Synthetic utility of glycosyl triazoles in carbohydrate chemistry

Article abstract of DOI:10.1016/j.tet.2006.06.001

We report herein a study of the synthetic utility of the glucosyl triazole moiety in carbohydrate chemistry. A model glucosyl triazole was prepared by a modified Huisgen 1,3-dipolar cycloaddition reaction. The relative rate of cycloaddition was investigat

Full text of DOI:10.1016/j.tet.2006.06.001

Tetrahedron 62 (2006) 8115–8125
Synthetic utility of glycosyl triazoles in carbohydrate chemistry
Brendan L. Wilkinson,a Laurent F. Bornaghi,a Sally-Ann Poulsena and Todd A. Houstonb,
*
aEskitis Institute for Cell and Molecular Therapies, Griffith University, 170 Kessels Road, Nathan, Queensland 4111, Australia
bInstitute for Glycomics, Griffith University, PMB 50 Gold Coast Mail Centre, Gold Coast, Queensland 9726, Australia
Received 15 April 2006; revised 30 May 2006; accepted 1 June 2006
Available online 22 June 2006
Abstract—We report herein a study of the synthetic utility of the glucosyl triazole moiety in carbohydrate chemistry. A model glucosyl tri-
azole was prepared by a modified Huisgen 1,3-dipolar cycloaddition reaction. The relative rate of cycloaddition was investigated using a
variety of alcohol co-solvents and reaction temperatures. It was found that the reaction proceeded with similar efficiency irrespective of
co-solvent, however mildly elevated temperatures (40 ꢀC cf. rt) increased the speed of reaction significantly (2 h cf. 8 h). The robustness
of the triazole moiety was then interrogated under conditions typically encountered in carbohydrate chemistry reaction sequences—alcohol
group protection/deprotection, nucleophilic displacement, and O-glycosylation. The triazole integrity was retained in all cases studied as
evidenced from full compound characterization. Finally, a diverse set of triazole-linked glycoconjugates was synthesized. Collectively,
our results demonstrated that the glucosyl triazole moiety was indeed a robust entity for carbohydrate chemistry.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
In the past three years, there has been a flourish of activity in
the literature concerning the 1,3-dipolar cycloaddition reac-
tion (1,3-DCR) of organic azides with terminal acetylenes
(Huisgen reaction).11 This interest stems largely from the
optimization of 1,3-DCR by Sharpless12 and Meldal13
with respect to ease and efficiency of catalysis and regio-
selectivity of the triazole product. The reaction involves
a step-wise Cu(I)-catalyzed dipolar cycloaddition of a termi-
nal acetylene to an organic azide to form, exclusively, the
1,4-disubstituted-1,2,3-triazole (Scheme 1).12,13 The highly
exothermic and kinetically controlled reaction is conducted
favorably in water and is also tolerant to a wide variety of
organic co-solvents and as such has become a premier com-
ponent of ‘click chemistry’.12b
Oligosaccharides linked to proteins and lipids via N- or
O-glycosidic linkages (glycoconjugates) have been shown
to govern crucial life processes and disease states.1–7 Glyco-
sylation patterns for proteins and lipids are exquisitely con-
trolled via mechanisms independent from that of the
genomic transcription and as a result glycoconjugates from
natural sources often exist as heterogeneous isoforms (glyco-
forms). The isolation of homogeneous material from crude
biological extracts in sufficient quantities for study can,
therefore, be difficult. Medicinal chemistry, through provi-
sion of an impressive array of synthetic methodologies,
offers a potentially more reliable route to homogeneous
glycoconjugates leading to either exact copies of naturally
occurring glycoconjugates or, alternatively, incorporating
unnatural glycosidic linkages. An appreciable benefit of the
latter approach is that the ‘artificial’ glycoconjugate may
retain the geometric and spatial characteristics of the native
glycoform8,9 yet exhibit stability toward N- and O-glycosyl
hydrolase activity and inhibit these enzymes to some ex-
tent,10 so increasing the potential for a wide array of in vivo
applications. In addition, the artificial linkage may be fine
tuned as an inert functionality toward subsequent synthetic
transformations necessary elsewhere within the target mole-
cule synthesis.
R1 N3
R2
(0.25 - 0.5 M)
+
Cu(I)
R1
N
N
N
R2
(1 eq)
1,4-disubstituted-1,2,3-triazole
Scheme 1. Cu(I)-catalyzed 1,3-dipolar cycloaddition reaction of azides and
terminal alkynes.
The modified 1,3-DCR has shown great versatility and util-
ity on non-saccharide substrates in medicinal chemistry,
chemical biology, and materials science.14,15 The applica-
tion to ‘traditional’ carbohydrate chemistry16 has been
somewhat slower, but presents as an attractive reaction for
several reasons. Glycosyl azides are generally stable crystal-
line solids, inert toward a wide range of reaction conditions
and are available diastereomerically pure.17 In traditional
Keywords: Carbohydrate; Glycoconjugate; Huisgen reaction; Click
chemistry.
* Corresponding author. Tel.: +61 7 3735 4115; fax: +61 7 3735 7656;
e-mail: t.houston@griffith.edu.au
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.001

8116
B. L. Wilkinson et al. / Tetrahedron 62 (2006) 8115–8125
Table 1. Study of formation of glycosyl triazole 2a
carbohydrate synthesis they serve primarily as stable precur-
sors of glycosylamines (for glycopeptide synthesis) and are
also less commonly precursors to glycosylfluoride donors.18
Glycosyl azides are readily synthesized through the stereo-
selective bimolecular displacement of a glycosyl halide
with an azide nucleophile17 and 2-azido sugars are obtained
through the triflyl azide-mediated diazotransfer of amino
sugars.19 Preparation of carbohydrates containing a terminal
acetylene moiety is also readily achieved either by the alkyl-
ation of carbohydrates (to synthesize propargyl ethers) or
Lewis-acid-catalyzed glycosylation (to synthesize O-prop-
argyl glycosides).20 The 1,3-DCR utilizes low cost and rela-
tive non-toxic reagents and solvents so alleviating the need
to use often expensive and highly toxic glycosylation and
peptide coupling reagents, the risk and costs of which are
acute on bulk scales. Finally, product purification is simple;
in many cases, chromatography is not necessary with either
precipitation21 or liquid–liquid extraction sufficient to ob-
tain pure product.
OAc
OAc
OH
O
O
AcO
AcO
AcO
AcO
OH
N3 +
N
N
N
OAc
OAc
1
2
Entry
Co-solvent
Temp (ꢀC)
Time (h)
Yieldb (%)
1
2
3
4
5
6
Methanol
Ethanol
Isopropanol
tert-Butanol
Propargyl alcohol
tert-Butanol
40
40
40
40
40
25
2
2
2
2
2
8
79
88
91
92
85
90
a
All reactions were carried out using 1 (0.5 M), propargyl alcohol (0.5 M),
20 mol % CuSO4, 40 mol % sodium ascorbate (relative to substrate) in 1:1
water/alcohol (with the exception of entry 5).
b
Yield calculated following liquid–liquid extraction into CH2Cl2.
Noteworthy is that when the coupling partner propargyl
alcohol was employed also as bulk co-solvent this did not
substantially increase the rate of reaction. An increased reac-
tion time (8 h) was necessary to afford complete conversion
when the reaction was conducted at room temperature (Table
1, compare entries 4 and 6), although the yields were similar
(90 cf. 92%). The reactants were initially insoluble in all sol-
vent media, but as the reaction progressed, a deep yellow,
homogeneous mixture was observed. In all cases, the yield
(following liquid–liquid extraction into CH2Cl2) was high
and exhibited minimal variability (79–92%). This simple
work up provided material sufficiently pure for most ensuing
synthetic purposes, however a final solid-phase extraction
(SPE) purification step was employed to remove trace para-
magneticCu(II)saltsforthepurposeofNMRanalysisandthe
provision of analytically pure material. Reaction conditions
were simple, requiring only vigorous stirring at the desig-
nated temperature within capped scintillation vials under air.
The incorporation of an azide and/or an alkyne moiety on a
carbohydrate scaffold unleashes the potential to access a
new dimension of structural diversity to complement the
vast structural diversity already inherent to carbohydrates
and so it is anticipated that interest in the 1,3-DCR with car-
bohydrate substrates will grow. A detailed synthetic analysis
concerning the utility of this reaction and the stability of
the formed glycosyl triazole linkage toward typical carbo-
hydrate reaction sequences would be beneficial to assess
the viability of the glycosyl triazole linker as a tool for carbo-
hydrate chemistry, and was the inspiration for the study
described herein. Specifically, we report (i) an investigation
of the rate of formation of the glycosyl triazole linkage with
variable solvent and temperature parameters, (ii) the stability
of this linkage toward conditions commonly used in carbo-
hydrate reaction sequences, including hydroxyl group pro-
tection/deprotection, O-glycosylations, and nucleophilic
displacement, (iii) an examination of the retention of anome-
ric stereochemistry and the rates of triazole formation with
respect to the glycosyl azide precursor configuration (a/b),
and (iv) the versatility of the 1,3-DCR of various sugar
azides with a diverse array of acetylene partners.
Next, the stability of the glycosyl triazole linkage toward
commonly used carbohydrate chemistry reaction conditions
was investigated (Scheme 2). Silyl, trityl, acetyl, benzoyl,
and benzyl alcohol protecting groups were all incorporated
smoothly on to the alcohol moiety of 2 to generate com-
pounds 3–7, respectively, with the triazole linkage remain-
ing intact. Reaction conditions to remove these protecting
groups were also compatible with the triazole linkage, either
regenerating 2 or the globally deprotected analogue 11. Pro-
tection and deprotection yields were excellent with no base-
line decomposition observed by TLC. Interestingly, the
hydrogenation of the benzylated compound 7 was sluggish
using typical conditions (H2, 5% Pd/C), necessitating basic
hydrogenation conditions (i.e., H2, 30% Pd(OH2)/C). Re-
moval of the benzyl ether in the 2-position of the sugar
was potentially problematic, quite possibly due to steric hin-
drance imposed by the glucosyl triazole. Despite this, the
free glucosyl triazole 11 was recovered in good yield
(78%) after 24 h. Glycosylation of the triazole acceptor 2
using either typical Lewis acid catalysis (BF3$Et2O) or
Koenigs–Knorr conditions (AgOTf) successfully generated
8 and 9, respectively, although yields were not high (53%
and 41%, respectively). This was possibly due to the weak
glycosyl acceptor nature of the triazole alcohol. Alter-
natively, the triazole may interfere with activation of
the glycosyl donor through interaction with the Lewis
2. Results and discussion
The model glycosyl triazole employed to investigate the
study of rate of triazole formation was the glucosyl triazole
compound 2.16f Compound 2 was prepared by 1,3-DCR of
propargyl alcohol with 2,3,4,6-tetra-O-acetyl-b-D-glucopyr-
anosyl azide (1) using a procedure adapted from the litera-
ture.12,13 Reaction of propargyl alcohol with the azide
partner 1 in the presence of a CuSO4/ascorbate mixture in
aqueous alcohol, affords exclusively the 1,4-disubstituted
b-D-glucosyl triazole 2 with complete retention of anomeric
stereochemistry and in high yield. This configuration has
been confirmed by X-ray crystallography.22 The effect of
alcohol co-solvents methanol, ethanol, isopropanol, tert-
butanol, and propargyl alcohol on reaction completion time
is presented in Table 1. Irrespective of the co-solvent em-
ployed, the reaction to form 2 was complete within 2 h (as
evidenced by TLC) when the reaction was carried out at a
slightly elevated temperature (40 ꢀC) (Table 1, entries 1–5).

B. L. Wilkinson et al. / Tetrahedron 62 (2006) 8115–8125
8117
OAc
OTBDMS
O
AcO
AcO
N
N
OAc
N
OAc
OTr
O
3
AcO
AcO
N
N
N
OAc
4
OAc
OAc
a.
b.
O
c.
AcO
AcO
N
N
d.
N
N
OAc
h.
e.
f.
5
OAc
OAc
OH
OH
OBz
O
O
AcO
AcO
OH
AcO
i.
O
N
HO
HO
N
AcO
N
N
OAc
N
N
OAc
N
N
OH
2
6
g.
j.
11
OBn
OBn
O
m.
k, l.
BnO
BnO
N
N
N
N
OBn
7
R'
AcO
OAc
AcO
O
R
OAc
O
OAc
O
AcO
AcO
N3
O
N
N
AcO
AcO
OAc
N
N
N
OAc
8: R = OAc, R' = H
9: R = H, R' = OAc
10
Scheme 2. Protecting group and glycosylation chemistry on model glucosyl triazole 2. Conditions: (a) TBDMSCl, imidazole, DCM, rt, 1 h, 88%; (b) TBAF,
THF, rt, 15 min, 82%; (c) TrCl, pyridine, 40 ꢀC, o/n, 90%; (d) camphor sulfonic acid, DCM, rt, 4 h, 85%; (e) Ac2O/pyridine, rt, 2 h, 90%; (f) BzCl, Et3N, DCM,
o/n, 82%; (g) (i) NaOCH3, CH3OH, rt, 2 h; then (ii) NaH, BnBr, DMF, rt, o/n, 68%; (h) NaOCH3, CH3OH, rt, 30 min, 90%; (i) NaOCH3, CH3OH, rt, 12 h, 92%;
(j) H2, 30% Pd(OH)2/C, CH3OH/DCM, rt, 24 h, 78%; (k) 2,3,4,6-tetra-O-acetyl-a-D-glucopyranosyl bromide (1.0 equiv), AgOTf, DCM, 52% of 8; (l) b-D-
galactose pentaacetate (1.0 equiv), BF3$Et2O, DCM, rt, o/n, 43% of 9; (m) (i) MsCl, Et3N, DCM, rt, 30 min; then (ii) NaN3, DMF, o/n, rt, 53%.
acid; nonetheless, this provides rapid entry into disaccharide
mimics. Finally, the azide displacement of the crude mesy-
lated intermediate from 2 to form triazole azide 10 provides
a system for carrying out iterative click reactions.
triazole 15. Interestingly, while the reaction for 15 took
20 h to reach completion, the estradiol analogue 14 required
only 30 min for completion under identical reaction con-
ditions. Furthermore, both compounds were isolated by pre-
cipitation from cold water, although a final chromatographic
purification step was required for these two compounds in
order to remove traces of starting materials and Cu salts.
Having established some of the chemical modifications
available, we set out to synthesize a variety of glycoconju-
gates with diversity in both the carbohydrate and aglycone
moieties. Derivatives of hydrophobic bioactive compounds
and synthetic precursors to more complex glycoconjugates
were sought as part of our general focus on carbohydrate-
based therapeutics. Table 2 shows compounds synthesized
from our model glucosyl azide 1 (compounds 12–15), methyl
2,3,4-tri-O-acetyl-1-azido-1-deoxy-b-D-glucopyranuronate23
(compound 16), 2,3,4-tri-O-acetyl-a-D-arabinopyranosyl
azide (compound 17), 2-acetamido-3,4,6-tri-O-acetyl-2-
deoxy-b-D-glucopyranosyl azide (compound 1816f), and
2,3,4,6-tetra-O-benzyl-a-D-glucosyl azide (compound 19).
Minimal or no chromatography was required in all cases to
obtain samples of sufficient purity for further synthetic trans-
formation. Reaction rates and yields varied somewhat
depending on the acetylene dipolarophilicity and solubility.
While the reaction is reported as reasonably insensitive to
substrate solubility, more hydrophobic substrates generally
took longer to react, as is shown for the steroidal glucosyl
Our attention then shifted to examining the rate dependence
on anomeric configuration and the nature of the saccharide
protecting groups. The reaction of 2,3,4,6-tetra-O-benzyl-
a-D-glucosyl azide to a-glucosyl triazole 19 proceeded
with complete a-retention of anomeric stereochemistry. The
reaction was slow, requiring a total of ca. 48 h at 60 ꢀC to
reach completion. Doubling of the Cu(II) and ascorbate cata-
lyst load (i.e., 0.4 equiv Cu(II), 0.8 equiv ascorbate) was
also required since gradual oxidation of the Cu(I)-complex
intermediate was observed using standard conditions and
no conversion was observed after 8 h by either TLC or
ESI-MS. The sluggish nature of this reaction was rational-
ized as resulting from increased steric bulk surrounding
the anomeric center upon transformation from the linear
azide to the triazole, increased hydrophobicity imparted by
the benzyl groups, and stabilization of the azide dipole by
the anomeric effect.

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B. L. Wilkinson et al. / Tetrahedron 62 (2006) 8115–8125
Table 2. Examples of glycosyl triazoles
R1
R1
O
O
RO
RO
N3
N
N
N
Compounda
Time (yield)b
30 min (92%)
Compounda
Time (yield)b
30 min (85%)c
O
OAc
H3CO
AcO
AcO
O
O
N
N
H
O
AcO
AcO
SO2NH2
N
N
N
N
OAc
OAc
N
N
12
16
O
N
NHBoc
OAc
N
N
N
O
AcO
AcO
N
H
O
N
N
20 min (77%)
10 min (94%)
N
N
OAc
N
OAc
N
OAc
AcO
AcO
17
13
OH
OAc
H
H
OAc
OH
O
H
30 min (71%)
3 h (62%)
O
N
AcO
AcO
AcO
N
AcNH
N
OH
N
OAc
N
18
14
OBn
O
O
BnO
BnO
H
H
BnO
OAc
H
N
20 h (64%)
N
48 h (73%)
O
AcO
AcO
N
N
OH
N
N
OAc
OH
15
19
a
General reaction conditions: azide (0.5 M), acetylene (0.5 M), CuSO4$5H2O (0.2 equiv), sodium ascorbate (0.4 equiv), 1:1 t-BuOH/H2O, 40 ꢀC, with the
exception of 19, which used acetylene (4.2 equiv), CuSO4$5H2O (0.4 equiv), sodium ascorbate (0.8 equiv) at 60 ꢀC.
Standard purification as described in Section 4.
b
c
Molar yield calculated after precipitation and filtration.
The scope of the reaction can be expanded further by install-
ing the azide/acetylene functionality into other positions on
the carbohydrate ring and/or on to different carbohydrate
partners to serve as a convenient and direct route to tri-
azole-tethered disaccharide mimics. The triazole-tethered
disaccharide 20 was formed in 78% yield from the 1,3-
DCR of a 6-azido glucose analogue and a glucose-derived
propargyl ether. This yield is an improvement over the
glycosylations on 2 to synthesize the structurally related
triazole-tethered disaccharides 8 (52%) and 9 (43%). 1,3-
DCR can therefore serve as a useful means of rapidly gen-
erating artificial cyclodextrins,24 glycodendrimers,25 and
glycopolymers26 under kinetically controlled conditions.
3. Conclusions
The facile Cu(I)-catalyzed 1,3-dipolar cycloaddition reac-
tion has emerged of late as a potent tool in accessing diverse
molecular architectures. Its versatility and potential is now
starting to be realized in glycochemistry, providing expedi-
ent access to an interesting and relatively new family of
pharmacologically relevant heterocyclic carbohydrates.
Owing to the inherent complex nature of carbohydrate
chemistry, especially concerning anomeric stereochemistry
and stability, the reaction has not been sufficiently scruti-
nized as a viable alternative or addition to classical methods.
We have successfully explored the utility of the reaction
by examining the compatibility and tolerance of the condi-
tions to pre-installed saccharide protecting groups, but
also the stability of the installed triazole linkage under
protection/deprotection sequences and glycosylations. The
reaction is forgiving, mild, high yielding, simple to purify,
and stereo- and regiospecific. Owing to such impressive
versatility, we envisage the reaction to be useful addition
to the arsenal of traditional solution-based reactions within
carbohydrate chemistry. Further exploration of the scope
of this chemistry will also include modification of other
OAc
O
AcO
O
AcO
OAc
N
N
N
O
AcO
AcO
AcO
OCH3
20

B. L. Wilkinson et al. / Tetrahedron 62 (2006) 8115–8125
8119
hydrophobic drug molecules to improve their water solubil-
ity.27 Furthermore, due to the inherent robustness of the gly-
cosyl triazole linkage, it is reasonable to expect the reaction
to be compatible with existing solution- and solid-phase,
convergent (block) and linear glycoprotein/peptide strate-
gies. Finally, recent regioselective access to the 1,5-disubsti-
tuted triazole from azide and alkyne precursors will expand
the structural diversity available from the chemistry pre-
sented here.28
(OAc), 20.9 (OAc), 56.6 (CH2OH), 61.8 (C-6), 67.9 (C-2),
70.6 (C-3), 72.9 (C-4), 75.3 (C-5), 86.1 (C-1), 120.9 (triazole
CH), 148.5 (triazole C), 169.3 (OAc), 169.6 (OAc), 170.2
(OAc), 170.7 (OAc). HRESIMS calcd for C17H23N3O10
Na+: 452.127565. Found: 452.126953. Anal. Calcd for
C17H23N3O10: C, 47.55; H, 5.40; N, 9.79. Found: C, 47.33;
H, 5.39; N, 9.51.
4.1.2. 4-tert-Butyldimethylsilyloxymethyl-1-(20,30,40,60-
tetra-O-acetyl-b-D-glucopyranosyl)-1,2,3-triazole (3). A
solution of alcohol 2 (200 mg, 0.47 mmol) and imidazole
(95 mg, 1.40 mmol, 3 equiv) was prepared in dry CH2Cl2
(5 mL) under nitrogen and tert-butyldimethylsilyl chloride
(85 mg, 0.56 mmol, 1.2 equiv) was added in a single portion.
The solution was stirred at rt under nitrogen for 2 h at which
time, TLC indicated reaction completion (8:2 ethyl acetate/
hexanes). CH2Cl2 (5 mL) was then added and the solution
was washed with 1 N HCl (5 mL), saturated NaHCO3
(5 mL), and brine (5 mL). The organic layer was dried
(MgSO4), filtered, and evaporated to a crude oil, which was
purified by flash silica chromatography (4:6 ethyl acetate/
hexanes) to afford a white solid (225 mg, 0.41 mmol,
88%). Mp: 100–101 ꢀC. Rf¼0.74 (8:2 ethyl acetate/
hexanes). 1H NMR (400 MHz, CDCl3): d 0.08 (s, 6H,
2ꢁSiCH3), 0.90 (s, 9H, t-Bu), 1.85 (s, 3H, OAc), 2.01 (s,
3H, OAc), 2.05 (s, 3H, OAc), 2.06 (s, 3H, OAc), 3.98 (ddd,
4. Experimental
4.1. General
Glycosyl azide precursors were prepared by phase transfer
nucleophilic displacement of corresponding peracetylated
a-glycosylbromide.17 All reagents were purchased from
commercial sources and were used without further purifi-
cation. All solvents were available commercially dried
or freshly dried and distilled prior to use. 1H NMR
(400 MHz), 13C NMR (100 MHz), 2D gCOSY, and gHSQC
spectra were recorded on a 400 MHz spectrometer with
chemical shift values given in parts per million (d) relative
to TMS (0.00 ppm) using CDCl3 solvent unless otherwise
stated. Melting points are reported as uncorrected. High res-
olution electrospray ionization mass spectra (HRESIMS)
were recorded on a 4.7T Fourier transform mass spectro-
meter in positive ion mode unless otherwise stated. Reaction
progress was monitored by TLC using Silica gel-60 F254
plates with detection by short wave UV fluorescence
(l¼254 nm) and staining with 10% (v/v) H2SO4 in ethanol
char. Flash chromatography was conducted using flash silica
gel (60–240 mesh). Solid-phase extraction (SPE) was con-
ducted using cartridges prepacked with silica sorbent.
3
3
3
J5–4¼10.4 Hz, J5–6 ¼5.2 Hz, J5–6¼2.4 Hz, 1H, H-50),
0
2
3
4.14 (dd, J6–6 ¼12.8 Hz, J6–5¼2.4 Hz, 1H, H-60), 4.23
0
(dd, 2J6 –6¼12.8 Hz, 3J6 –5¼5.2 Hz, 1H, H-600), 4.82 (s, 2H,
0
0
CH2OSi), 5.21–5.26 (m, 1H, H-40), 5.37–5.41 (m, 1H,
3
H-30), 5.44–5.48 (m, 1H, H-20), 5.85 (d, J1–2¼9.2 Hz,
1H, H-10), 7.67 (s, 1H, triazole CH); 13C NMR (100 MHz,
CDCl3): d ꢂ5.2 (SiCH3), ꢂ5.1 (SiCH3), 18.5 (TBDMS quart
C), 20.4 (OAc), 20.71 (OAc), 20.74 (OAc), 20.9 (OAc), 26.1
(t-Bu), 57.9 (CH2OTBDMS), 61.8 (C-6), 67.9 (C-4), 70.4 (C-
3), 73.0 (C-2), 75.3 (C-5), 85.8 (C-1), 120.1 (triazole CH),
149.6 (triazole C), 169.1 (OAc), 169.6 (OAc), 170.1 (OAc),
170.7 (OAc). HRESIMS calcd for C23H37N3O10SiNa+:
566.214042. Found: 566.215711. Anal. Calcd for
C23H37N3O10Si: C, 50.81; H, 6.86; N, 7.73. Found: C,
50.89; H, 7.07; N, 7.61.
4.1.1. 4-Hydroxymethyl-1-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-1,2,3-triazole (2). To a vigorously stirring
suspension of 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl
azide (2.0 g, 5.35 mmol) in tert-butyl alcohol (11 mL) was
added propargyl alcohol (1.3 mL, 22.43 mmol, 4.2 equiv).
The reaction was initiated by the addition of a solution of
CuSO4$5H2O (270 mg, 1.08 mmol, 0.2 equiv) and sodium
ascorbate (424.5 mg, 2.14 mmol, 0.4 equiv) in distilled H2O
(11 mL). The deep yellow suspension was stirred vigorously
at 40 ꢀC for 2 h. At this time, TLC indicated reaction com-
pletion (1:1 ethyl acetate/hexanes). Distilled H2O (20 mL)
was added and the aqueous layer extracted twice with
CH2Cl2 (2ꢁ50 mL). The combined organic extracts were
dried (MgSO4), filtered, and evaporated to afford a crude
yellow solid residue, which was recrystallized from hot
absolute ethanol to afford triazole 1 as off-white crystalline
solid (2.1 g, 92%). Mp: 150–151 ꢀC (lit. mp: 148–150 ꢀC as
a mixture of 4- and 5-hydroxymethyl regioisomers16f).
4.1.3. Deprotection of silyl ether 3/2. A portion of silyl
ether 3 (25 mg, 0.05 mmol) was then dissolved in dry THF
(1.0 mL) and a 1.0 M solution of tetrabutylammonium fluo-
ride (500 mL, 0.5 mmol, 10 equiv) was added. The solution
was stirred for 15 min at rt when found complete by TLC
(8:2 ethyl acetate/hexanes). Evaporation and purification
by flash silica chromatography (8:2 ethyl acetate/hexanes)
afforded alcohol 2 as white solid (13 mg, 61%).
4.1.4. 4-Trityloxymethyl-1-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-1,2,3-triazole (4). To a solution of alcohol
2 (200 mg, 0.47 mmol) and dry pyridine (5 mL) was added
trityl chloride (230 mg, 0.84 mmol, 1.8 equiv). The solution
was warmed to 40 ꢀC and stirred for 24 h. The solvent was
evaporated under reduced pressure and the remaining crude
yellow solid was purified by flash silica chromatography
(1:9 ethyl acetate/petroleum ether) to afford a crude white
solid. A final recrystallization from hot absolute ethanol to
remove trace trityl alcohol afforded a white crystalline solid
(283 mg, 90%). Mp: 192–193 ꢀC. Rf¼0.63 (7:3 ethyl ace-
1
Rf¼0.22 (8:2 ethyl acetate/hexanes). H NMR (400 MHz,
CDCl3): d 1.87 (s, 3H, OAc), 2.01 (s, 3H, OAc), 2.05 (s,
3
3H, OAc), 2.06 (s, 3H, OAc), 3.99 (ddd, J5–4¼10.2 Hz,
3
3
2
J5–6 ¼5.2 Hz, J5–6¼2.4 Hz, 1H, H-50), 4.13 (dd, J6–6
¼
¼
0
0
3
2
12.4 Hz, J6–5¼2.4 Hz, 1H, H-60), 4.28 (dd, J6 –6
0
3
12.4 Hz, J6 –5¼5.2 Hz, 1H, H-600), 4.79 (s, 2H, CH2OH),
5.20–5.25 (m, 1H, H-40), 5.38–5.45 (m, 2H, H-30/H-20),
5.86–5.88 (m, 1H, H-10), 7.78 (s, 1H, triazole H); 13C NMR
(100 MHz, CDCl3): d 20.4 (OAc), 20.7 (OAc), 20.75
0
1
tate/hexanes). H NMR (400 MHz, CDCl3): d 1.87 (s, 3H,

8120
B. L. Wilkinson et al. / Tetrahedron 62 (2006) 8115–8125
OAc CH3), 2.02 (s, 3H, OAc CH3), 2.06 (s, 3H, OAc
CH3), 2.09 (s, 3H, OAc CH3), 4.00 (ddd, J5–4¼10 Hz,
(3 mL) and a 1.0 M solution of sodium methoxide in dry
methanol (30 mL, 0.03 mmol) was added. The resulting
pale yellow solution was stirred at rt for 15 min before reac-
tion completion. The solution was neutralized by the addi-
tion of dry Amberlite IR-120 acidic ion-exchange resin,
filtered, and evaporated to dryness under reduced pressure
to afford pentol 11 as white solid (53 mg, 96%). See com-
pound 11 for analytical details.
3
3
3
2
J5–6 ¼4.8 Hz, J5–6¼2 Hz, 1H, H-50), 4.16 (dd, J6–6
¼
0
0
3
12.8 Hz, J6–5¼2.4 Hz, 1H, H-60), 4.28 (s, 2H, CH2OTr),
2
3
4.31 (dd, J6 –6¼12.8 Hz, J6 –5¼5.2 Hz, 1H, H-600), 5.23–
0
0
5.28 (m, 1H, H-40), 5.39–5.44 (m, 1H, H-30), 5.47–5.51
3
(m, 1H, H-20), 5.87 (d, J1–2¼9.6 Hz, 1H, H-10), 7.22–7.32
(m, 10H, Ar H), 7.46–7.49 (m, 5H, Ar H), 7.75 (s, 1H, tri-
azole CH); 13C NMR (100 MHz, CDCl3): d 20.4 (OAc),
20.76 (OAc), 20.77 (OAc), 20.9 (OAc), 58.8 (C-5), 61.8
(C-6), 68.0 (C-4), 70.4 (C-2), 73.0 (C-3), 75.4 (CH2OTr),
85.9 (C-1), 87.6 (CPh3), 120.5 (triazole CH), 127.4 (Ar
CH), 128.2 (Ar CH), 128.9 (Ar CH), 143.8 (triazole C),
147.1 (Ar C), 169.1 (OAc), 169.6 (OAc), 170.2 (OAc),
170.7 (OAc). HRESIMS calcd for C36H37N3O10Na+:
694.237116. Found 694.237058. Anal. Calcd for
C36H37N3O10: C, 64.37; H, 5.55; N, 6.26; O, 23.82. Found:
C, 64.12; H, 5.38; N, 6.35.
4.1.8. 4-Benzyloxymethyl-1-(20,30,40,60-tetra-O-acetyl-b-
D-glucopyranosyl)-1,2,3-triazole (6). To a solution of alco-
hol 2 (200 mg, 0.47 mmol) in dry CH2Cl2 (5 ml) and Et3N
(195 mL, 1.41 mmol, 3 equiv) was added benzoyl chloride
(52 mL, 0.71 mmol, 1.5 equiv) dropwise. The reaction
stirred at rt for 2 h when found complete by TLC. CH2Cl2
(5 mL) was then added and the organic layer washed con-
secutively with 1 N HCl (2ꢁ5 mL), saturated NaHCO3
(2ꢁ5 mL), and brine (5 mL). The organic layer was dried
(MgSO4), filtered, and evaporated to afford crude off-white
solid, which was recrystallized from hot absolute ethanol to
afford benzoyl ester 5 as an off-white, amorphous solid
(220 mg, 88%). Mp: 180–181 ꢀC. Rf¼0.53 (7:3 ethyl ace-
4.1.5. Deprotection of trityl ether 4/2. A portion of trityl
ether 4 (42 mg, 0.06 mmol) was dissolved in 1:1 CH2Cl2/
methanol (3 mL). A catalytic amount of camphor sulfonic
acid was then added and the solution was stirred vigorously
at 40 ꢀC for 1 h, at which time TLC indicated reaction com-
pletion (7:3 ethyl acetate/hexanes). The solution was neu-
tralized by the addition of Et3N (10 mL, 0.07 mmol) and
extracted twice with CH2Cl2 (2ꢁ2 mL). The combined or-
ganic extracts were washed with distilled H2O (4 mL) and
the organic layer was dried (MgSO4), filtered, and evapo-
rated. The resulting crude residue was purified by gradient
flash silica chromatography (2:8 ethyl acetate/hexanes to
neat ethyl acetate gradient) to afford alcohol 2 as white solid
(25 mg, 95%).
1
tate/hexanes). H NMR (CDCl3, 400 MHz): d 1.82 (s, 3H,
OAc), 2.00 (s, 3H, OAc), 2.04 (s, 3H, OAc), 2.06 (s, 3H,
0
3
3
3
OAc), 3.99 (ddd, J5–4,¼10.2 Hz, J5–6¼5.2 Hz, J5–6
¼
2
3
2 Hz, 1H, H-50), 4.13 (dd, J6–6 ¼12.8 Hz, J6 –5¼2.0 Hz,
0
0
2
3
1H, H-600), 4.28 (dd, H6–6 ¼12.8 Hz, J6–5¼4.8 Hz, 1H,
0
H-60), 5.20–5.25 (m, 1H, H-40), 5.37–5.41 (m, 1H, H-30),
3
5.41–5.50 (m, 3H, H-20, CH2OBz), 5.87 (d, J1–2¼9.2 Hz,
1H, H-10), 7.39 (m, 2H, Ar H), 7.52 (m, 1H, Ar H), 7.91
(s, 1H, triazole H), 8.02–8.04 (m, 2H, Ar H); 13C NMR
(100 MHz, CDCl3): d 20.3 (OAc), 20.70 (OAc), 20.73
(OAc), 20.9 (OAc), 58.1 (C-5), 61.7 (C-6), 67.9 (C-4),
70.5 (CH2OBz), 72.8 (C-3), 75.4 (C-2), 86.0 (C-1), 122.6
(triazole CH), 128.6 (Ar CH), 129.9 (Ar CH), 130.0 (Ar
CH), 133.5 (Ar C), 143.9 (triazole C), 166.5 (OBz C]O),
169.0 (OAc C]O), 169.5 (OAc C]O), 170.1 (OAc C]O),
170.7 (OAc C]O). HRESIMS calcd for C24H27N3O11Na+:
556.15378. Found: 556.153103. Anal. Calcd for
C24H27N3O11: C, 54.03; H, 5.10; N, 7.88. Found: C, 53.91;
H, 5.12; N, 7.74.
4.1.6. 4-Acetoxymethyl-1-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-1,2,3-triazole (5). Alcohol 2 (200 mg,
0.47 mmol) was dissolved in dry pyridine (2 mL) and acetic
anhydride (1 mL) and a catalytic amount of DMAP was
added. The solution was stirred at rt for 1 h when TLC indi-
cated reaction completion (1:1 ethyl acetate/hexanes).
Removal of the solvent under reduced pressure afforded
a crude off-white solid, which was recrystallized from hot
absolute ethanol to afford peracetate 5 as an off-white amor-
phous solid (185 mg, 84%). Mp: 143–144 ꢀC. Rf¼0.48 (7:3
ethyl acetate/hexanes). 1H NMR (400 MHz, CDCl3): d 1.86
(s, 3H, OAc), 2.01 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.07
(s, 3H, OAc), 2.08 (s, 3H, OAc), 3.98 (ddd, 3J5–4¼10.0 Hz,
4.1.9. Deprotection of benzoyl ester 6/11. A portion of
benzoyl ester 6 (25 mg, 0.047 mmol) was suspended in dry
methanol (2 mL) and a 1.0 M solution of sodium methoxide
(10 mL, 0.01 mmol) in dry methanol was added. The pale
yellow solution was stirred o/n at 40 ꢀC to effect complete
benzoyl deprotection. TLC indicated reaction comple-
tion after 12 h (8:2 ethyl acetate/hexanes and 1:9 water/
acetonitrile) and the solution was neutralized by the addition
of Amberlite IR-120 acidic ion-exchange resin. Filtration
and evaporation to dryness under reduced pressure afforded
pentol 11 as white solid (10 mg, 82%).
3
3
2
0
0
0
J5–6¼4.8 Hz, J5–6 ¼2 Hz, 1H, H-5 ), 4.14 (dd, J6 –6
¼
3
2
12.8 Hz, J6 –5¼2 Hz, 1H, H-600), 4.29 (dd, J6–6 ¼12.8 Hz,
3J6–5¼5.2 Hz, 1H, H-60), 5.20 (s, 2H, CH2OAc), 5.21–5.24
(m, 1H, H-40), 5.39–5.41 (m, 2H, H-20, H-30), 5.84–5.86
(m, 1H, H-10), 7.82 (s, 1H, triazole CH); 13C NMR
(100 MHz, CDCl3): d 20.3 (OAc), 20.69 (OAc), 20.72
(OAc), 20.9 (OAc), 21.0 (OAc), 57.6 (C-5), 61.7 (C-6),
67.9 (C-4), 70.5 (CH2OAc), 72.8 (C-3), 75.4 (C-2), 86.0
(C-1), 122.3 (triazole CH), 143.9 (triazole C), 169.1 (OAc),
169.5 (OAc), 170.1 (OAc), 170.7 (OAc), 171.0 (OAc).
HRESIMS calcd for C19H25N3O11Na+: 494.13810. Found:
494.137458. Anal. Calcd for C19H25N3O11: C, 54.03; H,
5.10; N, 7.88. Found: C, 53.91; H, 5.12; N, 7.74.
0
0
4.1.10. 4-Benzyloxymethyl-1-(20,30,40,60-tetra-O-benzyl-
b-D-glucopyranosyl)-1,2,3-triazole (7). To a solution of
pentol 11 (140 mg, 0.54 mmol) in dry DMF (5 mL) under
nitrogen was added at 0 ꢀC a 60% sodium hydride mineral
oil dispersion (130 mg, 3.24 mmol, 6 equiv). The heteroge-
neous mixture was allowed to warm to room temperature and
stirred for an additional 30 min before benzyl bromide
(380 mL, 3.24 mmol, 6 equiv) was added. The deep yellow
solution was stirred at rt for 8 h. The solution was then
4.1.7. Deprotection of peracetate 5/11. A portion of
the peracetate (100 mg) was suspended in dry methanol

B. L. Wilkinson et al. / Tetrahedron 62 (2006) 8115–8125
8121
3
3
3
cooled again to 0 ꢀC and methanol was added gradually.
Bulk solvent was then removed and CH2Cl2 (20 mL) was
added. The organic extract was washed consecutively with
1 N HCl (2ꢁ5 mL), saturated NaHCO3 (2ꢁ5 mL), and brine
(5 mL). The organic layer was dried (MgSO4), filtered, and
evaporated under reduced pressure to afford a pale yellow
oil, which was purified by flash silica chromatography (2:8
ethyl acetate/hexanes) to afford pentabenzyl ether 7 as white
crystalline solid (330 mg, 86%). Mp¼98–99 ꢀC. Rf¼0.43
J5–4¼10.4 Hz, J5–6¼4.8 Hz, J5–6 ¼2 Hz, 1H, GlcN
0
2
3
H-50), 4.13 (dd, J6 –6¼12.4 Hz, J6 –5¼2.0 Hz, 1H, GlcN
0
0
2
3
H-600), 4.18 (dd, J6 –6¼12.4 Hz, J6 –5¼2.4 Hz, 1H, GlcO
H-600), 4.26–4.32 (m, 2H, GlcN H-60, GlcO H-60), 4.54 (d,
3J1–2¼8 Hz, 1H, GlcO H-10), 4.78–4.92 (m, 2H, CH2O),
0
0
3
3
4.98 (dd, J2–3¼9.6 Hz, J2–1¼8.4 Hz, 1H, GlcO H-20),
5.06–5.11 (m, 1H, GlcO H-40), 5.15–5.20 (m, 1H, GlcO
H-30), 5.21–5.26 (m, 1H, GlcN H-40), 5.39–5.42 (m, 2H,
GlcN H-20, H-30), 5.84–5.86 (m, 1H, GlcN H-10), 7.80 (s,
1H, triazole H); 13C NMR (100 MHz, CDCl3): d 20.3
(OAc), 20.72 (2ꢁOAc), 20.79 (3ꢁOAc), 20.86 (OAc),
20.89 (OAc), 61.7 (GlcN or GlcO C-6), 62.0 (GlcN or
GlcO C-6), 62.1 (CH2O), 67.9 (GlcN C-4), 68.6 (GlcO
C-4), 70.6 (GlcN C-2 or C-3), 71.3 (GlcO C-2), 72.0
(GlcO C-5), 72.6 (GlcN C-2 or C-3), 72.8 (GlcO C-3),
75.5 (GlcN C-5), 86.1 (GlcN C-1), 99.0 (GlcO C-1), 122.3
(triazole CH), 169.55 (OAc), 169.57 (OAc), 169.62 (OAc),
170.05 (OAc), 170.1 (OAc), 170.4 (OAc), 170.6 (OAc),
170.9 (OAc). HRESIMS calcd for C31H41N3O19Na+:
782.22267. Found: 782.223136. Anal. Calcd for
C31H41N3O19: C, 49.01; H, 5.44; N, 5.53; O, 40.02. Found:
C, 48.93; H, 5.61; N, 5.17.
1
(6:4 ethyl acetate/hexanes). H NMR (400 MHz, CDCl3):
d 3.65–3.76 (m, 3H, H-50, H-60, H-600), 3.78–3.89 (m, 2H,
H-30, H-40), 4.02–4.06 (m, 2H, H-20), 4.07–4.09 (m, 2H,
CH2OBn), 4.47–4.56 (m, 4H, CH2Ph), 4.59–4.67 (m,
2H, CH2Ph), 4.67–4.73 (m, 2H, CH2Ph), 4.88–4.95 (m,
3
2H, CH2Ph), 5.96 (d, J1–2¼9.6 Hz, 1H, H-10), 6.93–6.97
(m, 2H, Ar CH), 7.16–7.19 (m, 4H, Ar CH), 7.27–7.34
(m, 19H, Ar CH), 7.66 (s, 1H, triazole CH); 13C NMR
(100 MHz, CDCl3): d 63.8 (CH2Ph), 68.6 (C-6), 72.2
(CH2Ph), 73.8 (CH2Ph), 75.1 (CH2OBn), 75.4 (CH2Ph),
76.0 (CH2Ph), 77.5 (C-3 or C-4), 78.2 (C-5), 81.0 (C-2),
85.7 (C-3 or C-4), 87.8 (C-1), 122.2 (triazole CH), 127.94
(Ar C), 127.99 (Ar C), 128.01 (Ar C), 128.03 (Ar C),
128.06 (Ar C), 128.09 (Ar C), 128.17 (Ar C), 128.18
(Ar C), 128.23 (Ar C), 128.46 (Ar C), 128.59 (Ar C),
128.64 (Ar C), 128.67 (Ar C), 128.72 (Ar C), 137.2 (Ar C),
137.9 (Ar C), 138.0 (2ꢁAr C), 138.4 (Ar C), 145.7 (triazole
C). HRESIMS calcd for C44H45N3O6Na+: 734.320057.
Found¼734.320207. Anal. Calcd for C44H45N3O6: C,
74.24; H, 6.37; N, 5.90; O, 13.49. Found: C, 74.64; H,
6.49; N, 5.71.
4.1.13. [1-(2,3,4,6-Tetra-O-acetylglucopyranosyl)-1H-
1,2,3-triazol-4-yl]methyl-2,3,4,6-tetra-O-acetyl galacto-
pyranoside (9). A solution of alcohol 2 (157 mg, 0.37 mmol)
and b-D-galactose pentaacetate (143 mg, 0.37 mmol, 1 equiv)
in dry CH2Cl2 (5 mL) was prepared under nitrogen and cooled
to 0 ꢀC. Boron trifluoride etherate (113 mL, 0.92 mmol,
2.5 equiv) was then added dropwise and the reaction was
allowed to warm to rt. The reaction was found complete
by TLC (8:2 ethyl acetate/hexanes) after stirring under nitro-
gen o/n. CH2Cl2 (5 ml) was added and washed with satu-
rated NaHCO3 (2ꢁ5 mL) and brine (5 mL). The organic
layer was dried (MgSO4), filtered, and evaporated to a pale
yellow oil, which was purified by flash silica chromato-
graphy to afford the galactoside 10 as a clear gum, which
slowly crystallized on standing in the refrigerator (165 mg,
59%). Mp: 106–107 ꢀC. 1H NMR (400 MHz, CDCl3):
d 1.85 (s, 3H, OAc), 1.92 (s, 3H, OAc), 1.93 (s, 3H, OAc),
2.00 (s, 3H, OAc), 2.03 (s, 3H, OAc), 2.04 (s, 3H, OAc),
2.05 (s, 3H, OAc), 2.12 (s, 3H, OAc), 3.92–3.96 (m, 1H,
4.1.11. Deprotection of perbenzyl ether 7/11. Perbenzyl
ether 6 (20 mg, 0.03 mmol) was dissolved in dry 1:2 CH2Cl2/
methanol (w2 mL) and a catalytic amount of activated 30%
Pd(OH)2/C was added. Thevesselwas placed under nitrogen,
evacuated and then placed under an atmosphere of hydrogen
and stirred at rt for 24 h. TLC indicated near reaction comple-
tion after ca. 24 h (8:2 ethyl acetate/hexanes and 1:9 water/
acetonitrile). The mixture was filtered on Celite and eluted
several times with methanol. Evaporation of the filtrate
afforded pentol 11 as clear gum (6 mg, 78%).
3
3
3
Gal H-50), 4.00 (ddd, J5–4¼7.2 Hz, J5–6¼5.2 Hz, J5–6
¼
0
2 Hz, 1H, Glc H-50), 4.07–4.13 (m, 2H, Glc H-600, Gal H-600),
4.1.12. [1-(2,3,4,6-Tetra-O-acetylglucopyranosyl)-1H-
1,2,3-triazol-4-yl]methyl-2,3,4,6-tetra-O-acetyl glucopyr-
anoside (8). A solution of alcohol 2 (100 mg, 0.23 mmol)
and 2,3,4,6-tetra-O-acetyl-a-D-glucosyl bromide (172 mg,
0.42 mmol, 1.8 equiv) in dry CH2Cl2 (5 mL) was prepared
under nitrogen. Silver trifluoromethanesulfonate (66 mg,
0.26 mmol, 1.1 equiv) was then added and the mixture
stirred at rt for 4 h when found complete by TLC (7:3 ethyl
acetate/hexanes). The solution was neutralized by the addi-
tion of diisopropylethylamine (100 mL, 0.57 mmol). Insolu-
ble silver salts were removed by filtration on Celite and the
crude product was eluted with CH2Cl2 (w20 mL). Concen-
tration of the filtrate under reduced pressure and flash silica
chromatography of the crude residue (4:6 ethyl acetate/
hexanes) afforded glucoside 8 as a white foam (98 mg,
4.21 (dd, 2J6–6 ¼11.6 Hz, J6–5¼6.4 Hz, 1H, Gal H-60), 4.27
3
0
2
3
(dd, J6–6 ¼12.8 Hz, J6–5¼5.2 Hz, 1H, Glc H-60), 4.46 (d,
0
3J1–2¼8 Hz, 1H, Gal H-10), 4.76–4.92 (m, 2H, CH2O),
3
3
5.17 (dd, J2–3¼10.8 Hz, J2–1¼8 Hz, 1H, Gal H-20), 4.98
3
3
(dd, J3–2¼10.4 Hz, J3–4¼3.2 Hz, 1H, Gal H-30), 5.21–
5.26 (m, 1H, Glc H-40), 5.35–5.43 (m, 3H, Glc H-20, Glc
H-30, Gal H-40), 5.85 (d, 3J1–2¼8.8 Hz, 1H, Glc H-10), 7.80
(s, 1H, triazole H); 13C NMR (100 MHz, CDCl3): d 20.3
(OAc), 20.69 (OAc), 20.71 (OAc), 20.75 (OAc), 20.83
(2ꢁOAc), 20.87 (OAc), 20.9 (OAc), 61.5 (CH2O), 61.6
(Gal C-6), 61.7 (Glc C-6), 67.3 (Gal C-4), 67.9 (Gal C-2),
68.8 (Glc C-4), 70.7 (Gal C-5), 70.8 (Glc C-3), 71.0 (Gal
C-3), 72.6 (Glc C-2), 75.4 (Glc C-5), 86.0 (Glc C-1), 99.1
(Gal C-1), 122.2 (triazole CH), 144.3 (triazole C), 169.3
(OAc), 169.6 (OAc), 169.7 (OAc), 170.0 (OAc), 170.2
(OAc), 170.5 (OAc), 170.6 (OAc), 170.7 (OAc). HRESIMS
calcd for C31H41N3O19Na+: 782.222647. Found:
782.223784. Anal. Calcd for C31H43N3O20 (monohydrate):
C, 47.88; H, 5.57; N, 5.40. Found: C, 47.62; H, 5.26; N, 5.07.
1
56%). H NMR (400 MHz, CDCl3): d 1.88 (s, 3H, OAc),
1.95 (s, 3H, OAc), 1.97 (s, 3H, OAc), 2.00 (s, 3H,
OAc), 2.02 (s, 3H, OAc), 2.05 (s, 3H, OAc), 2.06 (s, 3H,
3
OAc), 2.10 (s, 3H, OAc), 3.74 (ddd, 1H, J5–4¼10.2 Hz,
3
3
0
0
J5–6¼4.4 Hz, J5–6 ¼2.4 Hz, 1H, GlcO H-5 ); 3.99 (ddd,

8122
B. L. Wilkinson et al. / Tetrahedron 62 (2006) 8115–8125
4.1.14. 4-Azidomethyl-1-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-1,2,3-triazole (10). To a solution of alco-
hol 2 (200 mg, 0.47 mmol) in dry CH2Cl2 (5 mL) was added
Et3N (195 mL, 1.41 mmol, 3 equiv) and methanesulfonyl
chloride (55 mL, 0.71 mmol, 1.5 equiv). The solution was
stirred at rt under nitrogen for 30 min, at which time, TLC
indicated reaction completion (7:3 ethyl acetate/hexanes).
CH2Cl2 (5 mL) was then added and the solution was washed
consecutively with 1 N HCl (2ꢁ5 mL), saturated NaHCO3
(5 mL), and brine (5 mL). The organic layer was dried
(MgSO4), filtered, and evaporated to afford the mesylate as
a pale yellow oil, which was used in the subsequent step
without further purification. The crude mesylate was dis-
solved in dry DMF (2 mL) and NaN3 (153 mg, 2.35 mmol,
5 equiv) was added. The mixture was warmed to 40 ꢀC
and stirred for 24 h. The bulk solvent was then removed
under reduced pressure and CH2Cl2 (5 mL) was added.
The extract was washed with distilled H2O (2 mL) and brine
(2 mL). The organic layer was dried (MgSO4), filtered, and
evaporated to afford a crude off-white solid. Recrystalliza-
tion from hot absolute ethanol afforded azide 10 as amor-
phous white solid (102 mg, 48%). Mp: 110–111 ꢀC. 1H
NMR (400 MHz, CDCl3): d 1.87 (s, 3H, OAc), 2.02 (s,
3H, OAc), 2.06 (s, 3H, OAc), 2.07 (s, 3H, OAc), 4.00
4.1.17. 4-Pyridin-2-yl-1-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-1,2,3-triazole (12). White amorphous
solid (92%). Mp: 195–196 ꢀC. Rf¼0.42 (8:2 ethyl acetate/
hexane). 1H NMR (400 MHz, CDCl3): d 1.87 (s, 3H,
OAc), 2.02 (s, 3H, OAc), 2.06 (s, 3H, OAc), 2.08 (s, 3H,
3
3
3
0
OAc), 4.01 (ddd, J5–4¼10.4 Hz, J5–6 ¼4.8 Hz, J5–6
¼
2
2.0 Hz, 1H, H-50), 4.15 (dd, J6–6 ¼12.8 Hz, J6–5¼2.0 Hz,
0
2
3
1H, H6), 4.29 (dd, J6 –6¼12.4 Hz, J6 –5¼4.8 Hz, H-600),
0
0
5.23–5.28 (m, 1H, H-40), 5.40–5.45 (m, 1H, H-30), 5.50–
3
5.55 (m, 1H, H-20), 5.90 (d, J1–2¼9.2 Hz, 1H, H-10),
7.30–7.33 (m, 1H, Ar H), 7.85–7.88 (m, 1H, Ar H), 8.21–
8.23 (m, 1H, Ar H), 8.65 (br s, 1H, triazole H); 13C NMR
(100 MHz, CDCl3): d 20.4 (OAc), 20.73 (s, 3H, OAc),
20.74 (s, 3H, OAc), 20.9 (s, OAc), 61.7 (C-6), 67.9 (C-4),
70.7 (C-3), 72.9 (C-2), 75.3 (C-5), 86.1 (C-1), 120.7 (triazole
CH), 121.0 (Ar C), 123.5 (Ar CH), 137.3 (Ar CH), 148.9
(triazole C), 149.5 (Ar CH), 149.6 (Ar C), 169.0 (OAc),
169.5 (OAc), 170.2 (OAc), 170.7 (OAc). HRESIMS calcd
for C21H24N4O9Na+: 499.143549. Found: 499.142640.
Anal. Calcd for C21H24N4O9: C, 52.44; H, 5.08; N, 11.76;
O, 30.22. Found: C, 52.17; H, 5.04; N, 11.36.
4.1.18. 4-Amidomethyl-L-NBocVal-1-(20,30,40,60-tetra-
O-acetyl-b-D-glucopyranosyl)-1,2,3-triazole (13). White
foam (77%). 1H NMR (400 MHz, CDCl3): d 0.85 (d,
3
3
3
0
(ddd, J5–4¼10.4 Hz, J5–6¼5.2 Hz, J5–6 ¼2.4 Hz, 1H,
2
3
3
H-50), 4.14 (dd, J6–6 ¼12.8 Hz, J6 –5¼2.4 Hz, 1H, H-600),
3J¼6.4 Hz, 3H, Val i-pr CH3); 0.91 (d, J¼7.2 Hz, Val i-pr
0
0
2
3
4.30 (dd, J6–6 ¼12.4 Hz, J6–5¼5.2 Hz, 1H, H-60), 4.48 (s,
2H, CH2N3), 5.20–5.25 (m, 1H, H-40), 5.38–5.44 (m, 2H,
H-20, H-30), 5.84–5.90 (m, 1H, H-10), 7.79 (s, 1H, triazole
CH); 13C NMR (100 MHz, CDCl3): d 20.3 (OAc), 20.7
(OAc), 20.8 (OAc), 20.9 (OAc), 45.7 (N3CH2), 61.7 (C-6),
67.9 (C-4), 70.5 (C-3), 72.7 (C-2), 75.5 (C-5), 86.1 (C-1),
121.0 (triazole CH), 169.2 (OAc), 169.6 (OAc), 170.1
(OAc), 170.7 (OAc). HRESIMS calcd for C17H22N6O9Na+:
477.134047. Found 477.134673. Anal. Calcd for
C17H22N6O9: C, 44.94; H, 4.88; N, 18.50. Found: C,
44.72; H, 4.90; N, 18.27.
CH3); 1.41 (s, 9H, Boc CH3), 1.84 (s, 3H, OAc), 2.00 (s,
3H, OAc), 2.04 (s, 3H, OAc), 2.06 (s, OAc), 2.13 (m, 1H,
Val i-pr CH), 3.92 (m, 1H, BocNH), 3.980 (ddd,
0
3
3
3
0
J5–4¼10.2 Hz, J5–6¼4.4, J5–6 ¼2.0 Hz, 1H, H-5 ), 4.12
2
3
(dd, J6–6 ¼12.8 Hz, J6–5¼2.4 Hz, 1H, H-60), 4.27 (dd,
0
2
3
J6 –6¼12.4 Hz, J6 –5¼4.8 Hz, 1H, H-600), 4.26 (br s, 2H,
0
0
CH2CONH), 5.06–5.1 (m, 1H, Val a-CH), 5.20–5.25 (m,
1H, H-40), 5.37–5.43 (m, 1H, H-20), 5.83–5.85 (m, 1H,
H-10), 6.73 (br s, 1H, CONH), 7.78 (s, triazole CH); 13C
NMR (100 MHz, CDCl3): d 17.8 (Val CH3), 19.5 (Val
CH3), 20.3 (OAc), 20.7 (OAc), 20.7 (OAc), 20.9 (OAc),
28.5 (t-Bu), 31.0 (Val i-pr CH), 35.0 (CH2CONH), 60.0
(Val a-C), 61.70 (C-5), 67.9 (C-6), 70.5 (C-2), 72.8 (C-3),
75.3 (C-4), 86.0 (C-1), 156.1 (Boc C]O), 169.0 (OAc
C]O), 169.5 (OAc C]O), 170.2 (OAc C]O), 170.7
(OAc C]O), 170.6 (CONH C]O). HRESIMS calcd for
C27H41N5O12Na+: 650.264393. Found: 650.26406.
4.1.15. 1-(b-D-Glucopyranosyl)-4-hydroxymethyl-1,2,3-
triazole (11). White solid (various yields: see text). Mp:
162–163 ꢀC. Rf¼0.15 (1:9 water/acetonitrile). 1H NMR
(400 MHz, D2O): d 3.46–3.50 (m, 1H), 3.55–3.67 (m, 3H,
H-30, H-50, H-60), 3.75–3.78 (m, 1H, H-600), 3.84–3.89 (m,
3
1H, H-20), 4.60 (s, 2H, CH2OH), 5.61 (d, J1–2¼9.2 Hz,
1H, H-10), 8.06 (s, 1H, triazole CH); 13C NMR (100 MHz,
D2O): d 54.7 (CH2OH), 60.6 (C-6), 69.1 (C-4), 72.4 (C-2),
76.1 (C-3), 79.0 (C-5), 87.6 (C-1), 123.5 (triazole CH).
HRESIMS calcd for C9H15N3O6Na+: 284.085310. Found:
284.085457.
4.1.19. 4-(17a-Estradiol)-1-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-1,2,3-triazole (14). Pale yellow solid
(71%). Mp: 133–134 ꢀC. 1H NMR (400 MHz, CDCl3):
d 0.45–0.60 (m, 1H, CH), 1.02 (s, 3H, estradiol CH3),
1.20–1.60 (m, 6H, estradiol), 1.83 (s, 3H, OAc), 1.85–1.91
(m, 2H, estradiol CH2), 1.96–2.12 (m, 6H, estradiol H),
2.02 (s, 3H, OAc), 2.05 (s, 6H, 2ꢁOAc), 2.46–2.54 (m,
2H, estradiol CH2), 2.70 (br s, 1H, OH), 2.72–2.81 (m, 2H,
4.1.16. Preparation of compounds 12–18, 20. To a vigor-
ously stirring suspension or solution of the azide (0.5 M)
and acetylene (0.5 M) in the selected co-solvent, was added
a solution of CuSO4$5H2O (0.2 equiv) and sodium ascorbate
(0.4 equiv) in deionized H2O. The deep yellow mixture
was stirred vigorously at 40 ꢀC and the reaction progress was
monitored by TLC. Once complete, the crude mixture
was extracted with three equal amounts of CH2Cl2, com-
bined, dried (MgSO4), filtered, and evaporated to afford
the glycosyl triazole as off-white to white solid. A portion
or the entire crude solid was purified by SPE, flash chroma-
tography or recrystallization from hot absolute ethanol to
afford analytically pure compound.
3
3
3
0
estradiol), 3.99 (ddd, J5–4¼10 Hz, J5–6 ¼4.8, J5–6
¼
2
3
2.0 Hz, 1H, H-50), 4.14 (dd, J6–6 ¼12.8 Hz, J6–5¼2.0 Hz,
0
2
3
1H, H-60), 4.30 (dd, J6 –6¼12.4 Hz, J6 –5¼4.8 Hz, 1H,
0
0
H-600), 5.22–5.27 (m, 1H, H-40), 5.37–5.42 (m, 1H, H-30),
3
5.44–5.48 (m, 1H, H-20), 5.86 (d, J1–2¼8 Hz, 1H, H-10),
6.52–6.58 (m, 2H, 2ꢁAr CH), 7.02–7.04 (m, 1H, Ar CH),
7.70 (s, 1H, triazole CH); 13C NMR (100 MHz, CDCl3):
d 14.4 (C-18), 20.3 (OAc), 20.7 (OAc), 20.8 (OAc), 20.9
(OAc), 23.9 (estradiol), 26.5 (estradiol), 27.5 (estradiol),
29.8 (estradiol), 33.0 (estradiol), 38.20 (estradiol), 39.6
(estradiol), 43.6 (estradiol), 47.6 (estradiol), 48.6 (estradiol),

B. L. Wilkinson et al. / Tetrahedron 62 (2006) 8115–8125
8123
2
3
2
61.8 (C-60), 68.0 (C-40), 70.5 (C-20), 72.9 (C-30), 75.3 (C-50),
82.8 (estradiol C-17), 85.9 (C-1), 112.9 (Ar CH), 115.5 (Ar
CH), 120.3 (triazole CH), 126.5 (Ar CH), 132.5 (Ar C),
138.4 (Ar C), 153.9 (triazole C), 154.8 (phenol C), 169.1
(OAc), 169.7 (OAc), 170.2 (OAc), 170.9 (OAc). HRESIMS
calcd for C34H43N3O11Na+: 692.27898. Found: 692.279186.
J5–5 ¼13.6, J5–4¼1.2 Hz, 1H, H-50), 4.11 (dd, J5 –5
¼
0
0
3
3
13.6 Hz, J5 –4¼2 Hz, 1H, H-500), 5.19 (dd, J3–2¼10 Hz,
0
3
3
3
J3–4¼3.2 Hz, 1H, H-30), 3.58 (ddd, J4–3¼3.6 Hz, J4–5
¼
0
3
2 Hz, J4–5¼1.2 Hz, 1H, H-40), 5.43–5.48 (m, 1H, H-20),
3
5.66 (d, J1–2¼11.2 Hz, 1H, H-10), 5.92–6.03 (m, 2H, Bt-
CH2), 7.33–7.37 (m, 1H, Ar H), 7.43–7.47 (m, 1H, Ar H),
7.64–7.66 (m, 1H, Ar H), 7.81 (s, triazole CH), 8.03–8.05
(m, 1H, Ar H); 13C NMR (100 MHz, CDCl3): d 20.3 (OAc),
20.7 (OAc), 21.1 (OAc), 43.9 (Bt-CH2), 67.5 (C-5), 67.8
(C-4), 68.4 (C-2), 70.5 (C-3), 87.0 (C-1), 110.2 (Ar CH),
120.1 (Ar CH), 121.9 (triazole CH), 124.3 (Ar CH), 127.9
(Ar CH), 169.1 (OAc), 170.0 (OAc), 170.3 (OAc); HRESIMS
calcd for C20H22N6O7Na+: 481.144218. Found: 481.14411.
Anal. Calcd for C20H22N6O7: C, 52.40; H, 4.84; N, 18.33;
O, 24.43. Found: C, 52.39; H, 4.94; N, 18.05; O, 24.62.
4.1.20. 4-Ethisterone-1-(20,30,40,60-tetra-O-acetyl-b-D-
glucopyranosyl)-1,2,3-triazole (15). White crystalline solid
(64%). Mp: 124 -125 ꢀC. 1H NMR (400 MHz, CDCl3):
d 0.32–0.396 (m, 1H, ethisterone CH), 0.65–0.71 (m, 1H,
ethisterone CH), 1.04 (s, 3H, ethisterone CH3), 1.16 (s,
3H, ethisterone CH3), 1.33–1.66 (m, 7H, ethisterone), 2.01
(s, 3H, OAc), 2.02–2.04 (m, 4H, ethisterone), 2.05 (s, 3H,
OAc), 2.06 (s, 6H, 2ꢁOAc), 2.22–2.41 (m, 5H, ethisterone),
2.44–2.52 (m, 1H, ethisterone CH), 3.99 (ddd, 3J5–4¼10 Hz,
3
3
2
J5–6 ¼4.8 Hz, J5–6¼2.0 Hz, 1H, H-50), 4.14 (dd, J6–6
¼
4.1.23. 1-(20-Deoxy-20-acetamido-30,40,60-tri-O-acetyl-b-
D-glucopyranosyl)-4-(hydroxymethyl)-1,2,3-triazole
(18).16f Off-white foam (62%). 1H NMR (400 MHz, DMSO-
0
0
12.8 Hz, 3J6–5¼2.0 Hz, 1H, H-60), 4.30 (dd, 2J6-6¼12.8 Hz,
3
J6 –5¼4.8 Hz, 1H, H-600), 5.20–5.25 (m, 1H, H-40), 5.36–
0
5.44 (m, 2H, H-20, H-30), 5.68 (s, 1H, ethisterone C]CH),
5.83–5.85 (m, 1H, H-10), 7.66 (s, 1H, triazole CH); 13C
NMR (100 MHz, CDCl3): d 14.4 (ethisterone CH3), 17.6
(ethisterone CH3), 20.3 (OAc), 20.7 (OAc), 20.8 (OAc),
20.9 (OAc), 24.1 (ethisterone), 31.8 (ethisterone), 32.7
(ethisterone), 33.0 (ethisterone), 34.1 (ethisterone), 35.9
(ethisterone), 36.5 (ethisterone), 38.0 (ethisterone),
38.8 (ethisterone), 47.1 (ethisterone), 49.0 (ethisterone),
53.6 (ethisterone), 61.3 (C-6), 68.0 (C-4), 70.5 (C-2 or
C-3), 72.8 (C-2 or C-3), 75.4 (C-5), 82.5 (ethisterone
C-17), 86.0 (C-1), 119.9 (triazole CH), 124.0 (ethisterone
C]CH), 154.5 (triazole C), 168.9 (OAc), 169.6 (OAc),
170.1 (OAc), 170.7 (ethisterone C]CH), 171.4 (OAc),
199.7 (ethisterone C]O). HRESIMS calcd for
C35H47N3O11Na+: 708.31028. Found: 708.310775. Anal.
Calcd for C35H47N3O11: C, 61.30; H, 6.91; N, 6.13; O,
25.66. Found: C, 61.31; H, 6.99; N, 5.98.
d6): d 1.57 (s, 3H, NHAc), 1.92 (s, 3H, OAc), 1.97 (s, 3H,
2
0
OAc), 1.98 (s, 3H, OAc), 3.99–4.03 (dd, J6–6 ¼12.4 Hz,
3
3
2
J6–5¼2.4 Hz, 1H, H-60), 4.09–4.13 (dd, J6 –6¼12.4 Hz,
0
3
3
J6 –5¼5.2 Hz, 1H, H-600), 4.19 (ddd, J5–4¼10 Hz, J5–6
¼
¼
0
0
3
4.8 Hz, J5–6¼2.4 Hz, 1H, H-50), 4.47 (d, JCH ꢂOH
3
2
4:4 Hz, 2H, CH2OH), 5.04–5.09 (m, 1H, H-30), 5.20–5.21
(m, 1H, CH2OH), 5.29–5.34 (m, 1H, H-40), 6.06 (d, 3J1–2
¼
10 Hz, 1H, H-10), 8.04 (d, 3JNH–H ¼9.6 Hz, 1H, NHAc NH),
2
8.09 (s, 1H, triazole CH); 13C NMR (100 MHz, DMSO-d6):
d 25.7 (OAc), 25.9 (OAc), 26.0 (OAc), 27.8 (NHAc),
57.4 (C-2), 60.0 (CH2OH), 67.3 (C-4), 73.4 (C-5), 77.9
(C-3), 78.7 (C-6), 90.0 (C-1), 126.8 (triazole CH), 153.6
(triazole C), 174.8 (C]O), 174.9 (C]O), 175.0 (C]O),
175.5 (C]O). HRESIMS calcd for C17H24N4O9Na+:
541.143549. Found: 451.142863.
4.1.24. 4-Hydroxymethyl-1-(20,30,40,60-tetra-O-benzyl-a-
D-glucopyranosyl)-1,2,3-triazole (19). To a vigorously stir-
ring solution of 2,3,4,6-tetra-O-benzyl-a-D-glucopyranosyl
azide (100 mg, 0.18 mmol) in hot tert-butyl alcohol
(500 mL at ca. 60 ꢀC), was added propargyl alcohol (45 mL,
0.74 mmol, 4.2 equiv) and a solution of CuSO4$5H2O
(18 mg, 0.08 mmol, 0.4 equiv) and sodium ascorbate
(30 mg, 0.15 mmol, 0.8 equiv) in distilled H2O (500 mL).
The deep yellow suspension was stirred at 60 ꢀC for approx.
2 d, at which time TLC indicated reaction completion (1:1
ethyl acetate/hexanes). The aqueous phase was then ex-
tracted with CH2Cl2 (2ꢁ10 mL), and the combined organic
extracts were dried (MgSO4), filtered, and evaporated to
afford a pale yellow syrup, which crystallized on standing
to afford a white amorphous solid. (79 mg, 73%), Mp: 82–
4.1.21. 4-(4-Sulfamoylamidomethyl)-1-(methyl 20,30,40-
tri-O-acetyl-b-D-glucuronate)-1,2,3-triazole (16). Off-
white amorphous solid (85%). Mp (decomp): 221–222 ꢀC.
1
Rf¼0.08 (8:2 ethyl acetate/hexanes). H NMR (DMSO-d6,
400 MHz): d 1.76 (s, 3H, OAc), 1.95 (s, 3H, OAc), 1.98
3
(s, 3H, OAc), 3.59 (s, 3H, CO2CH3), 4.51 (d, JCH ꢂNH
¼
2
3
5:2 Hz, 2H, NHCH2), 4.76 (d, J5–4¼10 Hz, 1H, H-50),
5.19–5.24 (m, 1H, H-40), 5.44–5.59 (m, 1H, H-30), 5.72–
3
5.76 (m, 1H, H-20), 6.34 (d, J1–2¼9.6 Hz, 1H, H-10), 7.45
(br s, 2H, SO2NH2), 7.86–8.01 (m, 4H, Ar H), 8.35 (s, 1H,
C
triazole H), 9.23 (t, 3JNHꢂCH ¼5:6 Hz, 1H, ArCONH); 13
2
NMR (DMSO-d6, 100 MHz): 20.6 (OAc CH3), 20.9 (OAc
CH3), 21.0 (OAc CH3), 35.5 (CH2NH), 53.3 (CO2CH3),
69.0 (C-4), 70.4 (C-2), 72.3 (C-3), 73.5 (C-5), 84.4 (C-1),
122.9 (triazole CH), 126.3 (Ar CH), 128.7 (Ar CH), 137.6
(Ar C), 146.4 (Ar C), 147.1 (triazole C), 165.9 (C]O),
167.3 (C]O), 169.1 (C]O), 170.0 (C]O), 170.2
(C]O). HRESIMS (ꢂve ion) calcd for C23H26N5O12Sꢂ:
596.130416. Found: 596.132499. Anal. Calcd for
C23H27N5O12S: C, 46.23; H, 4.55; N, 11.72; O, 32.13; S,
5.37. Found: C, 46.10; H, 4.66; N, 11.51.
1
83 ꢀC. Rf¼0.19. H NMR (400 MHz, CDCl3): d 3.51 (dd,
2
3
2
J6–6 ¼10.8 Hz, J6–6¼2.0 Hz, 1H, H-60), 3.67 (dd, J6 –6
¼
0
0
10.8 Hz, J6 –5¼2.8 Hz, 1H, H-600), 3.81 (dd, 3J¼10 Hz,
3
0
3J¼8.4 Hz, 1H, H-40), 3.89–3.93 (m, 1H, H-50), 4.02 (dd,
3J2–3¼9.6 Hz, J2–1¼6 Hz, 1H, H-20), 4.39–4.53 (m, 2H,
3
OBn CH2), 4.49–4.73 (m, 2H, OBn CH2), 4.52–4.85 (m,
2H, OBn CH2), 4.60–4.64 (m, 1H, H-30), 4.80 (s, 2H,
3
OCH2), 4.84–4.94 (m, 2H, OBn CH2), 5.80 (d, J1–2
¼
5.6 Hz, 1H, H-10), 7.13–7.16 (m, 4H, OBn CH), 7.25–7.33
(m, 16H, OBn CH), 7.51 (s, triazole CH); 13C NMR
(100 MHz, CDCl3): d 56.8 (OCH2), 68.3 (C-6), 73.7 (C-5),
73.9 (OBn CH2), 74.4 (OBn CH2), 75.0 (OBn CH2), 75.8
(OBn CH2), 77.4 (C-4), 78.8 (C-2), 82.0 (C-3), 84.3 (C-1),
4.1.22. 4-Methylenebenzotriazole-1-(20,30,40-tri-O-acetyl-
a-D-arabinosyl)-1,2,3-triazole (17). White solid (94%).
1
Mp: 215–216 ꢀC. H NMR (400 MHz, CDCl3): d 1.80 (s,
3H, OAc), 1.98 (s, 3H, OAc), 2.17 (s, 3H, OAc), 3.87 (dd,

8124
B. L. Wilkinson et al. / Tetrahedron 62 (2006) 8115–8125
4. (a) Fernandes, B.; Sagman, U.; Auger, M.; Demetrio, M.;
Dennis, J. W. Cancer Res. 1991, 51, 718–723; (b) Ohyama,
C.; Tsuboi, S.; Fukuda, M. EMBO J. 1999, 18, 1516–1525.
5. (a) Feizi, T.; Larkin, M. Glycobiology 1990, 1, 17–23; (b)
Pichlmaier, H.; Uhlenbruck, H.; Pulverer, G.; Ko, G.; Beuth,
J. Glycoconjugate J. 1995, 12, 1–6; (c) Schofield, L.; Hewitt,
M. C.; Evans, K.; Siomos, M.-A.; Seeberger, P. H. Nature
2002, 418, 785–789.
124.0 (triazole CH), 127.9 (OBn CH), 127.93 (OBn CH),
127.97 (OBn CH), 128.1 (OBn CH), 128.2 (OBn CH),
128.4 (OBn CH), 128.5 (OBn CH), 128.59 (OBn
CH), 128.62 (OBn CH), 128.7 (OBn CH), 128.9 (OBn
CH), 137.7 (OBn C), 137.8 (OBn C), 138.3 (OBn C),
138.7 (OBn C). HRESIMS calcd for C37H39N3O6Na+:
644.273116. Found: 644.272986.
6. Wharton, S. A.; Weis, W.; Skehel, D. C.; Wiley, D. C. The
Influenza Virus; Plenum: New York, NY, 1989.
7. (a) Varki, A. Essentials of Glycobiology, 2nd ed.; Cold Spring
Harbor Laboratory: New York, NY, 1999; (b) Ellgaard, L.;
Molinari, M.; Helenius, A. Science 1999, 286, 1882–1888;
(c) Roth, J. Chem. Rev. 2002, 102, 285–303.
8. (a) Herzner, H.; Reipen, T.; Schultz, M.; Kunz, H. Chem. Rev.
2000, 100, 4495–4537; (b) Kiefel, M. J.; von Itzstein, M. Chem.
Rev. 2002, 102, 471–490; (c) Davis, B. G. Chem. Rev. 2002,
102, 579–601.
9. Schriver, Z.; Raguram, S.; Sasisekharan, R. Nat. Rev. Drug
Discov. 2004, 3, 863–873.
4.1.25. Methyl 2,3,4-tri-O-acetyl-6-deoxy-6-(4-{[(2,3,4,6-
tetra-O-acetyl-b-D-glucopyranosyl)oxy]methyl}-1H-
1,2,3-triazol-1-yl)-a-D-glucopyranoside (20). White foam
1
(78%). H NMR (400 MHz, CDCl3): d 1.96 (s, 3H, OAc),
1.99 (s, 6H, 2ꢁOAc), 2.00 (s, 3H, OAc), 2.04 (s, 3H,
OAc), 2.08 (s, 6H, 2ꢁOAc), 3.14 (s, 3H, OCH3), 3.72
3
3
3
0
(ddd, J5–4¼10 Hz, J5–6¼5.2 Hz, J5–6 ¼2.8 Hz, 1H, bGlc
2
3
H-50), 4.14 (dd, J6–6 ¼12.4 Hz, J6–5¼2.4 Hz, 1H, bGlc
0
2
H-60), 4.17–4.20 (m, 1H, aGlc H-50), 4.26 (dd, J6 –6
¼
0
3
2
12.4 Hz, J6 –5¼4.62, 1H, bGlc H-600), 4.39 (dd, J6–6
¼
0
0
3
14.4 Hz, J6–5¼8.4 Hz, 1H, aGlc H-60), 4.56 (dd,
2
3
J6 –6¼14.6 Hz, J6 –5¼2.4 Hz, 1H, aGlc H-600), 4.52 (d,
0
0
3J1–2¼8.4 Hz, 1H, bGlc H-10), 4.73–4.82 (m, 3H, aGlc
10. (a) Lillelund, V. H.; Jensen, H. H.; Liang, X.; Bols, M. Chem.
Rev. 2002, 102, 515–553; (b) Houston, T. A.; Blanchfield,
J. T. Mini Rev. Med. Chem. 2003, 3, 669–678. See also Refs.
16c and d.
3
H-20, aGlc H-40, CH2O), 4.89 (d, J1–2¼3.6 Hz, 1H, aGlc
3
3
H-10), 4.99 (dd, J¼9.2 Hz, J2–1¼8 Hz, 1H, bGlc H-20),
5.05–5.09 (m, 1H, bGlc H-40), 5.14–5.19 (m, 1H, aGlc H-
30), 7.16 (s, 1H, triazole H); 13C NMR (100 MHz, CDCl3):
d 50.9 (bGlc C-5), 55.8 (OCH3), 62.0 (bGlc C-6), 62.9
(CH2O), 67.8 (aGlc C-5), 68.5 (bGlc C-4), 69.9 (aGlc
C-3), 70.0 (aGlc C-2), 70.9 (aGlc C-4), 71.3 (bGlc C-2),
72.1 (bGlc H-5), 72.9 (aGlc C-3), 96.9 (aGlc C-1), 99.7
(bGlc C-1), 124.6 (triazole CH), 144.4 (triazole C), 169.5
(OAc), 169.6 (OAc), 170.0 (OAc), 170.2 (OAc), 170.4
(OAc), 170.5 (OAc), 170.9 (OAc). HRESIMS calcd for
C30H41N3O18Na+: 754.227733. Found 754.226711. Anal.
Calcd for C30H41N3O18: C, 49.25; H, 5.65; N, 5.74; O,
39.36. Found: C, 48.92; H, 5.71; N, 5.49.
11. Fan, W.-Q.; Katritzky, A. R. Comprehensive Heterocyclic
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The authors gratefully acknowledge financial support from
the Australian Research Council as well as the Eskitis Insti-
tute for Cell and Molecular Therapies and the School of
Science, GU.
Supplementary data
1H NMR (400 MHz) spectra for compounds 2–20 are pro-
vided. Supplementary data associated with this article can
be found in the online version, at doi:10.1016/j.tet.2006.
06.001.
15. (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.;
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