0.200 mmol), 4-bromobenzyl bromide (75.0 mg,





(br), 1592 (w), 1487 (m), 1340 (m), 1265 (m), 1140 (s), 1062 (s), 891 (m), 735 (s) cm-1; 1H

NMR (400 MHz, CDCl3): δ 7.41 (apparent dt, J = 8.8, 2.4 Hz, 2H, ArH), 7.18 (apparent dt, J =

8.8, 2.4 Hz, 2H, ArH), 4.70 (d, J = 3.6 Hz, 1H, H-1), 4.61 (d, J = 1.2 Hz, 1H, ArCH2), 3.92–3.86

O

OMeHOBnO

HO

O

OMeHOO

HO

Br

124

(m, 2H, H-2 and H-4), 3.67–3.60 (m, 2H, H-5a and H-5b), 3.53 (dd, J = 9.2, 3.2 Hz, 1H, H-3),

3.33 (s, 3H, OCH3), 2.54 (s, 1H, C4-OH), 2.22 (d, J = 8.0 Hz, 1H, C2-OH); 13C NMR (100 MHz,

CDCl3): δ 136.9, 131.7, 129.4, 121.9, 99.9, 77.9, 71.4, 68.7, 67.0, 61.8, 55.5; HRMS m/z calcd

for C13H21BrNO5 [M+NH4]+: 350.0603. Found 350.0586.

Methyl-3-O-(2-naphthyl)methyl-β-L-arabinopyranoside (2.42)

Methyl-β-L-arabinopyranoside 2.09 (32.8 mg, 0.200 mmol), 2-(bromomethyl)naphthalene (66.3





(m), 1604 (w), 1444 (w), 1343 (m), 1135 (s), 1060 (s), 924 (m), 859 (s), 699 (m) cm-1; 1H NMR

(400 MHz, CDCl3): δ 7.87–7.82 (m, 4H, ArH), 7.47–7.54 (m, 3H, ArH), 4.90 (d, J = 12.0 Hz,

1H, ArCH2), 4.86 (d, J = 12.0 Hz, 1H, ArCH2), 4.81 (d, J = 3.6 Hz, 1H, H-1), 4.05 (ddd, J = 9.2,

8.0, 3.6 Hz, 1H, H-2), 4.04–3.97 (m, 1H, H-4), 3.79–3.68 (m, 3H, H-3, H-5a and H-5b), 3.41 (s,

3H, OCH3), 2.79 (s, 1H, C4-OH), 2.45 (d, J = 8.0 Hz, 1H, C2-OH); 13C NMR (100 MHz,

CDCl3): δ 135.3, 133.2, 133.1, 128.5, 127.9, 127.7, 126.7, 126.3, 126.1, 125.7, 100.0, 77.7, 72.3,

68.7, 67.0, 61.8, 55.5; HRMS m/z calcd for C17H24NO5 [M+NH4]+: 322.1654. Found 322.1642.

Methyl-3-O-benzyloxymethyl-β-L-arabinopyranoside (2.43)

Methyl-β-L-arabinopyranoside 2.09 (32.8 mg, 0.200 mmol), benzyloxymethyl chloride (41.7 µL,



O

OMeHOO

HO

O

OMeHOBOMO

HO

125



(m), 1454 (w), 1342 (w), 1192 (w), 1115 (m), 1139 (s), 1040 (s), 844 (w), 734 (s) cm-1; 1H NMR


6.8 Hz, 1H, OCH2O), 4.80 (d, J = 3.6 Hz, 1H, H-1), 4.72 (d, J = 11.6 Hz, 1H, ArCH2O), 4.67 (d,

J = 11.6 Hz, 1H, ArCH2O), 4.02–3.98 (m, 1H, H-4), 3.98–3.91 (m, 1H, H-2), 3.81 (dd, J = 9.6,

3.6 Hz, 1H, H-3), 3.78–3.69 (m, 2H, H-5a and H-5b), 3.42 (s, 3H, OCH3), 2.57–2.53 (m, 2H, C4-

OH and C2-OH); 13C NMR (100 MHz, CDCl3): δ 137.2, 128.6, 128.0, 127.9, 99.9, 94.8, 77.6,

70.3, 68.3, 61.8, 55.5; HRMS m/z calcd for C14H24NO6 [M+NH4]+: 302.1603. Found 302.1592.

3,6-Di-O-(4-bromobenzyl)-D-galactal (2.44)

D-Galactal 2.10 (29.2 mg, 0.200 mmol), 4-bromobenzyl bromide (124.9 mg, 0.500 mmol), 2-

aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O (97.3 mg, 0.420 mmol) were stirred

in acetonitrile (2 mL, 0.1 M) under argon atmosphere at 40 °C for 48 hr. Flash chromatographic

purification (pentanes/EtOAc, 85:15) afforded the title compound as a colourless oil (76.1 mg,

79%); Rf = 0.46 (pentanes/EtOAc, 70:30); FTIR (νmax) 3558 (br), 3073 (br), 2859 (w), 1648 (m),

1400 (m), 1233 (s), 1160 (m), 1011 (s), 871 (s), 744 (m) cm-1; 1H NMR (400 MHz, CDCl3): δ

7.49–7.46 (m, 4H, ArH), 7.24–7.20 (m, 4H, ArH), 6.42 (dd, J = 6.4, 1.6 Hz, 1H, H-1), 4.70 (dd,

J = 6.4, 2.0 Hz, 1H, H-2), 4.61–4.50 (m, 4H, ArCH2), 4.20–4.18 (m, 1H, H-3), 4.09–4.07 (m,

1H, H-4), 4.02 (apparent t, J = 6.0 Hz, 1H, H-5), 3.78 (d, J = 6.0 Hz, 2H, H-6), 2.50 (d, J = 3.6

Hz, 1H, C4-OH); 13C NMR (100 MHz, CDCl3): δ 145.1, 136.8, 136.6, 131.7, 131.6, 129.4,

129.3, 121.9, 121.7, 99.2, 75.3, 72.9, 70.8, 69.7, 69.3, 63.0; HRMS m/z calcd for C20H21Br2O4

[M+H]+: 482.9806. Found 482.9816.

OOHO

O

Br

Br

126

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-allyl-α-D-mannopyranoside (2.45)

Methyl-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside 2.01 (61.7 mg, 0.200 mmol), allyl

bromide (25.9 µL, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O

(50.9 mg, 0.220 mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon atmosphere at 40

°C for 48 hr. Flash chromatographic purification (pentanes/EtOAc, 85:15) afforded the title

compound as a colourless oil (36.9 mg, 53%); Rf = 0.43 (pentanes/EtOAc, 70:30); 1H NMR (400

MHz, CDCl3): δ 5.98 (dddd, J = 16.0, 11.6, 10.4, 5.6 Hz, 1H, CH2CHCH2), 5.32 (dq, J = 16.0,

1.2 Hz, 1H, CH2CHCH2), 5.21 (dq, J = 10.4, 1.2 Hz, 1H, CH2CHCH2), 4.73 (d, J = 1.6 Hz, 1H,

H-1), 4.11–4.22 (m, 2H, CH2CHCH2), 3.98–3.95 (m, 1H, H-2), 3.91–3.81 (m, 3H, H-3, H-4 and

H-5), 3.63–3.57 (m, 2H, H-6a and H-6b), 3.36 (s, 3H, OCH3), 3.03 (d, J = 1.6 Hz, 1H, C4-OH),

2.40 (d, J = 2.8 Hz, 1H, C2-OH), 0.90 (s, 9H, Si(C(CH3)3)(CH3)2), 0.09 (s, 6H,

Si(C(CH3)3)(CH3)2).

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-allyl-α-D-galactopyranoside (2.46)

Methyl-6-(tert-butyldimethylsilyloxy)-α-D-galactopyranoside 2.05 (61.7 mg, 0.200 mmol), allyl

bromide (25.9 µL, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O

(50.9 mg, 0.220 mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon atmosphere at 40

°C for 48 hr. Flash chromatographic purification (pentanes/EtOAc, 85:15) afforded the title

compound as a colourless oil (11.8 mg, 17%); Rf = 0.43 (pentanes/EtOAc, 70:30); 1H NMR (400

MHz, CDCl3): δ 5.94 (dddd, J = 16.0, 11.6, 10.4, 5.6 Hz, 1H, CH2CHCH2), 5.28 (dq, J = 16.0,

1.2 Hz, 1H, CH2CHCH2), 5.18 (dq, J = 10.4, 1.2 Hz, 1H, CH2CHCH2), 4.41 (ddt, J =12.8, 5.6,

1.2 Hz, 1H, CH2CHCH2), 4.73 (d, J = 7.6 Hz, 1H, H-1), 4.16 (ddt, J =12.8, 5.6, 1.2 Hz, 1H,

CH2CHCH2), 4.03–4.05 (m, 1H, H-4), 3.93 (dd, J = 10.4, 6.4 Hz, 1H, H-6a), 3.85 (dd, J = 10.4,

O

OTBS

HOAllylO

OH

OMe

O

OTBS

AllylO

OMe

OH

HO

127

5.2 Hz, 1H, H-6b), 3.60–3.55 (m, 1H, H-2), 3.53 (s, 3H, OCH3), 3.47–3.44 (m, 1H, H-5), 3.44–

3.37 (m, 1H, H-3), 2.68 (d, J = 1.6 Hz, 1H, C4-OH), 2.59 (d, J = 2.8 Hz, 1H, C2-OH), 0.90 (s,

9H, Si(C(CH3)3)(CH3)2), 0.09 (s, 6H, Si(C(CH3)3)(CH3)2).

Methyl-3-O-allyl-α-L-fucopyranoside (2.47)

Methyl-α-L-fucopyranoside 2.08 (35.6 mg, 0.200 mmol), allyl bromide (25.9 µL, 0.300 mmol),

2-aminoethyl diphenylborinate (4.5 mg, 10 mol %) and Ag2O (50.9 mg, 0.220 mmol) were

stirred in acetonitrile (2 mL, 0.1 M) under argon atmosphere at 40 °C for 48 hr. Flash


colourless oil (24.4 mg, 56%); Rf = 0.23 (pentanes/EtOAc, 60:40); 1H NMR (400 MHz,

CDCl3): δ 5.94 (dddd, J = 16.0, 11.6, 10.4, 5.6 Hz, 1H, CH2CHCH2), 5.32 (dq, J = 16.0, 1.2 Hz,

1H, CH2CHCH2), 5.19 (dq, J = 10.4, 1.2 Hz, 1H, CH2CHCH2), 4.76 (d, J = 7.6 Hz, 1H, H-1),

4.20–4.15 (m, 2H, CH2CHCH2), 4.03–3.81 (m, 3H, H-2, H-4 and H-5), 3.54 (dd, J = 10.0, 3.6

Hz, H-3), 3.41 (s, 3H, OCH3), 2.49 (d, J = 8.0 Hz, 1H, C2-OH), 2.34 (s, 1H, C4-OH), 1.29 (d, J =

6.8 Hz, 3H, CHCH3).

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(4-methoxybenzyl)-α-D-mannopyranoside (2.48)


methoxybenzyl bromide (40.7 µL, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol

%) and Ag2O (50.9 mg, 0.220 mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon


afforded the title compound as a colourless oil (36.0 mg, 42%); Rf = 0.34 (pentanes/EtOAc,

70:30); 1H NMR (400 MHz, CDCl3): δ 7.24–7.16 (m, 2H, ArH), 6.82–6.77 (m, 2H, ArH), 4.63

O

OMeMe

OHOAllyl

OH

O

OTBS

HOPMBO

OH

OMe

128

(d, J = 1.2 Hz, 1H, H-1), 4.53 (s, 2H, ArCH2), 3.87–3.83 (m, 1H, H-2), 3.79–3.73 (m, 3H, H-4,

H-6a and H-6b), 3.71 (s, 3H, ArOCH3), 3.57 (dd, J = 9.2, 3.2 Hz, 1H, H-3), 3.50 (apparent dt,

J = 10.0, 5.2 Hz, 1H, H-5), 3.27 (s, 3H, OCH3), 2.84 (d, J = 1.6 Hz, 1H, C4-OH), 2.32 (d, J = 2.8

Hz, 1H, C2-OH), 0.90 (s, 9H, Si(C(CH3)3)(CH3)2), 0.09 (s, 6H, Si(C(CH3)3)(CH3)2).

1,6-Anhydro-2-O-(4-methoxybenzyl)-β-D-mannopyranoside (2.49)

1,6-Anhydro-β-D-mannopyranoside 2.02 (32.4 mg, 0.200 mmol), 4-methoxybenzyl bromide




colourless oil (34.4 mg, 61% yield); Rf = 0.21 (pentanes/EtOAc, 40:60); 1H NMR (400 MHz,

CDCl3): δ 7.20–7.16 (m, 2H, ArH), 6.85–6.80 (m, 2H, ArH), 5.27–5.24 (m, 1H, H-1), 4.54 (d,

J = 11.2 Hz, 1H, ArCH2), 4.46 (d, J = 11.2 Hz, 1H, ArCH2), 4.36–4.39 (m, 1H, H-5), 4.11 (dd,

J = 7.2, 0.8 Hz, 1H, H-6a), 3.75 (s, 3H, OCH3), 3.74–3.73 (m, 1H, H-3), 3.70–3.65 (m, 2H, H-4

and H-6b), 3.60 (ddd, J = 11.2, 5.6, 2.0 Hz, 1H, H-2), 2.96 (d, J = 11.6 Hz, 1H, C3-OH), 2.27 (d,

J = 10.0 Hz, 1H, C4-OH).

Methyl-6-(tert-butyldimethylsilyloxy)-3-O-(4-methoxybenzyl)-β-D-galactopyranoside (2.50)

Methyl-β-D-galactopyranoside 2.06 (61.7 mg, 0.200 mmol), 4-methoxybenzyl bromide (40.7 µL,





O

OOH

OH

OPMB

O

OTBS

PMBO OMe

OH

OH

129

CDCl3): δ 7.32–7.27 (m, 2H, ArH), 6.91–6.86 (m, 2H, ArH), 4.86 (d, J = 11.2 Hz, 1H, ArCH2),

4.59 (d, J = 11.2 Hz, 1H, ArCH2), 4.26 (d, J = 7.6 Hz, 1H, H-1), 4.01 (apparent t, J = 2.8 Hz, 1H,

H-4), 3.92 (dd, J = 10.4, 6.0 Hz, 1H, H-6a), 3.84 (dd, J = 10.4, 5.6 Hz, 1H, H-6b), 3.81 (s, 3H,

ArOCH3), 3.59–3.51 (m, 1H, H-2), 3.57 (s, 3H, OCH3), 3.52–3.43 (m, 2H, H-3 and H-5), 2.61

(d, J = 3.2 Hz, 1H, C4-OH), 2.32 (d, J = 4.0 Hz, 1H, C2-OH), 0.90 (s, 9H, Si(C(CH3)3)(CH3)2),

0.09 (s, 6H, Si(C(CH3)3)(CH3)2).

1,6-Anhydro-4-O-(4-methoxybenzyl)-β-D-galactopyranoside (2.51)

1,6-Anhydro-β-D-galactopyranoside 2.07 (32.4 mg, 0.200 mmol), 4-methoxybenzyl bromide





CDCl3): δ 7.29–7.24 (m, 2H, ArH), 6.92–6.88 (m, 2H, ArH), 5.38–5.36 (m, 1H, H-1), 4.62 (d,

J = 11.6 Hz, 1H, ArCH2), 4.56 (d, J = 11.6 Hz, 1H, ArCH2), 4.37 (apparent t, J = 5.6 Hz, 1H, H-

5), 4.28 (d, J = 7.2 Hz, 1H, H-6a), 4.01–3.96 (m, 1H, H-3), 3.81 (s, 3H, OCH3), 3.81–3.78 (m,

2H, H-2 and H-4), 3.66–3.61 (m, 1H, H-6b), 2.68 (d, J = 2.0 Hz, 1H, C3-OH), 2.06 (d, J = 9.6

Hz, 1H, C2-OH).

Methyl-3-O-(4-methoxybenzyl)-α-L-fucopyranoside (2.52)

Methyl-α-L-fucopyranoside 2.08 (35.6 mg, 0.200 mmol), 4-methoxybenzyl bromide (40.7 µL,



O

O

PMBOOH

OH

O

OMeMe

OHOPMB

OH

130



CDCl3): δ 7.35–7.29 (m, 2H, ArH), 6.94–6.88 (m, 2H, ArH), 4.79 (d, J = 4.0 Hz, 1H, H-1), 4.67

(s, 2H, ArCH2), 3.98–3.93 (m, 1H, H-2), 3.92–3.86 (m, 1H, H-5), 3.82 (s, 3H, ArOCH3), 3.84–

3.80 (m, 1H, H-4), 3.63 (dd, J = 9.6, 3.2 Hz, 1H, H-3), 3.43 (s, 3H, OCH3), 2.41–2.39 (m, 1H,

C4-OH), 2.16 (d, J = 8.0 Hz, 1H, C2-OH), 1.31 (d, J = 6.4 Hz, 3H, CHCH3).

Methyl-3-O-(4-methoxybenzyl)-β-L-arabinopyranoside (2.53)

Methyl-β-L-arabinopyranoside 2.09 (32.8 mg, 0.200 mmol), 4-methoxybenzyl bromide (40.7 µL,




colourless oil (23.9 mg, 42% yield); 1H NMR (400 MHz, CDCl3): δ 7.32–7.27 (m, 2H, ArH),

6.91–6.87 (m, 2H, ArH), 4.79 (d, J = 3.6 Hz, 1H, H-1), 4.87 (d, J = 11.2 Hz, 1H, ArCH2), 4.63

(d, J = 11.2 Hz, 1H, ArCH2), 3.99–3.92 (m, 2H, H-2 and H-4), 3.81 (s, 3H, ArOCH3), 3.73–3.71

(m, 2H, H-5a and H-5b), 3.63 (dd, J = 9.2, 3.2 Hz, 1H, H-3), 3.42 (s, 3H, OCH3), 2.49 (s, 1H,

C4-OH), 2.11 (d, J = 7.6 Hz, 1H, C2-OH).

Isopropyl-6-(tert-butyldimethylsilyloxy)-β-D-thiogalactopyranoside (2.55)

Isopropyl-6-(tert-butyldimethylsilyloxy)-β-D-thiogalactopyranoside 2.54 (69.6 mg, 0.200 mmol),

benzyl bromide (35.6 µL, 0.300 mmol), 2-aminoethyl diphenylborinate (4.5 mg, 10 mol %),

tetrabutylammonium iodide (73.9 mg, 0.200 mmol) and potassium carbonate (30.4 mg, 0.220



OPMBO OMe

OH

OH

OOTBSHO

BnOHO

SiPr

131


CDCl3): δ 7.35–7.15 (m, 5H, ArH), 4.72 (d, J = 11.6 Hz, 1H, ArCH2), 4.68 (d, J = 11.6 Hz, 1H,

ArCH2), 4.30 (d, J = 9.6 Hz, 1H, H-1), 4.00–3.97 (m, 1H, H-4), 3.80 (dd, J = 10.4, 6.4 Hz, 1H,

H-6a), 3.76–3.72 (m, 2H, H-2 and H-6b), 3.51 (apparent t, J = 5.6 Hz, 1H, H-5), 3.39–3.33 (m,

2H, H-3 and C2-OH), 3.20–3.09 (m, 1H, C4-OH), 2.59 (t, J = 5.6 Hz, 1H, SCH(CH3)2), 1.26 (d, J

= 6.8, 1.2 Hz, 6H, SCH(CH3)2), 0.89 (s, 9H, Si(C(CH3)3)(CH3)2), 0.07 (s, 6H,

Si(C(CH3)3)(CH3)2).

5.1.5 General Procedure E: Borinic Acid-Catalyzed Glycosylation

The glycosyl donor (1.0 equiv), glycosyl acceptor (1.1 equiv), Ag2O (1.0 equiv) and 2-

aminoethyl diphenylborinate (10 mol %) were added to an oven-dried round bottom flask, under

an argon atmosphere. Dry acetonitrile (0.13 M) was added and the resulting mixture was stirred

vigorously (750-1000 rpm). The reaction was then diluted with dichloromethane and filtered

through a plug of Celite®. The resulting crude material was purified by flash chromatography on

silica gel.

Carbohydrate substrates 3.01108, 3.0293, 3.0394, 3.04109, 3.0595, 3.0695, 3.0796, 3.0896 were

prepared following literature methods. Spectral data were consistent with those presented in the

literature.

5.1.6 General Procedure F: Borinic Acid-Catalyzed Synthesis of Sugar Substrates

Bearing a Carbonate at O-2 and O-3

The sugar substrate (1 equiv), 1,1’-carbonyl diimidazole (1.1 equiv), 2-aminoethyl

diphenylborinate (10 mol %) and diisopropylethylamine (1.1 equiv) were stirred in acetonitrile

(0.2 M) under argon atmosphere at 40 °C for 16 hr. The reaction was subsequently diluted with

methanol and washed with water twice. The organic layer was dried (MgSO4), concentrated and

purified by silica gel chromatography.

108 Bianchi, A.; Bernardi, A. J. Org. Chem. 2006, 71, 4565–4577. 109 Mitchell, S. A.; Pratt, M. R.; Hruby, V. J.; Polt, R. J. Org. Chem. 2001, 66, 2327–2342.

132

Methyl-2,3-O-carbonate-α-L-rhamnopyranoside (3.16)

Methyl-2,3-O-carbonate-α-L-rhamnopyranoside was synthesized following General Procedure F

using methyl-α-L-rhamnopyranoside. Flash chromatographic purification (pentanes/EtOAc,

80:20) afforded the title compound as a colourless oil (72%); Rf = 0.22 (pentanes/EtOAc, 80:20); 1H NMR (400 MHz, CDCl3): δ 4.85 (s, 1H, H-1), 4.61 (d, J = 6.4 Hz, 1H, H-3), 4.56 (dd, J =

7.2, 0.9 Hz, 1H, H-2), 3.75–3.66 (m, 1H, H-5), 3.49 (dd, J = 8.4, 6.4 Hz, 1H, H-4), 3.36 (s, 3H,

OCH3), 2.55 (br s, 1H, C4-OH), 1.29 (d, J = 6.4 Hz, 3H, CHCH3).

Methyl-2,3-O-carbonate-4-O-benzoyl-α-L-rhamnopyranoside (3.17)

To a solution of methyl-2,3-O-carbonate-α-L-rhamnopyranoside 3.16 (355.9 mg, 1.0 mmol) in

pyridine (0.5 M) was added benzoyl chloride (127.8 µL, 1.1 mmol). The mixture was stirred

overnight at room temperature and was then diluted in dichloromethane. After washing twice

with water, the organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Toluene

was added and the solution was concentrated in vacuo to azeotrope pyridine. The resulting crude

material was purified by silica gel chromatography (pentane/EtOAc, 90:10) to yield the desired

product as a pale yellow solid in quantitative yield; Rf = 0.29 (pentanes/EtOAc, 85:15); 1H NMR

(400 MHz, CDCl3): δ 7.99–7.96 (m, 2H, ArH), 7.57–7.52 (m, 1H, ArH), 7.43–7.37 (m, 2H,

ArH), 5.08 (dd, J = 9.6, 6.8 Hz, 1H, H-4), 4.95 (s, 1H, H-1), 4.83 (apparent t, J = 7.2 Hz, 1H, H-

3), 4.62 (d, J = 7.2 Hz, 1H, H-2), 3.95–3.86 (m, 1H, H-5), 3.49 (s, 3H, OCH3), 1.24 (d, J = 6.4

Hz, 3H, CHCH3).

O

OMeMe

HOO OO

O

OMeMe

BzOO O

O

133

Methyl-2,3-O-carbonate-4-O-benzoyl-α-L-rhamnosyl bromide (3.18)

To a solution of methyl-2,3-O-carbonate-4-O-benzoyl-α-L-rhamnopyranoside 3.17 (308.1mg, 1.0

mmol) was added hydrogen bromide (33% solution in acetic acid, 2.1 mL). The mixture was

stirred overnight hours at room temperature. The crude mixture was diluted in dichloromethane

and washed twice with ice-cold water to pH neutral. The organic layer was dried over MgSO4,

filtered, and concentrated in vacuo. The resulting crude material was purified over a plug of

silica (10 cm, pentanes/EtOAc, 80:20) to yield the desired product as a yellow solid in 45%

yield; Rf = 0.27 (pentanes/EtOAc, 80:20); 1H NMR (400 MHz, CDCl3): δ 8.10–8.04 (m, 2H,

ArH), 7.65–7.60 (m, 1H, ArH), 7.51–7.45 (m, 2H, ArH), 6.65 (s, 1H, H-1), 5.25 (dd, J = 9.6, 6.8

Hz, 1H, H-4), 5.14–5.06 (m, 2H, H-2 and H-3), 4.31–4.22 (m, 1H, H-5), 1.35 (d, J = 6.4 Hz, 3H,

CHCH3).

Methyl-2,3-O-carbonate-α-D-mannopyranoside (3.19)

Methyl-2,3-O-carbonate-6-(tert-butyldimethylsilyloxy)-α-D-mannopyranoside was synthesized

following General Procedure F using methyl-6-(tert-butyldimethylsilyloxy)-α-D-

mannopyranoside. Flash chromatographic purification (pentanes/EtOAc, 80:20) afforded the title

compound as a colourless oil (>99%); Rf = 0.26 (pentanes/EtOAc, 80:20); 1H NMR (400 MHz,

CDCl3): δ 4.59 (d, J = 1.6 Hz, 1H, H-1), 3.81–3.75 (m, 2H, H-2 and H-3), 3.73–3.75 (m, 3H, H-

5, H-6a and H-6b), 3.46 (dt, J = 9.2, 5.2 Hz, 1H, H-4), 3.26 (s, 3H, OCH3), 3.23 (br s, 1H, C4-

OH), 0.89 (s, 9H, Si(C(CH3)3)(CH3)2), 0.07 (s, 6H, Si(C(CH3)3)(CH3)2).

O

BrMe

BzOO O

O

O

OTBS

HO OO

OMe

O

134

5.1.7 General Procedure G: Borinic Acid-Catalyzed Glycosylation with Halide

Catalysis

The glycosyl donor (1.0 equiv), glycosyl acceptor (1.1 equiv), 2-aminoethyl diphenylborinate (10

mol %), halide salt (1.0 equiv), potassium carbonate (1.1 equiv) were weighed into a 1-dram vial,

and dissolved in dry acetonitrile (0.2 M). The reaction vessel was capped with a septum and

purged with argon. The mixture was stirred vigorously (750-1000 rpm) and for the allotted time.

The resulting mixture was diluted with dichloromethane, filtered through Celite® and

concentrated to dryness. The resulting crude material was purified by flash chromatography on

silica gel.

Methyl-6-O-tert-butyldimethylsilyl-3-O-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-α-D-

mannopyranoside (3.21)

2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl bromide (82.0 mg, 0.200 mmol), methyl-6-O-tert-

butyldimethysilyl-α-D-mannopyranose (67.8 mg, 0.220 mmol), 2-aminoethyl diphenylborinate

(4.5 mg, 10 mol %), tetrabutylammonium iodide (73.9 mg, 0.200 mmol) and potassium

carbonate (30.4 mg, 0.220 mmol) were stirred in acetonitrile (2 mL, 0.1 M) under argon

atmosphere at 80 °C for 24 hr. Flash chromatographic purification (toluene/iPrOH, 95:5)

afforded the title compound as a white solid (48.5 mg, 38%); Rf = 0.40 (toluene/iPrOH, 90:10); 1H NMR (400 MHz, CDCl3): δ 5.23 (dd, J = 9.6, 9.6 Hz, 1H, H-3'), 5.06–5.01 (m, 2H, H-4' and

H-2'), 4.73 (d, J = 1.6 Hz, 1H, H-1), 4.61 (d, J = 8.0 Hz, 1H, H-1'), 4.21 (dd, J = 12.4, 2.4 Hz,

1H, H-6a'), 4.15 (dd, J = 12.4, 6.0 Hz, 1H, H-6b'), 3.96 (dd, J = 11.2, 2.4 Hz, 1H, H-6a), 3.83–

3.69 (m, 5H, H-6b, H-2, H-3, H-5' and H-4), 3.54 (ddd, J = 8.8, 6.0, 2.4 Hz, 1H, H-5), 3.37 (s,

3H, OCH3), 3.36 (d, J = 1.6 Hz, 1H, C4-OH), 2.21 (d, J = 3.6 Hz, 1H, C2-OH), 2.08 (s, 3H,

OCOCH3), 2.06 (s, 3H, OCOCH3), 2.03 (s, 3H, OCOCH3), 2.01 (s, 3H, OCOCH3), 0.89 (s, 9H,

Si(C(CH3)3)(CH3)2), 0.07 (s, 6H, Si(C(CH3)3)(CH3)2).

OOTBSHO

HOOMe

O

OAc

AcOAcO AcO

O

135

Methyl-6-O-tert-butyldimethylsilyl-3-O-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-α-D-

galactopyranoside (3.22)

2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl bromide (82.0 mg, 0.200 mmol), methyl-6-O-tert-

butyldimethysilyl-α-D-galactopyranose (67.8 mg, 0.220 mmol), 2-aminoethyl diphenylborinate

(4.5 mg, 10 mol %), potassium iodide (33.2 mg, 0.200 mmol) and potassium carbonate (30.4 mg,


hr. Flash chromatographic purification (toluene/iPrOH, 95:5) afforded the title compound as a

white solid (37.0 mg, 29%); Rf = 0.39 (toluene/iPrOH, 90:10); 1H NMR (400 MHz, CDCl3): δ

5.23 (dd, J = 9.6, 9.6 Hz, 1H, H-3'), 5.07 (dd, J = 10, 9.6 Hz, 1H, H-4'), 5.02 (dd, J = 10, 8 Hz,

1H, H-2'), 4.81 (d, J = 8 Hz, 1H, H-1'), 4.79 (d, J = 3.6 Hz, 1H, H-1), 4.23 (dd, J = 12.4, 4.8 Hz,

1H, H-6a'), 4.12 (dd, J = 12.4, 2.4 Hz, 1H, H-6b'), 4.06 (d, J = 3.2 Hz, 1H, H-4), 3.97 (dd, J =

9.2, 3.6 Hz, 1H, H-2), 3.85 (ddd, J = 8.8, 4.8, 4.8 Hz, 1H, H-5), 3.80−3.74 (m, 3H, H-6a, H-6b,

and H-3), 3.71 (ddd, J = 10, 4.8, 2.4 Hz, 1H, H-5'), 3.42 (s, 3H, OCH3), 2.08 (s, 3H, OCOCH3),

2.05 (s, 3H, OCOCH3), 2.02 (s, 3H, OCOCH3), 2.01 (s, 3H, OCOCH3), 0.88 (s, 9H,

Si(C(CH3)3)(CH3)2), 0.07 (s, 6H, Si(C(CH3)3)(CH3)2).

5.1.8 General Procedure H: Borinic Acid-Mediated Glycosylation

In a large test tube with a screw cap, the glycosyl acceptor (1.0 equiv) and boronic acid (1.0

equiv) was refluxed in toluene (0.2 M) for 16 hrs after which the solvent was then removed. To

the crude was then added the glycosyl donor (1.0 equiv), Ag2O (1.0 equiv), triethylamine (1.0

equiv) and dry acetonitrile (0.2 M). The reaction vessel was capped with a septum and purged

with argon. The mixture was stirred vigorously (750-1000 rpm) at room temperature for 16 hrs.

The resulting mixture was quenched with MeOH and extracted with water twice. The organic

layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude material

was purified by flash chromatography on silica gel.

OOTBSHO

HOOMe

O

OAc

AcOAcO AcO

O

136

Methyl-3-O-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-α-L-rhamnopyranoside (3.23)

Methyl-3-O-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-α-L-rhamnopyranoside was

synthesized following General Procedure H using 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl

bromide (1.0 equiv), methyl-α-L-rhamnopyranoside (1.0 equiv) and 8-quinolinyl borinic acid

(1.0 equiv). Flash chromatographic purification (pentanes/EtOAc, 60:40) afforded the title

compound as a white solid (82%); Rf = 0.26 (pentanes/EtOAc, 60:40); 1H NMR (400 MHz,

CDCl3): δ 5.38 (dd, J = 1.2, 1.2 Hz, 1H, H-1), 5.26 (dd, J = 3.4, 0.7 Hz, 1H, H-4'), 5.20 (dd,

J = 10.5, 7.9 Hz, 1H, H-2'), 5.03 (dd, J = 10.5, 3.4 Hz, 1H, H-3'), 4.54 (apparent t, J = 5.2 Hz,

1H, H-5), 4.50 (d, J = 7.9 Hz, 1H, H-1'), 4.29 (d, J = 7.6 Hz, 1H, H-6a), 4.04–4.00 (m, 2H, H-4

and H-3), 3.89 (qd, J = 6.4, 0.7 Hz, 1H, H-5'), 3.83 (br s, 1H, H-2), 3.67 (dd, J = 7.2, 5.2 Hz, 1H,

H-6b), 2.28 (d, J = 1.9 Hz, 1H, C2-OH), 2.09 (s, 3H, OCOCH3), 2.05 (s, 3H, OCOCH3), 2.03 (s,

3H, OCOCH3), 2.01 (s, 3H, OCOCH3), 1.24 (d, J = 6.4 Hz, 3H, C6'-CH3).

5.1.9 General Procedure I: Glycosylation Kinetic Experiments

Into an oven-dried 1 dram vial were added 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide,

methyl-6-O-tert-butyldimethysilyl-α-D-mannopyranose, 2-aminoethyl diphenylborinate and

Ag2O. The reaction vial was capped with a septum and purged with argon. Dry acetonitrile (0.13

M) was added and the resulting mixture was stirred vigorously (750 rpm) at room temperature.

The initial time of each kinetic run corresponds to the time at which dry acetonitrile was added to

the reaction vial. During the course of the reaction, aliquots of the reaction mixture were

removed and filtered over Celite® to remove the silver oxide, thus stopping the reaction. The

solvent was then removed and the resulting samples were analyzed by 1H-NMR spectroscopy for

the formation of product with mesitylene as an internal standard. Integrations for the internal

standard peak and the anomeric peak of the product were used to calculate moles of product

formed and therefore % conversion.

O

OAc

AcOAcO

AcO

O

OMeMeHO

OOH

3.23

137

Appendix A: NMR Spectra

195

Appendix B: DFT Calculations

Calculations were carried out with the Gaussian ’09 software package,110 on a Linux workstation

equipped with two quad-core AMD Shanghai processors built by HardData, Inc. (Edmonton,

Alberta, Canada). Geometry optimizations of the diphenylborinate esters of 1,6-anhydro-β-D-

mannopyranoside, 3,4,6-tri-O-benzyl-D-mannopyranoside and 1,6-anhydro-β-D-

galactopyranoside were carried out using density functional theory (B3LYP functional), with the

6-311+G** basis set. Condensed Fukui functions were calculated according to the method of

Yang and Mortier:111 a single-point energy calculation of the one-electron-oxidized form was

carried out, and the difference in Mulliken charges between the diphenylborinate adduct and its

oxidized form was calculated for each oxygen atom.

1,6-Anhydro-β-D-mannopyranoside 2,3-diphenylborinate

Atom Mulliken charge f-k

O-2 –0.360 0.137

O-3 –0.288 0.102

O-4 –0.240 0.023

110 Gaussian 09, Revision B.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009. 111 Yang, W.; Mortier, W. J. J. Am. Chem. Soc. 1986, 108, 5708–5711.

OOO

OH

OB Ph

Ph

123

196

3,4,6-Tri-O-benzyl-β-D-mannopyranoside 2,3-diphenylborinate


O-1 –0.264 0.078

O-2 –0.182 0.151

1,6-Anhydro-β-D-galactopyranoside 3,4-diphenylborinate


O-2 –0.233 0.024

O-3 –0.263 0.106

O-4 –0.324 0.135

O

OBn

BnOBnO

OO

B PhPh

12

OO

OO

OH

BPh

Ph

123

197

Cartesian Coordinates

1,6-Anhydro-β-D-mannopyranoside 2,3-diphenylborinate

Coordinates (Angstroms) Centre

Number

Atomic

Number Atomic Type

X Y Z

1 6 0 2.623082 0.192709 1.362262

2 6 0 2.674682 -1.242290 -1.129925

3 1 0 2.791560 0.375767 2.425148

4 1 0 2.454807 -1.102341 -2.191036

5 8 0 2.494533 1.441969 0.717073

6 8 0 3.809098 -0.388337 0.796640

7 6 0 1.435899 -0.771006 1.127455

8 1 0 1.614447 -1.631748 1.793941

9 8 0 0.209908 -0.168823 1.406970

10 6 0 2.979427 1.270934 -0.620699

11 1 0 3.730078 -2.043744 0.812136

12 1 0 2.154265 1.354517 -1.329540

13 8 0 0.412255 -0.372465 -0.941453

14 6 0 1.338052 -1.250293 -0.355589

15 1 0 0.965146 -2.286884 -0.367135

16 6 0 3.600723 -0.141343 -0.612981

17 1 0 4.574650 -0.194288 -1.102714

18 6 0 -1.824802 -1.125260 0.138687

OOO

HO

OB Ph

Ph

198

19 6 0 -2.582281 -1.366527 1.297989

20 6 0 -2.190448 -1.847969 -1.008421

21 6 0 -3.646329 -2.268281 1.314563

22 1 0 -2.318997 -0.837892 2.209852

23 6 0 -3.252671 -2.755987 -1.007790

24 1 0 -1.614413 -1.700736 -1.917949

25 6 0 -3.990173 -2.969515 0.156462

26 1 0 -4.209062 -2.429180 2.230822

27 1 0 -3.503887 -3.300078 -1.914979

28 1 0 -4.817643 -3.673140 0.163696

29 6 0 -1.148814 1.479399 -0.079671

30 6 0 -0.949524 2.477909 0.885961

31 6 0 -1.851091 1.855789 -1.237463

32 6 0 -1.422135 3.780474 0.711164

33 1 0 -0.396631 2.220056 1.782726

34 6 0 -2.319608 3.155743 -1.430978

35 1 0 -2.037780 1.112247 -2.007683

36 6 0 -2.109822 4.128330 -0.451515

37 1 0 -1.248212 4.528390 1.480813

38 1 0 -2.853832 3.411230 -2.342654

39 1 0 -2.476796 5.140888 -0.593581

40 5 0 -0.591322 -0.037827 0.129333

41 8 0 3.359342 -2.500024 -1.028102

42 1 0 3.682824 -2.556880 -0.120348

199

3,4,6-Tri-O-benzyl-β-D-mannopyranoside 2,3-diphenylborinate


Number

Atomic

Number Atomic Type

X Y Z

1 6 0 -0.027994 1.622977 -0.669089

2 6 0 1.674403 -0.070443 -1.363629

3 1 0 0.125192 2.164825 -1.615002

4 1 0 1.745600 0.422142 -2.349280

5 8 0 0.675369 -1.074450 -1.374379

6 8 0 -1.557662 -0.028035 0.287644

7 6 0 -1.117062 0.569014 -0.897708

8 1 0 -1.952906 1.050291 -1.436993

9 6 0 1.315877 0.993534 -0.305557

10 1 0 1.243364 0.508232 0.673597

11 8 0 2.344142 1.994952 -0.293238

12 8 0 -1.540368 -1.626577 -1.462904

13 6 0 3.015273 -0.739618 -1.068239

14 1 0 3.756425 0.035913 -0.873024

15 1 0 2.912643 -1.362233 -0.171382

16 8 0 3.542222 -1.496028 -2.156587

17 6 0 2.972330 -2.800999 -2.364433

18 1 0 3.439403 -3.146566 -3.290502

19 1 0 1.894833 -2.721626 -2.516798

O

OBn

BnOBnO

OOB PhPh

200

20 6 0 -0.657735 -0.633055 -1.756168

21 1 0 -0.634453 -0.416438 -2.836892

22 6 0 2.668702 2.497000 0.990619

23 1 0 3.026288 1.674818 1.631600

24 1 0 1.777307 2.917885 1.468625

25 8 0 -0.367566 2.577152 0.345710

26 6 0 -0.919248 3.809190 -0.072247

27 1 0 -0.546082 4.560190 0.635402

28 1 0 -0.526185 4.084773 -1.061720

29 6 0 -2.438914 3.877867 -0.092267

30 6 0 -3.234615 2.839541 0.393552

31 6 0 -3.053985 5.032978 -0.590507

32 6 0 -4.626205 2.952618 0.366159

33 1 0 -2.769656 1.932890 0.765242

34 6 0 -4.441414 5.150700 -0.604792

35 1 0 -2.442341 5.845609 -0.974926

36 6 0 -5.233501 4.105460 -0.126471

37 1 0 -5.228880 2.121789 0.715789

38 1 0 -4.903801 6.050770 -0.997486

39 1 0 -6.315191 4.186262 -0.149151

40 6 0 3.747622 3.550766 0.888869

41 6 0 4.424006 3.806305 -0.305631

42 6 0 4.091658 4.287195 2.028818

43 6 0 5.426440 4.776328 -0.356666

44 1 0 4.154432 3.243853 -1.189939

201

45 6 0 5.093384 5.252567 1.979692

46 1 0 3.568059 4.102561 2.962479

47 6 0 5.766702 5.501659 0.782744

48 1 0 5.941941 4.964148 -1.292781

49 1 0 5.346119 5.813333 2.873454

50 1 0 6.545918 6.255073 0.740773

51 6 0 3.265730 -3.772505 -1.241167

52 6 0 2.268399 -4.124562 -0.326297

53 6 0 4.547052 -4.316633 -1.087728

54 6 0 2.545390 -5.004816 0.721088

55 1 0 1.275887 -3.697606 -0.424727

56 6 0 4.825918 -5.197776 -0.046154

57 1 0 5.328401 -4.041500 -1.789838

58 6 0 3.822598 -5.543578 0.861763

59 1 0 1.759290 -5.253406 1.425051

60 1 0 5.822339 -5.615227 0.058751

61 1 0 4.038613 -6.227911 1.675844

62 6 0 -1.653832 -2.497481 1.004234

63 6 0 -1.804944 -3.870037 0.742598

64 6 0 -1.105924 -2.151007 2.249144

65 6 0 -1.432504 -4.845427 1.667652

66 1 0 -2.224120 -4.180259 -0.210665

67 6 0 -0.735242 -3.116493 3.188721

68 1 0 -0.964388 -1.098962 2.477043

69 6 0 -0.897893 -4.471781 2.902824

202

70 1 0 -1.562055 -5.897894 1.429414

71 1 0 -0.317214 -2.811874 4.144678

72 1 0 -0.614219 -5.226267 3.630879

73 6 0 -3.763421 -1.321736 -0.193018

74 6 0 -4.561123 -1.076962 0.939283

75 6 0 -4.441554 -1.493940 -1.409678

76 6 0 -5.951211 -0.994573 0.864821

77 1 0 -4.079383 -0.953631 1.905816

78 6 0 -5.834427 -1.419151 -1.499678

79 1 0 -3.855621 -1.690985 -2.301832

80 6 0 -6.598052 -1.165771 -0.361379

81 1 0 -6.533777 -0.804497 1.762589

82 1 0 -6.324695 -1.558005 -2.459847

83 1 0 -7.680614 -1.107168 -0.425332

84 5 0 -2.127933 -1.376707 -0.076668

203

1,6-Anhydro-β-D-galactopyranoside 3,4-diphenylborinate


Number

Atomic

Number Atomic Type

X Y Z

1 6 0 -3.708834 -0.046508 -0.443750

2 1 0 -4.707450 -0.127624 -0.879914

3 8 0 -3.260259 1.288650 -0.532311

4 8 0 -3.800803 -0.341684 0.947961

5 6 0 -2.499200 1.556080 0.666529

6 1 0 -2.993174 2.370624 1.205484

7 1 0 -1.479710 1.835670 0.409968

8 8 0 -0.444896 -0.246028 -0.937520

9 6 0 -1.380936 -1.127663 -0.376019

10 1 0 -1.038102 -2.170750 -0.467901

11 6 0 -2.565414 0.235943 1.445441

12 1 0 -2.672927 0.386626 2.520244

13 8 0 -3.409564 -2.333479 -1.098311

14 1 0 -3.638607 -2.528820 -0.181589

15 6 0 -2.749136 -1.056054 -1.092751

16 1 0 -2.581009 -0.794729 -2.138497

17 8 0 -0.168776 -0.155787 1.405046

18 6 0 -1.412084 -0.738218 1.136990

19 1 0 -1.572899 -1.632840 1.759567

OO

OO

OH

BPh

Ph

204

20 6 0 1.769549 -1.189826 0.035696

21 6 0 2.341995 -1.577621 -1.188092

22 6 0 2.253662 -1.834003 1.185519

23 6 0 3.340491 -2.548797 -1.265091

24 1 0 1.986667 -1.108852 -2.101775

25 6 0 3.257302 -2.804426 1.125629

26 1 0 1.817932 -1.570018 2.144816

27 6 0 3.807624 -3.167534 -0.103435

28 1 0 3.756794 -2.826160 -2.230236

29 1 0 3.607227 -3.282392 2.037366

30 1 0 4.586195 -3.923001 -0.157187

31 6 0 1.255282 1.457527 -0.048719

32 6 0 2.071421 2.009861 0.953469

33 6 0 1.028225 2.252019 -1.183885

34 6 0 2.626466 3.284112 0.837345

35 1 0 2.272665 1.427608 1.848463

36 6 0 1.584558 3.526895 -1.317277

37 1 0 0.389000 1.860758 -1.969061

38 6 0 2.387633 4.051177 -0.304996

39 1 0 3.248142 3.681073 1.635751

40 1 0 1.386993 4.114340 -2.210294

41 1 0 2.819946 5.042856 -0.402190

42 5 0 0.607013 -0.029105 0.104490

138

5.925.92

9.199.19

0.9740.974

0.9740.974

33

1.031.03

1.021.02

3.033.03

11

22

1.011.01

4.634.63

-1-100112233445566778899ppm

O

OMe

OTBSOH

BnOHO

4a

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMe

OTBSOH

BnOHO

4a

400 MHz, CDCl3

100 MHz, CDCl3

2.11

2.11

139

0 0112233445566778899ppmppm

0

1

2

3

4

5

6

7

8

9

O

OMe

OTBSOH

BnOHO

4a

5.875.87

9.369.36

0.9780.978

0.970.97

3.013.01

1.011.01

11

4.074.07

2.042.04

0.9780.978

1.981.98

1.831.83

-1-100112233445566778899ppm

O

OMe

OTBSOH

OHOBr

5a

400 MHz, CDCl3

400 MHz, CDCl3

2.11

2.12

140

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMe

OTBSOH

OHOBr

5a

-1 -1001122334455667788ppmppm

-1

0

1

2

3

4

5

6

7

8

O

OMe

OTBSOH

OHOBr

5a

400 MHz, CDCl3

100 MHz, CDCl3

2.12

2.12

141

5.825.82

9.19.1

0.9680.968

0.9620.962

2.992.99

11

11

33

11

0.9820.982

22

2.862.86

3.873.87

-1-100112233445566778899ppm

O

OMe

OTBSOH

OHO

6a

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMe

OTBSOH

OHO

6a

400 MHz, CDCl3

100 MHz, CDCl3

2.13

2.13

142

0 01122334455667788ppmppm

0

1

2

3

4

5

6

7

8

O

OMe

OTBSOH

OHO

6a

5.885.88

9.269.26

0.8910.891

2.942.94

0.9280.928

11

44

11

3.193.19

22

5.335.33

-1-100112233445566778899ppm

O

OMe

OTBSOH

BOMOHO

7a

400 MHz, CDCl3

400 MHz, CDCl3

2.13

2.14

143

0 02020404060608080100100120120140140160160180180200200ppmppm

LC-IV-2-F2-3/CDCl3/400 MHz

O

OMe

OTBSOH

BOMOHO

O

OMe

OTBSOH

BOMOHO

7a

10

0112233445566778899ppmppm

0

1

2

3

4

5

6

7

8

9

O

OMe

OTBSOH

BOMOHO

7a

400 MHz, CDCl3

100 MHz, CDCl3

2.14

2.14

144

11

11

1.011.01

1.111.11

11

11

1.041.04

11

1.021.02

1.051.05

0.970.97

4.994.99

-1-100112233445566778899ppm

O

OOH

OH

OBn

4b

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OOH

OH

OBn

4b

400 MHz, CDCl3

100 MHz, CDCl3

2.15

2.15

145

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

O

OOH

OH

OBn

4b

0.940.94

0.9290.929

11

1.111.11

0.9960.996

11

1.031.03

0.990.99

1.071.07

1.051.05

0.04520.0452

0.9020.902

2.072.07

1.911.91

-1-100112233445566778899ppm

OOOH

OH

OBr

5b

400 MHz, CDCl3

400 MHz, CDCl3

2.15

2.16

146

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OOH

OH

OBr

5b

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

O

OOH

OH

OBr

5b

100 MHz, CDCl3

400 MHz, CDCl3

2.16

2.16

147

0.9490.949

11

1.031.03

1.231.23

1.031.03

1.081.08

1.11.1

1.031.03

1.161.16

1.111.11

0.9390.939

3.083.08

4.284.28

00112233445566778899ppm

OOOH

OH

O

6b

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OOH

OH

O

6b

100 MHz, CDCl3

400 MHz, CDCl3

2.17

2.17

148

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

O

OOH

OH

O

6b

0.9310.931

0.9050.905

2.012.01

1.031.03

11

11

11

1.061.06

11

2.092.09

0.8950.895

4.94.9

-1-100112233445566778899ppm

OOOH

OH

OBOM

7b

400 MHz, CDCl3

400 MHz, CDCl3

2.17

2.18

149

0 02020404060608080100100120120140140160160180180200200ppmppm

OOOH

OH

OBOM

7b

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

OOOH

OH

OBOM

7b

100 MHz, CDCl3

400 MHz, CDCl3

2.18

2.18

150

0.9410.941

0.9910.991

0.9990.999

11

1.011.01

1.011.01

0.9780.978

11

5.085.08

1.021.02

2.072.07

2020

-1-100112233445566778899ppm

OOBn

OBnOH

BnOBnO

4c

0 02020404060608080100100120120140140160160180180200200ppmppm

OOBn

OBnOH

BnOBnO

4c

100 MHz, CDCl3

400 MHz, CDCl3

2.19

2.19

151

3.063.06

0.9310.931

0.9370.937

33

33

11

11

1.991.99

4.64.6

-1-100112233445566778899ppm

O

OMeMeHOBnO

OH

4d

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMeMeHOBnO

OH

4d

100 MHz, CDCl3

400 MHz, CDCl3

2.20

2.20

152

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

O

OMeMeHOBnO

OH

4d

33

0.9040.904

0.9320.932

2.952.95

33

0.9770.977

11

11

0.9430.943

1.871.87

1.761.76

-1-100112233445566778899ppm

O

OMeMeHO

OOH

Br5d

400 MHz, CDCl3

400 MHz, CDCl3

2.20

2.21

153

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMeMeHO

OOH

Br5d

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

O

OMeMeHO

OOH

Br5d

100 MHz, CDCl3

400 MHz, CDCl3

2.21

2.21

154

3.023.02

0.9420.942

0.9540.954

33

33

0.9980.998

22

11

2.822.82

3.833.83

-1-100112233445566778899ppm

O

OMeMeHO

OOH

6d

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMeMeHO

OOH

6d

100 MHz, CDCl3

400 MHz, CDCl3

2.22

2.22

155

3.083.08

0.9550.955

0.9660.966

33

11

22

11

22

11

11

11

4.54.5

-1-100112233445566778899ppm

O

OMeMeHOBOMO

OH

7d

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMeMeHOBOMO

OH

7d

100 MHz, CDCl3

400 MHz, CDCl3

2.23

2.23

156

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

O

OMeMeHOBOMO

OH

7d

5.975.97

9.019.01

0.970.97

0.9750.975

33

1.011.01

11

11

11

11

11

22

11

4.684.68

-1-100112233445566778899ppm

O

OMe

OTBS

HOBnO

HO

4e

400 MHz, CDCl3

400 MHz, CDCl3

2.23

2.24

157

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMe

OTBS

HOBnO

HO

4e

5.945.94

99

0.9650.965

0.9760.976

33

1.011.01

11

11

11

11

11

22

11

1.991.99

1.871.87

-1-100112233445566778899ppm

O

OMe

OTBS

HOO

HO

Br

5e

100 MHz, CDCl3

400 MHz, CDCl3

2.24

2.25

158

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMe

OTBS

HOO

HO

Br

5e

-1 -1001122334455667788ppmppm

-1

0

1

2

3

4

5

6

7

8

O

OMe

OTBS

HOO

HO

Br

5e

100 MHz, CDCl3

400 MHz, CDCl3

2.25

2.25

159

5.855.85

9.029.02

0.9370.937

0.9480.948

2.972.97

11

11

11

11

22

11

22

2.912.91

3.933.93

-1-100112233445566778899ppm

O

OMe

OTBS

HOO

HO

6e

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMe

OTBS

HOO

HO

6e

100 MHz, CDCl3

400 MHz, CDCl3

2.26

2.26

160

-1 -100112233445566778899ppmppm

-1

0

1

2

3

4

5

6

7

8

9

O

OMe

OTBS

HOO

HO

6e

5.955.95

99

0.9890.989

0.9310.931

33

3.013.01

11

11

11

22

11

22

4.74.7

-1-100112233445566778899ppm

O

OMe

OTBS

HOBOMO

HO

7e

400 MHz, CDCl3

400 MHz, CDCl3

2.26

2.27

161

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMe

OTBS

HOBOMO

HO

7e

-1 -1001122334455667788ppmppm

-1

0

1

2

3

4

5

6

7

8

O

OMe

OTBS

HOBOMO

HO

7e

100 MHz, CDCl3

400 MHz, CDCl3

2.27

2.27

162

5.795.79

9.179.17

1.951.95

22

33

22

11

11

11

22

4.584.58

-1-100112233445566778899ppm

OOMe

OTBS

HOBnO

HO

4f

0 02020404060608080100100120120140140160160180180200200ppmppm

OOMe

OTBS

HOBnO

HO

4f

100 MHz, CDCl3

400 MHz, CDCl3

2.28

2.28

163

5.795.79

9.019.01

1.921.92

22

33

22

11

11

11

22

22

1.831.83

-1-100112233445566778899ppm

OOMe

OTBS

HOO

HO

Br

5f

0 02020404060608080100100120120140140160160180180200200ppmppm

OOMe

OTBS

HOO

HO

Br

5f

100 MHz, CDCl3

400 MHz, CDCl3

2.29

2.29

164

0 01122334455667788ppmppm

-1

0

1

2

3

4

5

6

7

8

OOMe

OTBS

HOO

HO

Br

5f

5.835.83

99

0.9680.968

0.9330.933

11

11

2.992.99

22

11

11

11

22

2.882.88

3.883.88

-1-100112233445566778899ppm

OOMe

OTBS

HOO

HO

6f

400 MHz, CDCl3

400 MHz, CDCl3

2.29

2.30

165

0 02020404060608080100100120120140140160160180180200200ppmppm

OOMe

OTBS

HOO

HO

6f

-1 -1001122334455667788ppmppm

-1

0

1

2

3

4

5

6

7

8

OOMe

OTBS

HOO

HO

6f

100 MHz, CDCl3

400 MHz, CDCl3

2.30

2.30

166

5.995.99

9.289.28

0.9420.942

0.9930.993

11

4.014.01

11

11

11

11

11

22

22

4.684.68

-1-100112233445566778899ppm

OOMe

OTBS

HOBOMO

HO

7f

0 02020404060608080100100120120140140160160180180200200ppmppm

OOMe

OTBS

HOBOMO

HO

7f

100 MHz, CDCl3

400 MHz, CDCl3

2.31

2.31

167

0 011223344556677ppmppm

0

1

2

3

4

5

6

7

OOMe

OTBS

HOBOMO

HO

7f

0.9960.996

0.9560.956

11

22

11

11

11

11

11

0.9620.962

4.714.71

-1-100112233445566778899ppm

OOOH

BnO

OH4g

400 MHz, CDCl3

400 MHz, CDCl3

2.31

2.32

168

0 02020404060608080100100120120140140160160180180200200ppmppm

OOOH

BnO

OH4g

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

OOOH

BnO

OH4g

100 MHz, CDCl3

400 MHz, CDCl3

2.32

2.32

169

11

0.930.93

1.111.11

2.022.02

1.021.02

11

11

11

11

11

2.062.06

2.012.01

-1-100112233445566778899ppm

OOOH

O

OH

Br

5g

0 02020404060608080100100120120140140160160180180200200ppmppm

OOOH

O

OH

Br

5g

400 MHz, CDCl3

100 MHz, CDCl3

2.33

2.33

170

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

OOOH

O

OH

Br

5g

0.9610.961

0.9210.921

1.031.03

2.012.01

11

11

1.011.01

1.011.01

11

0.9290.929

3.013.01

4.014.01

-1-100112233445566778899ppm

OOOH

O

OH6g

400 MHz, CDCl3

400 MHz, CDCl3

2.33

2.34

171

0 02020404060608080100100120120140140160160180180200200ppmppm

OOOH

O

OH6g

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

OOOH

O

OH6g

400 MHz, CDCl3

100 MHz, CDCl3

2.34

2.34

172

0.9880.988

0.8940.894

1.061.06

1.011.01

22

1.021.02

11

22

2.022.02

0.9230.923

-1-100112233445566778899ppm

OOOH

BOMO

OH7g

0 02020404060608080100100120120140140160160180180200200ppmppm

OOOH

BOMO

OH7g

400 MHz, CDCl3

100 MHz, CDCl3

2.35

2.35

173

1 1223344556677ppmppm

1

2

3

4

5

6

7

OOOH

BOMO

OH7g

3.093.09

0.9610.961

0.9750.975

33

11

11

11

11

22

11

4.64.6

-1-100112233445566778899ppm

O

OMeMe

HOOBnOH

4h

400 MHz, CDCl3

400 MHz, CDCl3

2.35

2.36

174

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMeMe

HOOBnOH

4h

0 01122334455667788ppmppm

0

1

2

3

4

5

6

7

8

O

OMeMe

HOOBnOH

4h

400 MHz, CDCl3

100 MHz, CDCl3

2.36

2.36

175

33

0.9660.966

0.9920.992

33

1.011.01

11

11

11

22

11

1.961.96

1.871.87

-1-100112233445566778899ppm

O

OMeMe

HOOOH

Br5h

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMeMe

HOOOH

Br5h

400 MHz, CDCl3

100 MHz, CDCl3

2.37

2.37

2.37

176

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

O

OMeMe

HOOOH

Br5h

33

11

0.9920.992

33

1.011.01

1.991.99

1.021.02

11

22

3.013.01

4.024.02

-1-100112233445566778899ppm

O

OMeMe

HOOOH

6h

400 MHz, CDCl3

400 MHz, CDCl3

2.37

2.38

177

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMeMe

HOOOH

6h

0 0112233445566778899ppmppm

0

1

2

3

4

5

6

7

8

9

O

OMeMe

HOOOH

6h

400 MHz, CDCl3

100 MHz, CDCl3

2.38

2.38

178

33

0.9520.952

0.9760.976

33

22

22

2.012.01

11

11

11

4.954.95

-1-100112233445566778899ppm

O

OMeMe

HOOBOMOH

7h

0 02020404060608080100100120120140140160160180180200200ppmppm

O

OMeMe

HOOBOMOH

7h

400 MHz, CDCl3

100 MHz, CDCl3

2.39

2.39

179

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

O

OMeMe

HOOBOMOH

7h

0.9620.962

0.990.99

33

33

22

33

4.654.65

-1-100112233445566778899ppm

4i

O

OMeHOBnO

HO 400 MHz, CDCl3

400 MHz, CDCl3

2.39

2.40

180

0 02020404060608080100100120120140140160160180180200200ppmppm

4i

O

OMeHOBnO

HO

1 122334455667788ppmppm

1

2

3

4

5

6

7

84i

O

OMeHOBnO

HO

400 MHz, CDCl3

100 MHz, CDCl3

2.40

2.40

181

0.9750.975

0.9720.972

33

11

22

22

22

11

22

1.891.89

-1-100112233445566778899ppm

5i

O

OMeHOO

HO

Br

0 02020404060608080100100120120140140160160180180200200ppmppm

5i

O

OMeHOO

HO

Br

400 MHz, CDCl3

100 MHz, CDCl3

2.41

2.41

182

1 122334455667788ppmppm

1

2

3

4

5

6

7

85i

O

OMeHOO

HO

Br

0.9950.995

11

33

3.093.09

2.012.01

11

22

2.972.97

44

-1-100112233445566778899ppm

6i

O

OMeHOO

HO 400 MHz, CDCl3

400 MHz, CDCl3

2.41

2.42

183

0 02020404060608080100100120120140140160160180180200200ppmppm

6i

O

OMeHOO

HO

1 122334455667788ppmppm

1

2

3

4

5

6

7

86i

O

OMeHOO

HO

400 MHz, CDCl3

100 MHz, CDCl3

2.42

2.42

184

1.911.91

33

2.032.03

1.011.01

1.011.01

11

2.012.01

11

2.022.02

4.644.64

-1-100112233445566778899ppm

7i

O

OMeHOBOMO

HO

0 02020404060608080100100120120140140160160180180200200ppmppm

7i

O

OMeHOBOMO

HO

400 MHz, CDCl3

100 MHz, CDCl3

2.43

2.43

185

1 122334455667788ppmppm

1

2

3

4

5

6

7

87i

O

OMeHOBOMO

HO

0.8790.879

22

11

11

11

4.084.08

0.9960.996

0.9430.943

3.983.98

3.743.74

-1-100112233445566778899ppm

OOHO

O

Br

Br

5j

400 MHz, CDCl3

400 MHz, CDCl3

2.43

2.44

186

0 02020404060608080100100120120140140160160180180200200ppmppm

OOHO

O

Br

Br

5j

1 122334455667788ppmppm

1

2

3

4

5

6

7

8

OOHO

O

Br

Br

5j

400 MHz, CDCl3

100 MHz, CDCl3

2.44

2.44

187

5.875.87

9.399.39

0.9570.957

0.960.96

33

22

3.063.06

11

2.012.01

0.9510.951

0.9070.907

0.9230.923

0.8260.826

-1-100112233445566778899ppm

O

OTBS

HOAllylO

OH

OMe2.45

6.146.14

10.610.6

1.011.01

11

1.031.03

1.11.1

3.063.06

1.151.15

1.11.1

1.091.09

1.061.06

1.091.09

1.071.07

1.041.04

0.9650.965

11

0.9190.919

-1-100112233445566778899ppm

O

OTBS

AllylO

OMe

OH

HO2.46

400 MHz, CDCl3

400 MHz, CDCl3

188

3.663.66

1.081.08

1.041.04

3.263.26

1.171.17

1.131.13

2.222.22

22

1.081.08

1.051.05

1.071.07

11

-1

-100112233445566778899ppm

O

OMeMe

OHOAllyl

OH

2.47

5.615.61

99

0.890.89

0.8940.894

2.92.9

0.9950.995

0.9920.992

3.433.43

3.033.03

0.9770.977

1.951.95

0.9360.936

2.242.24

2.032.03

-1-100112233445566778899ppm

O

OTBS

HOPMBO

OH

OMe2.48

400 MHz, CDCl3

400 MHz, CDCl3

189

0.9910.991

11

1.071.07

2.252.25

4.194.19

1.141.14

1.071.07

1.181.18

1.161.16

0.9880.988

2.142.14

2.442.44

-1-100112233445566778899ppm

O

OOH

OH

OPMB

2.49

5.585.58

10.110.1

0.8760.876

0.8770.877

2.362.36

4.014.01

3.643.64

1.191.19

1.141.14

11

0.980.98

1.21.2

11

2.392.39

2.292.29

-1-100112233445566778899ppm

O

OTBS

PMBO OMe

OH

OH2.50

400 MHz, CDCl3

400 MHz, CDCl3

190

0.8530.853

0.8560.856

1.071.07

4.94.9

1.011.01

0.9790.979

0.9910.991

0.9990.999

11

0.8950.895

1.891.89

22

-1-100112233445566778899ppm

O

O

PMBOOH

OH2.51

3.133.13

0.9330.933

0.9180.918

3.013.01

1.041.04

4.924.92

1.11.1

1.11.1

22

0.9550.955

2.32.3

2.42.4

-1-100112233445566778899ppm-16.017

1.317

1.333

3.433

3.824

3.832

4.672

O

OMeMe

OHOPMB

OH

2.52

400 MHz, CDCl3

191

0.9510.951

0.9620.962

3.173.17

1.081.08

2.032.03

3.233.23

2.132.13

1.081.08

1.131.13

1.011.01

2.012.01

22

-1-100112233445566778899ppm

OPMBO OMe

OH

OH2.53

6.236.23

9.39.3

6.056.05

1.521.52

0.9620.962

2.032.03

1.461.46

2.082.08

1.091.09

11

11

2.132.13

13.413.4

-1-100112233445566778899ppm

OOTBSHO

BnOHO

SiPr

2.55

400 MHz, CDCl3

400 MHz, CDCl3

192

3.343.34

0.9440.944

3.13.1

11

1.041.04

0.9590.959

0.8940.894

0.9670.967

-1-100112233445566778899ppm

O

OMeMe

HOO O

O3.16

3.353.35

3.243.24

1.041.04

1.041.04

1.041.04

0.9870.987

0.9560.956

2.362.36

1.141.14

1.951.95

-1-100112233445566778899ppm

O

OMeMe

BzOO O

O3.17

400 MHz, CDCl3

400 MHz, CDCl3

193

3.523.52

1.121.12

2.272.27

1.021.02

0.9920.992

2.412.41

1.151.15

2.192.19

-1-100112233445566778899ppm

O

BrMe

BzOO O

O3.18

6.166.16

9.579.57

4.014.01

1.081.08

3.633.63

2.122.12

11

-1-100112233445566778899ppm

3.19

O

OTBS

HO OO

OMe

O

400 MHz, CDCl3

400 MHz, CDCl3

194

33

3.083.08

13.213.2

1.011.01

0.960.96

0.9820.982

1.961.96

0.8420.842

1.691.69

0.7850.785

0.7850.785

0.8090.809

0.7540.754

00112233445566778899ppmppm

O

OMeMe

HOO

OBN

400 MHz, CDCl3

Documents

Regioselective Functionalization of Polyols via Organoboron