Carbohydrate Research 381 (2013) 112–122

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Carbohydrate Research
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Applications of organoboron compounds in carbohydrate chemistry

and glycobiology: analysis, separation, protection, and activation
Corey A. McClary, Mark S. Taylor ⇑
Department of Chemistry, University of Toronto, 80 St. George St., Toronto, ON M5S 3H6, Canada

a r t i c l e i n f o a b s t r a c t

Article history: The reversible covalent interactions between organoboron compounds and diols have been applied for
Received 15 July 2013 many years in carbohydrate chemistry. They form the basis of efficient methods for the detection of car-
Received in revised form 4 September 2013 bohydrates, and applications in cellular imaging and glycoprotein analysis are beginning to emerge. The
Accepted 6 September 2013
interactions are also of widespread utility in carbohydrate synthesis: depending upon the coordination
Available online 16 September 2013
geometry at boron, either protection or activation of a bound diol motif may be achieved. This review
article uses recent examples to illustrate the breadth of applications of organoboron compounds in car-
Keywords:
bohydrate chemistry.
Carbohydrates
Boronic acids
Ó 2013 Elsevier Ltd. All rights reserved.
Fluorescence
Drug delivery
Glycosylation
Catalysis

1. Introduction 2. Boronic acid–carbohydrate interactions

Interactions between carbohydrates and boron-based com-
pounds have a rich history. As part of his landmark work on the
structural elucidation of the sugars, Emil Fischer noted that the rel-
atively low specific rotations of the hexitols could be increased by
carrying out the measurements in the presence of boric acid.1
Benner and co-workers have proposed that complexation of
pentose-type sugars by borate guided the prebiotic synthesis of
the carbohydrates from formaldehyde and glycolaldehyde, thus
suggesting a key role for these interactions in the origin of life on
Earth.2 Given these auspicious beginnings, it is perhaps not surpris-
ing that boron compounds play important and diverse roles in mod-
ern carbohydrate chemistry, with applications as analytical probes,
components of chromatographic stationary phases, and tools for
chemical synthesis. The goal of this review article is to illustrate
the broad range of ways in which organoboron–saccharide interac-
tions have been exploited by carbohydrate chemists, with a focus
on results obtained since the publication of previous review articles
related to this topic.3,4 A brief introduction to the nature of the
interactions will be followed by discussion of their applications in
carbohydrate detection, biological imaging, drug delivery, and sep-
aration science. The final two sections of the review highlight the
utility of organoboron compounds in carbohydrate synthesis,
including protection and activation of hydroxyl (OH) groups.
⇑ Corresponding author. Tel.: +1 416 946 0571; fax: +1 416 978 8775.
E-mail address: mtaylor@chem.utoronto.ca (M.S. Taylor).
Key equilibria involved in boronic acid–diol complexation are
shown in Scheme 1. Since the early 1950s, it has been recognized
that diols and boronic acids can undergo reversible condensation
reactions to generate cyclic boronic esters (Eq. 1).5 In non-coordinat-
ing solvent, these complexes are tricoordinate at boron and thus can
act as Lewis acids through intra- or intermolecular interaction with a
Lewis base (Eq. 2). Complexation of a Lewis base has significant ef-
fects on the reactivity of the bound diolate ligands, as discussed in
Sections 6 and 7 of this review. In aqueous solvent, coordination of
water to boron acidifies the OH groups so that ionization to a hydro-
nium ion/borate pair can take place (Eq. 3).6 In general, the pKa of a
cyclic boronic ester is lower than that of its parent boronic acid, due
to relief of angle strain in tetrahedral versus trigonal cyclic boro-
nates. For example, the pKa of phenylboronic acid is 8.8 whereas that
of its fructose ester is 4.6.7 The increase in Brønsted acidity that
accompanies boronic ester formation has important consequences.
It enables indirect determination of boronic acid–diol association
constants by measuring changes in solution pH, as was first demon-
strated by Lorand and Edwards in 1959.6 It also implies that there ex-
ists a pH range at which a given boronic acid will exist largely in its
neutral, tricoordinate form while the anionic, tetracoordinate form
will predominate for a corresponding cyclic boronic ester.
2Molecules that can ‘report’ this change in coordination number
(e.g., due to changes in optical absorbance or emission) have the po-
tential to act as carbohydrate sensors. Compounds of this type are
discussed in Sections 3 and 4.

0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.09.001
 C. A. McClary, M. S. Taylor / Carbohydrate Research 381 (2013) 112–122
Scheme 1. Equilibria involved in boronic acid–diol complexation.
Carbohydrates generally contain several hydroxyl groups, and
thus a given monosaccharide can give rise to numerous boronic
ester regioisomers. The majority of the applications discussed
below hinge on the fact that organoboron–carbohydrate interac-
tions do not take place indiscriminately, but rather are sensitive
to differences in conformational, steric, and electronic properties
of the diol motif in question. Generalizations that can be made in
this regard include the favorable complexation of: 1,2- versus
1,3-diol motifs; cis- versus trans-1,2-diol stereoisomers in cyclic
systems; and furanosides versus pyranosides.8 Complexation of
nonreducing sugars (e.g., hexopyranosides) by boronic acids is gen-
erally less favorable than that of carbohydrates having a free 1-OH
group: the groups of Hall9 and Wang10 have recently disclosed
examples of organoboron compounds able to bind to this former
class of analytes.
3. Organoboron-based carbohydrate sensors
Since Czarnik and Yoon reported the first example of a fluores-
cent chemosensor capable of signaling the binding of fructose
based on the pKa modulation concept described in the previous
section (Scheme 2),11 the selective detection of saccharides in the
aqueous phase has attracted considerable interest. Applications
of such systems can be envisioned in medical diagnostics, indus-
trial process monitoring, and quality control. Boronic acid probes
offer the key advantage of thermodynamically favorable binding
to carbohydrates in polar protic solvents, which typically compete
Scheme 2. Anthrylboronic acid sensor for polyols developed by Czarnik and Yoon.
113
with binding of guests to hydrogen bonding-based receptors. For
example, the association constant between phenylboronic acid
and fructose is 210 M–1 in pH 7.5 phosphate buffer.7
Shinkai and co-workers provided an important breakthrough
with their report of a benzylboronate-functionalized anthrace-
nylmethylamine that showed enhanced emission in the presence
of polyols (Scheme 3).12 It was proposed that polyol binding re-
sulted in a more favorable B–N interaction than in the unbound
boronic acid, thus reducing the extent of photoinduced electron
transfer (PET) and quenching of anthracene fluorescence. More re-
cent investigations by the groups of Wang13 and Anslyn14 have
pointed toward an alternative structure for boronic esters of such
(aminomethyl)arylboronic acids, in which a solvent molecule is
interposed between the B and N atoms. Whether the direct, dative
B–N interaction or the solvent-inserted boronate–ammonium
dominates is dependent on the identity of the solvent, as well as
the steric and electronic properties of the boronate and amine moi-
eties. While these details continue to be unraveled, the design dis-
closed by Shinkai and co-workers has proved to be general, and has
served as the basis for a large number of the organoboron-based
carbohydrate sensors developed to date.
The use of boronic acids in saccharide sensors has been the sub-
ject of several definitive review articles.3 The following paragraphs
highlight some of the most recent developments in the field. After
the initial demonstrations that boronic acids could be used as the
basis for fluorescent chemosensors for carbohydrates, the focus
shifted to the development of methods for selective saccharide
detection15 and the introduction of more efficient fluorophores.
Receptors composed of multiple boronic acid residues linked by
different spacer groups have proved to be useful in achieving these
goals, with spatial and/or stereochemical complementarity be-
tween the boronic acid moieties in the receptor and diols in the
analyte imparting selectivity.
Chiral fluorescent receptors have been employed for differentia-
tion between enantiomeric pairs of sugars and sugar derivatives.16
Recently disclosed examples are shown in Figure 1. Bis-boronic acid
receptors (R,R)- and (S,S)-1 exhibited substantially different associ-
ation constants for the two antipodes of various sugar alcohols,
with enantioselectivity factors (KR : KS) as high as 1:2000 being ob-
served in the case of D-mannitol (in a methanol/brine mixture).17,18
The receptors displayed higher affinity for sugar alcohols derived
from hexoses than for those derived from pentoses or tetroses.
The chirality of the receptor also had an effect on chemoselectivity:
for example, the enantiomeric receptors (S,S)- and (R,R)-1
displayed selectivities for binding D-glucaric acid over D-sorbitol
of 260:1 and 790:1, respectively. Discrimination between D- and
L-tartaric acid, as well as selective binding of disaccharides and gin-
senosides Re and Rb1 (Fig. 2), was achieved with phenothiazine
sensors 2 and 3.19
The geometry and properties of the linker group play key roles
in tuning the selectivity of bis-boronic acid receptors. The groups
of Anslyn and Sessler designed a porphyrin-based receptor for
ginsenosides, based on the idea that the boronic acids would inter-
act with the saccharide moieties on the periphery while bringing
the hydrophobic surfaces of the steroid and the porphyrin into
contact (Fig. 3).20 Receptor 4 showed association constants of
3900 M–1 and 2500 M–1 for ginsenosides Re and Rb1, respectively,
in DMSO/aqueous HEPES buffer. Bis-boronic acid receptor S,S-3
(Fig. 2) displayed higher affinity for these two analytes
(6.79  105 and 2.88  105 M–1, respectively, in pH 7.4 methanol/
water). While association constants determined in different
solvents cannot be compared directly, it appears that the bis-boro-
nic acid binding pocket of S,S-3 shows particularly good
complementarity with ginsenoside analytes.
Libraries of boronic acid sensors have been developed for pat-
tern-based discrimination of saccharides based on array sensing
114 C. A. McClary, M. S. Taylor / Carbohydrate Research 381 (2013) 112–122

Scheme 3. An amine–boronic acid chemosensor for carbohydrates.

Figure 1. Chiral fluorescent receptors for sugars and sugar derivatives.

Figure 2. Ginsenosides Re and Rb1.

 C. A. McClary, M. S. Taylor / Carbohydrate Research 381 (2013) 112–122 115

4. Applications of boronic acid–carbohydrate interactions in

cellular imaging and drug delivery

Carbohydrate-based biomarkers—for example, the sialyl Lewis

Figure 3. Porphyrin-based bis(boronic acid) receptor for ginsesolides.
schemes and multicomponent indicator displacement assays.21
These modular, versatile, and easily implemented assays employ
indicator dyes (e.g., catechol derivatives) capable of reversible
covalent interaction with a boronic acid group. Interaction of an
analyte with the boronic acid group triggers a change in color or
fluorescence quantum yield of the solution due to the release of
the indicator dye. Using a suite of bis-boronic acid receptors having
various linkers, the group of Anslyn developed an indicator ensem-
ble that enabled discrimination between structurally similar ginse-
nosides and ginsengs.22
The group of James has developed a fluorescent ‘molecular
tweezer’ for carbohydrate sensing (Fig. 4). The presence of the
two pyrene units increases the hydrophobicity of the binding pock-
et and also offers the possibility of sensing through modulation of
excimer (excited state dimer) emission. The distinct modes of
fluorescence response observed were attributed to binding-in-
duced decreases in PET or excimer emission upon formation of
1:2 or 1:1 complexes with carbohydrates. Association constants
of 5 for monosaccharides ranged from 200 to 2660 M–1 in pH 8.2
phosphate buffer (methanol/water), and followed the order D-glu-
cose  D-galactose > D-mannose.23
James and co-workers have employed boronic acid-containing
polyacrylamide hydrogels (borogels) in indicator-displacement
assays for carbohydrate analytes.24 The borogels were exposed
to alizarin red-S (ARS), an indicator dye that undergoes a hypso-
chromic shift (manifested in a color change from red to orange)
upon complexation of the catechol to boron.21 Washing with
phosphate buffer then removed any residual dye that was not
bound to boron. Exposure of the borogels bound to ARS to fruc-
tose caused the release of the dye into solution as fructose dis-
placed the dye through transesterification. This technique was
used to determine the relative amounts of saccharides in fruit
juice samples.
(HO) 2B
O derived from healthy tissue.
N
N The group of Miyahara has developed a self-regulated insulin
H delivery system based on stimulus-responsive ‘smart gels’.29 By
H the authors sought to create a system in which insulin release
N
O
N could be triggered by increases in glucose concentration, thus
(HO) 2B
5 tion) of the gel and release of encapsulated insulin. At lower
Figure 4. A boronic acid–based bis(pyrene) ‘molecular tweezer’.
X (sLeX), sialyl Lewis Y (sLeY) and sialyl Lewis a (sLea) antigens
(Fig. 5)—have been correlated with the development and progres-
sion of certain diseases. The development of gastrointestinal, pan-
creatic, and breast cancers has been linked with the overexpression
of sLeX-containing mucins on cell surfaces.25 In an effort to develop
sensors capable of selectively identifying cells expressing the sLeX
antigen, the group of Wang explored a series of molecules contain-
ing two boronic acid moieties capable of binding to vicinal-diol
structural motifs in sLeX, interspaced with a linker (Fig. 6).26 The
length and nature of the linker were varied with the goal of achiev-
ing a complementary spatial arrangement between the boronic
acid groups of the sensor and the diol structures of sLeX. To trans-
duce the binding event into a measurable signal, the Wang group
adopted the anthracene-based PET fluorescence system previously
developed by Shinkai.12b
By measuring the change in fluorescence intensity upon binding
with sLeX (methanol/0.1 M phosphate buffer) for a suite of
compounds having various linkers R, the authors discovered that
a simple phenyl linker (6) gave the greatest response. Changing
the linker had a profound effect on the selectivity of the probe
compound. Receptor 6 showed no affinity for sLeY, whereas 7
showed high selectivity for sLeY over sLeX and 8 had poor affinity
for both sLeX and sLeY. To test whether 6 could be used to label
cells expressing sLeX, a series of cell lines were incubated with 6
and then examined under fluorescence microscopy. The HEPG2 cell
line was chosen as a cell line known to selectively express sLeX on
the cell surface, whereas HEP3B expresses only the Lewis Y antigen
and COS7 does not express the fucosylated antigens associated
with carcinoma progression. As judged by fluorescence micros-
copy, 6 labeled the HEPG2 cell line (expressing sLeX), 7 labeled
the HEP3B cell line, and 8 labeled neither. The COS7 control cell
line did not undergo labeling by any of the probe compounds.
The work provides a compelling demonstration of the ability of
small organic molecules to selectively label cells based on the rec-
ognition of distinct cell-surface oligosaccharides.
The Wang group adapted their bis-boronic acid receptor
design for use in Targeted Multiplex Mass Spectrometry Imaging
(TAMSIM).27 This technique employs affinity molecules outfitted
with photo-cleavable tags of characteristic mass/charge ratio,
which are released upon laser irradiation. It provides a way to
probe the distribution of one or several analytes in a tissue sec-
tion.28 A derivative of sLeX-selective receptor 6 was conjugated to
a trityl thioether by copper-catalyzed azide–alkyne cycloaddition
(9, Fig. 7). Frozen renal tissue samples containing both normal
and tumor regions were incubated with 9, washed with buffer to
remove unbound material and then analyzed by MALDI–TOF with-
out addition of matrix material. Irradiation with the laser triggered
fragmentation and loss of the substituted trityl cation, which was
detected as arising from the tumor region but not from the sections
incorporating substituted arylboronic acid groups into the gels,
mimicking the function of a biofeedback system. The design
hypothesis is shown in Scheme 4. Interactions with glucose gener-
ate the tetracoordinate, anionic adduct, causing swelling (hydra-
glucose concentrations, the equilibrium is shifted toward the un-
charged, tricoordinate form, triggering dehydration and collapse
116 C. A. McClary, M. S. Taylor / Carbohydrate Research 381 (2013) 112–122

HO
OH
OH OH
HO COOH OH O
OH OH OH
O O O O O
AcHN O O OH HO O O
HO OH NHAc O O OH
OH O OH NHAc
OH OH O
OH OH
HO OH
HO
sLe x sLe y

Figure 5. Structures of the sialyl Lewis X and sialyl Lewis Y tetrasaccharides.

of the gel and the formation of a skin layer30 that inhibits the re-
–R– = lease of insulin. The acrylamide monomers used to prepare the glu-
(HO) 2B B(OH) 2
CH 3 CH3 cose-responsive gels are depicted in Figure 8. An electron-deficient
N N 6
arylboronic acid component was employed with the goal of
improving the function of the system under physiological condi-
tions. By reducing the pKa of the boronic acid group (from 8.8 in
the parent phenylboronic acid to 7.2 in 10), the introduction of
7 these substituents increased the fraction of tetracoordinate adduct
N N
generated at pH 7.4 and 37 °C.
O R O The gels were treated with fluorescently labeled insulin in the
8 presence of glucose, then sealed in the absence of glucose. Subse-
quent additions of glucose triggered release of the labeled insulin,
Figure 6. Bis-boronic acid receptors for sLeX. and switching between on/off states of insulin release was shown
to be robust upon repeated cycles between high and low glucose
concentrations. This creative application of boronic acid–carbohy-
drate interactions may represent an important step toward devel-
oping new treatment options for patients suffering from diabetes.
Organoboron functionalization may alter the interactions of
biomolecules with cell-surface oligosaccharides, thus influencing
B(OH) 2 (HO) 2B
NCH 3 H 3CN
the rates of cell uptake and providing opportunities to target par-
ticular cell types. The group of Raines has shown that conjugation
of benzoxaborole (2-hydroxymethylphenylboronic acid, a com-
pound known to interact tightly with pyranoside sugars9) to RNase
A increased the rate of uptake of the enzyme into Chinese hamster
N N
ovary and human erythroleukemia cells.31 Inhibition of uptake
OCH 3
upon addition of fructose, a competitive binder to the benzoxabo-
O O role groups, was consistent with the involvement of a specific
O interaction with carbohydrates displayed on the cell surface. Fur-
H ther studies of the mechanism of enhanced uptake, and refine-
N N N S
N OCH 3 ments of the method to enable targeted delivery based on
O different surface glycosylation patterns, would be of great interest.
9

H 3CO 5. Organoboron compounds in carbohydrate separation

The ability to quantify components of mixtures of carbohydrates

NH or glycated proteins is needed for the diagnosis and study of such
O
indications as diabetes,32 cancer,33 Alzheimer’s disease,34 and
autoimmune diseases.35 Because monosaccharides generally do
Figure 7. Bis-boronic acid photoreactive probe used for MALDI-based histological
not differ greatly in polarity and lack chromophore groups, the sep-
analysis of cancer tissue.
aration of mixtures of carbohydrate-derived analytes is often a
challenging task. Incorporation of boronic acid functionality to a
chromatographic stationary phase provides the opportunity for dis-
crimination of carbohydrate-derived analytes based on specific,
strong interactions. Organoboron derivatives of several classes of

Scheme 4. Design hypothesis for glucose-triggered insulin release. Figure 8. Monomer composition of the glucose-responsive hydrogel.
 C. A. McClary, M. S. Taylor / Carbohydrate Research 381 (2013) 112–122
materials, including cellulose,36 polystyrene,37 polyacrylamides,38
and porous silica,39 have been employed for this purpose. Boronate
affinity chromatography (BAC)40 which employs cross-linked aga-
rose covalently modified with 3-aminophenylboronic acid through
a carbamate linkage, has been used to measure the degree of glyco-
sylation of hemoglobin, a variable important in diagnosing diabetes
mellitus. As a wide range of N- and O-linked glycosylated products
are retained using this stationary phase, further separation of the
mixture is often required in order to identify each component.
Several novel separation methods that employ boronic
acid-functionalized polyacrylamide gels have been developed in
recent years. One such technique is boronate affinity saccharide
electrophoresis (BASE),41 a modification of the established
fluorophore-assisted carbohydrate electrophoresis (FACE) method.
The latter involves covalent attachment of a fluorophore such as
disodium 8-amino-naphthalene-1,3,6-trisulfonate or 2-aminoacri-
done (AMAC) to the oligosaccharide analytes, followed by
separation by gel electrophoresis. 42 Problematic cases for FACE
include oligosaccharide mixtures that are not easily separated on
the basis of size and charge, and analytes lacking a free reducing
terminus for fluorophore conjugation. Incorporation of a
polymerizable boronic acid precursor (11, Fig. 9) drastically altered
the retention and separation of various saccharides in electrophore-
sis experiments on polyacrylamide gel. Separations of
carbohydrates, particularly of mono- from disaccharides, were
significantly improved by incorporation of 0.5% of monomer 11 into
a 20% polyacrylamide gel. Using standard FACE protocols, AMAC-
labeled glucose migrated more slowly than AMAC-labeled maltose,
a trend inconsistent with the respective molecular size of the
two analytes. This inverted migration pattern was corrected using
BASE.
Adaptations of the BASE approach have been developed for the
analysis of carbohydrate-modified proteins.43 When Sbi-III–IV—a
recombinant immunoglobulin-binding protein of potential utility
as a therapeutic for acute inflammatory diseases—was incubated
with D-(+)-gluconic acid d-lactone, mass spectrometry revealed a
species corresponding to the expected mass of the protein, along
with a signal corresponding to an undesired Amadori-type d-gluc-
onolactone modification at the N-terminus. Although these two
bands could not be efficiently resolved by conventional SDS–PAGE,
separation was achieved using the boronic acid-functionalized gel.
The modified protein appeared at a position corresponding to a
molecular mass of roughly four times that of Sbi-III–IV, reflecting
a specific interaction between the carbohydrate moiety and the
boronic acid residues in the acrylamide gel. Consistent with this
hypothesis, variation of the content of 11 in the gel had a signifi-
cant effect on the retention factors of carbohydrate-bearing pro-
teins, but not on those of the parent analytes. BASE analysis of
various glycoforms of human serum albumin revealed that enzy-
matically glycosylated proteins were resolved less efficiently than
non-enzymatically glycated products (especially protein adducts
with d-gluconolactone and glucose). The differences were attrib-
uted to interactions with specific motifs (i.e., anomeric 1,2-diol
moieties, with stabilization of the boronate by an adjacent amino
group) characteristic of Amadori-type glycation but absent in
enzymatically glycosylated proteins.
Figure 9. Boronic ester monomer used in the preparation of polyacrylamide gels for
BASE.
117
6. Boronic acids as protective groups for carbohydrates
Boronic esters serve as useful protective groups for carbohy-
drates due to several attractive properties. Selective formation of
cyclic boronates at 1,2-cis-diols as well as 4,6-diols of carbohy-
drates allows for reliable blocking of two hydroxyl groups, as the
partial p character of the B–O bonds (sharing of nonbonding elec-
trons with the empty, boron-centered p orbital) significantly atten-
uates the nucleophilicity of the boron-bound alkoxy groups.
Preparation and hydrolysis of carbohydrate-derived boronic esters
are operationally simple, usually taking place under mild condi-
tions and without the need for strong Brønsted or Lewis acid cata-
lysts. Applications of boronic esters as protective groups in
carbohydrate chemistry have been discussed in review articles.4
In 2000, the group of Boons made use of boronic acids to accom-
plish both hydroxyl group protection and attachment to a polymer
support.44 In an effort to address the difficulty of forming isomer-
ically pure 1,2-cis-linked glycosides on solid phase, a sequence
involving glycosylation, cleavage of the mixture of anomers from
the support, purification, and reloading to continue the synthesis
was envisioned. A polymer support that would enable rapid, oper-
ationally simple loading and release steps was targeted for this
application. Polystyrylboronic acid was judged to meet this crite-
rion, as loading of the glycosyl acceptor onto the polymer (via for-
mation of a boronate ester at the 4,6-diol) requires only heating in
pyridine, and removal from the support is achieved by treatment
with a mixture of acetone and water.45 Whereas the boronic acid
complexation approach was not tolerant of glycosyl trichloroace-
timidate or glycosyl fluoride donors (with activation by TMSOTf
and Cp2ZrCl2/AgOTf, respectively), the authors found that glycosyl-
ation could be achieved efficiently using thioglycoside donors un-
der NIS/TMSOTf activation conditions. Donors having either a
participating group or non-participating group at C-2 underwent
efficient glycosylation, although a mixture of anomers was ob-
tained in the latter case (Scheme 5).
As a challenge to the loading–release–reloading strategy, the
synthesis of a trisaccharide in which one of the glycosylation reac-
tions gave a mixture of anomers was undertaken (Scheme 6).46
Polymer-bound galactopyranoside 13 was glycosylated at C-2
using a thioglycoside donor (18) in the presence of NIS/TMSOTf
to give 19-a/b. The Fmoc protective group was removed using
NEt3 in CH2Cl2 without removing the disaccharide from the sup-
port to give 20a/b. Cleavage of the disaccharide from the resin, fol-
lowed by purification of the a-anomer and reloading, yielded
polymer-complexed disaccharide 20-a. Glycosylation of the free
hydroxyl group with thioglycoside donor 15, followed by cleavage
from the resin with acetone/H2O gave the free trisaccharide (21-a).
While the lability of boronic esters toward hydrolysis may repre-
sent a disadvantage under certain circumstances, the preceding
example illustrates that this feature can be useful for solid phase
synthesis by enabling the straightforward removal, purification,
and reloading of intermediates.
Crich has elegantly shown that 4,6-O-polystyrylboronate do-
nors can be employed for the solid-phase synthesis of b-manno-
sides.47 The challenge in stereocontrol posed by this type of
glycosidic linkage has inspired several creative strategies,48
including examples using polymer supports.49 The method
pioneered by Crich involves the low-temperature activation of a
4,6-O-benzylidene-protected mannopyranosyl sulfoxide with tri-
flic anhydride.50 The reaction is proposed to proceed through the
formation of an a-mannosyl triflate, which undergoes an SN2-type
displacement by the alcohol acceptor to give the b-mannoside. The
4,6-O-benzylidene group contributes in an important way to the
b-selectivity, torsionally disarming the intermediate mannosyl tri-
flate and thus disfavoring the formation of free oxocarbenium ions.
118 C. A. McClary, M. S. Taylor / Carbohydrate Research 381 (2013) 112–122

1) BnO OBn HO OH
O O
BnO SEt BnO OMe
OBn BnO
14 OBn O
O
2) NIS/TMSOTf, BnO
CH 2Cl 2 OBn
3) Acetone/H2O 16- α /β
n 91 %, α:β = 1:1
HO OH B
pyridine, Δ O O
O OH
BnO OMe + O
1) OBn HO
OH BnO OMe BnO O O
B(OH) 2 OH BnO SEt BnO BnO OM
e
OBz BnO O O
12 13 15 BnO
2) NIS/TMSOTf, OBz
CH 2Cl 2 17-β
3) Acetone/H2O 95 %, β-only

Scheme 5. Disaccharide synthesis on polystyreneboronic acid support.

AcO OBn
O
n FmocO SEt
HO OH B B
OBn
pyridine, Δ O O 18 O O
O
BnO OMe + O NIS/TMSOTf O
OH BnO OMe BnO OMe
CH 2Cl 2 AcO OBn O
B(OH) 2 OH
O
12 13 RO
OBn
NEt 3 19- α/β, R = F moc
CH 2Cl 2 20-α/β, R = H

1) OBn OH OH
B BnO O O
O O BnO SEt BnO OMe
OBz O
1) acetone/H2O, 60 °C O
20-α/β BnO OMe 15 O OBn
BnO
2) Separation of anomers O NIS/TMSOTf, CH 2Cl 2
by chromatography O OBn 2) acetone/H2O 60 °C BnO AcO
3) polystyreneboronic acid BnO O
BnO O
pyridine, Δ BnO
AcO
HO OBz
20-α 21-α

Scheme 6. Polymer-supported trisaccharide synthesis using a loading–release–reloading strategy.

1) O
HO S
OBn N
HO O
BnO (BSP)
SPh TTBP, Tf2O, OH
22 B O OBn OBn OCH3
pyridine, Δ CH 2Cl 2, 60 °C
+ O O HO O O
BnO 2) OCH3 BnO O
n O
23 SPh O O
HO
O
O 25

B(OH) 2
24
3) Acetone/H2O

Scheme 7. Polymer-supported synthesis of a b-mannoside.

4,6-O-Arylboronate esters, formed from either phenylboronic or
polystyrylboronic acid, were found to exhibit similar torsionally
disarming properties as the benzylidene group. Thiomannoside
22 was loaded onto solid support by treatment with polystyrylbo-
ronic acid in pyridine (Scheme 7). Activation of the bound glycosyl
donor by 1-benzenesulfinyl piperidine (BSP) and Tf2O in the pres-
ence of 2,4,6-tri-tert-butylpyrimidine (TTBP) at 60 °C was fol-
lowed by addition of glycosyl acceptor 24. b-Mannopyranoside
25 was liberated from the polymer support by heating in a mixture
of acetone and water.
Kaji has reported a regioselective glycosylation of unprotected
methyl hexopyranosides using arylboronic acids as transient
 C. A. McClary, M. S. Taylor / Carbohydrate Research 381 (2013) 112–122 119

1) 1,2-DCE, 23 °C, 16 h
OCH 3 OBz BzO OCH3
(HO) 2B OCH3
BzO O BzO O O
HO O SPh O
BzO BzO
HO BzO 2) NIS/TMSOTf, –30 °C, BzO HO
OH OH
18 min
26
89%

HO OH
HO OH
O
HO OMe 1) 1,2-DCE, 23 °C, 16 h O
OH PivO OPiv HO OH HO OMe
(HO) 2B OCH3 O
+ O O +
OPiv PivO O OMe PivO O
PivO 2) Ag(I) silica-alumina, OPiv
PivO OH
O 0 °C, 24 h PivO
PivO
27a PivO 27b
PivO
Br 78 %, 27a: 27b = 92:8

Scheme 8. Regioselective glycosylation of pyranosides by transient protection with an arylboronic acid.

OCH3
OCH3 H 3C O OCH3
1) PhB(OH) 2 OH n-BuI
H 3C O O H 3C O OH
OH O
OH 2) Ag2O, NEt 3 B On-Bu
HO HO
benzene, reflux Et N Ph
3 50%

Scheme 9. Regioselective alkylation of methyl fucopyranoside through complexation induced activation.

Scheme 10. Selective glycosylation with an internally coordinated organoboron promoter.

were consistent with deactivation of the 1,2-cis-diol moieties by

complexation to the boronic acid (e.g., 26, Scheme 8). For the galac-
to- and glucopyranosides, complexation of the 4,6-diol group was
inferred, followed by selective glycosylation of the less sterically
hindered free hydroxyl group (e.g., 27a). Oxidative cleavage of
the boronic ester was then effected with NaBO3
4H2O.52

7. Selective activation of carbohydrate OH groups with

organoboron reagents and catalysts

In contrast to the behavior described in the preceding section,

Scheme 11. Representative monofunctionalizations of pyranoside substrates using
borinic ester pre-catalyst 29.
masking groups for 1,2-cis-diol or 4,6-diol moieties.51 Treatment of
fuco-, rhamno-, galacto-, and glucopyranoside substrates with 4-
methoxyphenylboronic acid in the presence of molecular sieves,
followed by addition of a thioglycoside or glycosyl bromide donor
(with activation by NIS/TMSOTf or Ag(I) silica–alumina, respec-
tively) resulted in regioselective formation of disaccharides. The
selectivities obtained for fuco- and rhamnopyranoside substrates
organoboron compounds may also be used as activating groups
for diol motifs found in carbohydrates. Coordination number (tri-
vs tetracoordinate) plays a key role in determining whether
complexation to boron attenuates or enhances the nucleophilic
reactivity of bound alkoxy groups, as the delocalization of
nonbonding electrons from oxygen to boron that is possible in tri-
coordinate complexes is suppressed for tetracoordinate adducts.
While a variety of organoboron reagents and catalysts have been
employed for regioselective activation of OH groups in carbohy-
drates, complexation to a tetracoordinate boron center is a
unifying mechanistic theme for these processes.
The group of Aoyama has taken advantage of the selective com-
plexation of boronic acids to vicinal cis-diols or 4,6-diol moieties
and combined it with the ability of tetrahedral boronate complexes
120 C. A. McClary, M. S. Taylor / Carbohydrate Research 381 (2013) 112–122
Scheme 12. Proposed catalytic cycle for diol activation with 29; structures of
heteroboraanthracene-derived borinic acids 30 and 31.
to activate diols, leading to the development of processes for regio-
selective alkylation and glycosylation of pyranoside substrates. The
initial report from the Aoyama laboratory described the formation
of the cyclic phenylboronate of methyl-a,L-fucopyranoside,
followed by activation with an external Lewis base, triethylamine
Scheme 13. Regioselective activation of representative glycosyl acceptors catalyzed by 29.
(Scheme 9).53 Complexation of the Lewis base was proposed to re-
sult in activation of the bound alkoxy groups, allowing alkylation
at the less sterically hindered equatorial position of the cis-diol.
This idea was further extended to glycosylation reactions, using
borinic acid-derived promoter 28 (Scheme 10).54 In this case, the
key tetracoordinate boronate intermediate was proposed to arise
from protodeboronation of 28 to the corresponding boronic acid,
followed by condensation with the carbohydrate substrate and
coordination of the pendant benzylic hydroxyl group. Exposure
of the activated diol to a glycosyl bromide and Ag(I) promoter al-
lowed the regioselective glycosylation of the equatorial positions
of a variety of vincinal-cis-diols as well as the simultaneous
3,6-O-bis-glycosylation of galacto- and mannopyranosides. Com-
patibility with thioglycoside acceptors was demonstrated, enabling
subsequent use of the formed di- or trisaccharides as donors.
Building on the reactivity explored in Aoyama’s work, our group
has developed methodology for the organoboron-catalyzed
regioselective functionalization of carbohydrates. Whereas the
examples discussed above are based on coordination of an external
or pendant Lewis base to generate a tetrahedral boronate, the cat-
alytic protocols employ a borinic acid derivative (R2BOH) that
forms a tetracoordinate adduct without the need for complexation
of an additional Lewis base. Catalyst-controlled regioselective
monoacylation,55 sulfonylation,56 alkylation,57 and glycosylation58
of carbohydrate derivatives have been achieved, with selective
functionalization occurring at the equatorial position of cis-vicinal
diol motifs for each of these four electrophile types (Scheme 11).
Investigations into the kinetics of the sulfonylation reaction are
consistent with the catalytic mechanism depicted in Scheme 12.
The borinic ester precatalyst enters into the catalytic cycle by bis-
sulfonylation of the ethanolamine ligand. Complexation of the cis-
diol generates an activated tetrahedral borinate intermediate,
which undergoes turnover-limiting sulfonylation. Displacement of
 C. A. McClary, M. S. Taylor / Carbohydrate Research 381 (2013) 112–122
the bound product by diol substrate regenerates the catalyst resting
state. Taking into account the data from kinetics experiments, cat-
alyst optimization has been focused on increasing the nucleophilic-
ity of the tetracoordinate borinic acid–diol adduct.
Heteroboraanthracene derivatives 30 and 31, despite binding only
weakly to diols (due to delocalization of electron density from the
heteroatom to the boron center) display high catalytic activity
and improved stability toward oxidation relative to the parent
diphenylborinic acid.59 The observed trends in regioselectivity ap-
pear to be influenced by several effects. Functionalization of the
equatorial position over the axial position in a 1,2-cis-diol is consis-
tent with a steric component to the selectivity. Computational
modeling of the proposed tetrahedral borinate intermediates sug-
gests that electronic effects may also contribute.
Representative examples of regioselective glycosylation cata-
lyzed by borinic ester 29 are depicted in Scheme 13. The method-
ology employs glycosyl halides (bromides or chlorides) with Ag2O
as the activating reagent, and tolerates a variety of donors, includ-
ing armed and disarmed systems. The observation of first order
kinetics in both acceptor and donor, as well as the formation of
an orthoester product from b- but not a-acetochloroglucose, sug-
gested a glycosylation mechanism involving significant SN2 charac-
ter and minimal formation of oxocarbenium intermediates.60 The
stereochemical outcomes of the reactions were also consistent
with an SN2-like mechanism, as inversion of configuration at the
anomeric center was observed. The protocol can be applied to rel-
atively complex glycosyl acceptors, including the cardiac glycoside
digitoxin.61 That the methodology is compatible with the fragile b-
2-deoxyglycosidic linkages of digitoxin highlights the mild reac-
tion conditions employed for the catalyst-controlled glycosylation.
Extensions of this result to other classes of polyol natural products
may be of interest, as catalyst-controlled selective glycosylation
represents an attractive avenue for late-stage modification of
bioactive secondary metabolites.
8. Conclusions and outlook
Applications of organoboron compounds in carbohydrate
chemistry are remarkably widespread, and touch upon research
in several subdisciplines, including glycobiology, the design of
therapeutic agents and probes, and oligosaccharide synthesis. Both
the ability to use organic synthesis to tune the affinity and selectiv-
ity of the organoboron binding group for a specific application, and
the ease of incorporation of boronic acid groups into complex or-
ganic molecules and macromolecules, can be identified as advanta-
geous features of this class of compounds. Impressive progress has
been achieved in using boronic acids as synthetic hosts capable of
specific binding to mono- or oligosaccharides. It can be anticipated
that these advances will help to fuel the development of new,
highly selective probes for glycobiology, or new catalysts that are
able to activate more complex and densely functionalized oligosac-
charide substrates. Organoboron–carbohydrate interactions show
much promise in the area of targeted drug delivery, and the oppor-
tunities for fundamental insight and novel designs appear to be
widespread in this area. The pace of ongoing work, and the diver-
sity of researchers involved, suggest that organoboron chemistry
will continue to provide tools that drive progress in many aspects
of carbohydrate research.
Acknowledgments
The authors acknowledge NSERC (Discovery Grants Program,
Canada Research Chair to M.S.T.) and the A. P. Sloan Foundation
(Research Fellowship to M.S.T.) for financial support.
121
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