Glycosyl Methanesulfonates in Regio- and Stereoselective Glycosylations Catalyzed by Borinic Acids

by

Kyan Anthony D’Angelo

A thesis submitted in conformity with the requirements for the degree of Master of Science

Department of Chemistry University of Toronto

© Copyright by Kyan A. D’Angelo 2015

ii

Glycosyl Methanesulfonates in Regio- and Stereoselective

Glycosylations Catalyzed by Borinic Acids

Kyan A. D’Angelo

Master of Science

Department of Chemistry

University of Toronto

2015

Abstract

Stoichiometric and catalytic activation of unprotected glycosyl acceptors toward reaction with

glycosyl donors represent a growing breadth of methodologies recently developed with the goal

of simplifying the synthesis of important carbohydrate targets. Most of these methods rely on

glycosyl halides, a class of donor which has been essentially deprecated in recent literature by

the advent of more convenient and versatile species. This report describes the development and

use of glycosyl methanesulfonates in borinic acid-catalyzed glycosylations of partially protected

acceptors. Good to high yields and selectivities for 1,2-trans-linked disaccharides are obtained

without the need for a participating group. Studies of glycosylations with variously protected and

configured donors and acceptors suggest wide applicability of the method to the preparation of

important classes of linkages and protecting group patterns. Finally, mechanistic insights from

NMR observation of the intermediate methanesulfonates are reported and discussed to develop a

rationale for the observed catalyst-controlled stereoselectivity.

iii

Acknowledgments

The support and guidance from my supervisor (Mark S. Taylor), the Taylor group, friends and

family are all sincerely appreciated and have made this work possible.

iv

Table of Contents

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

Acknowledgments ........................................................................................................................ iii

Table of Contents ......................................................................................................................... iv

List of Abbreviations ................................................................................................................... vi

List of Tables ................................................................................................................................ xi

List of Schemes ............................................................................................................................ xii

List of Figures ............................................................................................................................. xiii

List of Appendices ...................................................................................................................... xiv

1 Introduction .............................................................................................................................. 1

1.1 Chemical Glycosylation and the Globo-H Antigen ............................................................ 1

1.2 Glycosylation of Unprotected Glycosyl Acceptors via Orthoester Intermediates .............. 3

1.3 Glycosylation of Unprotected Glycosyl Acceptors by Selective Activation ...................... 4

1.4 Glycosyl Sulfonates in Glycosylation Reactions ................................................................ 9

1.5 Research Objectives .......................................................................................................... 12

2 Results and Discussion ........................................................................................................... 14

2.1 Reaction Development and Optimization ......................................................................... 14

2.2 Scope Studies .................................................................................................................... 18

2.2.1 Glycosylations of Pyranose Acceptors ................................................................. 18

2.2.2 Perbenzylated Donor Variants .............................................................................. 20

2.2.3 Glycosidations of 4,6-O-Benzylidene Protected Donors ...................................... 23

2.2.4 Glycosylation of Isopropylidene Glucofuranose .................................................. 25

2.3 Mechanistic Studies and the Origin of Stereoselectivity .................................................. 28

3 Summary and Future Work .................................................................................................. 36

4 Experimental .......................................................................................................................... 37

v

4.1 Materials and Methods ...................................................................................................... 37

4.1.1 General .................................................................................................................. 37

4.1.2 Materials ............................................................................................................... 37

4.1.3 Instrumentation ..................................................................................................... 37

4.2 General Experimental Procedures ..................................................................................... 38

4.2.1 General Procedure for Formation of Glycosyl Methanesulfonates ...................... 38

4.2.2 General Procedure for Glycosylations with Glycosyl Methanesulfonates ........... 38

4.3 Characterization Data ........................................................................................................ 39

4.3.1 Glycosyl Methanesulfonates ................................................................................. 39

4.3.2 Glycoside Products ............................................................................................... 45

4.4 Acceptor Synthesis ............................................................................................................ 62

References .................................................................................................................................... 63

Appendix A: 1H,

13C and 2D NMR Spectra .............................................................................. 69

Appendix B: DFT Calculations ................................................................................................ 140

vi

List of Abbreviations

Å Angstrom

Ac Acetyl

All Allyl

Aq. Aqueous

Ar Aryl

Ara Arabinose or Arabinosyl

[B] Boron-Containing Species, Identity of

B3LYP Becke, three-parameter, Lee-Yang-Parr (DFT)

Bn Benzyl

br. Broad

Bu n-Butyl

Bz Benzoyl

cat. Catalytic or catalyst

CIP Contact Ion Pair

∆ Heat or Heating

δ Chemical Shift (NMR)

d Doublet (NMR)

DABCO 1,4-Diazabicyclo[2.2.2]octane

DART Direct Analysis in Real Time

vii

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

DCE 1,2-Dichloroethane

DMF N,N ʹ-Dimethylformamide

DFT Density Functional Theory

DMST Dimethyl(methylthio)sulfonium Triflate

DTBMP 2,6-di-tert-butyl-4-methylpyridine

eq. Equivalent(s)

ESI Electrospray Ionization

Et Ethyl

f Furanose

f −k Condensed Fukui Function (for Electrophilic Attack)

Fuc Fucose or Fucosyl

g Gram(s)

Gal Galactose or Galactosyl

gCOSY Gradient-Selected Homonuclear Correlation Spectroscopy

Glc Glucose or Glucosyl

h Hour(s)

HMBC Heteronuclear Multiple Bond Correlation Spectroscopy

HPLC High-Performance Liquid Chromatography

HRMS High-Resolution Mass Spectrometry

viii

HSQC Heteronuclear Single Quantum Correlation Spectroscopy

Hz Hertz

iPr Isopropyl

J Coupling Constant (NMR)

kcal Kilocalorie

KHMDS Potassium hexamethyldisilazide

L Liter(s)

M Molar

μL Microliter

m Complex Multiplet (NMR)

m/z Mass-to-Charge Ratio (HRMS)

Man Mannose or Mannosyl

Me Methyl

mg Miligram(s)

MHz Megahertz

min Minute(s)

mL Milliliter(s)

mmol Millimole(s)

MS Molecular Sieves

Ms Methanesulfonyl

ix

MW Molecular Weight

NMR Nuclear Magnetic Resonance

OH Hydroxyl

o/n overnight

p Pyranose

Ph Phenyl

Piv Pivaloyl (Trimethylacetyl)

PMB para-Methoxybenzyl (4-Methyloxybenzyl)

PMP 1,2,2,6,6-Pentamethylpiperidine

ppm Parts per Million

iPr Isopropyl

Py Pyridine

q Quartet (NMR)

R Radical or Generic Residue

Rf Retardation Factor (TLC)

s Singlet (NMR)

s sym-

sat. Saturated

SSIP Solvent-Separated Ion Pair

t Triplet (NMR)

x

tr Retention Time (HPLC)

TBAB Tetrabutylammonium Bromide

TBAF Tetrabutylammonium Fluoride

TBAI Tetrabutylammonium Iodide

TBDPS tert-Butyldiphenylsilyl

TBS tert-Butyldimethylsilyl

Tf Trifluoromethanesulfonyl

THF Tetrahydrofuran

TIPS Triisopropylsilyl

TLC Thin-Layer Chromatography

TMS Trimethylsilyl

Tol para-Tolyl (4-Methylphenyl)

TOF Time of Flight

Ts para-Toluenesulfonyl (4-methylbezenesulfonyl)

TTBP 2,4,6-Tri-tert-butylpyrimidine

UDP Uridine diphosphate

X Halide or Pseudohalide

xi

List of Tables

Table 1: Initial Coupling of Glucosyl Hemiacetal 46 with Me 6-O-TBS-α-Manp (35) ............... 14

Table 2: Evaluation of Bases for Methanesulfonylation of Hemiacetal 46 .................................. 15

Table 3: Revised Model Coupling with Substitution of Base for iPr2NEt ................................... 15

Table 4: Evaluation of Reaction Solvents ..................................................................................... 16

Table 5: Evaluation of Reaction Temperature and Catalysts ........................................................ 17

Table 6: Evaluation of Ms2O Stoichiometry and Bases ................................................................ 18

Table 7: Evaluation of Catalyst Loading and Acceptor Stoichiometry ........................................ 19

Table 8: Scope of Couplings of Glucosyl Hemiacetal 46 with Various Pyranoside Acceptors ... 20

Table 9: Evaluation of Catalysts for Coupling of Glucosyl Hemiacetal 46 with 1,3-diol 59 ....... 21

Table 10: Scope of Couplings of Various Perbenzylated Hemiacetals with Acceptors 62 and 35

....................................................................................................................................................... 22

Table 11: Couplings of 4,6-O-Benzylidene Protected Hemicetals with Acceptor 35 .................. 23

Table 12: Effect of Catalyst on Glycosylation of 35 with 4,6-O-Benzylidene Galacto Donor 71 24

Table 13: DFT Calculated Parameters for 1,2-Diphenyl Borinates Derived from 73 .................. 26

Table 14: Anomeric Ratios of Glycosyl Methanesulfonates Determined by 1H

NMR ................ 30

xii

List of Schemes

Scheme 1: Synthesis of the Globo-H antigen. ................................................................................ 2

Scheme 2: Glycosylation of Unprotected Glycosyl Acceptors via Orthoester Rearrangement ..... 4

Scheme 3: Regioselective Glycosylation of Me β-D-Galp via its Stannylene Acetal .................... 5

Scheme 4: O-3-Selective Glycosylation of Methyl β-D-Galp Catalyzed by an Organotin Halide 6

Scheme 5: Boron-Based Glycosylation of Unprotected Acceptors via Tetracoordinate Adducts . 7

Scheme 6: Stereoselective Borinic Acid-Catalyzed Glycosylations without Participating Groups 8

Scheme 7: Early Studies of Glycosyl Sulfonate Derivatives in Glycosylations ............................. 9

Scheme 8: Crich 4,6-O-Benzylidene Directed β-Mannosylation ................................................. 11

Scheme 9: Reagent-Controlled Synthesis of β 2-Deoxy Glycosides ............................................ 12

Scheme 10: Coupling of Araf Acceptor 74 with Glcf Acceptor 73 .............................................. 25

Scheme 11: Reactive Intermediates Potentially Involved in Glycoside Formation ..................... 29

Scheme 12: Woerpel’s Model for Stereoselectivity in Reactions of Gluco Oxocarbenium Ions . 34

Scheme 13: Preparation of Isopropyl 2,3-di-O-benzyl β-D-thiogalactopyranoside ..................... 62

xiii

List of Figures

Figure 1: DFT Calculated Structures of the 1,2-Diphenyl Borinates 77 and 78 Derived from 73

....................................................................................................................................................... 27

Figure 2: Variable Temperature 1H NMR Spectra of 2-Deoxy Methanesulfonate 83 ................. 43

xiv

List of Appendices

Appendix A: 1H,

13C and 2D NMR Spectra ................................................................................. 69

Appendix B: DFT Calculations .................................................................................................. 140

1

1 Introduction

1.1 Chemical Glycosylation and the Globo-H Antigen

Carbohydrates represent a broad class of biological macromolecules that serve varied and diverse

roles in biological systems. In the new millennium, the field of glycobiology has expanded

significantly to discover previously unknown roles of carbohydrates in a number of disease

processes. The promise of carbohydrate-based therapeutics has also drawn considerable attention

to the field, with numerous candidates in various stages of clinical trials for the treatment of

diabetes, cancer, and inflammatory diseases.

A major target in the realm of glycoscience is the synthesis development of carbohydrate-based

vaccines against various forms of cancer.1–3

By exploiting the unique glycosylation patterns

present on cancer cells, these vaccines could selectively trigger immune responses against

unhealthy tissue. Danishefsky and Wong have devoted much study to the development of a

vaccine targeting Globo-H, a carbohydrate residue often found on the surface of breast cancer

cells. The recent account of their efforts illustrates one of the major challenges in glycoscience:

the development of robust synthetic routes to access meaningful quantities of complex

carbohydrates for biological study and therapeutic applications.4

Glycosylation reactions, which join carbohydrate fragments through the formation of glycosidic

linkages between them, are the cornerstone of oligosaccharide synthesis. In a glycosylation

reaction, a glycosyl acceptor, the nucleophilic component, reacts with a glycosyl donor, the

electrophilic component, forming the desired linkage. Control of regioselectivity, specifically

which hydroxyl group of the acceptor is functionalized, has traditionally been obtained by the

judicious application of protecting group chemistry to mask undesired sites of reactivity. This

strategy is featured in an early synthesis of the ABC trisaccharide of the Globo-H antigen (1) by

Danishefsky and coworkers. (Scheme 1) Orthogonally protected glycal 2, when coupled to

masked glycal 3 via the intermediacy of its α-epoxide derivative, yields disaccharide 4 with a

free 2-OH group.5,6

Protecting group manipulations, amounting to four steps, are then used to

mask the 2-OH group in 4 and reveal the 4-OH in 5 for subsequent glycosylation with β-

configured donor 6.The glycosylation completes the synthesis of the ABC domain.

2

Scheme 1: Synthesis of the Globo-H antigen.

A) The Globo-H antigen. B) Chemical synthesis of the ABC Trisaccharide. C) Comparison of

the molecular weights of protected and unprotected ABC trisaccharide. D) Chemoenzymatic

synthesis of the ABC trisaccharide.

3

The extensive reliance on protecting group chemistry exemplified in the synthesis of 7 places

severe limits on the overall efficiency of the process in the synthesis of Globo-H. Indeed, the

majority of the mass of trisaccharide intermediate 7 can be attributed to the protecting groups.

(Scheme 1C) Furthermore, protecting group manipulations account for the majority of the steps

used in its synthesis. Though improvements to the route were made to allow for preparation of

suitable quantities of the derivative for phase I clinical trials,7–9

an enzyme-based strategy was

eventually selected and developed to produce large scale quantities of Globo-H for phase III

trials.10

(Scheme 1D) Enzymatic preparation of the ABC domain was achieved through

glycosylation of readily available allyl lactose 9 with UDP-galactose, catalyzed by α-1,4

galactosyltransferase, allowing for the preparation of 11 in a single step. By avoiding tedious

protecting group manipulations and exploiting the power of site-selective functionalization of

inexpensive carbohydrate feedstocks, glycosyl transferases have significantly streamlined the

preparation of this and other complex carbohydrates. Enzymatic glycosylations, however, are

severely limited by the low availability of UDP donors and are far less versatile than chemical

methods in the laboratory synthesis of carbohydrates, often requiring optimization of reaction

conditions and enzyme manipulation to produce useful quantities of glycosides.11–13

Comparably

powerful chemical methods are therefore highly attractive targets for the synthetic community.

1.2 Glycosylation of Unprotected Glycosyl Acceptors via Orthoester Intermediates

Strategies for the site-selective functionalization of unprotected glycosyl acceptors have been

developed over the past several decades with the primary goal of reducing reliance on protecting

group manipulations in the chemical synthesis of complex oligosaccharides.14

Glycosylations via

orthoester intermediates initially reported by Ogawa and later by Kong, represent a useful

example of such a strategy.15–17

In the seminal report (Scheme 2A), methyl α-mannose acceptor

12 was partially stannylated, (see section 1.3) then treated with participating donor 13 in the

absence of a promoter, yielding bis-orthoester 14 in low yield. Subsequent benzylation and

rearrangement under the influence of mercuric bromide yielded mannose trisaccharide 16. Two

decades later, Kong discovered that prior activation of the acceptor with tin was unnecessary,

and treatment of unprotected or partially unprotected acceptors with halide or imidate donors

bearing participating groups yielded orthoesters selectively with an initial preference for O-6,

then for O-3 of the acceptor. (Scheme 2B) Isomerization with trimethylsilyl triflate affords the

4

desired glycoside, generally with β configuration. A number of complex oligosaccharides have

been expeditiously synthesized employing these and related methodologies.18–20

Implementations

of the orthoester method have not been limited to those intermediates derived from halide

donors, and have been extended to imidate donors by Kong, and pentenyl orthoesters by Fraser-

Reid with good success.21–23

Scheme 2: Glycosylation of Unprotected Glycosyl Acceptors via Orthoester Rearrangement

A) Ogawa’s Synthesis of a mannose trisaccharide by orthoester rearrangement. B) Kong’s

variant of the Ogawa methodology.

1.3 Glycosylation of Unprotected Glycosyl Acceptors by Selective Activation

Another means of carrying out regioselective glycosylations of unprotected or partially protected

acceptors has been through the activation of glycosyl acceptors in a selective fashion.24

Tin-

based approaches represent the bulk of these methods developed to date.25,26

The electropositive

5

nature of tin increases electron density on the bound oxygen atoms, activating them relative to

unbound hydroxyl groups. Depending on the degree of alkyl substitution on the tin center, tin

compounds are capable of reversibly binding in a one-point or two-point fashion to polyols as

stannyl ethers or stannylene acetals respectively.27

Their structures are complex; variable degrees

of oligomerization are common and reactivity is greatly influenced by the presence of

neighboring Lewis basic functionality and exogenous Lewis bases.28–30

Through selective

activation of the bound hydroxyl group(s), regioselective glycosylation may be observed upon

treatment with a suitable donor.

Scheme 3: Regioselective Glycosylation of Me β-D-Galp via its Stannylene Acetal

A) Glycosylation with β-halide and β-thioglycoside donors to give α(1→6) and β(1→6)

products. B) Lewis Base-controlled regioselective glycosylation with α-halide 23.

6

Glycosylations of stoichiometrically prepared stannylene acetals have been reported employing a

variety of donors. The stannylene acetal of methyl β-galactopyranoside can be readily

glycosylated at O-6 to give both α- and β-linked (1→6) disaccharides by combination with a

reactive perbenzylated glycosyl bromide in the presence of iodide or with a thioglycoside donor

in presence of the thiophilic promoter DMST respectively.31

(Scheme 3A) Glycosylation with α-

halide donors that are activated with a heterogenous silver promoter similarly afford β-linked

(1→6) disaccharides.32

(Scheme 3B) Attempts to modify the regioselectivity through blocking of

the 6-OH were unsuccessful; however it was later discovered that through addition of a fluoride

Lewis Base, the β-linked (1→3) product 25 could be selectively prepared in modest yield.29

The

observed regioselectivity was rationalized taking into account the selective complexation of tin

to the cis 1,2-diol over the trans 1,2-diol, a well-established empirical rule.

Recently, a catalytic tin-based glycosylation methodology was reported employing an organotin

halide as the calayst.33

(Scheme 4) This method affords β-linked (1→3) products in high yield

and selectivity, in direct contrast to the regioselectivity of procedures involving stoichiometric

tin-activation. Notably, the authors acknowledged that the use of other classes of glycosyl donor

with this system, namely thioglycosides and glycosyl fluorides, were unsuccessful.

Scheme 4: O-3-Selective Glycosylation of Methyl β-D-Galp Catalyzed by an Organotin Halide

Bipyridyl = 5,5′-dimethyl-2,2′-bipyridyl.

Although tin-based glycosylation and protection methodologies are now well-established in the

literature, the inherent toxicity of organotin compounds and their challenging removal during

post-reaction purification severely impairs their potential for large-scale application. Boron-

based methodologies thus represent a highly attractive alternative to those based on tin, and have

since been studied extensively beginning with the seminal work of Aoyama and coworkers.

7

Scheme 5: Boron-Based Glycosylation of Unprotected Acceptors via Tetracoordinate Adducts

A) Regioselective glycosylation of Me β-Fucp (30) mediated by an internally-coordinated

boronic acid. B) Proposed mechanism; a tetracoordinated “-ate” complex is postulated to be the

active nucleophile. C) Regioselective glycosylation of Me β-Fucp catalyzed by a borinic acid

derivative. D) Proposed mechanism.

Through stoichiometric preactivation of an unprotected acceptor with internally coordinated

borinate 31, followed by Koenigs-Knorr glycosylation of the intermediate with a glycosyl halide,

β(1→3) and doubly glycosylated β(1→3) and β(1→6) products could be isolated in high yield

and selectivity34,35

. (Scheme 5A) The intermediate derived from preactivation is presumed to be

8

a nucleophilic tetracoordinate “-ate” complex resulting from deprotonation and subsequent

complexation to the 1,2-cis diol of 30. (Scheme 5B) Tetracoordinate adducts of boron

compounds with carbohydrates, exploited previously in the fields of molecular recognition and

chemosensing, possess intrinsically higher nucleophilicity than their uncomplexed polyols or

their analogous tricoordinate adducts.36–38

Recently, this laboratory has developed a suite of

catalytic methods for the functionalization of polyols based on the reversible interaction of

borinic acids with diols and polyols, including Koenigs-Knorr glycosylations of carbohydrate-

derived acceptors.39,40

(Scheme 5C) In a similar sense to the work of Aoyama, a putative

tetracoordinate adduct is formed from initial release of ethanolamine from commerically

available borinate precatalyst 33, with subsequent binding of the released diphenyl borinic acid

to the acceptor. (Scheme 5D) The resulting tetracoordinate adduct is activated towards reaction

with a glycosyl halide and, in the presence of a heterogenous silver promoter, forms a β-

configured glycosidic linkage. It is proposed that the β-stereoselectivity arises from an SN2-like

transition state that is favored over competing dissociative pathways due to the increased

nucleophilicity of the activated acceptor. On this basis, β(1→3) and β(1→6)-linked products

have been prepared stereoselectively from donors lacking participating groups, such as

perbenzylated and 2-deoxy glycosyl halides.41

(Scheme 6)

Scheme 6: Stereoselective Borinic Acid-Catalyzed Glycosylations without Participating Groups

A) Glycosylation of Me 6-O-TBS-α-Manp with a perbenzylated donor gives the β(1→3) product

stereoselectively. B) Glycosylation of an analogous acceptor with a 2-deoxy glycosyl halide

proceeds with good β stereoselectivity in the absence of a participating group.

9

1.4 Glycosyl Sulfonates in Glycosylation Reactions

Glycosyl-1-O-sulfonyl derivatives have been under-explored by the carbohydrate community as

a class of glycosyl donor.42

Though glycosyl sulfonates were reported relatively early in the

burgeoning field of chemical glycosylation, they would not be evaluated as glycosyl donors for

several decades following their initial report as the product of the reaction of between

acetobromoglucose and silver para-tolunesulfonate and methanesulfonate in 1929 and 1938

respectively.43,44

In the 1970’s, Schuerch reported the preparation of glycosyl triflates, and later,

glycosyl toluensulfonates, from perbenzylated glycosyl bromides and chlorides.45,46

(Scheme

7A) Low temperatures (−78 °C) and inert atmosphere techniques were necessary when preparing

the triflates, but the corresponding toluenesulfonates exhibited greater stability and could be

prepared at ambient temperatures. An 1H NMR spectrum of the intermediate glycosyl

toluensulfonate derived from perbenzyl glucose donor 41 in CDCl3 confirmed the presumed α-

stereochemistry of the donor on the basis of its anomeric resonance, δ = 6.1 ppm, 3J1,2 = 3.5 Hz.

Treatment with methanol afforded the β-glycoside as the major product with variable selectivity.

Scheme 7: Early Studies of Glycosyl Sulfonate Derivatives in Glycosylations

A) Metathesis of perbenzylated glycosyl chlorides or halides with a silver sulfonate gives a

highly reactive glycosyl sulfonate. B) Application of glycosyl sulfonates in the preparation of β-

manno- and rhamnosides. C) Glycosyl sulfonates can be prepared by direct sulfonation of

hemiacetals with methanesulfonic anhydride.

10

Glycosyl toluenesulfonates and triflates of peracylated donors were also studied, though in

agreement with later work, they gave anomeric mixtures of glycosides and their corresponding

orthoesters on treatment with glycosyl acceptors. Further work on the role of the O-6 substituent

was carried out, as well as studies of the galacto-configured toluensulfonates and triflates.47,48

Applying glycosyl sulfonates to the preparation of a challenging class of glycosidic linkage,

Schuerch in later years reported that 1,2-di-O-sulfonyl donors derived from mannose and

rhamnose underwent highly stereoselective couplings to acceptors, giving β 1,2-cis configured

products.49,50

(Scheme 7B). The synthetic utility of the methodology, however, was diminished

on account of the challenges associated with deprotection of the 2-O-methanesulfonyl

protecting/directing group, as well as with the sensitivity of the intermediate sulfonates.

Shortly after the reports of Schuerch in the early and mid-1970s, Arthur Perlin reported a new

preparation of glycosyl sulfonates from glycosyl hemiacetals rather than glycosyl halides.51,52

By

employing the anhydrides of various sulfonic acids, it was presumed that glycosyl sulfonates

could be accessed directly from glycosyl hemiacetals, in contrast to Schuerch’s silver metathesis

of glycosyl halides. However, upon combination of trifluoromethanesulfonic anhydride, tetra-O-

beznyl glucosyl hemiacetal 46, and s-collidine, a highly unstable intermediate was produced that

gave a poor yield of alkyl glycoside upon addition of methanol. With the addition of TBAB, the

same procedure afforded a 95 % yield of 42, presumably by trapping of the intermediate fleeting

triflate with exogenous bromide. The use of methanesulfonic anhydride (Ms2O), again in

combination with TBAB and s-collidine, similarly gave a 61 yield % of 42, α:β 2.3:1.

Interestingly though, and in direct contrast to trifluoromethanesulfonates, without the addition of

TBAB, the same procedure gave an 87 % yield of 42, α:β 1.5:1. (Scheme 7C) Based on these

observations, it was concluded that the glycosyl methanesulfonate of 46 was more stable than its

triflate, as it did not require exogenous trapping like the latter, and furthermore, it was highly

reactive as a glycosyl donor on its own. The analogous reactions of the hemiacetal with methane-

and para-toluenesulfonyl chlorides gave the corresponding glycosyl chlorides, presumably

through initial sulfonylation, followed by return of chloride ion. The use of sulfonyl chlorides as

activators of glycosyl hemiacetals was subsequently exploited by Koto and Szeja to achieve α-

selective 1,2-cis glycosylations.53–55

With the exception of studies not focused on glycosylation,

these were the only reports of glycosyl sulfonates apart from triflates for decades. 56–58

11

Modern investigations of glycosyl sulfonates have been dominated by 4,6-O-benzylidene

directed β-mannosylation, first reported by Sun and Crich in the late 1990s.59,60

(Scheme 8) At

the time, Kahne had reported that glycosyl sulfoxides underwent activation with triflic anhydride

in the presence of DTBMP or TTBP as a triflic acid scavenger to give a highly reactive

intermediate, later identified as a glycosyl triflate.61–63

Sun discovered that a variation in the

order of reagent addition, adding the acceptor last rather than triflic anhydride, stereoselectively

afforded β-mannosides from benzylidene protected donors. 59

The mechanism of this reaction, as

well as its α-glucosylation variant, has been the subject of intense study by measurements of 1H

and 13

C kinetic isotope effects, intramolecular clock reactions, and variable-temperature NMR

studies of the glycosyl triflate intermediates.64–67

The currently accepted view is that both β-

mannosides and α-glucosides are derived from SN2-like inversions of interconverting α- and β-

triflate species respectively, with the α-triflate being favored in manno series due to the

antiperiplanar orientation of the diaxial dipoles of the C1-OTf and C2-OBn bonds.

Scheme 8: Crich 4,6-O-Benzylidene Directed β-Mannosylation

Recently, Bennett and co-workers reported an approach to the preparation of β 2-deoxy

glycosides employing glycosyl toluensulfonates as the donor species.68

(Scheme 9) Formation of

the toluenesulfonate donor was accomplished through deprotonation of the corresponding 2-

deoxy hemiacetal followed by trapping with toluenesulfonic anhydride. Subsequent addition of

the acceptor, as its potassium alkoxide, provides the β 2-deoxy glycosides in moderate yields but

high stereoselectivity. Analogous to previous work on borinic-acid-catalyzed synthesis of β 2-

deoxy glycosides, it was proposed in this report that enhancing the nucleophilicity of the

acceptor, specifically by deprotonation to its potassium alkoxide, favors an SN2 pathway leading

to the observed stereoselectivity. NMR study of the intermediate sulfonate confirmed that it

exists exclusively as its α anomer.

12

Scheme 9: Reagent-Controlled Synthesis of β 2-Deoxy Glycosides

1.5 Research Objectives

Recently this laboratory has demonstrated that boron-mediated glycosylations of unprotected

acceptors with glycosyl halides are an highly efficient strategy for the rapid synthesis of complex

carbohydrates with the syntheses of a pentasaccharide fragment of a Spergularia-derived saponin

and novel bioactive glycosides of the natural product digitoxin.69,70

Glycosyl halides as class of

glycosyl donor, however, posses a number of major shortcomings which we sought to address to

improve the versatility and synthetic utility of our regioselective glycosylations. These include

the necessity of a heavy-metal heterogenous promoter (e.g. Ag2O, Hg(CN)2, or HgBr2), a

discrete synthetic and isolation step to prepare the halides, and variable hydrolytic instability,

especially with deoxygenated donors and/or those bearing arming protecting groups such as

benzyl or silyl ethers. Moreover, the use of strongly acidic reagents (e.g. HBr, HCl, BCl3)

typically used for the preparation of glycosyl halides poses a direct challenge to the synthesis of

halide donors with acid-labile functionality, such as silyl ethers, isopropylidene and benzylidene

acetals, and most significantly, those donors bearing other glycosidic linkages. For these reasons,

glycosyl halides have been largely superseded in the literature by a variety of newer glycosyl

donors with enhanced stability, versatility, and activation conditions.

In surveying these newer classes of glycosyl donors, the majority (e.g. glycosyl (thio)imidates,

phosphates, phosphites, alkenyl- and thioglycosides) generally require activation with or in

conjunction with Brønsted or Lewis acids, which are incompatible with the basic conditions

necessary to reversibly complex borinic acids to diol motifs.71

Indeed, previous work in this

laboratory found that representative members of the thioglycoside, phosphate, and

trichloroacimidate donor classes failed to yield any appreciable amount of glycoside product in

borinic acid-catalyzed glycosylation. Notably, O'Doherty has recently utilized borinic acids in

13

combination with palladium π-allyl species as the donor to prepare α rhamnosyl glycosides in the

efficient syntheses of the mezzettiaside family of natural products.72

As candidate donors

however, the scope of potential linkages that might be accessible from these species did not

appear to be comparable to those which could be reliably accessed from halides. At the time,

Bennett’s report of reagent-controlled 2-deoxy glycoside synthesis by acceptor activation under

basic conditions was intriguing, (Scheme 9) and it was envisioned that glycosyl sulfonates might

act as donors in borinic-acid-catalyzed glycosylations. However, the complexity associated with

preparation of the glycosyl toluensulfonates, requiring cryogenic temperatures and a very strong

anionic base, was discouraging.

Perlin’s glycosyl methanesulfonate appeared more promising and a potentially more practical

choice of sulfonate to investigate, as this donor appeared to be rapidly and efficiently formed

from the simple combination of a glycosyl hemiacetal, commerically available methanesulfonic

anhydride, and an organic base at ambient temperature. (Scheme 7C) A number of potential

practical advantages of glycosyl methanesulfonates as donors over glycosyl halides were

recognized, including the widespread availability and higher stability of glycosyl hemiacetals

compared to halides, net dehydrative glycosylation without the need to isolate or purify a

reactive intermediate, and the absence of a heavy-metal promoter. Applying glycosyl sulfonates

to the formation of new glycosyl linkages that had not yet been accessible by borinic acid

catalysis, such as those from furanose and mannose donors bearing axial C-2 substituents, was

also of interest.

14

2 Results and Discussion

2.1 Reaction Development and Optimization

Investigations began with an initial coupling of glucosyl hemiacetal 46 with partially protected

mannose acceptor 35. Formation of the methanesulfonate was carried out under similar

conditions to those previously reported by addition of a solution of methanesulfonic anhydride to

a solution of the hemiacetal and collidine at room temperature.52

To the resulting solution was

then added a catalytic amount of the dimer of diphenyl borinic acid (52), followed by the

acceptor. A promising yield of glycoside was isolated, but anomeric selectivity was low and in

favour of the α-glycoside. (Table 1) A control experiment in the absence of added catalyst gave

similar results, suggesting that catalyst-controlled glycosylation was not taking place.

Table 1: Initial Coupling of Glucosyl Hemiacetal 46 with Me 6-O-TBS-α-Manp (35)

Entry [B] (mol %) Yielda α:β

b

1 52 (10) 52 % 2:1

2 - 57 % 2.5:1

a Isolated yield following column chromatography.

b Anomeric ratio of purified product as

determined by HPLC analysis.

We hypothesized that collidine might not be a competent base to facilitate the binding of the

borinic acid catalyst to the cis-diol of the acceptor. To test this, a solution of 52, cis-1,2-

cyclohexanediol, and s-collidine were combined in CD3CN. No evidence of a tetracoordinate

complex was observed by 1H and

11B NMR spectroscopy of the resulting solution, confirming

our prediction. The use of a stronger tertiary amine, iPr2NEt (Hünig’s base), with which

complexation had been previously observed in an analogous experiment,40

was then investigated.

Unsure whether an amine base would be conducive to formation of the methanesulfonate

however, hemiacetal 46 was sulfonated under identical conditions with the two different bases,

then trapped with methanol. (Table 2) In comparison to s-collidine, iPr2NEt gave a somewhat

diminished yield of methyl glycoside 46 with similarly weak anomeric selectivity.

15

Table 2: Evaluation of Bases for Methanesulfonylation of Hemiacetal 46

Entry Base Yielda α:β

b

1 s-collidine 77 % 2.0:1

2 iPr2NEt 66 % 1.8:1

a Isolated yield following column chromatography.

b Anomeric ratio of purified product as

determined by 1H NMR spectroscopy.

Confident that iPr2NEt was competent in the preparation of the donor, the previously attempted

coupling was revisited with the change of base. (Table 3) A promising reversal of anomeric

selectivity compared to the uncatalyzed reaction in favor of the 1,2-trans linked disaccharide was

observed. The moderate selectivity, however, suggested that the catalytic pathway was active,

but accompanied by a competing weakly α-selective background manifold.

Table 3: Revised Model Coupling with Substitution of Base for iPr2NEt

Entry [B] (mol %) Yielda α:β

b

1 52 (10) 57 % 1:5.0

2 - n/d 2.3:1

a Isolated yield following column chromatography.

b Anomeric ratio of purified product as

determined by HPLC analysis.

Further optimization of both the yield and stereoselectivity were warranted, and an HPLC assay

was developed to determine both the stereoselectivity and relative conversion of the hemiacetal

donor. Because the α,β(1→3) linked disaccharides and unreacted hemiacetal 46 account for a

large majority of the total peak area in the chromatogram, the relative proportion of 46 could be

used an estimate of the reaction yield. The remaining peaks were identified on the basis of their

UV spectra to be regioisomers and the added catalyst.

16

The first parameter that was investigated was the reaction solvent, an important factor in

stereoselective glycosylations with non-participating donors. (Table 4) Ethereal solvents had

minimal effect on the anomeric selectivity despite their established capacity to favor 1,2-cis

selective glycosylations.73

Acetonitrile, used extensively as a solvent and co-solvent in 1,2-trans

selective glycosylations with donors lacking a participating substituent,74

again had minimal

effect on stereoselectivity when compared to dichloromethane. The use of toluene improved

donor conversion at the expense of anomeric selectivity. Dichloromethane, appearing to have the

best balance of selectivity and conversion, remained the solvent of choice.

Table 4: Evaluation of Reaction Solvents

Entry Solvent Conv. 46a α:β

b

1 MeCN 43 % 1:3.9

2 PhMe 77 % 1:2.9

3 THF 47 % 1:4.3

4 Et2O 45 % 1:6.2

a Conversion of 46 calculated as 100 % - Area Percent(46) determined by HPLC analysis of the

crude reaction mixture. b

Determined by HPLC analysis of the crude reaction mixture.

Lowering reaction temperature can often assist in improving the selectivities of glycosylations

and other stereoselective reactions and was thus investigated by carrying out the glycosylation at

−78 °C with slowly warming to ambient temperature. (Table 5) Recent results in the laboratory

had shown that oxo-boraanthracene 53 could be used to improve regioselectivity in an

unselective glycosylation by permitting glycosylation at lower temperatures where the competing

background reaction was suppressed.69,75

Interested to see if the enhanced activity of 53 could be

used to further outcompete the background manifold through a similar approach, we included it,

as well as precatalyst 33, in this screen. No apparent enhancement in selectivity with decreased

temperature was evident with diphenyl borinic acid catalyst 53 (entry 1), suggesting that it likely

becomes active at or close to ambient temperature. Precatalyst 33 (entry 2) gave a diminished

yield of glycoside and reduced stereoselectivity related to its uncomplexed dimer. The drop in

17

conversion is similar to the catalyst loading, suggesting sacrificial monofunctionalization of the

ethanolamine ligand with the intermediate methanesulfonate to reveal the catalytically active

borinic acid. In line with the aforementioned results, boraanthracene 53 (entry 3) was indeed

superior to diphenyl borinic acid, providing an appreciable improvement in stereoselectivity. To

ascertain whether this improvement could be attributed to retardation of the background reaction,

the coupling was carried out at 23 °C. (entry 4) Stereoselectivity appeared to suffer slightly,

suggesting only a marginal lowering of the onset temperature of catalytic glycosylation.

Table 5: Evaluation of Reaction Temperature and Catalysts

Entry [B] (mol %) Conv. 46a α:β

b

1 52 (10 mol %) 64 % 1:5.0

2 33 (20 mol %) 43 % 1:1.3

3

53 (20 mol %)

64 % 1:8.6

4c 53 (20 mol %) 66 % 1:7.2

a Conversion of 46 calculated as 100 % - Area Percent(46) determined by HPLC analysis of the

crude reaction mixture. b

Determined by HPLC analysis of the crude reaction mixture. c Donor

preparation and glycosylation carried out at 23 °C

At this point, it appeared as though donor conversion was determined by the efficiency of the

donor preparation, as the presence or identity of the catalyst used had shown essentially no effect

on this parameter. It seemed logical to turn our attention to the evaluation of the reaction

stoichiometry and base in an effort to improve the efficiency of the reaction. A significant

improvement in conversion was realized when the amount of methanesulfonic anhydride

employed in the sulfonylation step was increased to 1.5 equivalents, but at the expense of some

stereoselectivity. (Table 6) A screen of bases at this constant amount of Ms2O identified the

sterically hindered tertiary amine pentamethylpiperidine (PMP) as providing both a moderate

improvement in conversion and stereoselectivity. Other less hindered bases gave lower

conversion and stereoselectivies.

18

Table 6: Evaluation of Ms2O Stoichiometry and Bases

Entry Base (eq.) eq. Ms2O Conv. 46a α:β

b

1 iPr2NEt (3.4) 1.2 66 % 1:7.2

2 iPr2NEt (3.4) 1.5 83 % 1:6.0

3 c iPr2NEt (3.4) 1.8 85 % 1:5.4

4 Et3N (3.5) 1.5 76 % 1:2.4

5 N-Methylmorpholine (3.5) 1.5 78 % 1:1.2

6 N,N'-Dimethylpiperazine (3.5) 1.5 56 % 1:1.4

7 PMP (3.5) 1.5 88 % 1:8.7

8 DBU (3.5) 1.5 30 % 1:1.7

9 DABCO (3.5) 1.5 < 5 % -

a Conversion of 46 calculated as 100 % - Area Percent(46) determined by HPLC analysis of the

crude reaction mixture. b

Determined by HPLC analysis of the crude reaction mixture.

In the final stages of optimization, the catalyst loading and stoichiometry of the coupling partners

were addressed. (Table 7) Reduction of the acceptor to 1.2 equivalents and catalyst loading to 10

mol % had minimal effect on conversion and stereoselectivity. Further reduction in catalyst

loading was not tolerated. Using the donor in slight excess as opposed to the acceptor, improved

the stereoselectivity to >1:10 with negligible effect on donor conversion. These conditions were

adopted as optimal and were employed for subsequent couplings. Donor concentration was also

evaluated during the course of the optimization studies, which identified a relatively dilute

concentration of 0.05 M as providing the greatest stereoselectivity.

2.2 Scope Studies

2.2.1 Glycosylations of Pyranose Acceptors

With glycosylation conditions in hand, a campaign to evaluate the scope of the reaction began.

These studies began with couplings of model glucosyl hemiacetal 46 to a number of pyranose

acceptors. (Table 8)

19

Table 7: Evaluation of Catalyst Loading and Acceptor Stoichiometry

Entry eq. 53 eq. 35 Conv. 46a α:β

b

1 0.10 1.2 85 % 1:8.4

2 0.05 1.2 85 % 1:5.6

3 0.08 0.8 83 % 1:11

a Conversion of 46 calculated as 100 % - Area Percent(46) determined by HPLC analysis of the

crude reaction mixture. b

Determined by HPLC analysis of the crude reaction mixture.

The model coupling of hemiacetal 46 with acceptor 35 proceeded with similar selectivity to that

determined by HPLC and gave a good yield of glycoside 37. A major shortcoming of the

previously developed borinic acid-catalyzed glycosylation with glycosyl halides was the

incompatibility of thioglycoside acceptors as coupling partners. Because the present method does

not employ silver oxide, galacto-, manno-, and gluco-configured thioglycoside acceptors were

comfortably tolerated. Turning to glycosylations of 2,3-protected acceptors, the coupling of 46 to

Me 2,3-di-O-Bn-α-Glcp (59) was initially investigated. Co-elution in the process of

chromatographic purification necessitated derivatization of the crude reaction mixture with acetic

anhydride in pyridine to give the isolable 4-O acetate derivative. The selectivity however,

estimated from the 1H NMR spectrum of the purified glycoside, was low and required

improvement to be made synthetically useful. A possible explanation for the low selectivity

might be the lower affinity of the 1,3-diol of acceptor 59 for oxo-boraanthracene catalyst 53

compared to 35. Tetracoordinate adducts derived from boraanthracene 53 are presumed to

exhibit higher nucleophilicity than those derived from diphenyl borinic acid, however, the

overall activity of the catalyst is balanced by reduced binding affinity as a result of disruption of

the 6π-aromatic system .75

The use of diphenyl borinic acid, as predicted from its greater affinity,

gave improved anomeric selectivity as determined by HPLC than catalyst 53 and the sulfur-

containing boraanthracene analogue 61. (Table 9) Diphenyl borinic catalyst 52 was thus used in

glycosylations of gluco- (57) and galacto-configured (58) thioglycoside acceptors. 57 was

isolated as a mixture in low yield due to purification challenges that will need to be addressed in

future work. Galacto-configured product 58, which was separated from its α-anomer during

20

purification, appeared to give a higher yield and stereoselectivity than the precursor glucose

acceptors of 56 and 57.

Table 8: Scope of Couplings of Glucosyl Hemiacetal 46 with Various Pyranoside Acceptors

Entry Product Yieldb α:β

c

37

81 % 1:10

54

83 % 1:16

55

89 % 1:8.6

56d

63 % 1:2.2

57e

42 % 1:4.7

58e

66 % -

a Reaction Conditions: 46 (1 eq.), PMP (3.2 eq.), Ms2O (1.5 eq.), 53 (0.08 eq.), glycosyl

acceptor (0.8 eq.) b Isolated yield following column chromatography.

c Anomeric ratio of

purified product as determined by 1H NMR spectroscopy.

d Isolated as the acetate following

derivatization with Ac2O/Py e 52 was used as catalyst.

2.2.2 Perbenzylated Donor Variants

Thiophenyl 6-O-TBS-α-Manp acceptor 62 was selected as model acceptor for further studies as

it displayed convenient chromatographic and spectroscopic properties relative to methyl acceptor

37. Couplings of this acceptor and 35 with various benzylated donors are shown in Table 10.

21

Table 9: Evaluation of Catalysts for Coupling of Glucosyl Hemiacetal 46 with 1,3-diol 59

Entry [B] α:βa

1 52 1:3.6

2 53 1:1.4

3 61 1:1.2

a Determined by HPLC analysis of the crude reaction mixture.

In combination with both acceptor 35 and 62, the corresponding galactosyl hemiacetal appeared

to give diminished stereoselectivity and yield relative to glucosyl hemiacetal 46. With

perbenzylated 2-azido-2-deoxy glucosyl hemiacetal, a surprisingly high stereoselectivity was

observed through analysis of the crude NMR of the reaction mixture, with the corresponding

glycoside isolated in good yield. β 2-Azido glycosides, previously inaccessible from their

peracylated chloride donor derivatives in borinic acid-catalyzed glycosylations, are highly

valuable as precursors to 2-N-acetyl glycosides found extensively throughout nature, and are

well-established targets for methodology development.76–79

Investigation of other classes of

linkages that would be of potential value in oligosaccharide synthesis identified

arabinofuranosides (Araf) as a synthetic target.80

α-1,2-trans selective glycosylations with

arabinofuranose donors are virtually always achieved through neighboring group participation

with a 2-O-acyl stereodirecting group. There is only one relevant report of a directing group-free

variant,81

despite a report demonstrating the potential synthetic value of perbenzylated Araf

analogues in terms of enhanced reactivity and reduced reliance on orthogonal protecting

groups.82

Coupling of commercially available 2,3,5-tri-O-beznyl-β-D-Araf with acceptor 62,

afforded a good yield of an α:β mixture enriched in the 1,2-trans glycoside. Because

decomposition was observed when the donor was prepared at ambient temperature, the

glycosylation was initially carried out at −20 °C overnight, and was then allowed to slowly warm

to ambient temperature. While previous glycosylations with halide donors were limited to β-1,2-

trans linkages, methanesulfonates facilitated the selective formation of an α-1,2-trans linkage in

this example, presumably because they can exist as and interconvert between α and β forms.

22

Table 10: Scope of Couplings of Various Perbenzylated Hemiacetals with Acceptors 62 and 35

Entry Product Yieldb

α:βc

(Control)d

63

76 % 1:5.3

64

71 % -

65

80 % >1:20e

66f

86 % 3.0:1

e

(1:2.6)

67f

59 % 1:2.3

e

(5.1:1)

a Reaction Conditions: Hemiacetal Donor (1 eq.), PMP (3.2 eq.), Ms2O (1.5 eq.), 53 (0.08 eq.),

62 (0.8 eq.) b Isolated yield following column chromatography.

c Anomeric ratio of purified

product as determined by 1H NMR spectroscopy.

d Anomeric ratio from

1H NMR of

the crude

reaction mixture when carried out in the absence of 53. e Anomeric ratio from

1H NMR of

the

crude reaction mixture when carried out in the presence of catalyst 53. f Donor preparation and

glycosylation carried out at −20 °C overnight followed by warming to ambient temperature.

To establish that the stereoselectivity of 65 could be attributed to catalyst control, the coupling

was re-run in the absence of catalyst. Analysis of the crude 1H NMR spectrum from both

reactions showed a marked reversal in anomeric selectivity, validating that a catalyst-controlled

glycosylation was taking place. Another class of linkage that appeared worthy of study were the

β 2-deoxy-glcyosides, also found extensively in nature. Although this linkage has been

previously prepared through borinic acid-catalyzed glycosylation, the scope of donors was

limited to those bearing electron-withdrawing acyl groups.41

Seeking to potentially expand the

scope of this transformation to the synthesis of perbenzylated variants, coupling of 2-deoxy-

3,4,6-tri-O-benzyl Glcp with acceptor 62 was attempted. Lower temperatures during the donor

23

preparation and glycosylation, again appeared to be crucial to avoid decomposition, in this case

to its glucal congener. A good yield of β 2-deoxy-glcyoside 67 was obtained, but with weak

anomeric selectivity on the basis of 1H NMR analysis. Analysis of the uncatalyzed reaction

showed that it was more α-selective than that of the fully oxygenated glucosyl hemiacetal 46.

This higher selectivity can be understood in terms of a stronger “kinetic anomeric effect” in 2-

deoxy glycosides, enhancing the α-selectivity of their associated couplings.83

2.2.3 Glycosidations of 4,6-O-Benzylidene Protected Donors

Cognizant of effects of 4,6-O-benzylidene acetals on stereoselective glycosylations with glycosyl

triflates, benzylidene protected derivatives of glucose, galactose, and mannose were prepared and

subjected to the developed catalytic glycosylation conditions. (Table 11)

Table 11: Couplings of 4,6-O-Benzylidene Protected Hemicetals with Acceptor 35

Entry Product Yieldb α:β

c

68

66 % 1.2:1

69

70 % 1:7.7

70

25 % >20:1

a Reaction Conditions: Hemiacetal Donor (1 eq.), PMP (3.2 eq.), Ms2O (1.5 eq.), 53 (0.08 eq.),

62 (0.8 eq.) b Isolated yield following column chromatography.

c Anomeric ratio of purified

product as determined by 1H NMR spectroscopy.

The galactoside of 35 was isolated with poor selectivity, whereas the corresponding glucosyl

hemiacetal reacted efficiently to give the corresponding glycoside in good yield and selectivity.

The diminished yields compared with the perbenzylated variants may be explained by the

destabilizing effect of benzylidene acetals on the formation of nascent positive charge at the

anomeric center in the rate-determining transition state.84–86

24

Table 12: Effect of Catalyst on Glycosylation of 35 with 4,6-O-Benzylidene Galacto Donor 71

Entry [B] α:βa

1 53 1.6:1

2 - 30:1

a Determined by HPLC of the crude reaction mixture.

To investigate further the low selectivity observed with galactosyl hemiacetal 71, the uncatalyzed

reaction was carried out and the selectivity compared. (Table 12) Somewhat surprisingly, the

uncatalyzed reaction proceeded with virtually complete selectivity for the α 1,2-cis glycoside. In

reviewing the literature, we noted that 4,6-O-benzylidene protected galactosyl donors are known

to exhibit unusual α selectivity in glycosylations, even in cases where a participating substituent

is present.87,88

Given that the stereoselectivities of the catalyzed reaction in this and in other

couplings thus presented are proportional to the selectivity of the uncatalyzed reaction, it appears

as a general matter that catalyst-controlled glycosylation occurs through a mechanism whose

stereoselectivity is sensitive to the same particular aspects of the donor that determine its

substrate-controlled stereoselectivity.

Mannosides, being ubiquitous in nature as both their α and β forms have thus far been an elusive

target of borinic acid-catalyzed glycosylation. Because mannosyl donors usually exist elusively

as their α anomers, SN2 glycosylation cannot occur to give the α glycoside or incidentally, as a

result of other factors such as steric demand, the β form. Glycosyl methanesulfonates, on the

other hand, appear to exist as an interconverting mixture of anomers in line with the α-selective

coupling observed in the preparation of arabinfuranosyl glycoside 66. As such, α-1,2-trans

linked mannosyl glycoside 70 was isolated as a single anomer but in low yield. Again,

purification challenges made isolation of the glycoside challenging and diminished its yield

somewhat. An attempted coupling of 35 with the analogous perbenzylated mannosyl hemiacetal

lacking the benzylidene protecting group yielded a large number of regio- and stereoisomers and

showed no difference in catalyzed versus uncatalyzed glycosylations as assessed by 1H NMR and

25

HPLC analysis. This stark contrast in the extent of catalyst control substantiates an important

contribution of the benzylidene acetal in modulating the reactivity and potentially the anomeric

ratio of the intermediate methanesulfonate.

2.2.4 Glycosylation of Isopropylidene Glucofuranose

With the observation of a α-1,2-trans selective arabinofuranosylation of a pyranose acceptor, a

furanose acceptor was sought out to investigate the capacity of the methodology to prepare

furanose-furanose linkages. Commercially available 1,2-O-isopropylidene-α-D-glucofuranose

(73) was selected as a model furanose acceptor, to which the methanesulfonate of 2,3,5-tri-O-

benzyl-β-D-Araf (74) was added under the previously described conditions for 66. (Scheme 10)

Scheme 10: Coupling of Araf Acceptor 74 with Glcf Acceptor 73

a Yields are of isolated pure product following column chromatography. Anomeric ratios of

purified product as determined by 1H NMR spectroscopy. Donor preparation and glycosylation

carried out at −20 °C overnight followed by warming to ambient temperature.

The coupling proceeded efficiently giving a mixture of products which were characterized as

regioisomers. Surprisingly, the major isomer was identified as the O-5 derivative on the basis of

HMBC and COSY correlations, where the secondary O-5 was glycosylated over the primary O-6

hydroxyl group to give α(1→5) disaccharide 75 in a ratio of 8:1 with 76 on the basis of 1H NMR

analysis of the crude reaction mixture. The stark contrast in the stereoselectivities of the two

regioisomers suggests that 75 was formed through a catalyst-controlled pathway, while 76 was

formed through an uncatalyzed manifold. Assessment of the background reaction for this

coupling is warranted to verify this prediction.

To further investigate the unusual regioselectivity, computational studies of the borinates derived

from Glcf acceptor 73 were carried out. DFT (B3LYP/ 6-31+G**) optimized structures of the

two potential1,2-diphenylborinates of 73 were calculated and the Mulliken charges of each

hydroxyl group were recorded. (Table 13) Condensed Fukui functions (f –k) for each of the

26

oxygens were also calculated by the method of Yang and Mortier.89

The calculations identify that

O-5, the observed preferred site of glycosylation, exhibits both the largest gas-phase Mulliken

charge and Fukui index in both of the borinate complexes. In each structure, the unbound

hydroxyl (the 6-OH in 77 and the 3-OH in 78), is oriented towards O-5. (Figure 1) The short

distance, (approximately 2 Å in each complex) between the OH hydrogen and O-5 suggests an

exceptionally strong diffusion of electron density across these three atoms. This might be

predicted to diminish, rather than enhance electron density and therefore the nucleophilicity of

O-5, though the opposite is seen both experimentally and from the computational results in

Table 13. Although the basis of these conflicting results are not clear, it should be noted that

hydroxyl groups in diols and polyols that act as hydrogen bond donors to neighboring

heteroatoms are generally seen to undergo preferential functionalization.90–93

Table 13: DFT Calculated Parameters for 1,2-Diphenyl Borinates Derived from 73

Borinate Rel. Energy

(kcal) Atom Mulliken Charge f

−k

0

O-3 -0.492 0.880

O-5 -0.586 1.110

O-6 -0.499 0.969

−1.3

O-3 -0.473 0.921

O-5 -0.661 1.253

O-6 -0.570 1.000

27

Figure 1: DFT Calculated Structures of the 1,2-Diphenyl Borinates 77 and 78 Derived from 73

O-3 O-5

O-6

O-3

O-5

O-6

28

2.3 Mechanistic Studies and the Origin of Stereoselectivity

In discussing the mechanism and origin of stereoselectivity in the reactions of glycosyl

methanesulfonates with free and tetracoordinate borinate acceptors, it is useful to begin by

considering analogous reactions of glycosyl chlorides under similar conditions. A direct

comparison can be made in evaluating the reactions of acceptor 35 with perbenzylated glycosyl

chloride 36 and its corresponding glycosyl methanesulfonate. (Scheme 6B) The first major

observation is that the stereoselectivity observed in the coupling of the chloride is essentially β,

while the analogous coupling with the methanesulfonate gives a 1:10 α:β mixture. One possible

explanation for this is the fundamental difference between the two classes of donors in terms of

background reactivity. While chloride donor 36 does not undergo efficient coupling in the

absence of a borinic acid catalyst, methanesulfonates are reactive donors on their own. The

upshot of this is that an unselective background reaction, α:β ~2:1, is observed in the absence of

catalyst-control, with this pathway leading to the minor anomer. In the presence of the catalyst, a

more β-selective pathway is favored. The major questions that needed to be addressed given this

context were: 1) to what extent the catalyst-controlled pathway competes with the background

reaction, 2) the stereoselectivity of the catalyst-controlled pathway, and 3) how the catalyst-

controlled pathway differs in mechanism from the background reaction.

The stereoselectivities of the background and catalyzed reactions of 4,6-O-benzylidene galacto

donor 71 with acceptor 35 (Table 12), provide clear, and perhaps general evidence that the

catalyst-controlled pathway is not completely β-selective. In other words, α-glycoside does not

exclusively derive from a weakly competing background manifold. For this donor, the

uncatalyzed reaction yields almost exclusively the α-glycoside. If one is conservative and

assumes that a completely β-selective catalyzed reaction is marginally (e.g. 1-2 times) faster than

the background reaction, the β-glycoside would be the major anomer. However, the observed

selectivity in the presence of catalyst is near 1:1, with in fact a slight α-preference, demonstrating

that the catalyst-controlled manifold must not be completely β-selective. This is not to suggest

however, that the rate of the catalytic manifold completely obscures the background reaction. For

certain very selective couplings, α-glycoside may still derive predominately from a background

reaction.

29

The hypothesis that the catalyst-controlled pathway is not completely β-selective can be

understood by considering the intermediacy of multiple transient donor-derived species which

lead to dissimilar stereochemical outcomes.65,94

Scheme 11: Reactive Intermediates Potentially Involved in Glycoside Formation

Adapted from ref. 65.

A continium of potential intermediates with varying degrees of association are depicted in

Scheme 11. At the two extremes are covalently linked α and β methanesulfonates, with α and β

contact ion pairs (CIP) exhibiting lower degrees of association, and a facially indistinct solvent-

separated ion pair (SSIP) being fully dissociated. Intermediates that exhibit some form of facial

association are presumed to give the anomer of glycoside resulting from inversion, which results

from attack of the more accessible face. In contrast, the solvent-separated ion pair which lacks a

form of facial bias may yield both anomers of the glycoside. With this framework in hand, we

turn to consideration of which of the intermediates serves as the active electrophile(s) in the

catalyst-controlled and background manifolds. Two possible options exist, the first based on the

Curtin-Hammett principle. In this situation, two quasi-intermediates exist which each display

some degree of anomeric nucleofuge association, such as covalent sulfonates or contact ion pairs.

These two intermediates are in rapid equilibrium, and upon reaction with the acceptor, give the

glycoside resulting from inversion. Another potential explanation arises from reaction via a

solvent-separated ion pair.

To investigate the nature of the methanesulfonate intermediates, as well their formation and

stability, we prepared a select panel under the same conditions used in the glycosylations and

analyzed them by 1H and

13C NMR. (Table 14)

30

Table 14: Anomeric Ratios of Glycosyl Methanesulfonates Determined by 1H

NMR

Entry Methanesulfonate Temperaturea α:β

b Hemiacetal α:β

c

79

23 °C 10:1 2.6:1

80

23 °C 10:1 2.4:1

81

23 °C 16:1 4.9:1

82

23 °C 6.3:1 1.3:1

83

−25 °C >20:1 2.7:1

84

−25 °C 3.8:1 -

a Temperature at which NMR spectra were recorded.

b Determined by

1H NMR analysis of the

mixture. c Equilibrium anomeric ratio of hemiacetal precursor in CDCl3 at 23 °C. Values are

obtained from ref. 95 for 79 – 81, and ref. 78 for 82.

Rapid and virtually complete conversion of the hemiacetals to their corresponding

methanesulfonates was observed well within 15 minutes of addition of Ms2O. Glucosyl

hemiacetal-derived 79 was stable for over 20 hours in a sealed NMR tube in CD2Cl2 with less

than 15 % decomposition to its hemiacetal precursor. The anomeric ratio remained constant

during this time.

31

The methanesulfonate of perbenzylated 2-deoxy-glucose, 83, was observed at −25 °C to avoid

elimination to its glucal.58

It existed almost completely as its α anomer, though a small

population of its β anomer could be seen. It was stable at this temperature, but warming in 10 °

increments identified a decomposition temperature range of −5 °C to 5 °C whereupon the glucal

formed rapidly. (See section 4.3.1, Figure 2) These observations are highly similar to those of

the aforementioned toluenesulfonate as previously reported.68

(Scheme 9)

In contrast with glycosyl toluenesulfonates, which were previously prepared by prior activation

of the 1-OH by deprotonation with a strong base, methanesulfonates appear to be readily and

rapidly formed directly from hemiacetals. This can be attributed to the capacity of sulfonyl

electrophiles bearing α-hydrogens, such as methanesulfonates, to react via sulfene

intermediates.96–98

In the case of Ms2O, the simplest sulfene (H2C=S(O)2) is generated, which is

highly reactive and adds indiscriminately to available nucleophiles. Once sulfonylation of the

hemiacetal is complete, usually within a minute following the addition of Ms2O, the solutions

appear to take on a slight discoloration as the remaining methanesulfonic anhydride is consumed.

The resulting yellow decomposition products are highly polar, potentially dimers or oligomers of

the sulfene, and are readily removed by column chromatography in the glycosylations.

The α and β anomers of the methanesulfoantes show distinct chemical shifts corresponding to the

H-1 anomeric proton and CH3 of the mesyl group. The H-1 shifts and J1,2 couplings are very

similar to those observed by Schuerch in glycosyl toluensulfonates.46

In general, the resonances

for the H-1 proton are δ = ~6 ppm, 3J1,2 = 3.5 Hz and δ = ~5.3 ppm,

3J1,2 = 7.9 Hz for the major α

and minor β anomers respectively. Review of the anomeric ratios of the sulfonates presented in

Table 14Error! Reference source not found. shows in general that the equilibrium anomeric

ratios of the precursor hemiacetals correlate positively with the anomeric ratio of the

corresponding methanesulfonate. The methanesulfonates of gluco- and galacto- configured

perbenzylated hemiacetals had approximately the same anomeric ratio, despite a significant

difference in anomeric selectivity seen in their associated couplings with acceptor 35. However,

a much clearer trend can be seen from the other methanesulfonates that were studied. 4,6-O-

Benzylidene galacto methanesulfonate 81 has a greater bias to adopt the α-form than its

perbenzylated derivative 80. In contrast, 2-azido-2-deoxy methanesulfonate 82 has a lower

preference for the α-form than its fully benzylated derivative 79. When subjected to the catalytic

conditions however, 81 gives a 1:1 α:β mixture of glycoside 68, while 82 gives complete β-

32

selectivity in the preparation of 65. Perbenzyl methanesulfonate 79, having an intermediate α:β

ratio, gives an intermediate level of selectivity, approximately 1:10 for 37.

The observation that the α:β ratio of the methanesulfonate precursor correlates positively with the

selectivity of the corresponding catalytic coupling destabilizes a simplistic Curtin-Hammett

model of equilibrating facially-biased intermediates that react by inversion. Taking the example

of 4,6-O-benzylidene galacto methanesulfonate 81, if such a scheme were operative, this donor

should give a higher β-selectivity because relatively more of this donor exists as its α-anomer. In

other words, the equilibrium outlined in Scheme 11 lies further towards the left for this donor

relative to other donors, favoring the α-bound covalent methanesulfonate and contact ion pair

which lead to β-glycoside by inversion. Instead, donor 81 is the most α-selective observed in the

course of these studies, suggesting against reaction via inversion of a facially-biased

intermediate. An analogous argument can be constructed for the β-selective 2-azido-2-deoxy

sulfonate 82, which in a similar sense gives more β-glycoside from a donor with less α-bias.

Noting that 4,6-O-benzylidene galacto methanesulfonate 81 also gives a significantly more α-

selective background reaction relative to perbenzylated gluco methanesulfonate 79 (α:β 30:1 vs.

2:1) also suggests that the background reaction does not occur by inversion of two

interconverting facially-biased intermediates.

Another logical rationale for these data based on the framework presented in Scheme 11 is that

both background and catalyzed reactions take place from a dissociated solvent-separated ion pair.

This would substantiate a number of experimental observations, such as decreased

stereoselectivity resulting from increased donor concentration, and the incomplete β-selectivity

of the catalyst-controlled pathway in contrast to the analogous glycosyl chlorides. Indeed, α-

configured 2-deoxy methanesulfonate 83, which is analogous to its toluenesulfonate that affords

β-glycosides stereoselectively with activated acceptors by SN2 inversion, contrarily displays the

same α-selective background and catalyzed stereoselectivity seen for 81. (Table 10) Further

support can be found in a recent report which noted that perbenzylated mannosyl triflates react

through an SN1-type mechanism via the intermediacy of a solvent-separated ion pair, as reflected

by the low dependence of their rate of reaction on the acceptor concentration.67

With a solvent-separated ion pair as the key reactive intermediate, it is tempting to invoke so-

called “kinetic anomeric effect” to explain the observed stereoselectivity. This is a controversial

33

concept, but it is convenient to reduce it for our purposes to a theory that the aspects of a

particular donor which dictate the extent to which it adopts the α or β form at thermodynamic

equilibrium operate in an parallel sense in modulating the relative energies of competing

transition states leading to each anomer of glycoside. This would adequately explain how the

anomeric ratios of the methanesulfonates correlate positively with the selectivities of their

associated couplings.

The kinetic anomeric effect, however, is controversial for a number of reasons. A recent

perspective highlights the dangers of considering a difference in orbital interactions to explaining

the relative energies of competing SN1-like transition states.99

Indeed, hyperconjugative orbital

interactions that were previously considered to be an accepted basis for the thermodynamic

anomeric effect have been thoroughly discredited by recent ab initio calculations.100,101

But

debate rages on as to what a more realistic explanation of the anomeric effect might be.102–104

Whatever the origin of the anomeric effect, it is clear that the extent to which it operates in the

methanesulfonates reliably correlates with the selectivities of the associated catalytic couplings.

The differences in relative energies of the transition states leading to α and β glycosides are

probably best explained on the basis of the same intramolecular electrostatic interactions, which

include a steric component, that have been proposed to play some role in thermodynamic

anomeric effect. If sterics are considered to be important in determining the selectivity, an

explanation for the enhanced 1,2-trans selectivity of the catalyzed-manifold readily follows. The

nucleophile in this pathway is a large borinate nucleophile whose steric demands are much

greater than those of a simple alcohol. As a result, steric interactions between the electrophile

and incoming nucleophile are relatively exaggerated; leading to a larger difference in the

energies of the oxocarbenium-like early transition states resulting in selectivity for the 1,2-trans

glycoside.

Woerpel has studied the reactions of tetrahydropyranosyl oxocarbenium ions extensively and has

developed a model for rationalizing the stereoselectivities of their reactions with external

nucleophiles. Because coplanarity of the C5-O5 and C2-C1 bonds is necessary to achieve

maximum donation of the O5 lone pair into the empty p orbital at C1, oxocarbenium ions of

pyranoses likely either exist in boat or half-chair conformations.99

In Woerpel’s model, a Curtin-

Hammett scenario involving a balance between the relative stabilities of two half-chair

34

oxocarbenium intermediates, and the steric interactions associated with nucleophile addition to

each, are believed to be responsible for the observed selectivity.105

In the case of glucose, two

half-chair conformers are considered relevant, 3H4 and

4H3. (Scheme 12) The

4H3 conformer is

favored because most substituents in half chairs prefer to occupy psuedoequatorial positions.

This conformer leads to the α 1,2-cis glycoside as a result of the Fürst-Plattner rule, which states

that additions to 6-membered cyclic-cations occurs to give diaxial products. The less stable 3H4

conformer gives the β 1,2-trans glycoside by a similar reasoning.

Scheme 12: Woerpel’s Model for Stereoselectivity in Reactions of Gluco Oxocarbenium Ions

Adapted from ref. 106.

In studying the effect of substituents on the stereoselectivity of C-glycosylations of

tetrahydropyran-derived oxocarbenium ions, Woerpel recognized the steric demand of the C-2

substituent positively correlated with selectivity for the 1,2-trans product by examining C-

glycosylations of 2-substitued tetrahydropyrans.107

When a relatively small C-2 substituent such

as a benzyloxy ether was present, the 1,2-cis product was obtained selectively, presumably from

reaction of the more stable 4H3 half-chair. With a more sterically demanding substituent however

such as a tert-butyl residue, the 1,2-trans product was isolated exclusively. This isomer is

probably derived from reaction of a less stable oxocarbenium ion conformer where steric

interactions of the C-2 substituent with the incoming nucleophile would be minimized.

Extending this model to the system at hand here, the increased steric demand of a borinate

nucleophile with the C-2 substituent of pyranose donors would similarly be expected to favor the

1,2-trans product. From which conformer of oxocarbenium ion the 1,2-trans products are

derived is not necessarily clear, as reaction of the 3H4 conformer is predicted by Woerpel to be

subject to other steric clashes between the incoming nucleophile and the C-3 and C-5

substituents which would rival the effect of a clash with C-2 in attacking the 4H3 confomer.

106

Computational studies of nucleophilic additions to permethylated oxocarbenium ions suggest

that the other, less stable reactive conformer in the glucose series is a B2,5 boat, not the 3H4 half-

chair predicted by Woepel.65,108

Other conformers, such as the 5S1 skew-boat,

109,110 and twist-

35

boat structures proposed by Woerpel for 2-deoxy oxocarbenium ions,111

might also be the

relevant conformers in the catalyzed manifold leading to 1,2-trans selective couplings.

While the potential conformers of the active donor species and the particular steric interactions

that are exaggerated in the case of each donor studied are beyond the scope of this discussion, as

a general observation, the catalytic couplings carried out in this study selectively afforded either

α or β 1,2-trans glycosides over their 1,2-cis linked counterparts. The substituent closest to the

anomeric center, C-2, is likely of chief importance, as it is involved in steric interactions with the

incoming nucleophile that disfavor 1,2-cis glycosides derived a 4H3 conformers. The variation of

substituents, the presence of a conformationally restricting benzylidene acetal, and the

configurations of the donors that were explored in the course of these studies all play a dual role

in regulating both the steric interactions of the donors with incoming nucleophiles and their

conformational equilibria.112

These two factors likely act in concert to affect the relative

energies, and therefore the observed ratio, of the transition states leading to α- and β-glycosides.

36

3 Summary and Future Work

Glycosyl methanesulfonates are a highly reactive, yet conveniently prepared donor species in

chemical glycosylations. Their regio- and stereoselective reactions with partially protected

glycosyl acceptors can be achieved by catalytic activation of the acceptor in the form of a

tetracoordinate borinate adduct. The glycosides so obtained are enriched in their 1,2-trans linked

isomers for a number of differentially configured and substituted pyranose and furanose donors.

Observations of the methanesulfonates suggest that the mechanism of these glycosylations

involves a solvent-separated ion pair which can be facially discriminated on the basis of steric

interactions with the incoming borinate nucleophile that favor the 1,2-trans glycoside.

Further work will focus on solidifying the mechanistic hypotheses put forward by examination of

the kinetics of the reaction; in particular, whether the rate of reaction shows weak dependence on

the concentration of the acceptor that would be predicted for an SN1-like reaction that occurs

through a dissociative rate-limiting transition state. Most stereoselective glycosylations that

occur through an oxocarbenium intermediate are due to particular protecting groups and donor

configurations.112,113

Examples of acceptor-dependent stereoselectivies in glycosylations of

oxocarbenium ions are known, however, a reliable approach to achieve a consistent sense of

selectivity is not.113–116

Modulating the steric demand of the active acceptor, coupled with the

potential contributory effect of increased nucleophilicity, to achieve stereoselective glycosylation

of an oxocarbenium intermediate is a novel concept in this field.

Future work will also focus on further study of the capacity of methanesulfonates to facilitate the

construction of linkages to and between furanose sugars.

37

4 Experimental

4.1 Materials and Methods

4.1.1 General

All reactions were stirred using teflon-coated magnetic stir bars at ambient temperature (23 °C)

unless otherwise stated. Stainless steel needles and gas-tight syringes were used to transfer air-

and moisture-sensitive liquids. Borosilicate glass vials were obtained from VWR and dried at

140 °C for at least 24 h prior to use. Flash column chromatography was carried out using neutral

silica gel (60 Ǻ, 230-400 mesh) (Silicycle) using reagent grade solvents. Analytical TLC was

carried out using aluminium-backed silica gel 60 F254 plates (EMD Milipore) and visualized with

a UV254 lamp or with aqueous basic permanganate stain.

4.1.2 Materials

Where indicated, dry solvents are HPLC grade and purified using a solvent purification system

equipped with columns of activated alumina under nitrogen. (Innovative Technology, Inc.)

Distilled water was obtained from an in-house supply. Nuclear magnetic resonance (NMR)

solvents were obtained from Cambridge Isotope Laboratories. Methanesulfonic Anhydride was

purchased from Alfa Aesar and stored prior to use in a −17 °C glove box freezer under nitrogen.

Carbohydrates starting materials were purchased from Sigma Aldrich or Carbosynth Ltd.

(Berkshire, UK) or synthesized according to literature procedures. All other reagents and

solvents otherwise not indicated were purchased from Sigma Aldrich or Caledon and used

without further purification.

4.1.3 Instrumentation

1H and

13C NMR spectra were recorded in CDCl3 using a Bruker Avance III (400 MHz) or

Varian VnmrS (400 MHz) at the Centre for Spectroscopic Investigation of Complex Organic

Molecules and Polymers (CSICOMP) at the University of Toronto. 1

H NMR are reported in parts

per million (ppm) relative to tetramethylsilane and referenced to residual protium in the

solvent.117

Spectral features are reported in the following order: chemical shift (δ, ppm);

multiplicity; number of protons; coupling constants (J, Hz); assignment. Where reported,

assignments were made on the basis of coupling constants and gCOSY or HSQC spectra. High-

38

resolution mass spectra (HRMS) were obtained either on an Agilent 6538 UHD Q-TOF for ESI+

(electrospray ionization) or a JEOL AccuTOF JMS-T1000LC for DART+ (direct analysis in real

time) at the Advanced Instrumentation for Molecular Structure (AIMS) Mass Spectrometry

Laboratory at the University of Toronto. HPLC analysis was carried out using either Luna 5 µm

CN or Luna 5 μm Silica(2) columns (Chiral Technologies Inc.) on a Perkin-Elmer 200 series

HPLC with a mixture of hexanes/isopropanol as eluent. DFT calculations were carried out with

the Gaussian ’09 software package118

on a Linux workstation equipped with two quad-core AMD

Shanghai processors built by HardData, Inc. (Edmonton, Canada).

4.2 General Experimental Procedures

4.2.1 General Procedure for Formation of Glycosyl Methanesulfonates

To septum-capped oven-dried 2 dram vial was added the glycosyl hemiacetal (0.10 mmol, 1 eq.).

The vial was twice evacuated and purged with argon, then dry dichloromethane (1.5 mL) was

added, followed by pentamethylpiperidine (PMP) (58 μL, 0.32 mmol, 3.2 eq.). In a nitrogen

glove box, a separate oven-dried 1 dram vial was charged with methanesulfonic anhydride

(Ms2O) (41.8 mg, 0.24 mmol), which was then removed from the glove box and dissolved in dry

dichloromethane (0.8 mL) to give a 0.30 M solution of Ms2O. To the solution of the hemiacetal,

the freshly prepared solution of 0.30 M Ms2O in dichloromethane (0.5 mL, 0.15 mmol, 1.5 eq.)

was added slowly. The solution was stirred for at least 20 minutes, or until a persistent coloration

(very light yellow to yellow) was observed, prior to use in the glycosylation reactions.

4.2.2 General Procedure for Glycosylations with Glycosyl Methanesulfonates

To a septum-capped oven-dried 2 dram vial was added the glycosyl acceptor (0.08 mmol, 0.8

eq.) and the borinic acid catalyst, either 10-Hydroxy-9-oxa-10-bora-anthracene75

(53) (1.6 mg,

0.008 mmol, 0.08 eq.) or diphenylborinic anhydride119

(52) (1.4 mg, 0.004 mmol, 0.04 eq.). The

vial was evacuated and purged with argon twice. The 0.05 M solution of glycosyl

methanesulfonate (2 mL, 0.10 mmol, 1 eq.) prepared according to general procedure 4.2.1 was

then added. The septum was quickly replaced with a plastic cap, the vial sealed with Teflon tape,

and the mixture stirred overnight for at least 17 h. Volatiles were evaporated by a stream of air

and the resulting residue purified by silica gel chromatography to afford the desired glycoside.

39

Alternatively, the borinic acid, followed by the acceptor, may be added directly to the solution of

glycosyl methanesulfonate without apparent effect on yield or stereoselectivity.

4.3 Characterization Data

4.3.1 Glycosyl Methanesulfonates

2,3,4,6-tetra-O-Benzyl-1-O-methanesulfonyl D-glucopyranose (79)

Prepared from 2,3,4,6-tetra-O-benzyl D-glucopyranose (27.0 mg, 0.050 mmol) (Carbosynth Ltd.)

according to general procedure 4.2.1 where dichloromethane was substituted with chloroform-d.

The title compound was observed and characterized by 1H and

13C NMR with the

methanesulfonate of PMP.

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.34 – 7.20 (m, 17H, Ar-H), 7.15 – 7.07 (m, 3H, Ar-H),

5.93 (d, J = 3.5 Hz, 1H, H-1), 4.91 (d, J = 10.9 Hz, 1H, CH2Ph), 4.79 (dd, J = 10.9, 9.9 Hz, 2H,

CH2Ph), 4.73 – 4.65 (m, 2H, CH2Ph), 4.52 (d, J = 12.0 Hz, 1H, CH2Ph), 4.46 (d, J = 10.8 Hz,

1H, CH2Ph), 4.41 (d, J = 12.0 Hz, 1H, CH2Ph), 3.96 – 3.87 (m, 2H, H-3, H-5), 3.69 – 3.59 (m,

4H, H-2, H-4, H-6), 3.00 (s, 3H, SO2-CH3).

The minor β anomer had δ (ppm) = 5.30 (d, J = 7.7 Hz, 0.09 H, H-1), 3.06 (s, 0.29 H, SO2-CH3).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.4, 137.9, 137.7, 137.3, 128.6, 128.5, 128.5, 128.2,

128.2, 128.0, 127.9, 127.9, 127.9, 127.8, 98.7, 81.2, 78.3, 76.7, 75.8, 75.2, 73.6, 73.3, 73.3, 68.1,

39.7.

α:β = 10:1

2,3,4,6-tetra-O-Benzyl-1-O-methanesulfonyl D-galactopyranose (80)

40

Prepared from 2,3,4,6-tetra-O-benzyl D-galactopyranose (27.0 mg, 0.050 mmol) (Carbosynth

Ltd.) according to general procedure 4.2.1 where dichloromethane was substituted with

chloroform-d. The title compound was observed and characterized by 1H and

13C NMR with the

methanesulfonate of PMP.

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.36 – 7.16 (m, 20H), 5.95 (d, J = 3.7 Hz, 1H, H-1),

4.90 (d, J = 11.3 Hz, 1H, CH2Ph), 4.79 (d, J = 11.8 Hz, 1H, CH2Ph), 4.75 – 4.67 (m, 3H,

CH2Ph), 4.52 (d, J = 11.4 Hz, 1H, CH2Ph), 4.42 (d, J = 11.6 Hz, 1H, CH2Ph), 4.35 (d, J = 11.7

Hz, 1H, CH2Ph), 4.13 (dd, J = 10.1, 3.7 Hz, 1H, H-2), 4.05 (ddd, J = 6.4, 6.4 Hz, 1.0 Hz, 1H, H-

5), 3.95 (dd, J = 2.7, 1.1 Hz, 1H, H-4), 3.85 (dd, J = 10.1, 2.7 Hz, 1H, H-3), 3.52 (dd, J = 9.6, 6.4

Hz, 1H, H-6a), 3.45 (dd, J = 9.6, 6.1 Hz, 1H, H-6b), 2.96 (s, 3H, SO2-CH3).

The minor β anomer had δ (ppm) = 5.24 (d, J = 7.9 Hz, 0.10 H, H-1), 3.04 (s, 0.32 H, SO2-CH3).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.4, 138.2, 137.7, 128.5, 128.5, 128.4, 128.2, 128.1,

128.0, 127.9, 127.9, 127.8, 127.8, 127.6, 99.9, 78.3, 74.9, 74.8, 74.5, 73.6, 73.5, 73.3, 72.7, 68.8,

39.7.

α:β = 10:1

2,3-di-O-Benzyl-4,6-O-benzylidene-1-O-methanesulfonyl D-galactopyranose (81)

Prepared from 2,3-di-O-benzyl-4,6-O-benzylidene D-galactopyranose120

(22.4 mg, 0.050 mmol)

according to general procedure 4.2.1 where dichloromethane was substituted with chloroform-d.

The title compound was observed and characterized by 1H and

13C NMR with the

methanesulfonate of PMP.

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.48 – 7.44 (m, 2H, Ar-H), 7.38 – 7.23 (m, 13H, Ar-H),

6.04 (d, J = 3.4 Hz, 1H, H-1), 5.46 (s, 1H, CHPh), 4.81 (d, J = 11.2 Hz, 1H, CH2Ph), 4.76 (d, J =

12.3 Hz, 1H, CH2Ph), 4.73 – 4.65 (m, 2H, CH2Ph), 4.27 – 4.19 (m, 2H, H-4, H-6a), 4.16 (dd, J =

41

10.1, 3.5 Hz, 1H, H-2), 3.99 (dd, J = 12.7, 1.8 Hz, 1H, H-6b), 3.91 (dd, J = 10.1, 3.4 Hz, 1H, H-

3), 3.86 – 3.83 (ddd, J = 1.8, 1.8 Hz, 0.8 Hz, 1H, H-5), 2.94 (s, 3H, SO2-CH3).

The minor β anomer had δ (ppm) = 5.32 (d, J = 7.9 Hz, 0.06 H, H-1), 3.10 (s, 0.16 H, SO2-CH3)

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.3, 137.7, 137.6, 129.1, 128.5, 128.5, 128.5, 128.3,

128.2, 128.1, 127.9, 127.7, 126.3, 101.1, 100.7, 75.5, 74.2, 74.1, 73.7, 72.0, 68.9, 65.5, 39.7.

α:β = 16:1

2-Azido-3,4,6-tetra-O-benzyl-2-deoxy-1-O-methanesulfonyl D-glucopyranose (82)

Prepared from 2-azido-3,4,6-tetra-O-benzyl-2-deoxy D-glucopyranose77,121

(23.8 mg, 0.050

mmol) according to general procedure 4.2.1 where dichloromethane was substituted with

chloroform-d. The title compound was observed and characterized by 1H and

13C NMR with the

methanesulfonate of PMP.

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.38 – 7.17 (m, 12H, Ar-H), 7.18 – 7.07 (m, 3H, Ar-H),

5.90 (d, J = 3.5 Hz, 1H, H-1), 4.88 – 4.80 (m, 2H, CH2Ph), 4.77 (d, J = 10.9 Hz, 1H, CH2Ph),

4.55 – 4.49 (m, 2H, CH2Ph), 4.42 (d, J = 11.9 Hz, 1H, CH2Ph), 3.97 (ddd, J = 10.1, 3.6, 2.2 Hz,

1H, H-5), 3.89 (dd, J = 10.2, 8.9 Hz, 1H, H-3), 3.72 (dd, J = 10.1, 9.0 Hz, 1H, H-4), 3.67 (d, J =

3.8 Hz, 1H, H-6a), 3.65 (d, J = 2.2 Hz, 1H, H-6b), 3.61 (dd, J = 10.2, 3.5 Hz, 1H, H-1), 3.06 (s,

3H, SO2-CH3).

The minor β anomer had δ (ppm) = 5.09 (d, J = 7.9 Hz, 0.16 H, H-1), 3.08 (s, 0.46 H, SO2-CH3).

13C NMR (101 MHz, CDCl3): δ (ppm) = 137.6, 137.4, 128.6, 128.6, 128.5, 128.2, 128.1, 128.0,

128.0, 127.9, 127.7, 98.8, 80.2, 77.4, 75.8, 75.2, 73.7, 73.6, 67.9, 39.7.

α:β = 6.3:1

42

3,4,6-tetra-O-Benzyl-2-deoxy-1-O-methanesulfonyl α-D-glucopyranose (83)

Prepared from 3,4,6-tetra-O-benzyl-2-deoxy D-glucopyranose (21.7 mg, 0.050 mmol) according

to general procedure 4.2.1 where dichloromethane was substituted with chloroform-d . The

solution of hemiacetal and its methanesulfonate was maintained at or below −25 °C prior to

acquisition of spectra. The title compound was observed and characterized by 1H and

13C NMR

with the methanesulfonate of PMP, as well as small amount of 3,4,6-tetra-O-benzyl D-Glucal.

1H NMR (400 MHz, CDCl3, −25 °C): δ (ppm) = 7.35 – 7.21 (m, 13H, Ar-H), 7.11 – 7.03 (m,

2H, Ar-H), 6.06 (ddd, 1H, H-1a), 4.86 (d, J = 10.4 Hz, 1H, CH2Ph), 4.64 (d, J = 11.3 Hz, 1H,

CH2Ph), 4.61 – 4.53 (m, 2H, CH2Ph), 4.43 (d, J = 12.0 Hz, 1H, CH2Ph), 4.39 (d, J = 10.4 Hz,

1H, CH2Ph), 3.94 (ddd, J = 11.4, 8.9, 5.0 Hz, 1H, H-3), 3.88 (ddd, J = 10.1, 3.2, 3.2 Hz, 1H, H-

5), 3.70 – 3.62 (m, 2H, H-6), 3.58 (dd, J = 9.7, 9.2 Hz, 1H, H-4), 3.03 (s, 3H, SO2-CH3), 2.46

(ddd, J = 13.9, 5.0, 1.6 Hz, 2H, H-2a), 1.87 (ddd, J = 13.8, 11.5, 3.7 Hz, 2H, H-2b).

The minor β anomer had δ (ppm) = 5.33 (dd, J = 10.1, 1.9 Hz, 0.02 H, H-1), 3.11 (s, 0.07H, SO2-

CH3).

13C NMR (101 MHz, CDCl3, −25 °C): δ (ppm) = 137.6, 137.3, 137.1, 128.6, 128.5, 128.5,

128.0, 128.0, 127.9, 127.7, 100.5, 76.4, 76.0, 75.3, 73.3, 73.2, 71.9, 67.8, 39.8, 39.6.

α:β = >20:1

The solution of 83 was warmed in 10 ° increments from −25 °C to 25 °C and 1H spectra were

recorded. (Figure 2) The onset of decomposition is between −5 °C and 5 °C

43

Figure 2: Variable Temperature 1H NMR Spectra of 2-Deoxy Methanesulfonate 83

2,3,5-tri-O-Benzyl-1-O-methanesulfonyl D-arabinofuranose (84)

Prepared from 2,3,5-tri-O-Benzyl-1-O-methanesulfonyl β-D-arabinofuranose (21.0 mg, 0.050

mmol) (Carbosynth Ltd.) according to general procedure 4.2.1 where dichloromethane was

substituted with chloroform-d . The solution of hemiacetal and its methanesulfonate was

maintained at or below −25 °C prior to acquisition of spectra. The title compound was observed

and characterized by 1H and

13C NMR with the methanesulfonate of PMP.

1H NMR (400 MHz, CDCl3, −25 °C): δ (ppm) = 7.41 – 7.20 (m, 13H, Ar-H), 7.17 (dd, J = 7.4,

2.2 Hz, 2H, Ar-H), 6.06 (s, 1H, H-1), 4.57 (d, J = 11.7 Hz, 1Hz, CH2Ph), 4.51 (d, J = 12.0 Hz,

1H, CH2Ph), 4.48 (d, J = 12.2 Hz, 1H, CH2Ph), 4.44 (d, J = 11.7 Hz, 1H, CH2Ph), 4.39 (d, J =

25 °C

15 °C

5 °C

−5 °C

−15 °C

−25 °C

tri-O-Benzyl D-Glucal (H-1) Methanesulfonate 83 (H-1)

44

11.7 Hz, 1H, CH2Ph), 4.39 – 4.27 (m, 3H, CH2Ph, H-4), 4.17 (d, J = 2.1 Hz, 1H, H-2), 3.92 (dd,

J = 6.1, 2.3 Hz, 1H, H-3), 3.58 (dd, J = 10.7, 3.8 Hz, 1H, H-5a), 3.53 (dd, J = 10.7, 5.6 Hz, 1H,

H-5b), 3.08 (s, 3H, SO2-CH3).

The minor β anomer had δ (ppm) = 5.94 (d, J = 3.5 Hz, 0.26H, H-1), 2.81 (s, 0.98H, SO2-CH3).

13C NMR (101 MHz, CDCl3, −25 °C): δ (ppm) = 137.3, 136.7, 136.1, 128.6, 128.5, 128.4,

128.1, 127.9, 127.8, 106.8, 86.2, 83.6, 82.2, 76.8, 73.2, 72.1, 72.1, 68.4, 39.6.

α:β = 3.8:1

45

4.3.2 Glycoside Products

Methyl 2,3,4,6-tetra-O-benzyl D-glucopyranoside (42)

The methanesulfonate of 2,3,4,6-tetra-O-benzyl D-glucopyranose (54.6 mg, 0.10 mmol, 1 eq.)

was prepared in an analogus fashion to general procedure 4.2.1. Methanesulfonic anhydride

(0.5 mL, 0.30 M in dry dichloromethane, 0.15 mmol, 1.5 eq.) was added to a solution of the

hemiacetal (54.6 mg, 0.10 mmol, 1 eq.) and s-collidine (40 μL, 0.30 mmol, 3 eq.) or iPr2NEt (50

μL, 0.29 mmol, 2.9 eq.) in dry dichloromethane (1 mL). After 1 h, anhydrous methanol (10 μL,

0.25 mmol, 2.5 eq.) was added, and the resulting solution stirred for an additional 2 h. Volatiles

were evaporated by air stream and the resulting residue purified by silica gel column

chromatography (25 % ethyl acetate in hexanes) to afford the title glycoside as a colorless syrup.

Spectral features were in agreement with those previously reported. 122,123

Yield: s-collidine: 42.5 mg (77 %), iPr2NEt: 36.9 mg (66 %)

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.40 – 7.23 (m, 17H), 7.20 – 7.13 (m, 3H), 5.00 (d, J =

10.9 Hz, 1H, α), 4.95 (d, J = 10.9 Hz, 0.5 H, β), 4.94 (d, J =11.0 Hz, 0.5 H, β), 4.87 – 4.79 (m,

3.5H), 4.73 (d, J = 11.1 Hz, 0.5H, β), 4.71 – 4.45 (m, 6.5H), 4.33 (d, J = 7.8 Hz, 0.5H, β), 4.00

(dd, J = 9.6, 8.9 Hz, 1H, α), 3.81 – 3.55 (m, 7H), 3.52 – 3.43 (m, 1H, β), 3.40 (s, 3H, α).

α:β = 2.0:1 (s-Collidine), 1.8:1 (iPr2NEt)

46

Methyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl D-glucopyranosyl) α-D-

mannopyranoside (37)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3,4,6-tetra-O-

benzyl D-glucopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by general

procedure 4.2.1, to which the glycosyl acceptor methyl 6-O-tert-butyldimethylsilyl α-D-

mannopyranoside124

(24.7 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg,

0.008 mmol, 0.08 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (25 % ethyl acetate in hexanes) as a clear colorless glass (53.8 mg, 81 %).

Spectral features were in agreement with those previously reported.39

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.40 – 7.27 (m, 18H), 7.23 – 7.12 (m, 2H), 4.94 (d, J =

10.9 Hz, 2H), 4.86 – 4.78 (m, 3H), 4.75 (d, J = 1.7 Hz, 1H), 4.56 – 4.50 (m, 4H), 4.03 – 3.95 (m,

3H), 3.89 – 3.75 (m, 3H), 3.73 – 3.64 (m, 2H), 3.62 – 3.51 (m, 5H), 3.38 (s, 3H), 2.16 (d, J = 4.6

Hz, 1H), 0.94 (d, J = 1.5 Hz, 9H), 0.12 (d, J = 1.9 Hz, 6H).

The minor α anomer had δ (ppm) = 5.09 (d, J = 3.9 Hz, 0.10 H, H-1ʹ), 2.84 (d, J = 5.3 Hz, 0.09H,

OH)

α:β = 1:10

HPLC: Luna 5 µm CN, 5% iPrOH in hexanes, 1.0 mL/min, 257 nm: tr (min) = 6.6 (α), 7.3 (β).

47

Isopropyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl D-glucopyranosyl) β-D-

thiogalactopyranoside (54)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3,4,6-tetra-O-

benzyl D-glucopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by general

procedure 4.2.1, to which the glycosyl acceptor isopropyl 6-O-tert-butyldimethylsilyl β-D-

thiogalactopyranoside124

(28.2 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg,

0.008 mmol, 0.08 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (25 % ethyl acetate in hexanes) as a white solid (58.3 mg, 83 %).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.42 – 7.25 (m, 18H, Ar-H), 7.17 (dd, J = 7.1, 2.4 Hz,

2H, Ar-H), 5.05 (d, J = 10.9 Hz, 1H, CH2Ph), 4.95 (d, J = 11.0 Hz, 1H, CH2Ph), 4.85 – 4.75 (m,

3H, CH2Ph), 4.73 (d, J = 7.8 Hz, 1H, H-1ʹ), 4.63 – 4.47 (m, 3H, CH2Ph), 4.41 (d, J = 9.8 Hz, 1H,

H-1), 4.19 – 4.14 (m, 1H, H-4), 3.92 – 3.79 (m, 3H, H-2, H-6), 3.73 – 3.44 (m, 7H, H-3, H-6, H-

2ʹ, H-3ʹ, H-4ʹ, H-5ʹ), 3.24 (heptet, J = 6.7 Hz, 1H, CH(Me)2), 2.83 – 2.75 (m, 1H, 4-OH), 2.58 (d,

J = 2.0 Hz, 1H, 2-OH), 1.35 (dd, J = 6.7, 1.3 Hz, 6H, CH(CH3)2), 0.90 (s, 9H, Si(C(CH3)3), 0.09

(s, 6H, Si(CH3)2).

The minor α anomer had δ (ppm) = 4.92 (d, J = 3.6 Hz, 0.09H, H-1ʹ), 2.50 (d, J = 2.3 Hz, 0.06H,

OH).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.6, 138.3, 138.1, 138.0, 128.6, 128.5, 128.5, 128.5,

128.1, 128.0, 127.9, 127.9, 127.9, 127.8, 127.8, 103.9, 86.0, 84.8, 84.2, 81.8, 78.9, 77.7, 75.8,

75.2, 75.0, 74.9, 73.6, 69.4, 68.9, 68.2, 62.5, 35.3, 26.0, 24.3, 24.3, 18.4, −5.2, −5.3.

HRMS (ESI+, m/z): calculated for C49H70NO10SSi [M+NH4]

+: 892.44897, found: 892.45097

α:β = 1:16

48

Phenyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl D-glucopyranosyl) α-D-

thiomannopyranoside (55)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3,4,6-tetra-O-

benzyl D-glucopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by general

procedure 4.2.1, to which the glycosyl acceptor phenyl 6-O-tert-butyldimethylsilyl α-D-

thiomannopyranoside125

(30.9 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg,

0.008 mmol, 0.08 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (25 % to 30 % ethyl acetate in hexanes) as a white solid (64.5 mg, 89 %).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.57 – 7.48 (m, 2H, Ar-H), 7.39 – 7.26 (m, 21H, Ar-H),

7.19 (dd, J = 6.7, 2.9 Hz, 2H, Ar-H), 5.55 (d, J = 1.4 Hz, 1H, H-1), 4.98 – 4.90 (m, 2H, CH2PH),

4.89 – 4.78 (m, 3H, CH2Ph), 4.61 – 4.51 (m, 4H, CH2Ph, H-1ʹ), 4.25 – 4.20 (m, 1H, H-2), 4.16

(ddd, J = 9.6, 5.4, 2.3 Hz, 1H, H-5), 4.09 (d, J = 1.6 Hz, 1H, 4-OH), 4.02 – 3.87 (m, 3H, H-4, H-

6ʹ), 3.83 (dd, J = 9.0, 3.2 Hz, 1H, H-3), 3.76 – 3.66 (m, 2H, H-3, H-6ʹa), 3.62 – 3.51 (m, 4H, H-

2ʹ, H-4ʹ, H-5ʹ, H-6ʹb), 2.45 (d, J = 4.6 Hz, 1H, 2-OH), 0.92 (s, 9H, Si(C(CH3)3), 0.09 (s, 6H,

Si(CH3)2).

The minor α anomer had δ (ppm) = 5.34 (d, J = 1.4 Hz, 0.12H, H-1), 5.01 (d, J = 3.9 Hz, 0.15H,

H-1ʹ), 3.36 (s, 0.12H, OH), 3.26 (d, J = 5.6 Hz, 0.11H, OH).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.4, 138.0, 137.8, 137.7, 134.2, 131.7, 129.1, 128.7,

128.6, 128.6, 128.5, 128.3, 128.2, 128.1, 128.1, 128.0, 127.9, 127.9, 127.5, 103.2, 87.8, 84.8,

83.6, 81.8, 77.9, 75.9, 75.4, 75.2, 74.8, 74.1, 73.7, 71.7, 69.0, 66.3, 63.1, 26.1, 18.6, -5.1, -5.1.

HRMS (ESI+, m/z): calculated for C52H68NO10SSi [M+NH4]

+: 926.4328, found: 926.4301

α:β = 1:8.6

49

Methyl 4-O-acetyl-2,3-di-O-benzyl-6-O-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl D-glucopyranosyl) α-D-

glucopyranoside (56)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3,4,6-tetra-O-

benzyl D-glucopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by general

procedure 4.2.1, to which the glycosyl acceptor methyl 2,3-di-O-benzyl α-D-glucopyranoside126

(30.0 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg, 0.008 mmol, 0.08 eq.)

were added. The title glycoside was obtained following derivatization of the crude reaction

mixture with acetic anhydride/pyridine (1:1 v/v, 2 mL) and silica gel column chromatography

(25 % to 30 % ethyl acetate in hexanes) as a white solid (47.0 mg, 63 %). Spectral features were

in agreement with those previously reported.127

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.39 – 7.27 (m, 28H), 7.21 – 7.08 (m, 2H), 5.03 (d, J =

10.9 Hz, 1H), 4.95 – 4.88 (m, 3H), 4.82 – 4.73 (m, 3H), 4.70 – 4.65 (m, 3H), 4.63 – 4.60 (m,

1H), 4.60 – 4.56 (m, 2H), 4.53 (d, J = 11.5 Hz, 1H), 4.43 (d, J = 7.9 Hz, 1H), 4.01 – 3.92 (m,

3H), 3.77 – 3.66 (m, 2H), 3.65 – 3.60 (m, 2H), 3.60 – 3.51 (m, 2H), 3.50 – 3.41 (m, 2H), 3.31 (s,

3H), 1.90 (s, 3H).

The minor α anomer had δ (ppm) = 3.38 (s, 1.34H, OCH3), 1.92 (s, 1.32H, C(O)CH3).

α:β = 1:2.2

50

Phenyl 2,3-di-O-benzyl-6-O-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl D-glucopyranosyl) β-D-

thioglucopyranoside (57)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3,4,6-tetra-O-

benzyl D-glucopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by general

procedure 4.2.1, to which the glycosyl acceptor phenyl 2,3-di-O-benzyl β-D-

thioglucopyranoside128

(35.5 mg, 0.08 mmol, 0.8 eq.) and diphenylborinic anhydride 52 (1.4 mg,

0.004 mmol, 0.04 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (30 % to 35 % ethyl acetate in hexanes) as a crystalline white solid (32.7 mg,

42%).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.58 – 7.50 (m, 3H, Ar-H), 7.44 – 7.12 (m, 32H, Ar-H),

4.99 – 4.87 (m, 4H, CH2Ph), 4.87 – 4.65 (m, 6H, CH2Ph, H-1), 4.59 (d, J = 12.2 Hz, 1H,

CH2Ph), 4.56 – 4.46 (m, 3H, CH2Ph, H-1ʹ), 4.15 (dd, J = 11.2, 3.3 Hz, 1H, H-6a), 3.90 (dd, J =

11.2, 5.4 Hz, 1H, H-6b), 3.78 – 3.38 (m, 10H), 2.61 (d, J = 2.8 Hz, 1H. OH).

The minor α anomer had δ (ppm) = 3.06 (d, J = 2.4 Hz, 0.21H, OH).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.7, 138.7, 138.5, 138.2, 138.2, 138.1, 134.0, 132.4,

131.7, 129.1, 128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.1, 128.0, 128.0, 127.9, 127.8, 127.5,

103.9, 87.8, 86.2, 84.8, 82.2, 80.7, 78.6, 77.9, 75.8, 75.6, 75.5, 75.1, 75.0, 74.9, 73.6, 71.5, 69.6,

69.0.

α:β = 1:4.7

51

Isopropyl 2,3-di-O-benzyl-6-O-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl D-glucopyranosyl) β-D-

thiogalactopyranoside (58)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3,4,6-tetra-O-

benzyl D-glucopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by general

procedure 4.2.1, to which the glycosyl acceptor isopropyl 2,3-di-O-benzyl β-D-

thiogalactopyranoside (see section 4.4) (33.5 mg, 0.08 mmol, 0.8 eq.) and diphenylborinic

anhydride 52 (1.4 mg, 0.004 mmol, 0.04 eq.) were added. The title glycoside was obtained

following silica gel column chromatography (30 % to 35 % ethyl acetate in hexanes) as a clear

colorless glass (49 mg, 66 %).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.45 – 7.38 (m, 2H, Ar-H), 7.37 – 7.23 (m, 26H, Ar-H),

7.19 – 7.11 (m, 2H, Ar-H), 4.94 – 4.87 (m, 3H, CH2Ph), 4.84 – 4.74 (m, 3H, CH2Ph), 4.73 – 4.68

(m, 3H, CH2Ph), 4.60 – 4.55 (m, 2H, CH2Ph), 4.52 (d, J = 10.9 Hz, 1H, CH2Ph), 4.49 (d, J = 7.8,

Hz, 1H, H-1ʹ), 4.48 (d, J = 9.7 Hz, 1H, H-1) 4.12 – 4.04 (m, 2H, H-4, H-6a), 3.96 (dd, J = 10.7,

6.6 Hz, 1H, H-6b), 3.72 (dd, J = 10.7, 2.1 Hz, 1H, H-6ʹa), 3.70 – 3.55 (m, 5H, H-2, H-5, H-3ʹ, H-

4ʹ, H-6ʹb), 3.53 (dd, J = 9.0, 3.3 Hz, 1H, H-3), 3.50 – 3.42 (m, 2H, H-2ʹ, H-5ʹ), 3.20 (heptet, J =

6.7 Hz, 1H, CH(Me)2), 2.72 (d, J = 3.2 Hz, 1H), 1.27 (d, J = 6.7 Hz, 3H, CH(CH3)2a), 1.23 (d, J

= 6.7 Hz, 3H, CH(CH3)2b).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.7, 138.6, 138.4, 138.2, 138.1, 138.0, 128.6, 128.5,

128.5, 128.5, 128.4, 128.1, 128.1, 128.0, 128.0, 128.0, 127.9, 127.9, 127.8, 127.8, 127.7, 104.0,

84.8, 84.6, 82.4, 82.3, 78.3, 77.9, 77.2, 75.9, 75.8, 75.1, 74.8, 74.8, 73.6, 72.2, 68.9, 68.9, 66.7,

35.0, 24.1, 23.8.

HRMS (DART+, m/z): calculated for C57H68NO10S [M+NH4]

+: 958.4558, found: 958.4558.

52

Methyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl D-galactopyranosyl) α-D-

mannopyranoside (63)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3,4,6-tetra-O-

benzyl D-galactopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by general

procedure 4.2.1, to which the glycosyl acceptor methyl 6-O-tert-butyldimethylsilyl α-D-

mannopyranoside124

(24.7 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg,

0.008 mmol, 0.08 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (30 % to 35 % ethyl acetate in hexanes) as a clear colorless glass (50.6 mg,

76%). Spectral features were in agreement with those previously reported.39

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.43 – 7.23 (m, 20H), 4.94 (d, J = 11.6 Hz, 1H), 4.90 (d,

J = 10.9 Hz, 1H), 4.84 (d, J = 10.9 Hz, 1H), 4.77 – 4.72 (m, 3H), 4.61 (d, J = 11.7 Hz, 1H), 4.48

– 4.43 (m, 2H), 4.39 (d, J = 11.8 Hz, 1H), 4.00 – 3.75 (m, 8H), 3.62 – 3.51 (m, 4H), 3.42 (dd, J =

12.1, 8.6 Hz, 1H), 3.36 (s, 3H), 2.23 (d, J = 3.7 Hz, 1H), 0.91 (s, 9H), 0.09 (s, 6H).

The minor α anomer had δ (ppm) = 5.08 (d, J = 3.9 Hz, 0.19H, H-1).

α:β = 1:5.3

53

Phenyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ,3ʹ,4ʹ,6ʹ-tetra-O-benzyl β-D-glucopyranosyl) α-D-

thiomannopyranoside (64)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3,4,6-tetra-O-

benzyl D-galactopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by general

procedure 4.2.1, to which the glycosyl acceptor phenyl 6-O-tert-butyldimethylsilyl α-D-

thiomannopyranoside (30.9 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg,

0.008 mmol, 0.08 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (20 % to 25 % ethyl acetate in hexanes) as a clear colorless glass (51.2 mg,

71%).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.62 – 7.45 (m, 2H, Ar-H), 7.43 – 7.22 (m, 23H, Ar-H),

5.56 (s, 1H, H-1), 4.96 (d, J = 11.6 Hz, 1H, CH2Ph), 4.89 (d, J = 5.0 Hz, 2H, CH2Ph), 4.82 – 4.71

(m, 2H,CH2Ph), 4.62 (d, J = 11.6 Hz, 1H, CH2Ph), 4.56 – 4.45 (m, 2H, CH2Ph, H-1ʹ), 4.41 (d, J

= 11.8 Hz, 1H, CH2Ph), 4.23 (m, 1H, H-2), 4.18 – 4.07 (m, 1H, H-5), 4.02 – 3.83 (m, 6H, H-4,

H-6, H-2ʹ, H-4ʹ, 4-OH), 3.80 (dd, J = 9.1, 2.4 Hz, 1H, H-3), 3.69 – 3.54 (m, 3H, H-3ʹ, H-5ʹ, H-

6ʹa), 3.49 – 3.38 (m, 1H, H-6ʹb), 2.50 (s, 1H, 2-OH), 0.90 (s, 9H, Si(C(CH3)3), 0.07 (s, 6H,

Si(CH3)2).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.3, 138.2, 138.2, 137.6, 134.3, 131.6, 129.0, 128.7,

128.6, 128.6, 128.5, 128.4, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.4, 103.6, 87.6, 83.7,

82.5, 79.0, 75.7, 74.7, 74.1, 73.8, 73.3, 71.6, 69.0, 66.2, 63.1, 26.1, 18.6, -5.1, -5.1.

HRMS (ESI+, m/z): calculated for C52H68NO10SSi [M+NH4]

+: 926.4328, found: 926.4329

54

Phenyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ-azido-3ʹ,4ʹ,6ʹ-tri-O-benzyl-2-deoxy D-

glucopyranosyl) α-D-thiomannopyranoside (65)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2-azido-3,4,6-tri-O-

benzyl-2-deoxy D-glucopyranose77,121

(2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared

by general procedure 4.2.1, to which the glycosyl acceptor phenyl 6-O-tert-butyldimethylsilyl α-

D-thiomannopyranoside (30.9 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg,

0.008 mmol, 0.08 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (20 % to 25 % ethyl acetate in hexanes) as a white solid (54.0 mg, 80 %).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.50 – 7.37 (m, 2H, Ar-H), 7.32 – 7.18 (m, 16H, Ar-H),

7.16 – 7.03 (m, 2H, Ar-H), 5.49 (d, J = 1.5 Hz, 1H, H-1), 4.82 (d, J = 10.8 Hz, 1H, CH2Ph), 4.79

– 4.69 (m, 2H, CH2Ph), 4.52 – 4.40 (m, 3H, CH2Ph), 4.39 (d, J = 8.0 Hz, 1H, H-1ʹ), 4.24 (m, 1H,

H-2), 4.12 – 4.03 (m, 1H, H-5), 3.93 – 3.80 (m, 4H, H-4, H-6a, H-6b, 4-OH), 3.76 (dd, J = 9.0,

3.2 Hz, 1H, H-3), 3.66 – 3.55 (m, 1H, H-6ʹa), 3.53 – 3.35 (m, 5H, H-2ʹ, H-3ʹ, H-4ʹ, H-5ʹ, H-6ʹb),

2.51 (s, 1H, 2-OH), 0.83 (s, 9H, Si(C(CH3)3), 0.00 (s, 6H, Si(CH3)2).

13C NMR (101 MHz, CDCl3): δ (ppm) = 137.7, 137.5, 134.0, 131.7, 129.0, 128.5, 128.5, 128.1,

128.1, 128.0, 128.0, 128.0, 127.9, 127.5, 101.8, 87.6, 83.8, 82.9, 77.7, 75.7, 75.2, 74.9, 73.9,

73.6, 71.5, 68.6, 66.3, 66.1, 63.1, 26.0, 18.5, -5.2, -5.2.

HRMS (ESI+, m/z): calculated for C45H61N4O9SSi [M+NH4]

+: 861.3923, found: 861.3906

55

Phenyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ,3ʹ,5ʹ-tri-O-benzyl D-arabinofuranosyl) α-D-

thiomannopyranoside (66)

The methanesulfonate of 2,3,5-tri-O-Benzyl-1-O-methanesulfonyl β-D-arabinofuranose was

prepared at −20 ° C in a Schlenk tube according to general procedure 4.2.2 to a concentration of

0.67 M (1.5 mL, 0.10 mmol, 1.0 eq.). To this solution was added boraanthracene catalyst 53 (1.6

mg, 0.008 mmol, 0.08 eq.), followed by the glycosyl acceptor phenyl 6-O-tert-butyldimethylsilyl

α-D-thiomannopyranoside (0.5 mL, 016 M in CH2Cl2, 0.08 mmol, 0.8 eq.) dropwise down the

walls of the tube over 2 min. The resulting solution was stirred overnight and then allowed to

warm slowly to ambient temperature over 6-7 hours after which time it was concentrated by air

stream. The title glycoside was obtained following silica gel column chromatography (20 % to

30 % ethyl acetate in hexanes) as a white solid (54.3 mg, 86 %).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.57 – 7.44 (m, 2H, Ar-H), 7.42 – 7.21 (m, 18H, Ar-H),

5.57 (d, J = 1.3 Hz, 1H, H-1), 5.46 (d, J = 1.0 Hz, 1H, H-1ʹ), 4.65 (d, J = 12.5 Hz, 1H, CH2Ph),

4.61 – 4.53 (m, 5H, CH2Ph), 4.35 – 4.30 (m, 2H, H-2, H-4ʹ), 4.19 – 4.15 (m, 2H, H-5, H-2ʹ), 4.00

– 3.95 (m, 2H, H-4, H-3ʹ), 3.92 – 3.85 (m, 3H, H-3, H-6), 3.62 (dd, J = 10.3, 5.5 Hz, 1H, H-5ʹa),

3.58 (dd, J = 10.3, 5.3 Hz, 1H, H-5ʹb), 3.25 (br. s, 1H, OH), 3.10 (br. s, 1H, OH), 0.92 (s, 9H,

Si(C(CH3)3), 0.10 (s, 6H, Si(CH3)2).

The minor β anomer had δ (ppm) = 5.60 (d, J = 1.3 Hz, 0.37H, H-1), 5.03 (d, J = 4.5 Hz, 0.35H,

H-1ʹ).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.1, 137.6, 137.5, 134.3, 131.5, 129.1, 128.6, 128.6,

128.5, 128.5, 128.1, 128.1, 128.0, 128.0, 127.9, 107.3, 87.2, 87.1, 83.0, 82.4, 78.5, 73.5, 72.9,

72.3, 72.0, 71.6, 71.4, 70.0, 65.3, 26.0, 18.5, -5.4, -5.4.

HRMS (ESI+, m/z): calculated for C44H60NO9SSi [M+NH4]

+: 806.3753, found: 806.3746

α:β = 2.9:1

56

Phenyl 6-O-tert-butyldimethylsilyl-3-O-(3ʹ,4ʹ,6ʹ-tetra-O-benzyl-2ʹ -deoxy D-glucopyranosyl)

α-D-thiomannopyranoside (67)

The methanesulfonate of 3,4,6-tri-O-2-deoxy D-glucopyranoside was prepared at −20 ° C in a

Schlenk tube according to general procedure 4.2.2 to a concentration of 0.67 M (1.5 mL, 0.10

mmol, 1.0 eq.). To this solution was added boraanthracene catalyst 53 (1.6 mg, 0.008 mmol, 0.08

eq.), followed by the glycosyl acceptor phenyl 6-O-tert-butyldimethylsilyl α-D-

thiomannopyranoside (0.5 mL, 016 M in CH2Cl2, 0.08 mmol, 0.8 eq.) dropwise down the walls

of the tube over 2 min. The resulting solution was stirred overnight and then allowed to warm

slowly to ambient temperature over 6-7 hours after which time it was concentrated by air stream.

The title glycoside was obtained following silica gel column chromatography (25 % to 30 %

ethyl acetate in hexanes) as a white solid (37.7 mg, 59 %).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.51 – 7.39 (m, 2H, Ar-H), 7.34 – 7.08 (m, 18H, Ar-H),

5.48 (s, 1H, H-1), 4.83 (d, J = 10.9 Hz, 1H, CH2Ph), 4.67 – 4.42 (m, 6H, CH2Ph, H-1ʹ), 4.24 (br.

s, 1H, 4-OH), 4.12 (m, 1H, H-2), 4.09 – 4.02 (m, 1H, H-5), 3.91 (d, J = 11.1 Hz, 1H, H-6a), 3.86

– 3.76 (m, 2H, H-4, H-6b), 3.74 – 3.58 (m, 3H, H-3, H-3ʹ, H-6ʹb), 3.57 – 3.45 (m, 2H, H-5ʹ, H-

6ʹb), 3.40 (dd, J = 8.9 Hz, 8.9 Hz, 1H, H-4ʹ), 2.47 (s, 1H, 2-OH), 2.36 (dd, J = 12.6, 4.2 Hz, 1H,

H-2a), 1.72 (ddd, J = 11.4 Hz, 11.4 Hz, 11.4 Hz, 1H, H-2b), 0.83 (s, 9H, Si(C(CH3)3), 0.00 (s,

6H, Si(CH3)2).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.2, 138.2, 137.9, 134.2, 131.7, 129.1, 128.6, 128.5,

128.5, 128.2, 128.1, 128.0, 127.9, 127.9, 127.8, 127.5, 100.0, 87.7, 83.0, 79.2, 77.9, 75.2, 75.0,

74.2, 73.7, 72.0, 71.8, 69.3, 66.3, 63.1, 37.1, 26.1, 18.6, -5.1, -5.1.

57

Methyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ,3ʹ-di-O-benzyl-4ʹ,6ʹ-O-benzylidene D-

galactopyranosyl) α-D-mannopyranoside (68)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3-di-O-benzyl 4,6-

O-benzylidene D-galactopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by

general procedure 4.2.1, to which the glycosyl acceptor methyl 6-O-tert-butyldimethylsilyl α-D-

mannopyranoside (24.7 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg, 0.008

mmol, 0.08 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (30 % to 35 % ethyl acetate in hexanes) as a clear colorless glass (39.0 mg,

66%).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.59 – 7.46 (m, 4H, Ar-H), 7.44 – 7.26 (m, 26H, Ar-H),

5.48 (s, 0.96H, PhCHβ), 5.47 (s, 1.10H, PhCHα), 5.22 (d, J = 3.2 Hz, 1.08H, H-1ʹα), 4.92 – 4.84

(m, 3H, CH2Ph), 4.82 – 4.67 (m, 6H, CH2Ph), 4.48 (d, J = 7.7 Hz, 0.87H, H-1ʹβ), 4.31 – 4.18 (m,

3H), 4.16 – 4.05 (m, 4H), 4.04 – 3.94 (m, 4H), 3.94 – 3.88 (m, 3H), 3.86 – 3.75 (m, 7H), 3.66 –

3.53 (m, 4H), 3.51 (br. s, 1H, 4-OH), 3.38 (s, 3.65H, CH3α), 3.37 (s, 2.69H, CH3β), 2.23 (d, J =

4.0 Hz, 0.90H, 2-OHβ), 2.01 (s, 1H, 2-OHα), 0.92 (s, 9H, Si(C(CH3)3), 0.09 (s, 6H, Si(CH3)2).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.7, 138.4, 138.2, 138.1, 137.9, 137.8, 129.2, 129.0,

128.6, 128.6, 128.6, 128.5, 128.3, 128.3, 128.2, 128.0, 128.0, 128.0, 127.9, 127.8, 127.7, 126.5,

126.4, 102.7, 101.5, 101.4, 101.2, 100.9, 100.5, 82.6, 82.6, 79.7, 76.6, 75.7, 74.3, 73.5, 73.0,

72.4, 72.0, 71.8, 70.9, 69.6, 69.5, 69.0, 67.1, 66.9, 65.9, 63.5, 63.3, 63.3, 55.0, 54.7, 26.1, -5.1, -

5.2.

α:β = 1.2:1

HPLC: Luna 5 µm CN, 5% iPrOH in hexanes, 1.0 mL/min, 257 nm: tr (min) = 14.4 (α), 18.0 (β).

58

Methyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ,3ʹ-di-O-benzyl-4ʹ,6ʹ-O-benzylidene D-

glucopyranosyl) α-D-mannopyranoside (69)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3-di-O-benzyl 4,6-

O-benzylidene D-glucopyranose (2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared by

general procedure 4.2.1, to which the glycosyl acceptor methyl 6-O-tert-butyldimethylsilyl α-D-

mannopyranoside (24.7 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg, 0.008

mmol, 0.08 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (25 % to 30 % ethyl acetate in hexanes) as a clear colorless glass (41.1 mg,

70%).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.56 – 7.44 (m, 2H), 7.45 – 7.27 (m, 13H), 5.57 (s, 1H,

PhCH), 4.96 (d, J = 11.3 Hz, 1H, CH2Ph), 4.92 – 4.84 (m, 2H, CH2Ph), 4.80 (d, J = 11.3 Hz,

1H, CH2Ph), 4.74 (d, J = 1.5 Hz, 1H, H-1), 4.58 (d, J = 7.8 Hz, 1H, H-1ʹ), 4.36 (dd, J = 10.4, 5.0

Hz, 1H, H-6ʹa), 3.98 – 3.91 (m, 2H, H-2, H-6a), 3.90 – 3.86 (m, 1H, H-6b), 3.85 – 3.76 (m, 5H,

H-3, H-5, H-3ʹ, H-4ʹ, H-6ʹb), 3.73 (dd, J = 9.2, 9.2 Hz, 1H, H-4), 3.56 (dd, J = 8.1, 7.9 Hz, 1H,

H-2ʹ), 3.46 (ddd, J = 9.8, 9.8, 5.0 Hz, 1H, H-6ʹ), 3.37 (s, 3H, CH3), 3.33 (s, 1H, 4-OH), 2.20 (d, J

= 3.5 Hz, 1H, 2-OH), 0.92 (s, 9H, Si(C(CH3)3), 0.19 (s, 6H, Si(CH3)2).

The minor α anomer had δ (ppm) = 5.17 (d, J = 3.9 Hz, 0.14H, H-1ʹ), 4.72 (d, J = 1.7 Hz, H-1,

0.13H).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.4, 137.9, 137.2, 129.2, 128.7, 128.5, 128.4, 128.3,

128.2, 128.2, 127.9, 126.1, 102.2, 101.4, 100.5, 81.7, 81.5, 81.4, 81.3, 75.8, 75.3, 72.1, 68.8,

68.6, 66.7, 66.5, 63.8, 54.9, 26.1, 18.5, -5.2.

α:β = 1:7.7

59

Methyl 6-O-tert-butyldimethylsilyl-3-O-(2ʹ,3ʹ-di-O-benzyl-4ʹ,6ʹ-O-benzylidene α-D-

mannopyranosyl) α-D-mannopyranoside (70)

Prepared according to general procedure 4.2.2 from the methanesulfonate of 2,3-di-O-benzyl 4,6-

O-benzylidene D-mannopyranose129

(2 mL, 0.05 M in CH2Cl2, 0.10 mmol, 1.0 eq.) as prepared

by general procedure 4.2.1, to which the glycosyl acceptor methyl 6-O-tert-butyldimethylsilyl α-

D-mannopyranoside (24.7 mg, 0.08 mmol, 0.8 eq.) and boraanthracene catalyst 53 (1.6 mg,

0.008 mmol, 0.08 eq.) were added. The title glycoside was obtained following silica gel column

chromatography (30 % to 35 % ethyl acetate in hexanes) as a clear colorless glass (39.0 mg,

66%).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.57 – 7.44 (m, 2H, Ar-H), 7.44 – 7.26 (m, 13H, Ar-H),

5.64 (s, 1H, PhCH), 5.33 (d, J = 1.0 Hz, 1H, H-1), 4.87 – 4.72 (m, 3H, CH2Ph), 4.70 – 4.59 (m,

2H, CH2Ph, H-1ʹ), 4.33 – 4.20 (m, 2H, H-3ʹ, H-6ʹa), 3.99 – 3.84 (m, 8H, H-2, H-4, H-6, H-2ʹ, H-

4ʹ, H-6ʹb), 3.81 (dd, J = 10.1, 7.2 Hz, 1H, H-3), 3.65 – 3.53 (m, 1H, H-5), 3.37 (s, 3H, CH3), 3.10

(br. s, 1H, 2-OH), 2.05 (br. s, 1H, 4-OH), 0.93(s, 9H, Si(C(CH3)3), 0.12 (s, 6H, Si(CH3)2).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.8, 138.2, 137.8, 128.9, 128.5, 128.4, 128.3, 127.8,

127.7, 127.6, 126.2, 101.5, 100.9, 100.6, 79.2, 77.8, 76.3, 76.2, 73.4, 73.2, 71.2, 70.5, 70.0, 68.9,

65.7, 65.0, 55.1, 26.0, 18.4, -5.4, -5.4.

60

1,2-O-Isopropylidene 5-O-(2ʹ,3ʹ,5ʹ-tri-O-benzyl α-D-arabinofuranosyl) α-D-Glucofuranose

(75)

The methanesulfonate of 2,3,5-tri-O-Benzyl-1-O-methanesulfonyl β-D-arabinofuranose was

prepared at −20 ° C in a Schlenk tube according to general procedure 4.2.2 to a concentration of

0.67 M (1.5 mL, 0.10 mmol, 1.0 eq.). To this solution was added boraanthracene catalyst 53 (1.6

mg, 0.008 mmol, 0.08 eq.), followed by the glycosyl acceptor 1,2-O-isopropylidene α-

glucofuranose (17.6 mg, 0.08 mmol, 0.8 eq.). The resulting solution was stirred overnight and

then allowed to warm slowly to ambient temperature over 6-7 hours after which time it was

concentrated by air stream. The title glycoside was obtained following silica gel column

chromatography (45 % to 50 % ethyl acetate in hexanes) as a colorless glass. (37.6 mg, 76 %).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.40 – 7.20 (m, 15H, Ar-H), 5.90 (d, J = 3.6 Hz, 1H, H-

1), 5.32 (d, J = 1.3 Hz, 1H, H-1ʹ), 4.60 – 4.43 (m, 7H, CH2Ph, H-2), 4.33 (ddd, J = 5.2, 5.2 , 5.2

Hz, 1H, H-4ʹ), 4.22 (d, J = 2.7 Hz, 1H, H-3), 4.18 (ddd, J = 6.5, 6.5, 3.0 Hz, 1H, H-5), 4.08 (dd, J

= 6.0, 2.6 Hz, 1H, H-4), 4.02 (dd, J = 2.8, 1.4 Hz, 1H, H-2ʹ), 3.95 (dd, J = 5.2, 2.7 Hz, 1H, H-3ʹ),

3.83 (d, J = 12.2 Hz, 1H, H-6a), 3.71 (dd, J = 12.0, 6.8 Hz, 1H, H-6b), 3.58 (dd, J = 10.5, 3.4 Hz,

1H, H-5ʹa), 3.56 (dd, J = 10.5, 3.0 Hz, 1H, H-5ʹb), 3.29 (br. s, 1H, 3-OH), 3.11 (s, 1H, 6-OH),

1.49 (s, 3H, CH3a), 1.31 (s, 3H, CH3b).

The minor β anomer had δ (ppm) = 5.25 (d, J = 4.8 Hz, 0.04H, H-1ʹ)

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.0, 137.4, 137.3, 128.7, 128.6, 128.5, 128.2, 128.1,

128.1, 127.9, 127.8, 111.8, 106.9, 104.6, 87.1, 85.3, 82.9, 82.2, 79.0, 77.9, 75.4, 73.5, 72.4, 72.1,

69.8, 63.4, 26.9, 26.3.

HRMS (ESI+, m/z): calculated for C35H46NO10 [M+NH4]

+: 640.3116, found: 604.3118

61

1,2-O-Isopropylidene 6-O-(2ʹ,3ʹ,5ʹ-tri-O-benzyl D-arabinofuranosyl) α-D-Glucofuranose

(76)

Isolated separately as a colorless glass (6.7 mg, 13 %) admixed with a small amount of the O-5

regioisomer (75).

Selected resonances:

1H NMR (400 MHz, CDCl3): δ (ppm) = δ 5.95 (d, J = 3.7 Hz, 1H, H-1β), 5.10 (s, 0.71H, H-1ʹα),

4.85 (d, J = 4.5 Hz, 0.30H, H-1ʹβ).

α:β = 2.4:1

62

4.4 Acceptor Synthesis

Isopropyl 2,3-di-O-benzyl β-D-thiogalactopyranoside

Scheme 13: Preparation of Isopropyl 2,3-di-O-benzyl β-D-thiogalactopyranoside

Isopropyl 2,3-di-O-benzyl-4,6-O-benzylidene β-D-thiogalactopyranoside120

(253.2 mg, 0.50

mmol, 1.0 eq.), para-toluenesulfonic acid monohydrate (9.5 mg, 0.05 mmol, 10 mol %), and

methanol (5 mL) were combined in a scintillation vial and sonicated for a total of 2 hours with

15 minute cycles. The homogenous solution thus obtained was quenched with a few drops of

triethylamine, concentrated with a stream of air and purified by silica gel column

chromatography (70 % ethyl acetate in hexanes) to give the title compound as a white solid

(192.6 mg, 92 %).

1H NMR (400 MHz, CDCl3): δ (ppm) = 7.45 – 7.27 (m, 10H, Ar-H), 4.90 (d, J = 10.2 Hz, 1H,

CH2Ph), 4.82 – 4.65 (m, 3H, CH2Ph), 4.50 (d, J = 9.7 Hz, 1H, H-1), 4.04 (ddd, J = 3.3, 2.3, 1.1

Hz, 1H, H-4), 3.95 (ddd, J = 11.3, 6.8, 4.2 Hz, 1H, H-6a), 3.78 (ddd, J = 11.8, 8.4, 4.5 Hz, 1H,

H-6b), 3.65 (dd, J = 9.3 Hz, 9.3 Hz, 1H, H-2), 3.56 (dd, J = 8.9, 3.3 Hz, 1H, H-3), 3.48 (ddd, J =

6.8, 4.6, 1.1 Hz, 1H), 3.24 (heptet, J = 6.8 Hz, 1H, CH(Me)2), 2.65 (dd, J = 2.3, 1.1 Hz, 1H, 4-

OH), 2.18 (dd, J = 8.5, 4.3 Hz, 1H, 6-OH), 1.35 (d, J = 6.8 Hz, 6H, CH(CH3)2).

13C NMR (101 MHz, CDCl3): δ (ppm) = 138.3, 137.8, 128.7, 128.5, 128.4, 128.2, 128.0, 127.9,

84.9, 82.4, 78.2, 78.0, 76.0, 72.4, 67.5, 62.9, 35.6, 24.1.

HRMS (DART+, m/z): calculated for C23H34NO5S [M+NH4]

+: 436.21577, found: 436.21697.

63

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Appendix A: 1H,

13C and 2D NMR Spectra

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Appendix B: DFT Calculations

Geometry optimizations and single point energy calculations of the diphenylborinates and their

1-e- oxidised forms were carried out using density functional theory (B3LYP functional), with

the 6-31+G** basis set.

X Y Z

O -0.540247 3.231089 2.540667

C 1.076614 0.716829 -0.6864

C 2.895543 -0.09155 0.773661

C 1.187739 1.498576 0.649553

C 2.07345 -0.46052 -0.47627

O 2.530592 1.242018 1.124202

O 3.061345 -0.59209 -1.51417

C 0.136748 1.055645 1.682087

O -1.139687 1.065317 1.09057

O 4.244944 -0.18168 0.388994

C 4.319733 -0.1144 -1.04418

O -0.209923 0.362681 -1.08056

C 0.072777 1.993378 2.893662

C 4.576967 1.326489 -1.50264

C 5.409777 -1.07396 -1.50745

B -1.311166 0.156049 -0.08826

C -2.720618 0.549526 -0.81367

C -3.887263 0.802325 -0.067

C -5.1041 1.127706 -0.67533

C -5.193531 1.202592 -2.06993

C -4.050735 0.954252 -2.83725

C -2.838621 0.636586 -2.21301

C -1.363278 -1.42144 0.411917

C -1.796902 -1.78668 1.701202

C -1.897323 -3.1227 2.10721

C -1.567186 -4.15232 1.220028

C -1.138975 -3.82314 -0.07099

C -1.041022 -2.48218 -0.45791

141

H -1.241291 2.978166 1.913227

H 1.510746 1.337099 -1.4841

H 2.766603 -0.7517 1.637741

H 1.108276 2.578252 0.496863

H 1.542983 -1.4104 -0.39528

H 0.40276 0.045287 2.043582

H -0.503628 1.500464 3.692883

H 1.077757 2.212568 3.268936

H 5.547874 1.669845 -1.1302

H 4.576352 1.374975 -2.59643

H 3.806235 1.99376 -1.11369

H 5.461218 -1.08064 -2.60048

H 6.381428 -0.76566 -1.10914

H 5.180681 -2.08276 -1.15546

H -3.837078 0.749903 1.018618

H -5.98335 1.322585 -0.06323

H -6.137812 1.452186 -2.54973

H -4.1034 1.012773 -3.92346

H -1.951621 0.462642 -2.81708

H -2.060993 -0.99799 2.403436

H -2.232935 -3.36139 3.115327

H -1.643365 -5.19295 1.528273

H -0.880746 -4.61255 -0.77519

H -0.705815 -2.24357 -1.4655

Energy = -1291.09987349 Hartree

142

X Y Z

O -1.632533 -0.112263 1.951687

C 2.056738 1.095008 0.043966

C 3.405889 -0.531678 -1.143589

C 1.726138 -0.354593 0.460682

C 3.436546 0.913658 -0.593809

O 2.270705 -1.159112 -0.616830

O 4.463101 0.884108 0.402654

C 0.265555 -0.717851 0.709537

O -0.628517 -0.096934 -0.197116

O 4.628507 -1.117205 -0.682492

C 5.369266 -0.172408 0.095122

O 1.205318 1.614518 -0.954609

C -0.246504 -0.261378 2.095587

C 6.547198 0.355957 -0.733620

C 5.814795 -0.823673 1.398705

B -1.983008 -0.051675 0.493222

C -2.740612 1.343921 0.110968

C -3.048109 1.691291 -1.219060

C -3.688555 2.890722 -1.545311

C -4.059601 3.785591 -0.534999

C -3.775123 3.463360 0.795579

C -3.123672 2.263078 1.104906

C -2.881281 -1.359733 0.075785

C -2.680382 -2.052030 -1.133042

C -3.458898 -3.158442 -1.496002

C -4.475184 -3.609929 -0.648542

C -4.695213 -2.943703 0.563308

C -3.908176 -1.841598 0.911336

H 2.112465 1.758234 0.919388

H 3.371090 -0.637713 -2.230383

H 2.287911 -0.581798 1.381079

H 3.632041 1.679596 -1.351767

H 0.182896 -1.815169 0.632361

H 0.329004 1.169022 -0.829838

H 0.231036 0.695380 2.385180

143

H -0.009387 -1.000772 2.876953

H 6.179931 0.842575 -1.642137

H 7.124011 1.084600 -0.154895

H 7.204135 -0.469472 -1.025476

H 4.940638 -1.193395 1.939450

H 6.484487 -1.663386 1.190079

H 6.341630 -0.096322 2.024178

H -2.780442 1.004885 -2.020486

H -3.901714 3.127930 -2.586329

H -4.562430 4.718405 -0.782269

H -4.058279 4.149604 1.592501

H -2.896539 2.022048 2.140823

H -1.881051 -1.722327 -1.793825

H -3.269418 -3.671178 -2.437921

H -5.083447 -4.469087 -0.924386

H -5.478583 -3.288046 1.237069

H -4.082470 -1.343570 1.863158

Energy = -1291.10198926 Hartree