One-Pot Synthesis of Glycosyl-β-azido Ester via Diazotransfer Reaction Toward Access of Glycosyl-β-triazolyl Ester

Article abstract of DOI:10.1021/acs.joc.5b00179

(Chemical Equation Presented). A concise and efficacious one-pot protocol for the synthesis of novel glycosyl-β-azido ester 3 from glycosyl olefinic ester 1 under mild conditions has been devised. The β-aminoester, formed by the conjugate addition of ammo

Full text of DOI:10.1021/acs.joc.5b00179

Article
pubs.acs.org/joc
One-Pot Synthesis of Glycosyl-β-azido Ester via Diazotransfer
Reaction Toward Access of Glycosyl-β-triazolyl Ester
Amrita Mishra and Vinod K. Tiwari*
Department of Chemistry, Centre of Advanced Study, Faculty of Science, Banaras Hindu University, Varanasi 221005, India
S
* Supporting Information
ABSTRACT: A concise and efficacious one-pot protocol for the synthesis of novel glycosyl-β-azido ester 3 from glycosyl olefinic
ester 1 under mild conditions has been devised. The β-aminoester, formed by the conjugate addition of ammonia on olefinic
ester, undergoes a metal-catalyzed diazotransfer reaction to furnish glycosyl-β-azido ester. The optimized conditions for
diazotransfer reaction indicate that imidazole-1-sulphonyl azide and K2CO3 give the best results in the presence of ZnCl2. A
diverse range of novel regioselective triazolyl glycoconjugates 6a−u have been achieved in high yields via 1,3-dipolar
cycloaddition of compound 3 with various alkynes in the presence of CuI/DIPEA. Structures of all the compounds have been
elucidated using IR, NMR, MS, and elemental analysis, and four of them (3a, 3b, 4b, and 6a) have also been characterized by
single crystal X-ray diffraction analysis.
(click chemistry) has been extensively used in joining two
distinct building blocks, enabling easy access to regioselective
novel 1,4-disubstituted-1,2,3-triazolyl conjugates of simple to
complex molecular-level architectures.12−14 Although this
chemistry has exponentially expanding applications in various
disciplines of science, ranging from organic synthesis, material
science, and catalysis to chemical biology; however, special
attention has been received in the field of glycoscience because it
leads to an easy route for triazolyl glycoconjugation in diverse
applications.13e
INTRODUCTION
■
1,2,3-Triazoles are one of the most important classes of
heterocycles that have been studied over the past decade because
of their wide applicability in material science, biological research,
and medicinal chemistry.1 They possess antitumor,2 anti-HIV,3
cytostatic,4 and antibactericidal properties5 and can also act as
glycosidase6 and GABA inhibitors.7 The triazole moiety, because
of its close electronic and chemical resemblance to an amide
bond, serves as a bioisostere of peptide functionality and hence
plays a major role in the elaboration and composition of
biological systems.8
Carbohydrates and their conjugates play a fundamental role in
normal cell functions, including energy storage, modulation of
protein function, transport, adhesion, signal transduction, as well
as viral and bacterial cell surface recognition. Their role in
biodynamic applications has led to increased demand of
carbohydrate-based molecules for complete chemical, medicinal,
biological, and pharmacological investigations.9 In this context,
sugar derivatives with substituted C-5 amide functionality
possess significant bioactivity, such as antitubercular, antifilarial,
and α-glucosidase inhibition.9d,10,11 Thus, the pursuit of
introducing a triazole ring at the C-5 position of sugar derivatives
is quite relevant and demanding. In this perspective, the Huisgen
1,3-dipolar cycloaddition of terminal alkynes and organic azides
The role of azides in the click reaction is well established.15 For
the introduction of a triazole skeleton at the β-position (C-5) of
glycosyl olefinic ester, the presence of an azide group is necessary.
However, the introduction of azide functionality at the β-position
of olefinic esters is still a challenging task. Several established
strategies for the β-azidation of α,β-unsaturated carbonyl
compounds include conjugate addition of the azide via HN3 in
HOAc, HN3 with Lewis bases, and TMSN3 with HOAc. These
methods suffer from some limitations, including poor reaction
yields, requiring elevated temperature (353 K) and long reaction
times.16−18 A search of the available literature revealed that there
Received: January 26, 2015
© XXXX American Chemical Society
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is no report on the β-azidation of glycosyl olefinic esters. Our
current interest in azide chemistry, and the need for new and
specific flexible strategies that would provide potentially useful
routes for triazole synthesis, prompted us to determine a new
methodology for this purpose. In this article, we report a new and
remarkably mild synthesis of novel glycosyl-β-azido ester and its
application for the development of glycosyl-β-triazolyl esters in
good to excellent yields.
addition of amine on glycosyl olefinic ester followed by a metal-
catalyzed diazotransfer reaction of amine. Expectedly, the
reaction led to the formation of glycosyl-β-azido ester with
significant ease. Our synthetic protocol started from a cheap and
readily available compound, D-glucose, which undergoes a
number of high-yielding steps, such as isopropylidene protection,
3-O-benzyl protection, selective 5,6-isopropylidene deprotection
followed by NaIO4 oxidation, and finally Horner−Emmons−
Wadsworth Wittig olefination affording the glycosyl olefinic ester
(1R,2R,3S,4R)-ethyl-[3-O-benzyl-5,6-dideoxy-1,2-O-isopropyli-
dene-α-D-gluco]-heptfuran-5-en-uronate 1.19 Further, 1,4-con-
jugate addition of olefinic ester 1 with ammonia in dry ethanol
yielded (1R,2R,3S,4R)-ethyl-[5-amino-3-O-benzyl-5,6-dideoxy-
1,2-O-isopropylidene]-α-D-gluco- and -β-L-ido-heptofuranurnate
2a and 2b as a diastereomeric mixture (70:30) in good yield
(Scheme 1).19,20 The diastereoselectivity ratio was determined
by literature precedent.19,20 The major and minor isomers were
successfully isolated in pure form by flash column chromatog-
raphy. The observed diastereoselectivity can be rationalized by
Felkin−Anh-like transition states based on an alkene−arene π
stacking interaction as described by earlier studies.20,21 The
synthesized glycosyl-β-amino ester can undergo a diazotransfer
reaction to form glycosyl-β-azido ester. To achieve an efficient,
practical, and easy synthesis of novel glycosyl-β-azido esters, we
focused on the diazotransfer reaction and related chemistry. The
major isomer 2a was further used for the optimization studies.
The intermolecular diazotransfer reaction of compound 2 with
imidazole-1-sulphonyl azide22 as the donor of a diazo group in
the presence of CuSO4·5H2O and K2CO3 in dry ethanol afforded
ethyl-[5-azido-3-O-benzyl-5,6-dideoxy-1,2- O-isopropylidene]-
α-D-gluco- and -β-L-ido-heptofuranurnate 3 in 80% yield (Scheme
1). Separation of major and minor isomers was achieved by flash
column chromatography, and the structure was confirmed by
NMR (1H and 13C). Lastly, single crystal X-ray analysis
confirmed the unambiguous structure and stereochemistry at
the C-5 center in compounds 3a and 3b (Figure 1).
RESULTS AND DISCUSSION
■
We first investigated the conjugate addition of azide to glycosyl
olefinic ester 1 using previously reported reagents and reaction
conditions for β-azidation of α,β-unsaturated carbonyl com-
pounds.16−18 To our surprise, the reaction of compound 1 with
hydrogen azide in acidic media (HOAc)16 using a Lewis base
catalyst (Et3N) at two different temperatures (30 and 80 °C),17
TMSN3, HOAc with tertiary amine (Et3N) as catalyst,18a and
NaN3 in dry DMF at 80 °C, indicated the absence of product.
These results indicate that synthesis of glycosyl-β-azido ester was
indeed challenging using these earlier methods. Therefore, a
different route was developed for the synthesis of glycosyl-β-
azido ester.
Scheme 1. Synthesis of Novel Glycosyl-β-azido Ester 3
The success of this reaction prompted us toward the synthesis
of a new diazotransfer reagent. Hence, the reaction of indole-3-
carboxaldehyde (2.0 equiv) with chlorosulphonyl azide, prepared
in situ by the reaction of equimolar quantities of sodium azide
and sulfuryl chloride in MeCN, gave indole-3-carboxaldehyde-1-
sulphonyl azide I (40%, obtained after aqueous workup and
purification by flash column chromatography) as a yellow solid
(mp 174−176 °C) (Scheme 2).
It is known that azides can formally be considered diazo-
amines15 and can be prepared by a diazotransfer reaction of
amines. In light of this fact, we attempted a 1,4-conjugate
Figure 1. Molecular structure of 3a and 3b. Thermal ellipsoids of C, N, and O are set at 40% probability.
B
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Scheme 2. Synthesis of Indole-3-carboxaldehyde-1-sulphonyl
Azide I
Table 2. Diazotransfer Reaction of Glycosyl-β-amino Ester 2a
in the Presence of Various Diazotransfer Reagents
Then, the diazotransfer reaction of primary amines (1.0 equiv)
with indole-3-carboxaldehyde-1-sulphonyl azide I (1.2 equiv) in
the presence of CuSO4·5H2O catalyst (5 mol %) and K2CO3 (2.0
equiv) in dry methanol at room temperature was investigated,
which gave the corresponding azides (Table 1). Consequently,
a
Table 1. Synthesis of Azides from Primary Amines Utilizing
Indole-3-carboxaldehyde-1-sulphonyl Azide I (1.2 equiv),
K2CO3 (2.0 equiv), and CuSO4·5H2O Catalyst (5 mol %)
Reaction conditions: Glycosyl-β-amino ester 2a (1.0 equiv),
diazotransfer reagent (1.2 equiv), K2CO3 (2.0 equiv) [for all reagents
except benzotriazole-1-sulphonyl azide] and CuSO4·5H2O catalyst (5
mol %). Reaction time in hours. Isolated yield of product obtained
b
c
after purification by column chromatography.
obtained in excellent yield (86%). This was followed by copper
(80%), and decent results were also observed using nickel over a
5 h duration (Table 3). In a control experiment in which the
metal catalyst was omitted completely, the product was obtained
in low yields, indicating a decrease in the efficiency of the
reaction. The other metals, MgII, CoII, PdII, and CaII, had a
negligible effect with nearly the same reaction yield as that in the
absence of metal catalyst (entries 4−8, Table 3). Os(III) and
Ru(III) also have no effect on the reaction (Cu as sulfate, Zn, Mg,
Co, Ni, Ca, Pd, Os, and Ru as chlorides). These observations
suggest that the metal catalyst might increase the rate of the
reaction by lowering the activation energy barrier for the
reaction. It might also act as a Lewis acid catalyst to activate the
imidazole-1-sulphonyl azide toward the probable reaction via the
nucleophilic mechanism.24
Next, the effect of different bases was investigated. Upon
scanning the reaction for various inorganic/organic bases, it was
revealed that 2.0 equiv of either bicarbonate or carbonate bases
resulted in comparable product formation as was evident from
the results obtained in Table 4 (entries 1−3). Amine bases do not
affect the reaction to a great extent, and thus, low product yield
was obtained.
Finally, the reaction was screened for a variety of organic
solvents; the results are summarized in Table 5. It was observed
that the reaction performed well in terms of efficiency and had
good yields using ethanol and methanol solvents (entries 1 and 3,
Table 5). However, ethanol proved to be the solvent of choice for
the prescribed diazotransfer reaction because ethyl functionality
of the ester group in glycosyl-β-amino ester is preserved in the
product. Using methanol as the solvent, hydrolysis of the ester
functional group occurred by a BAC2 (bimolecular base-catalyzed
hydrolysis via acyl oxygen cleavage) mechanism. As a result, the
ethyl group present on the ester functionality was replaced by a
methyl group to afford methyl-[5-azido-3-O-benzyl-5,6-dideoxy-
1,2-O-isopropylidene]-α-D-gluco- and -β-L-ido-heptofuranurnate
(4a,b). The 1H NMR data of compound 4b corresponding to 23
proton resonances and a sharp singlet integrated to 3 proton
resonances appearing at δ 3.63 evidenced the presence of the
methyl group. The molecular ion peak [M + H]+ observed at m/z
378 and single crystal X-ray analysis confirmed the unambiguous
a
b
Reaction time in hours. Isolated yield of product obtained after
purification by column chromatography.
the diazotransfer reagent I was tested on glycosyl-β-amino ester
2a under same reaction conditions to give glycosyl-β-azido ester
3a in 25% yield (entry 3, Table 1). The NMR data of compound
3a matched with that of the major isomer obtained in Scheme 1.
We then compared the efficiency of conversion of glycosyl-β-
amino ester to glycosyl-β-azido ester in the presence of various
diazotransfer reagents, such as imidazole-1-sulphonyl azide,22
indole-3-carboxaldehyde-1-sulphonyl azide, or benzotriazole-1-
sulphonyl azide23 with CuSO4·5H2O and K2CO3 for all reagents
except for benzotriazole-1-sulphonyl azide with which no base
was used. The observed results indicated that the best reaction
yields and efficiency were achieved when imidazole-1-sulphonyl
azide was used as the diazotransfer reagent (entry 1, Table 2).
Then, with imidazole-1-sulphonyl azide as the well suited
diazotransfer reagent, we performed the next experiment
intended to determine the feasibility of screening metal catalysts
for this reaction. In one set of experiments, zinc chloride and zinc
nitrate were tested under homogeneous reaction conditions. It
was observed that the products were obtained in the same yields
with both metal salts having zinc in the +2 oxidation state but
different counterions. Thus, it can be concluded that the
counterion of zinc does not significantly affect the reaction
because it exhibits a similar effect.
In the other set of experiments, out of the several metal ions
tested under homogeneous reaction conditions given in Scheme
3, zinc chloride (5 mol %) gave the best result as the product was
C
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Scheme 3. One-Pot Synthesis for Novel Glycosyl-β-azido Ester 3
Table 3. Diazotransfer Reaction of Glycosyl-β-amino Ester in
the Presence of Various Metal Catalysts
Table 5. Diazotransfer Reaction of Glycosyl-β-amino Ester
(1.0 equiv) with Imidazole-1-sulphonyl Azide (1.2 equiv),
K2CO3 (2.0 equiv), and ZnCl2 (5 mol %)
a
b
entry
solvent
time
yield (%)
1
2
3
4
5
6
7
8
ethanol
DCM
5
5
5
5
5
5
5
5
>85
50
methanol
THF
>85
>40
30
a
b
entry
metal (M2+)
time
yield (%)
acetone
DMF
20
1
2
3
4
5
6
7
8
Cu
Ni
5
5
5
5
5
5
5
5
80
60
86
45
45
45
40
45
Et2O
30
acetonitrile
35
Zn
Ca
Mg
Co
Pd
a
b
Reaction time in hours. Isolated yield of product 3a.
a
b
Reaction time in hours. Isolated yield of product 3a.
Table 4. Diazotransfer Reaction of Glycosyl-β-amino Ester in
the Presence of Various Bases
a
b
entry
solvent
time
yield (%)
Figure 2. Molecular structure of 4b. Thermal ellipsoids of C, N, and O
are set at 40% probability.
1
2
3
4
5
6
7
8
9
Na2CO3
K2CO3
NaHCO3
DMAP
DIPEA
DBU
5
5
5
5
5
5
5
5
5
>80
>85
>80
40
time. The process gave compound 3 in good yields at room
temperature. Thus, a facile and efficacious one-pot methodology
for the synthesis of novel glycosyl-β-azido ester 3 from glycosyl
olefinic ester 1 has been developed (Scheme 3).
40
40
DABCO
Et3N
40
<30
<30
The stereochemistry at the C-5 stereogenic center has been
tentatively predicted on the basis of a precedent set in the
literature and mechanistic grounds.20,21 On the basis of Felkin−
Anh and Cram’s transition states, it can be predicted that the
major attack of nucleophilic ammonia at C-5 in olefinic ester
would take place from the side of the least bulky group
(hydrogen attached to C-4 of the furanose ring, the Si
diastereoface). Thus, the major reaction product has an S
configuration at C-5, whereas that of the minor one is R (Scheme
4). The diazotransfer reaction does not involve a change in
stereochemistry25 at the carbon (C-5) center, so the config-
uration at this stereocenter should be the same as that in the
pyridine
a
b
Reaction time in hours. Isolated yield of product 3a.
structure of compound 4b and the presence of the methyl group
at the ester functionality (Figure 2).
Therefore, efficient synthesis of glycosyl-β-azido ester from
glycosyl-β-amino ester (1.0 equiv) was achieved in ethanol with
imidazole-1-sulphonyl azide (1.2 equiv), K2CO3 (2.0 equiv), and
ZnCl2 (5 mol %). Upon observing the formation of glycosyl-β-
azido ester from olefinic ester 1, we found that both steps
involved in the reaction sequence proceeded in the same solvent.
Thus, after the conjugate addition of ammonia (24 h) in ethanol,
the reagents for the second step (diazotransfer reaction) were
added, and the reaction was stirred for the appropriate amount of
1
glycosyl-β-amino ester previously established. The H NMR
spectra of azide 3a (major isomer) showed J4,5 = 9.9 Hz,
evidenced a threo relationship between protons at C-4 and C-5,
and S configuration at new sterogenic center C-5 has been
D
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Scheme 4. Formation of L-Ido Isomer from Si Face Attack
Table 6. Study of the Solvent Effect on CuAAC of Glycosyl-β-
azido Ester 3a with 5a
a
entry
reaction conditions
yield (%)
1
MeOH/H2O (1:1)
t-BuOH/H2O (1:1)
CH2Cl2/H2O (1:1)
Et2O/H2O (1:1)
THF/H2O (1:1)
acetone/H2O (1:1)
acetone/H2O (1:05)
acetone
<20
30
2
3
>70
>70
60
4
5
6
>80
40
assigned to this isomer. Consequently, for the second isomer
(erythro) isolated as a minor ratio, the R stereochemistry could
easily be established at C-5. Therefore, the diazotransfer reaction
on glycosyl-β-amino ester 2a affords the corresponding glycosyl-
β-azido ester (1R,2R,3S,4R,5S)-ethyl-[5-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-β-L-ido-heptofuranurnate 3a.
7
b
8
nd
b
9
H2O
ta
b
10
acetone/H2O (1:1)
>70
a
b
Isolated yields in 10 h. Reaction under an argon atmosphere; ta =
1
trace amount, nd = not detected.
The H NMR spectrum of compound 3a corresponds to 25
protons, and a multiplet at δ 7.35 was observed for five Ar-H
protons. A doublet at δ 5.87 (J = 3.0 Hz) was identified for the
anomeric proton. The remaining 14 protons of glycosyl-β-azido
ester appeared in the range of δ 2.26−4.69 along with the six
protons of isopropylidene moiety, which appeared as singlets at δ
1.41 and 1.31. A triplet integrated to 3 proton resonances was
observed at δ 1.27 (J = 6.9 Hz) for the −CH2CH3 group. The IR
spectra showed a sharp absorption band at 2134 cm−1, indicating
the presence of an azide (-N3) group, and 19 carbon resonances
appeared in 13C NMR in addition to the molecular ion peak [M +
H]+ observed at m/z 392. Further, single crystal X-ray analysis
confirmed the unambiguous structure of compounds 3a and 3b
(Figure 1).
Once the synthesis of glycosyl-β-azido ester 3 was achieved in
excellent yields, we next turned our focus toward the application
of this compound for CuAAC click reactions. Such reactions, in
general, require a Cu(I) source directly introduced in the
reaction medium from CuI or by the reduction of Cu(II) salts in
form of CuSO4·5H2O or copper acetate in the presence of
sodium ascorbate, which is the most frequently used reducing
agent utilized in 3−4 fold excess to give commendable results in
aqueous medium. The latter reagents are more effective because
they maintain a high Cu(I) concentration during the reaction
course, and they are not affected by oxidizing atmosphere. Thus,
we primarily investigated the click reaction between the
developed compound 3a and 1-phenyl-2-propyn-1-ol 5a using
MeOH/H2O, t-BuOH/H2O, CH2Cl2/H2O, Et2O/H2O, THF/
H2O, and acetone/H2O as solvent mixtures. It is easy to verify
that most of the reactions afforded the corresponding
glycoconjugated triazole 6a using a variety of organic solvents
in combination with H2O (Table 6). However, the optimal yield
of 6a was achieved using a mixture of acetone/H2O (1:1) as the
solvent. A remarkable feature of this reaction is the H2O
dependence of the triazolyl glycoconjugate synthesis (tolerant to
pH range 6−9). Reactions using a mixture of acetone/H2O
(1:0.5) or acetone alone resulted in poor yield of desired product
6a (entries 7 and 8, Table 6). The probable reason is the
dependency toward aqueous media of the in situ generation of
Cu(I) species from the combination of CuSO4·5H2O and
sodium ascorbate. However, when the reaction was performed
only in H2O, the formation of product 6a was not observed
(entry 9, Table 6) because of the decreased solubility of
compound 3a in aqueous media compared to that in the organic
phase. These observations suggest that in the solvent mixture of
acetone and H2O, the Cu(I) species is generated in situ in
aqueous medium from CuSO4·5H2O and sodium ascorbate and
then catalyzes the click reaction between compounds 3a and 6a,
which are soluble in the organic phase. It is important to note that
the reactions are not very air sensitive, allowing for preparation of
the respective triazole 6a in an open atmosphere (entry 10, Table
6).
For the yield to be improved further, the reaction of 3a (400
mg, 1.02 mmol) with 5a (0.149 mL, 1.22 mmol) under catalysis
by CuI (5 mol %) and DIPEA (10 mol %) at room temperature
under inert reaction conditions was screened for a variety of
organic solvents to afford 6a in good to significant yields. The
results illustrated poor performance of t-BuOH, toluene,
benzene, DMF, and methanol in terms of yield and reaction
time (Table 7). Maximum yields of triazolyl glycoconjugate were
obtained using acetone and DCM (entries 1 and 3, Table 7).
Thus, under optimized conditions, alkyne 5a reacted with 3a
in the presence of CuI (5 mol %) and DIPEA (10 mol %) as click
Table 7. Optimization of Solvent for 1,3-Dipolar
Cycloaddition of Glycosyl-β-azido Ester 3a with 5a in the
presence of CuI and DIPEA
a
b
entry
solvent
time
yield (%)
1
2
3
4
5
6
7
8
9
acetone
t-BuOH
CH2Cl2
MeCN
THF
8
18
8
>80
30
>85
>75
70
8
9
toluene
benzene
MeOH
DMF
12
15
12
12
25
20
35
10
a
b
Reaction time in hours. Isolated yield of product 6a.
E
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catalysts in anhydrous CH2Cl2 under an argon atmosphere at
ambient temperature afforded corresponding 1-[ethyl-(3′-O-
benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-β-L-ido-heptofura-
nurnate-5-yl]-4-(1″-phenylmethan-1″-ol-1″-yl)-1H-[1,2,3]-tria-
zole 6a regioselectively in 94% yield. The regioisomeric nature of
compound 6a was established based on its spectroscopic data. In
mass spectrum, compound 6a displayed a molecular ion peak [M
+ H]+ at m/z 524, which corresponded to the molecular formula
of extensive spectral studies (IR, 1H, and 13C NMR) evidenced
the formation of the triazole ring in compound 6u.
Mechanistic Consideration. Ammonia adds to olefinic
ester via 1,4 conjugate additions, and its formation can be
rationalized by Felkin−Anh-like transition states based on
alkene-arene π stacking interactions as described in the
literature.19−21 The next step includes the diazotransfer reaction
with imidazole-1-sulphonyl azide. Imidazole-1-sulphonyl azide is
an efficient diazotransfer reagent that has the ability to transfer
the diazo group directly to the primary amine function to form
the corresponding azide.22 The exact mechanism of the
diazotransfer reaction is to date still controversial; however,
close examination of previous reports for these reactions suggests
that a dianionic tetrazene intermediate is formed during this
reaction and is stabilized by two monovalent metal ions (e.g.,
sodium).27 This proposed mechanism has been further extended
by Nyffeler et al. to incorporate a divalent metal ion in place of
the two monovalent ions.28 On the basis of these reports, we
propose a plausible mechanism for the transition metal-catalyzed
diazotransfer reaction of glycosyl-β-azido ester formation. The
mechanism proceeds via the initial complexation of the amine
substrate with the metal catalyst under basic conditions to give 7.
The amine of complex 7 undergoes nucleophilic attack on the
highly electrophilic imidazole-1-sulphonyl azide that, upon
further deprotonation, may possibly form zinc-stabilized mixed
tetrazene 8.29b This zinc-stabilized tetrazene undergoes break-
down possibly by a reverse [3 + 2] dipolar cycloaddition, which
leads to the formation of product glycosyl-β-azido ester and
zinc−imidazole sulphonyl imido complex 9. The computational
work on such similar structures by Brandt et al. suggests that
complex 9 would be in equilibrium with complex 11.29 From
here, two possible pathways could be operating: one leads to
amine complexation followed by consequent proton transfer to
give 9 and the other forms zinc−imido complex 11 via the
transamination of 10. Further, this zinc−imido complex is
employed in a [3 + 2] dipolar cycloaddition with imidazole-1-
sulphonyl azide to alternatively give 8 (Figure 4).
1
C28H33N3O7. In the H NMR spectrum, the signal for the
triazolyl proton and 8 phenyl protons were observed as a
multiplet in the range δ 7.17−7.38 and the remaining two Ar-H
protons appeared as multiplets at δ 7.08. The anomeric proton
(H-1) along with the proton at the hydroxyl group bearing the
carbon atom of alkyne appeared as a multiplet in the range δ
5.91−5.98. The remaining 11 protons of the cycloadduct
resonated between δ 3.35−5.17 along with the six protons of
isopropylidene moiety, which appeared as singlets at δ 1.49 and
1.29. A triplet of 3 protons appearing at δ 1.11 (J = 6.9 Hz) was
identified for −CH2CHx. The 13C NMR spectrum showed a
signal at δ 170.3 for carbonyl carbon, whereas the anomeric
carbon (C-1) of the furanose sugar resonated at δ 105.2. Single-
crystal X-ray analysis further confirmed the unambiguous
structure of compound 6a (Figure 3).
CONCLUSION
■
Figure 3. Molecular structure of 6a. Thermal ellipsoids of C, N, and O
are set at 40% probability.
In conclusion, we have developed a concise and readily adaptable
novel one-pot protocol for easy access to glycosyl-β-azido ester
from glycosyl olefinic ester under mild reaction conditions. This
method demonstrates high efficiency in terms of product yields.
The developed glycosyl-β-azido ester has been utilized for the
development of a diverse range of novel triazolyl glycoconju-
gates. On the basis of the presence of a substituted triazole
moiety incorporating various sugar, aryl, and alkyl side chains in
the glycoconjugates, they might prove to be potent scaffolds for
biological and pharmaceutical investigations. The short reaction
period, simple workup, high yield, and mild conditions of this
methodology underscore its significance. In addition, the
generality with respect to substrate scope and facile accessibility
to the starting materials is also highly appealing. Synthesis of a
novel glycosyl-β-azido ester from glycosyl olefinic ester has not
yet been realized for one-pot conditions; thus, this approach
should also be of interest to synthetic chemists. The developed
methodology also performs well in small as well as gram scale
synthesis of glycosyl-β-azido ester, suggesting that it may have
industrial significance. Biological screening of the developed
glycosyl-β-triazolyl esters is currently under way.
Utilizing the reaction conditions established above for the
regioselective cycloaddition of alkyne 5a and glycosyl-β-azido
ester 3a, we further explored the scope and possibility of using
various alkyl, aryl, and sugar-substituted terminal alkynes26 in
such a cycloaddition and prepared a library of glycoconjugated
triazoles 6a−u in efficient yields (Table 8). The structures of
compounds 6a−u were deduced using extensive spectral studies
(IR, 1H and 13C NMR, and MS) and single crystal X-ray analysis
for compound 6a.
After successfully isolating the triazole made from the highly
functionalized carbohydrates as well as aromatic and aliphatic
side chains in excellent yields, we next synthesized 1′-1″-[ethyl-
(3″-O-benzyl-5″,6″-dideoxy-1″,2″-O-isopropylidene)-α-D-glu-
coheptofuranurnate-5-yl]-ethisterone-1,2,3-triazole 6u by the
reaction of ethisterone 5u with glycosyl-β-azido ester 3a and
successfully executed the synthesis of ethisterone triazolyl
glycoconjugate in excellent yield under our standardized
conditions for click reactions (Scheme 5). Thus, the method-
ology is equally applicable to complex steroidal moieties. Analysis
F
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Table 8. Synthesis of Glycoconjugate Triazoles 6a−t via CuAAC Reaction
a
b
c
Molar ratios: alkynes, glycosyl-β-azido ester (1.2:1.0 equiv), CuI (5 mol %), and DIPEA (10 mol %). Triazolyl glycoconjugates. Reaction time: in
d
hours. Isolated yield of triazolyl glycoconjugates after purification by column chromatography.
EXPERIMENTAL SECTION
Scheme 5. Synthesis of Glycosyl-β-triazolyl Ester with
Steroidal Functionality
■
General Remarks. All of the reactions were executed in anhydrous
solvents under an argon atmosphere in glassware that was oven-dried for
1 h at 100 °C. All reagents and solvents were of pure analytical grade.
Thin layer chromatography (TLC) was performed on 60 F254 silica gel
precoated on aluminum plates and revealed with either a UV lamp (λmax
= 254 nm), a specific color reagent (Draggendorff reagent or iodine
vapors), or by spraying with a methanolic-H2SO4 solution and
subsequent charring by heating at 100 °C. H and 13C NMR were
1
recorded at 300 and 75 MHz, respectively. Chemical shifts are given in
ppm downfield from internal TMS, and J values are in Hz. Mass spectra
were recorded using electrospray ionization mass spectrometry (ESI-
G
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Figure 4. Proposed mechanism of the diazotransfer reaction of glycosyl-β-amino ester with imidazole-1-sulphonyl azide and zinc chloride as the catalyst.
MS). Infrared spectra were recorded as Nujol mulls in KBr plates.
Elemental analysis was performed using a C, H, N analyzer, and the
results were found to be within 0.4% of the calculated values. Single-
crystal X-ray data was collected on a CCD diffractometer.
chromatography using gradient mixtures of ethyl acetate and n-hexane
afforded pure azides.
1,2-Diazido-4,5-dimethyl-benzene (II). To a stirred solution of 1,2-
diamino-4,5-dimethyl-benzene (150 mg, 1.10 mmol) in dry MeOH (5.0
mL) were added indole-3-carboxaldehyde-1-sulphonyl azide I (330 mg,
1.32 mmol), K2CO3 (304 mg, 2.20 mmol), and CuSO4·5H2O (5 mol
%), and the resulting reaction mixture was stirred at room temperature
for 6 h. Aqueous workup and purification by flash chromatography as
described above afforded pure azide as a liquid; 62 mg, 30% yield; Rf =
0.55 (30% ethyl acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.91
(s, 2H), 2.53 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 142.4, 140.8, 127.8
(2C), 127.7 (2C), 20.6 (2C); IR (KBr) νmax 2923, 2824, 2107 (azide
-N3), 1491, 1453, 1359, 1027, 998, 859 cm−1; Anal. Calcd for C8H8N6 C
51.06, H 4.28, N 44.66; found C 51.03, H 4.32, N 44.65.
Procedure for the Synthesis of Indole-3-carboxaldehyde-1-
sulphonyl Azide (I). Sulfuryl chloride (1.10 mL, 13.6 mmol) was
added dropwise to an ice-cooled suspension of NaN3 (0.89 g, 13.6
mmol) in CH3CN (5.0 mL), and the mixture was stirred for 12 h at
room temperature. Indole-3-carboxaldehyde (3.97 g, 27.3 mmol) was
added to the ice-cooled reaction mixture, and the resulting slurry was
stirred at room temperature for 5 h. The mixture was diluted with EtOAc
(40 mL) and H2O (40 mL) and separated. The organic layer was washed
with H2O (40 mL) followed by saturated aqueous NaHCO3 (2 × 30
mL), dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude mass obtained was subjected to flash chromatog-
raphy using gradient mixtures of ethyl acetate and n-hexane to afford
pure compound I as a yellow solid; mp 174−176 °C; 1.36 g, 40% yield;
Rf = 0.48 (30% ethyl acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ
8.86 (s, 1H), 7.78 (d, J = 6.6 Hz, 1H), 7.74−7.31 (m, 1H), 7.47 (d, J = 7.2
Hz, 1H), 7.36−7.25 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 180.1,
134.8, 131.8, 126.9, 124.3, 122.3, 119.6, 115.8, 112.0; IR (KBr) νmax
3257, 2924, 2223 (azide-N3), 1709 (CO), 1621, 1583, 1522, 1433,
1239, 1110, 745, 737 cm−1; MS (m/z) 251 [M + H]+; Anal. Calcd for
C9H6N4O3S C 43.20, H 2.42, N 22.39; found C 43.30, H 2.48, N 22.41.
General Procedure for the Synthesis of Azides. To a stirred solution
of amine or ammonium salt substrate (1.0 equiv) in dry MeOH were
added indole-3-carboxaldehyde-1-sulphonyl azide I (1.2 equiv), K2CO3
(2.0 equiv), and CuSO4·5H2O (5 mol %), and the resulting reaction
mixture was stirred at room temperature for 6−7 h. The mixture was
concentrated in vacuo, diluted with H2O, acidified with concentrated
HCl and extracted with EtOAc 3 times. The combined organic layers
were dried on anhydrous Na2SO4, filtered, and concentrated. Flash
Methyl-2-azido-propan-1-oate (III). To a stirred solution of amine
substrate (150 mg, 1.45 mmol) in dry MeOH (5 mL) was added indole-
3-carboxaldehyde-1-sulphonyl azide I (436 mg, 1.74 mmol), K2CO3
(402 mg, 2.91 mmol), and CuSO4·5H2O (5 mol %), and the resulting
reaction mixture was stirred at room temperature for 7 h. Aqueous
workup and purification by flash chromatography as described above
afforded pure azide as a colorless liquid; 75 mg, 40% yield; Rf = 0.49
1
(25% ethyl acetate/n-hexane); H and 13C NMR spectroscopic data
were in agreement with published results;30 IR (KBr) νmax 2852, 2118
(azide -N3), 1463, 1257, 1054, 631 cm−1; Anal. Calcd for C4H7N3O2 C
37.21, H 5.46, N 32.54; found C 37.26, H 5.50, N 32.58.
Procedure for the Synthesis of Orthogonally Protected Sugars.
The protected sugars were prepared from readily available carbohy-
drates (D-glucose, D-galactose, D-mannose, D-fructose, and D-xylose)
using standard protection methodologies.31,32
General Procedure for the Synthesis of O-Propargyl Ethers of
Orthogonally Protected Sugars (5j−n). To a stirred solution of
orthogonally protected sugars (1.0 mmol) in dry DMF (10 mL) was
H
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added NaH (2.1 mmol) fractionwise at 0 °C, and the reaction was
allowed to stir for 10−15 min. Then, propargyl bromide (1.3 mmol) and
TBAB (50 mg, catalytic amount) were added to the reaction mixture and
stirring continued at room temperature for 10−12 h. Completion of the
reaction was confirmed by TLC (n-hexane/ethyl acetate 9:1); the
reaction mixture was extracted with ethyl acetate and dried over
anhydrous Na2SO4. Solvent evaporated under reduced pressure below
55 °C. Column chromatography (SiO2) of crude product was
performed using gradient mixtures of n-hexane/ethyl acetate (9:1) as
eluant, which afforded the desired sugar alkynes 5j−n.26
General Procedure for the Synthesis of Glycosyl-β-azido Ester (3a,
b). To a stirred solution of ethyl-[3-O-benzyl-5,6-dideoxy-1,2-O-
isopropylidene-α-D-gluco]-heptfuran-5-en-uronate 119 dissolved in dry
ethanol was passed NH3 gas for 3 h, and the reaction was allowed to stir
at room temperature for 24 h to afford ethyl-[5-amino-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-α-D-gluco- and -β-L-ido-heptofuranur-
nate19,20 (2a, 2b) as diastereomeric mixture. Then, in the same reaction
pot having glycosyl-β-aminoester 2 (1.0 equiv), imidazole-1-sulphonyl
azide22 (1.2 equiv), K2CO3 (2.0 equiv), and ZnCl2 in catalytic amount (5
mol %) were added and stirring continued for additional 5 h to afford
glycosyl-β-azido ester 3a and 3b with a major to minor ratio of 70:30.
After completion of the reaction (monitored by TLC), the reaction
mixture was concentrated in vacuo, diluted with H2O, extracted with
EtOAc, washed with brine solution, and dried over anhydrous Na2SO4.
The organic layer was concentrated under reduced pressure. Further
purification and separation using flash column chromatography using
gradient mixtures of ethyl acetate and n-hexane afforded pure compound
3 with 86% yield.
Ethyl-[5-(S)-azido-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene]-
β-L-ido-heptofuranurnate (3a, major isomer). To a stirred solution of
glycosyl-β-olefinic ester 1 (5.0 g, 0.014 mol) dissolved in dry ethanol
(50.0 mL) was passed NH3 gas for 3 h, and the reaction was allowed to
stir at room temperature for 24 h to afford ethyl-[5-amino-3-O-benzyl-
5,6-dideoxy-1,2-O-isopropylidene]-α-D-gluco- and -β-L-ido-heptofura-
nurnate (2a, 2b) as a diastereomeric mixture. Then, in the same
reaction pot, glycosyl-β-aminoester 2, imidazole-1-sulphonyl azide
(2.67g, 0.015 mol), K2CO3 (3.56g, 0.025 mol), and ZnCl2 in a catalytic
amount (5 mol %) were added and stirring continued for an additional 5
h to afford glycosyl-β-azido ester 3 (86% yield) with a major to minor
ratio of 70:30, which was separated by purification as described earlier to
afford 3a as white crystals; mp 82−84 °C; Rf = 0.52 (10% ethyl acetate/
n-hexane); 1H NMR (300 MHz, CDCl 3) δ 7.35 (m, 5H), 5.87 (d, J = 3.0
Hz,1H), 4.69−4.62 (m, 3H), 4.28 (dd, J = 9.9, 19.2 Hz, 1H), 4.18 (q, J =
6.9 Hz, 2H), 4.06 (m, 1H), 3.99 (d, J = 9.6 Hz, 1H), 2.90 (d, J = 16.5 Hz,
1H), 2.46 (dd, J = 10.2, 16.8 Hz, 1H), 1.48 (s, 3H), 1.31 (s, 3H), 1.27 (t, J
= 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 170.8, 136.9, 128.4 (2C),
128.0, 127.9 (2C), 111.9, 105.1, 81.8, 81.4, 80.8, 71.9, 60.7, 56.5, 37.4,
26.8, 26.1, 14.0; IR (KBr) ν max 2980, 2933, 2134 (azide- N3), 2096, 1742
(CO), 1465, 1399, 1081, 1037, 731 cm−1; MS (m/z) 392 [M + H]+;
Anal. Calcd for C19H25N3O6 C 58.30, H 6.44, N 10.74; found C 58.45, H
6.48, N 10.78.
Ethyl-[5-(R)-azido-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene]-
α-D-gluco-heptofuranurnate (3b, minor isomer). White crystalline
solid; mp 78 °C, Rf = 0.56 (10% ethyl acetate/n-hexane); 1H NMR (300
MHz, CDCl3) δ 7.32−7.25 (m, 5H), 5.98 (d, J = 3.3 Hz, 1H), 4.72 (d, J =
11.7 Hz, 1H), 4.66 (d, J = 3.6 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 4.20−
4.18 (m, 2H), 4.15−4.10 (m, 2H), 3.85 (m, 1H), 2.26−2.12 (m, 2H),
1.49 (s, 3H), 1.33 (s, 3H), 1.27 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 169.9, 136.5, 128.5 (2C), 128.3, 128.0 (2C), 112.0, 105.0,
81.9, 81.7, 81.0, 71.5, 60.9, 58.2, 35.8, 26.7, 26.2, 14.1; IR (KBr) νmax
2990, 2912, 2129 (azide- N3), 2091, 1736 (CO), 1455, 1381, 1081,
742, 698 cm−1; MS (m/z) 392 [M + H]+; Anal. Calcd for C19H25N3O6 C
58.30, H 6.44, N 10.74; found C 58.40, H 6.50, N 10.76.
mol %) were added to the reaction mixture and stirring continued for
additional 5 h to afford 4b as thin white crystals after purification as
described above; Rf = 0.57 (10% ethyl acetate/n-hexane); 1H NMR (300
MHz, CDCl3) δ 7.25−7.24 (m, 5H), 5.91 (d, J = 3.6 Hz, 1H), 4.65 (d, J =
12 Hz, 1H), 4.59 (d, J = 3.6 Hz, 1H), 4.34 (d, J = 12 Hz, 1H), 4.16−4.09
(m, 1H), 4.06−4.02 (m, 1H), 3.77 (d, J = 3.0 Hz, 1H), 3.63 (s, 3H),
2.20−2.04 (m, 2H), 1.42 (s, 3H), 1.26 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 168.9, 136.5, 128.9 (2C), 128.6, 128.1 (2C), 111.3, 104.9,
81.9, 81.5, 80.9, 73.3, 65.5, 58.1, 35.5, 26.8, 26.3; IR (KBr) νmax 2992,
2915, 2125 (azide- N3), 2092, 1732 (CO), 1453, 1386, 1084, 745, 696
cm−1; MS (m/z) 378 [M + H]+; Anal. Calcd for C18H23N3O6 C 57.29, H
6.14, N 11.13; found C 57.35, H 6.20, N 11.15.
General Procedure for the Synthesis of Glycosyl-β-triazolyl Esters
(6a−u). To a stirred solution of glycosyl-β-azido ester 3 (1.0 equiv) in
dry CH2Cl2 (10 mL) was added alkynes 5a−u (1.2 equiv) in the
presence of DIPEA (10 mol %) and CuI (5 mol %), and the reaction
mixture was allowed to stir at room temparature for 9−14 h under an
argon atmosphere. After completion of the reaction (monitored by
TLC), the reaction mixture was concentrated to obtain a crude residue
that was further purified by flash column chromatography using gradient
mixtures of ethyl acetate and n-hexane to afford pure compounds 6a−u
in good to excellent yields.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-β-L-
ido-heptofuranurnate-5-yl]-4-(1″-phenylmethan-1″-ol-1″-yl)-1H-
[1,2,3]-triazole (6a). To a stirred solution of ethyl-[5-(S)-azido-3-O-
benzyl-5,6-dideoxy-1,2-O-isopropylidene]-β-L-ido-heptofuranurnate 3a
(400 mg, 1.021 mmol) in dry dichloromethane (10 mL) was added 1-
phenyl-2-propyn-1-ol 5a (0.149 mL, 1.226 mmol) in the presence of
DIPEA (0.017 mL, 0.102 mmol) and CuI (5 mol %), and the reaction
was allowed to stir at room temparature under an argon atmosphere for
9 h followed by purification described above to afford compound 6a as a
white crystalline solid; mp 128−130 °C; 502 mg, 94% yield; Rf = 0.45
1
(45% ethyl acetate/n-hexane); H NMR (300 MHz, CDCl3) δ 7.38−
7.17 (m, 9H), 7.08 (m, 2H), 5.98−5.91 (m, 2H), 5.17−5.08 (m, 1H),
4.71 (d, J = 9.9 Hz, 1H), 4.54−4.51 (m, 1H), 4.40−4.31 (m, 1H), 4.02−
3.84 (m, 3H), 3.46 (d, J = 9.9 Hz, 1H), 3.35 (s, 1H), 3.22−3.16 (m, 2H),
1.49 (s, 3H), 1.29 (s, 3H), 1.11 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.3, 150.1, 141.9, 136.5, 128.5 (4C), 128.0 127.9, 127.8,
127.6, 126.3, 126.1, 123.1, 112.2, 105.2, 81.7, 81.1, 80.5, 72.0, 68.9, 60.8,
55.6, 37.2, 26.8, 26.1, 13.9; IR (KBr) νmax 3412, 2990, 3065, 1690 (C
O), 1610, 1563, 1478, 1420, 1282, 1108, 1072, 845, 786, 562; MS (m/z)
524 [M + H]+; Anal. Calcd for C28H33N3O7 C 64.23, H 6.35, N 8.03;
found C 64.35, H 6.38, N 8.05.
A click reaction between glycosyl-β-azido ester 3a and alkyne 5a using
CuSO4·5H2O/sodium ascorbate in aqueous medium at room temper-
ature affords glycosyl-β-triazolyl ester 6a in good yields. The physical
data closely matched that of developed molecule 6a, where the reaction
was carried out in dry CH2Cl2 solvent under an inert atmosphere at
room temperature.
1-(Ethyl-[3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene]-α-D-
gluco-heptofuranurnate-5′-yl)-4-(phenyl-1″-yl)-1H-[1,2,3]-triazole
(6b). To a stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate 3b (400
mg, 1.021 mmol) in dry dichloromethane (10 mL) was added
phenylacetylene 5b (0.134 mL, 1.226 mmol) in the presence of
DIPEA (0.017 mL, 0.102 mmol) and CuI (5 mol %), and the reaction
was allowed to stir at room temparature under an argon atmosphere for
10 h followed by purification as described above to afford compound 6b
as a yellow solid; mp 124−126 °C; 454 mg, 90% yield; Rf = 0.41 (50%
ethyl acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H),
7.82−7.79 (m, 2H), 7.40−7.28 (m, 8H), 5.91 (d, J = 3.6 Hz, 1H), 5.20−
5.13 (m, 1H), 4.76 (d, J = 12 Hz, 1H), 4.68 (d, J = 3.3 Hz, 1H), 4.63 (dd,
J = 3, 9.3 Hz, 1H), 4.47 (d, J = 11.4 Hz, 1H), 4.02−4.01 (m, 2H), 3.57
(m, 1H), 3.29−3.20 (m, 1H), 2.45 (dd, J = 2.4, 16.5 Hz, 1H), 1.43 (s,
3H), 1.29 (s, 3H), 1.14 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 169.4, 146.6, 136.3, 130.8, 128.68 (2C), 128.61 (2C), 128.4 (2C),
128.2 (2C), 127.8, 125.6, 121.9, 112.2, 105.0, 81.6, 81.5, 80.6, 71.6, 60.9,
57.3, 34.8, 26.7, 26.2, 13.9; IR (KBr) νmax 3414, 3077, 1695 (CO),
1607, 1565, 1484, 1449, 1424, 1279, 1101, 1075, 850, 784, 574; MS (m/
Methyl-[5-(R)-azido-3-O-benzyl-5,6-dideoxy-1,2-O-isopropyli-
dene]-α-D-gluco-heptofuranurnate (4b, minor). To a stirred solution
of glycosyl-β-olefinic ester 1 (0.8 g, 1.43 mmol) dissolved in dry
methanol (8.0 mL) was passed NH3 gas for 3 h, and the reaction was
allowed to stir at room temperature for 24 h. Then, in the same reaction
pot, glycosyl-β-aminoester, imidazole-1-sulphonyl azide (0.42 g, 0.46
mmol), K2CO3 (0.56, 4.10 mmol), and ZnCl2 in a catalytic amount (5
I
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z) 494 [M + H]+; Anal. Calcd for C27H31N3O6 C 65.71, H 6.33, N 8.51.;
found C 65.56, H 6.45, N 8.63.
benzyl-5,6-dideoxy-1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate
3b (400 mg, 1.021 mmol) in dry dichloromethane (10 mL) was added 3-
phenyl-1-propyne 5f (0.152 mL, 1.226 mmol) in the presence of DIPEA
(0.017 mL, 0.102 mmol) and CuI (5 mol %), and the reaction was
allowed to stir at room temparature under an argon atmosphere for 10 h
followed by purification as described above to afford compound 6f as a
white solid; mp 138−140 °C, 471 mg, 91% yield; Rf = 0.46 (45% ethyl
acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ 1H NMR (300 MHz,
CDCl3) δ 7.33−7.22 (m, 11H), 5.87 (d, J = 3 Hz, 1H), 5.07−5.00 (m,
1H), 4.72 (d, J = 11.7 Hz, 1H), 4.65 (d, J = 3 Hz, 1H), 4.57 (d, J = 9.3 Hz,
1H), 4.43 (d, J = 11.7 Hz, 1H), 4.05−3.97 (m, 5H), 3.17 (dd, J = 10.8,
16.5 Hz, 1H), 2.41 (d, J = 15.9 Hz, 1H), 1.43 (s, 3H), 1.29 (s, 3H), 1.14
(t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.4, 146.3, 139.0,
136.3, 128.7 (2C), 128.6, 128.44 (2C), 128.40 (2C), 128.1 (2C), 126.2,
123.6, 112.1, 104.9, 81.6, 81.4, 80.6, 71.6, 60.8, 57.1, 35.0, 32.1, 26.6,
26.2, 13.8; IR (KBr) νmax 3412, 3076, 1698 (CO), 1603, 1561, 1482,
1451, 1423, 1276, 1105, 1075, 856, 784; MS (m/z) 508 [M + H]+; Anal.
Calcd for C28H33N3O6 C 66.26, H 6.55, N 8.28; found C 66.53, H 6.49,
N 8.23.
1-(Ethyl-[3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene]-β-L-
ido-heptofuranurnate-5-yl)-4-(cyclohexan-1″-ol-1″-yl)-1H-[1,2,3]-
triazole (6g). To a stirred solution of ethyl-[5-(S)-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-β-L-ido-heptofuranurnate 3a (300 mg,
0.766 mmol) in dry dichloromethane (10 mL) was added 1-
ethynylcyclohexanol 5g (114 mg, 0.919 mmol) in the presence of
DIPEA (0.013 mL, 0.076 mmol) and CuI (5 mol %), and the reaction
was allowed to stir at room temparature under an argon atmosphere for
10 h followed by purification as described above to afford compound 6g
as a yellow liquid; 375 mg, 95% yield; Rf = 0.52 (75% ethyl acetate/n-
hexane); 1H NMR (300 MHz, CDCl3) δ 7.37−7.26 (m, 6H), 5.94 (m,
1H), 5.29−5.17 (m, 2H), 4.76 (d, J = 9.3 Hz, 1H), 4.57 (d, J = 3 Hz, 1H),
4.51 (d, J = 11.1 Hz, 1H), 4.09 (d, J = 11.7 Hz, 2H), 4.02 (dd, J = 6.9, 13.2
Hz, 1H), 3.56 (s, 1H), 3.22 (d, J = 6.9 Hz, 2H), 2.33 (m, 1H), 1.81 (m,
5H), 1.50 (m, 5H), 1.30 (s, 5H), 1.14 (t, J = 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 170.4, 154.2, 136.7, 128.6 (2C), 128.0, 127.4 (2C),
121.4, 112.2, 105.1, 81.8, 81.3, 80.5, 72.1, 60.8, 55.5, 38.1 (3C), 37.4,
26.7, 26.2, 25.3, 21.9 (2C), 13.9; IR (KBr) νmax 3443, 2929, 2855, 1737
(CO), 1607, 1498, 1454, 1376, 1221, 1164, 1075, 1026, 738; MS (m/
z) 516 [M + H]+; Anal. Calcd for C27H37N3O7 C 62.90, H 7.23, N 8.15;
found C 63.21, H 7.28, N 8.27.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-[1″-(4-methylpiperazin)-methan-
1″-yl]-1H-[1,2,3]-triazole (6h). To a stirred solution of ethyl-[5-(R)-
azido-3-O-benzyl-5,6-dideoxy-1,2-O-isopropylidene]-α-D-gluco-hepto-
furanurnate 3b (500 mg, 1.277 mmol) in dry dichloromethane (9.0 mL)
was added N-methyl,N-propargyl piperazine 5h (0.194 mL, 1.532
mmol) in the presence of DIPEA (0.022 mL, 0.127 mmol) and CuI (5
mol %), and the reaction was allowed to stir at room temparature under
an argon atmosphere for 16 h followed by purification as described
above to afford compound 6h as a yellow liquid; 588 mg, 87% yield; Rf =
0.41 (50% ethyl acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.63
(s, 1H), 7.35 (m, 5H), 5.89 (s, 1H), 5.12−5.09 (m, 1H), 4.76 (d, J = 15
Hz, 1H), 4.69 (m, 1H), 4.56 (m, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.04 (d,
J = 8.1 Hz, 2H), 4.00 (d, J = 6.6 Hz, 1H), 3.76−3.69 (m, 2H), 3.05−2.91
(m, 8H), 2.65 (s, 3H), 2.44−2.32 (m, 1H), 2.03 (d, J = 6.9 Hz, 1H), 1.41
(s, 3H), 1.25−1.14 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 169.3,
141.5, 136.3, 128.7 (2C), 128.5, 128.2 (2C), 125.4, 112.1, 104.9, 81.6,
81.5, 80.6, 71.6, 60.9, 57.1, 53.5 (2C), 52.2, 49.8 (2C), 43.8, 34.8, 26.7,
26.2, 14.0; MS (m/z) 530 [M + H]+; Anal. Calcd for C27H39N5O6 C
61.23, H 7.42, N 13.22; found C 61.30, H 7.38, N 13.21.
1-(Ethyl-[3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene]-β-L-
ido-heptofuranurnate-5-yl)-4-(cyclohexene-1″-yl)-1H-[1,2,3]-tria-
zole (6i). To a stirred solution of ethyl-[5-(S)-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-β-L-ido-heptofuranurnate 3a (300 mg,
0.766 mmol) in dry dichloromethane (10 mL) was added 1-
ethynylcyclohexene 5i (0.108 mL, 0.919 mmol) in the presence of
DIPEA (0.013 mL, 0.076 mmol) and CuI (5 mol %), and the reaction
was allowed to stir at room temparature under an argon atmosphere for
12 h followed by purification as described above to afford compound 6i
as a yellow liquid; 350 mg, 92% yield; Rf = 0.32 (45% ethyl acetate/n-
1-(Ethyl-[3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene]-α-D-
gluco-heptofuranurnate-5′-yl)-4-(toluene-4″-yl)-1H-[1,2,3]-triazole
(6c). To a stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate 3b (500
mg, 1.277 mmol) in dry dichloromethane (10 mL) was added 4-
ethynyl toluene 5c (0.194 mL, 1.532 mmol) in the presence of DIPEA
(0.022 mL, 0.127 mmol) and CuI (5 mol %), and the reaction was
allowed to stir at room temparature under an argon atmosphere for 10 h
followed by purification as described above to afford title compound 6c
as a yellow liquid; 602 mg, 93% yield; Rf = 0.41 (50% ethyl acetate/n-
hexane); 1H NMR (300 MHz, CDCl3) δ 7.83 (s, 1H), 7.70−7.68 (m,
2H), 7.34 (m, 5H), 7.20−7.17 (m, 2H), 5.91 (d, J = 3.6 Hz, 1H), 5.18−
5.12 (m, 1H), 4.76 (d, J = 11.7 Hz, 1H), 4.68 (d, J = 3.6 Hz, 1H), 4.63
(dd, J = 3, 9.3 Hz, 1H), 4.47 (d, J = 11.7 Hz, 1H), 4.01 (d, J = 2.7 Hz,
2H), 3.56 (m, 1H), 3.24 (dd, J = 10.8, 16.8 Hz, 1H), 2.47 (d, J = 13.8 Hz,
1H), 2.35 (s, 3H), 1.43 (s, 3H), 1.29 (s, 3H), 1.14 (t, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 169.4, 146.7, 137.5, 136.3, 129.3 (2C), 128.6
(2C), 128.4, 128.2 (2C), 127.9, 125.5 (2C), 121.5, 112.2, 104.8, 81.5,
80.7, 80.6, 71.6, 60.9, 57.2, 34.9, 26.7, 26.2, 21.2, 13.9; IR (KBr) νmax
3409, 3065, 1706 (CO), 1603, 1567, 1489, 1453, 1419, 1225, 1105,
855, 570; MS (m/z) 508 [M + H]+; Anal. Calcd for C28H33N3O6 C
66.26, H 6.55, N 8.28.; found C 66.37, H 6.71, N 8.41.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-β-L-
ido-heptofuranurnate-5-yl]-4-(fluorobenzene-4″-yl)-1H-[1,2,3]-tria-
zole (6d). To a stirred solution of ethyl-[5-(S)-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-β-L-ido-heptofuranurnate 3a (500 mg,
1.277 mmol) in dry dichloromethane (10 mL) was added 1-ethynyl-4-
fluorobenzene 5d (0.175 mL, 1.532 mmol) in the presence of DIPEA
(0.022 mL, 0.127 mmol) and CuI (5 mol %), and the reaction was
allowed to stir at room temparature under an argon atmosphere for 14 h
followed by purification as described above to afford desired compound
6d as a yellow liquid; 575 mg, 88% yield; Rf = 0.43 (55% ethyl acetate/n-
hexane); 1H NMR (300 MHz, CDCl3) δ 7.68−7.57 (m, 2H), 7.40−6.99
(m, 8H), 5.98 (d, J = 3 Hz, 1H), 5.23 (dd, J = 8.4, 14.1 Hz, 1H), 4.82 (d, J
= 9.9 Hz, 1H), 4.62 (d, J = 3 Hz, 1H), 4.56 (d, J = 11.7 Hz, 1H), 4.06 (d, J
= 11.1 Hz, 1H), 4.01 (d, J = 7.5 Hz, 2H), 3.64 (d, J = 2.7 Hz, 1H), 3.25
(d, J = 6 Hz, 2H), 1.52 (s, 3H), 1.32 (s, 3H), 1.14 (t, J = 6.9 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 170.5, 162.5 (d, J = 246 Hz), 145.5, 136.6,
134.1, 128.5 (2C), 128.1, 127.7 (2C), 127.3 (d, J = 8.9 Hz), 126.65,
126.61, 121.4, 115.5 (d, J = 21.6 Hz), 112.2, 105.3, 81.6, 81.2, 80.2, 72.1,
60.8, 55.7, 37.4, 26.8, 26.2, 13.9; IR (KBr) νmax 3412, 3079, 1701 (C
O), 1604, 1562, 1479, 1452, 1276, 1085, 1106, 1079, 858, 786, 576; MS
(m/z) 512 [M + H]+; Anal. Calcd for C27H30FN3O6 C 63.39, H 5.91, N
8.21; found C 63.55, H 5.99, N 8.17.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-β-L-
ido-heptofuranurnate-5-yl]-4-(pyridine-3″-yl)-1H-[1,2,3]-triazole
(6e). To a stirred solution of ethyl-[5-(S)-azido-3-O-benzyl-5,6-dideoxy-
1,2-O-isopropylidene]-β-L-ido-heptofuranurnate 3a (500 mg, 1.277
mmol) in dry dichloromethane (10 mL) was added 3-ethynylpyridine
5e (158 mg, 1.532 mmol) in the presence of DIPEA (0.022 mL, 0.127
mmol) and CuI (5 mol %), and the reaction was allowed to stir at room
temparature under an argon atmosphere for 12 h followed by
purification as described above to afford compound 6e as a yellow
solid; mp 120−124 °C; 568 mg, 90% yield; Rf = 0.45 (65% ethyl acetate/
n-hexane); 1H NMR (300 MHz, CDCl3) δ 8.84 (m, 1H), 8.56 (d, J = 4.5
Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.65 (m, 1H), 7.37−7.26 (m, 5H),
7.18 (d, J = 6.3 Hz, 1H), 5.99 (d, J = 3.3 Hz, 1H), 5.25 (dd, J = 9.6, 14.7
Hz, 1H), 4.82 (d, J = 9.9 Hz, 1H), 4.64 (d, J = 3 Hz, 1H), 4.59 (d, J =
11.4, 1H), 4.08−4.00 (m, 3H), 3.64 (m, 1H), 3.27 (d, J = 5.1 Hz, 2H),
1.52 (s, 3H), 1.32 (s, 3H), 1.14 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.4, 149.0, 146.9, 143.3, 136.4, 132.8, 128.6 (2C), 128.3,
127.7 (2C), 126.5, 123.6, 122.1, 112.3, 105.3, 81.7, 81.5, 80.2, 72.1, 60.9,
55.7, 37.3, 26.8, 26.2, 13.9; IR (KBr) νmax 3440, 3064, 2926, 1736 (C
O), 1605, 1574, 1455, 1409, 1376, 1220, 1164, 803, 707; MS (m/z) 495
[M + H]+; Anal. Calcd for C26H30N4O6 C 63.15, H 6.11, N 11.33; found
C 63.44, H 6.01, N 11.22.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(1″-phenyl-methan-1″-yl)-1H-
[1,2,3]-triazole (6f). To a stirred solution of ethyl-[5-(R)-azido-3-O-
J
DOI: 10.1021/acs.joc.5b00179
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
hexane); 1H NMR (300 MHz, CDCl3) δ 7.32−7.30 (m, 4H), 7.23−7.21
(m, 2H), 6.43 (s, 1H), 5.94 (s, 1H), 5.18 (dd, J = 8.4, 15.6 Hz, 1H), 4.77
(d, J = 6.9 Hz, 1H), 4.58 (m, 1H), 4.52 (d, J = 11.1 Hz, 1H), 4.11 (m,
1H), 4.06 (d, J = 9 Hz, 1H), 4.01 (d, J = 6 Hz, 1H), 3.59 (m, 1H), 3.21 (d,
J = 6 Hz, 2H), 2.25−2.09 (m, 4H), 1.73 (m, 2H), 1.66 (d, J = 5.7 Hz,
2H), 1.50 (s, 3H), 1.30 (s, 3H), 1.15 (t, J = 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 170.5, 148.1, 136.7, 128.5 (2C), 128.0, 127.6 (2C),
127.0, 124.8, 120.3, 112.2, 105.1, 81.7, 81.2, 80.3, 72.1, 60.7, 55.2, 37.4,
29.6, 26.7, 26.2, 25.2, 22.4, 22.1, 13.9; IR (KBr) νmax 3449, 2926, 2855,
1736 (CO), 1655, 1497, 1455, 1376, 1220, 1164, 1074, 1024, 854,
740; MS (m/z) 498 [M + H]+; Anal. Calcd for C27H35N3O6 C 65.17, H
7.09, N 8.44.; found C 64.99, H 7.23, N 8.57.
(s, 1H), 7.34 (m, 5H), 5.87 (d, J = 3 Hz, 1H), 5.12−5.06 (m, 1H), 5.02
(d, J = 12.9 Hz, 1H), 4.81 (d, J = 12.9 Hz, 1H), 4.78 (d, J = 11.7 Hz, 1H),
4.66 (d, J = 3 Hz, 1H), 4.54 (d, J = 9.3 Hz, 1H), 4.45 (d, J = 12 Hz, 1H),
4.35 (dd, J = 6.3, 12.9 Hz, 1H), 4.20−4.02 (m, 4H), 3.98 (d, J = 6.3 Hz,
2H), 3.81 (d, J = 8.7 Hz, 1H), 3.56 (m, 2H), 3.19 (dd, J = 11.4, 16.8 Hz,
1H), 2.41 (d, J = 16.8 Hz, 1H), 1.57 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H),
1.37 (s, 3H), 1.29 (s, 6H), 1.15 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 169.2, 144.0, 136.2, 128.6 (2C), 128.4, 128.2 (2C), 124.5,
112.1, 111.9, 109.0, 104.7, 104.1, 81.6, 81.5, 80.5, 75.7, 73.7, 71.6, 71.5,
64.8, 60.8, 60.0, 57.0, 51.8, 34.7, 28.0, 26.8, 26.6, 26.1 (2C), 25.8, 13.9;
IR (KBr) νmax 3453, 2926, 1739 (CO), 1640, 1457, 1380, 1220, 1117,
1080, 853; MS (m/z) 690 [M + H]+; Anal. Calcd for C34H47N3O12
C
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(1″,2″:3″,4″-di-O-isopropylidene-
6″-O-methyl-α-D-galacto-pyranose-6″-yl)-1H-[1,2,3]-triazole (6j).
To a stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-dideoxy-
1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate 3b (500 mg, 1.277
mmol) in dry dichloromethane (10 mL) was added 1,2:3,4-di-O-
isopropylidene-6-O-propargyl-α-D-galacto-pyranose 5j (456 mg, 1.532
mmol) in the presence of DIPEA (0.022 mL, 0.127 mmol) and CuI (5
mol %), and the reaction was allowed to stir at room temparature under
an argon atmosphere for 9 h followed by purification described earlier to
afford title compound 6j as a yellow liquid; 819 mg, 93% yield; Rf = 0.50
(60% ethyl acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.65 (s,
1H), 7.33 (m, 5H), 5.88 (s, 1H), 5.52 (s, 1H), 5.13−5.07 (m, 1H), 4.75
(d, J = 12.6 Hz, 2H), 4.67 (d, J = 7.5 Hz, 2H), 4.58 (d, J = 7.8 Hz, 2H),
4.45 (d, J = 12 Hz, 1H), 4.29−4.23 (m, 2H), 3.99 (m, 4H), 3.71−3.65
(m, 2H), 3.18 (dd, J = 10.8, 16.5 Hz, 1H), 2.43 (d, J = 16.8 Hz, 1H), 1.53
(s, 6H), 1.42 (s, 6H), 1.30 (s, 6H), 1.14 (t, J = 6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3) δ 169.2, 143.9, 136.3, 128.5 (2C), 128.3, 128.1 (2C),
124.5, 112.0, 109.0, 108.4, 104.9, 96.3, 81.5, 81.3, 80.6, 80.5, 71.5, 70.9,
70.5, 69.0, 66.5, 64.7, 60.8, 57.1, 34.9, 26.5, 26.1, 25.9, 25.8, 24.7, 24.3,
13.8; IR (KBr) νmax 3450, 2930, 1732 (CO), 1635, 1452, 1376, 1222,
1112, 1082, 856; MS (m/z) 690 [M + H]+; Anal. Calcd for C34H47N3O12
C 59.20, H 6.87, N 6.09; found C 58.92, H 6.83, N 6.06.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(1″,2″:5″,6″-di-O-isopropylidene-
3″-O-methyl-α-D-gluco-furanose-3″-yl)-1H-[1,2,3]-triazole (6k). To a
stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-dideoxy-1,2-O-
isopropylidene]-α-D-gluco-heptofuranurnate 3b (500 mg, 1.277
mmol) in dry dichloromethane (10 mL) was added 1,2:5,6-di-O-
isopropylidene-3-O-propargyl-α-D-gluco-furanose 5k (456 mg, 1.532
mmol) in the presence of DIPEA (0.022 mL, 0.127 mmol) and CuI (5
mol %), and the reaction was allowed to stir at room temparature under
an argon atmosphere for 9 h followed by purification as described above
to afford compound 6k as a yellow liquid; 810 mg, 92% yield; Rf = 0.46
(60% ethyl acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.71 (s,
1H), 7.34−7.27 (m, 5H), 5.89−5.86 (m, 2H), 5.08 (d, J = 9.6 Hz, 1H),
4.76−4.68 (m, 4H), 4.57−4.35 (m, 2H), 4.32 (dd, J = 6, 13.2 Hz, 1H),
4.13−3.99 (m, 7H), 3.57 (m, 1H), 3.21 (dd, J = 10.8, 16.5 Hz, 1H), 2.44
(d, J = 16.5 Hz, 1H), 1.48 (s, 3H), 1.42 (s, 6H), 1.36 (s, 3H), 1.29 (s,
6H), 1.15 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.2,
143.7, 136.3, 128.6 (2C), 128.4, 128.1 (2C), 124.7, 112.1, 111.7, 108.9,
105.2, 104.8, 82.4, 81.9, 81.7, 81.4, 81.1, 80.6, 72.3, 71.6, 67.2, 64.2, 60.8,
57.1, 34.7, 26.6 (2C), 26.1 (2C), 25.3 (2C), 13.9; IR (KBr) νmax 3453,
2926, 1739 (CO), 1640, 1457, 1380, 1220, 1117, 1080, 853; MS (m/
z) 690 [M + H]+; Anal. Calcd for C34H47N3O12 C 59.20, H 6.87, N 6.09;
found C 58.88, H 6.81, N 6.15.
59.20, H 6.87, N 6.09; found C 59.36, H 6.89, N 6.11.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(5″-O-benzyl-1″,2″-O-isopropyli-
dene-3″-O-methyl-α-D-xylo-furanose-3″-yl)-1H-[1,2,3]-triazole (6m).
To a stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-dideoxy-1,2-
O-isopropylidene]-α-D-gluco-heptofuranurnate 3b (500 mg, 1.277
mmol) in dry dichloromethane (10 mL) was added 5-O-benzyl-1,2-O-
isopropylidene-3-O-propargyl-α-D-xylo-furanose 5m (456 mg, 1.532
mmol) in the presence of DIPEA (0.022 mL, 0.127 mmol) and CuI (5
mol %), and the reaction was allowed to stir at room temparature under
an argon atmosphere for 9 h followed by purification described earlier to
afford compound 6m as a yellow liquid; 853 mg, 94% yield; Rf = 0.50
(60% ethyl acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.59 (s,
1H), 7.33−7.26 (m, 10H), 5.89 (s, 2H), 5.11−5.05 (m, 1H), 4.75 (d, J =
11.7 Hz, 1H), 4.69−4.54 (m, 8H), 4.49 (d, J = 10.2 Hz, 2H), 4.41 (d, J =
14.4 Hz, 1H), 4.00 (d, J = 7.5 Hz, 3H), 3.70 (d, J = 4.8 Hz, 2H), 3.18 (dd,
J = 10.8, 16.8 Hz, 1H), 2.41 (d, J = 15.9 Hz, 1H), 1.47 (s, 3H), 1.41 (s,
3H), 1.29 (s, 6H), 1.13 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 169.2, 143.5, 138.0, 136.2, 128.6 (2C), 128.4 (2C), 128.2 (2C), 128.1
(2C), 127.7, 127.5, 124.5, 112.1, 111.5, 105.0, 104.9, 82.3, 82.1, 81.5,
80.7, 80.6, 79.0, 73.3, 71.6, 67.5, 63.9, 60.8, 57.1, 34.7, 26.67, 26.62, 26.2,
26.1, 13.9; IR (KBr) νmax 3451, 2927, 1740 (CO), 1625, 1456, 1379,
1260, 1165, 1077, 1023, 851; MS (m/z) 711 [M + H]+; Anal. Calcd for
C37H48N3O11 C 62.52, H 6.81, N 5.91; found C 62.57, H 6.76, N 5.90.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuraurnate-5′-yl]-4-(2″,3″:5″,6″-di-O-isopropylidene-
1″-O-methyl-D-manno-furanose-1″-yl)-1H-[1,2,3]-triazole (6n). To a
stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-dideoxy-1,2-O-
isopropylidene]-α-D-gluco-heptofuranurnate 3b (500 mg, 1.277
mmol) in dry dichloromethane (9.0 mL) was added 2,3:5,6-di-O-
isopropylidene-1-O-propargyl-D-manno-furanose 5n (456 mg, 1.532
mmol) in the presence of DIPEA (0.022 mL, 0.127 mmol) and CuI (5
mol %), and the reaction was allowed to stir at room temparature under
an argon atmosphere for 10 h followed by purification as described
above to afford compound 6n as a white solid; mp 142−144 °C; 810 mg,
92% yield; Rf = 0.48 (60% ethyl acetate/n-hexane); 1H NMR (300 MHz,
CDCl3) δ 7.63 (s, 1H), 7.34−7.33 (m, 5H), 5.89 (d, J = 3.3 Hz, 1H),
5.09 (m, 2H), 4.76−4.53 (m, 7H), 4.46 (d, J = 15.3 Hz, 1H), 4.40 (d, J =
6 Hz, 1H), 4.14−3.99 (m, 6H), 3.19 (dd, J = 10.5 Hz, 16.5 Hz, 1H), 2.44
(d, J = 16.5 Hz, 1H), 1.45 (s, 6H), 1.43 (s, 3H), 1.38 (s, 3H), 1.38 (s,
3H), 1.30 (s, 3H), 1.15 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3)
δ 169.3, 142.9, 136.3, 128.6 (2C), 128.4, 128.1 (2C), 124.9, 112.5, 112.1,
109.1, 105.8, 105.0, 85.0, 81.6, 81.4, 80.7, 80.6, 79.5, 73.0, 71.6, 66.9,
60.9, 60.4, 57.1, 34.9, 26.7, 26.6, 26.2, 25.8, 25.1, 24.4, 13.9; IR (KBr)
νmax 3459, 2925, 1735 (CO), 1622, 1459, 1365, 1259, 1163, 1068,
1025, 858; MS (m/z) 690 [M + H]+; Anal. Calcd for C34H47N3O12
C
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(1″,2″:4″,5″-di-O-isopropylidene-
3″-O-methyl-D-fructo-pyranose-1″-yl)-1H-[1,2,3]-triazole (6l). To a
stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-dideoxy-1,2-O-
isopropylidene]-α-D-gluco-heptofuranurnate 3b (500 mg, 1.277
mmol) in dry dichloromethane (10 mL) was added 1,2,:4,5-di-O-
isopropylidene-3-O-propargyl-D-fructo-pyranose 5l (456 mg, 1.532
mmol) in the presence of DIPEA (0.022 mL, 0.127 mmol) and CuI
(5 mol %), and the reaction was allowed to stir at room temparature
under an argon atmosphere for 9 h followed by purification as described
above to afford compound 6l as a yellow liquid; 819 mg, 93% yield; Rf =
0.45 (65% ethyl acetate/n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.63
59.20, H 6.87, N 6.09; found C 59.15, H 6.80, N 6.07.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(octan-1″-ol-8″-yl)-1H-[1,2,3]-tria-
zole (6o). To a stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate 3b (500
mg, 1.277 mmol) in dry dichloromethane (9.0 mL) was added dec-9-
yne-1-ol 5o (0.271 mL, 1.532 mmol) in the presence of DIPEA (0.022
mL, 0.127 mmol) and CuI (5 mol %), and the reaction was allowed to
stir at room temparature under an argon atmosphere for 12 h followed
by purification as described above to afford compound 6o as a yellow
liquid; 648 mg, 93% yield; Rf = 0.48 (45% ethyl acetate/n-hexane); 1H
NMR (300 MHz, CDCl3) δ 7.36−7.33 (m, 5H), 5.90−5.87 (m, 1H),
K
DOI: 10.1021/acs.joc.5b00179
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5.07−5.04 (m, 1H), 4.80 (d, J = 12 Hz, 1H), 4.77 (dd, J = 12, 26.7 Hz,
1H), 4.66 (d, J = 3.9 Hz, 1H), 4.58 (dd, J = 3, 9.3 Hz, 1H), 4.51−4.42 (m,
1H), 4.05−3.96 (m, 3H), 3.65−3.54 (m, 3H), 3.29−3.15 (m, 1H),
2.69−2.60 (m, 2H), 2.42 (dd, J = 2.4, 16.5 Hz, 1H), 1.57−1.55 (m, 6H),
1.42 (d, J = 5.4 Hz, 2H), 1.32−1.10 (m, 13H); 13C NMR (75 MHz,
CDCl3) δ 169.5, 147.1, 136.3, 128.6 (2C), 128.4, 128.1 (2C), 122.7,
112.1, 104.9, 81.6, 81.4, 80.7, 71.6, 71.5, 62.8, 60.8, 56.8, 34.9, 32.6, 29.6,
29.1 (2C), 26.6, 26.1, 26.0, 25.7, 13.8; IR (KBr) νmax 3310, 2928, 2856,
1738 (CO), 1457, 1378, 1223, 1164, 1075, 1028, 888, 856; MS (m/z)
546 [M + H]+; Anal. Calcd for C29H43N3O7 C 63.83, H 7.94, N 7.70;
found C 63.90, H 7.82, N 7.65.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(hexan-1″-yl)-1H-[1,2,3]-triazole
(6p). To a stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate 3b (400
mg, 1.021 mmol) in dry dichloromethane (10 mL) was added 1-octyne
5p (0.180 mL, 1.226 mmol) in the presence of DIPEA (0.017 mL, 0.102
mmol) and CuI (5 mol %), and the reaction was allowed to stir at room
temparature under an argon atmosphere for 10 h followed by
purification as described above to afford compound 6p as a yellow
semisolid; 481 mg, 94% yield; Rf = 0.48 (50% ethyl acetate/n-hexane);
1H NMR (300 MHz, CDCl3) δ 7.26−7.19 (m, 6H), 5.82 (d, J = 3.3 Hz,
1H), 4.98 (d, J = 9.3 Hz, 1H), 4.67 (d, J = 11.7 Hz, 1H), 4.59 (d, J = 3.3
Hz, 1H), 4.51 (d, J = 6.3 Hz, 1H), 4.38 (d, J = 11.7 Hz, 1H), 3.93 (d, J =
10.5 Hz, 2H), 3.48 (m, 1H), 3.11 (dd, J = 10.5, 16.5 Hz, 1H), 2.61−2.56
(m, 2H), 2.36 (d, J = 14.7 Hz, 1H), 1.57 (m, 2H), 1.35 (m, 2H), 1.22−
1.85 (m, 10H), 1.06 (t, J = 6.9 Hz, 3H), 0.80 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 169.5, 136.3, 128.6 (2C), 128.3, 128.1 (2C), 122.7,
112.1, 104.9, 81.6, 81.4, 80.6, 71.6, 60.8, 56.9, 34.9, 31.4, 29.0, 28.8, 26.6,
26.2, 25.6 (2C), 22.4, 13.9 (2C); IR (KBr) νmax 3426, 2925, 2856, 1732
(CO), 1451, 1372, 1225, 1161, 1074, 1031, 879, 852, 702; MS (m/z)
502 [M + H]+; Anal. Calcd for C27H39N3O6 C 64.65, H 7.84, N 8.38;
found C 64.70, H 7.80, N 8.39.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(3″-cyanopropan-1″-yl)-1H-
[1,2,3]-triazole (6q). To a stirred solution of ethyl-[5-(R)-azido-3-O-
benzyl-5,6-dideoxy-1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate
3b (500 mg, 1.277 mmol) in dry dichloromethane (10 mL) was added 5-
cyanopentyne 5q (0.160 mL, 1.532 mmol) in the presence of DIPEA
(0.022 mL, 0.127 mmol) and CuI (5 mol %), and the reaction was
allowed to stir at room temparature under an argon atmosphere for 12 h
followed by purification as described above to afford compound 6q as a
yellow liquid; 575 mg, 93% yield; Rf = 0.51 (55% ethyl acetate/n-
hexane); 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 7.34−7.33 (m,
5H), 5.89 (d, J = 3.9 Hz, 1H), 5.06 (d, J = 9.6 Hz, 1H), 4.75 (d, J = 11.7
Hz, 1H), 4.67 (d, J = 3.6 Hz, 1H), 4.56 (dd, J = 3.0, 9.6 Hz, 1H), 4.47−
4.43 (m, 1H), 4.03−3.99 (m, 3H), 3.21−3.12 (m, 1H), 2.85−2.80 (m,
2H), 2.45−2.40 (m, 2H), 2.37 (d, J = 6.9 Hz, 1H), 2.05 (t, J = 6.9 Hz,
2H), 1.43 (s, 3H), 1.30 (s, 3H), 1.15 (t, J = 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 169.4, 144.3, 136.3, 128.6 (2C), 128.4, 128.2 (2C),
123.4, 119.3, 112.1, 104.9, 81.6, 81.4, 80.6, 71.6, 60.8, 57.1, 34.8, 29.6,
26.6, 26.1, 24.1, 16.4, 13.9; IR (KBr) νmax 3429, 2927, 2855, 2246 (−C
N), 1737 (CO), 1455, 1379, 1217, 1165, 1075, 1028, 856, 701; MS
(m/z) 485 [M + H]+; Anal. Calcd for C25H32N4O6 C 61.97, H 6.66, N
11.56.; found C 62.05, H 6.65, N 11.60.
Hz, 3H), 0.096 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 169.3,
149.9, 136.3, 128.6 (2C), 128.4, 128.2 (2C), 122.5, 112.1, 105.0, 81.6,
80.7, 80.6, 71.6, 68.3, 60.9, 57.1, 35.0, 30.1, 26.6, 26.2, 13.9, 9.7; IR (KBr)
νmax 3426, 2925, 2853, 1733 (CO), 1453, 1377, 1216, 1162, 1071,
1025, 851, 702; MS (m/z) 460 [M + H]+; Anal. Calcd for C24H33N3O6
C 62.73, H 7.24, N 9.14; found C 62.79, H 7.21, N 9.10.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(meth-1″-ol-1″-yl)-1H-[1,2,3]-tria-
zole (6s). To a stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate 3b (300
mg, 0.766 mmol) in dry dichloromethane (10 mL) was added propargyl
alcohol 5s (0.057 mL, 0.996 mmol) in the presence of DIPEA (0.013
mL, 0.076 mmol) and CuI (5 mol %), and the reaction was allowed to
stir at room temparature under an argon atmosphere for 10 h followed
by purification as described above to afford compound 6s as a white
solid; mp 150−152 °C; 322 mg, 94% yield; Rf = 0.51 (80% ethyl acetate/
n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.59 (s, 1H), 7.35−7.26 (m,
5H), 5.88 (d, J = 3.6 Hz, 1H), 5.14−5.02 (m, 1H), 4.77−4.67 (m, 4H),
4.56 (dd, J = 3, 9.6 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.03−3.98 (m,
3H), 3.18 (dd, J = 10.8, 16.5 Hz, 1H), 2.56 (s, 1H), 2.42 (d, J = 16.8 Hz,
1H), 1.42 (s, 3H), 1.29 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 169.3, 146.5, 136.3, 128.6 (2C), 128.4, 128.2 (2C),
123.7, 112.2, 104.8, 81.6, 81.4, 80.6, 71.6, 60.9, 57.2, 56.6, 34.8, 26.7,
26.2, 13.9; IR (KBr) νmax 3312, 2926, 2859, 1737 (CO), 1455, 1376,
1225, 1162, 1074, 1025, 883, 854; MS (m/z) 448 [M + H]+; Anal. Calcd
for C22H29N3O7 C 59.05, H 6.53, N 9.39; found C 59.10, H 6.56, N 9.43.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(butan-1″-yl)-1H-[1,2,3]-triazole
(6t). To a stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-dideoxy-
1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate 3b (500 mg, 1.277
mmol) in dry dichloromethane (9.0 mL) was added 1-hexyne 5t (0.174
mL, 1.532 mmol) in the presence of DIPEA (0.022 mL, 0.127 mmol)
and CuI (5 mol %), and the reaction was allowed to stir at room
temparature under an argon atmosphere for 12 h followed by
purification as described above to afford compound 6t as a yellow
liquid; 544 mg, 90% yield; Rf = 0.43 (55% ethyl acetate/n-hexane); 1H
NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.35−7.33 (m, 5H), 5.88 (d, J
= 3.6 Hz, 1H), 5.16−5.10 (m, 1H), 4.76 (d, J = 12 Hz, 1H), 4.68 (d, J =
3.3 Hz, 1H), 4.57−4.54 (m, 1H), 4.44 (d, J = 11.7 Hz, 1H), 4.04−3.99
(m, 3H), 3.17 (dd, J = 11.1, 16.5 Hz, 1H), 3.08−3.03 (m, 1H), 2.66 (d, J
= 7.2 Hz, 1H), 2.41 (d, J = 16.8 Hz, 1H), 1.79−1.72 (m, 2H), 1.42 (s,
3H), 1.25 (s, 6H), 1.15 (t, J = 6.9 Hz, 3H), 1.01- 0.96 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 169.0, 147.0, 136.2, 128.7 (2C), 128.5, 128.3 (2C),
127.6, 112.2, 105.0, 81.5, 80.4, 80.2, 71.6, 61.0, 57.7, 41.3, 34.6, 29.6,
26.6, 26.2, 25.3, 17.2, 13.9; IR (KBr) νmax 3424, 2921, 2857, 1737 (C
O), 1454, 1376, 1215, 1161, 1072, 1023, 886, 856, 701; MS (m/z) 474
[M + H]+; Anal. Calcd for C25H35N3O6 C 63.41, H 7.45, N 8.87; found
C 63.52, H 7.48, N 8.89.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-β-L-
ido-heptofuranurnate-5-yl]-4-(ethisterone-1″-yl)-1H-[1,2,3]-triazole
(6u). To a stirred solution of ethyl-[5-(S)-azido-3-O-benzyl-5,6-
dideoxy-1,2-O-isopropylidene]-β-L-ido-heptofuranurnate 3a (500 mg,
1.277 mmol) in dry dichloromethane (10 mL) was added ethisterone 5u
(478 mg, 1.532 mmol) in the presence of DIPEA (0.022 mL, 0.127
mmol) and CuI (5 mol %), and the reaction was allowed to stir at room
temparature under an argon atmosphere for 12 h followed by
purification as described above to afford compound 6u as a yellow
liquid; 782 mg, 87% yield; Rf = 0.45 (50% ethyl acetate/n-hexane); 1H
NMR (300 MHz, CDCl3) δ 7.45 (s, 1H), 7.34−7.33 (m, 5H), 5.87 (d, J
= 3.3 Hz, 1H), 5.69 (m, 1H), 5.11−5.05 (m, 1H), 4.74 (d, J = 11.5 Hz,
1H), 4.66 (d, J = 3.6 Hz, 1H), 4.55 (d, J = 9.3 Hz, 1H), 4.44 (d, J = 11.7
Hz, 1H), 4.01−3.94 (m, 3H), 3.13 (dd, J = 10.5, 16.5 Hz, 1H), 3.05 (m,
1H), 2.45−1.77 (m,11H), 1.62−1.47 (m, 7H), 1.41 (s, 3H), 1.27 (s,
3H), 1.12 (s, 3H), 1.07 (m, 3H), 1.03 (s, 3H), 0.68 (m, 1H), 0.37 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 199.5, 171.4, 169.2, 152.0, 136.3,
128.6 (2C), 128.4, 128.2 (2C), 123.7, 123.1, 112.2, 104.7, 81.7, 81.5,
80.6, 80.5, 71.7, 60.8, 57.2, 53.3, 48.9, 46.8, 38.5, 37.3, 36.1, 35.5, 35.0,
33.8, 32.8, 32.4, 31.6, 26.7, 26.2, 23.4, 20.6, 17.3, 14.17, 14.10; MS (m/z)
704 [M + H]+; Anal. Calcd for C40H53N3O8 C 68.26, H 7.59, N 5.97;
found C 68.20, H 7.55, N 5.95.
1-[Ethyl-(3′-O-benzyl-5′,6′-dideoxy-1′,2′-O-isopropylidene)-α-D-
gluco-heptofuranurnate-5′-yl]-4-(propan-1″-yl)-1H-[1,2,3]-triazole
(6r). To a stirred solution of ethyl-[5-(R)-azido-3-O-benzyl-5,6-dideoxy-
1,2-O-isopropylidene]-α-D-gluco-heptofuranurnate 3b (700 mg, 1.788
mmol) in dry dichloromethane (10.0 mL) was added 1-pentyne 5r
(0.228 mL, 2.146 mmol) in the presence of DIPEA (0.031 mL, 0.178
mmol) and CuI (5 mol %), and the reaction was allowed to stir at room
temparature under an argon atmosphere for 12 h followed by
purification as described above to afford compound 6r as a white
solid; mp 158−160 °C; 755 mg, 92% yield; Rf = 0.48 (60% ethyl acetate/
n-hexane); 1H NMR (300 MHz, CDCl3) δ 7.55 (s, 1H), 7.34−7.33 (m,
5H), 5.88 (m, 1H), 5.13−5.06 (m, 1H), 4.75 (d, J = 11.4 Hz, 2H), 4.67
(d, J = 3.3 Hz, 1H), 4.57 (d, J = 9.3 Hz, 1H), 4.45 (d, J = 12 Hz, 1H), 4.01
(d, J = 11.1 Hz, 3H), 3.17 (dd, J = 10.8, 16.5 Hz, 1H), 2.44 (d, J = 16.2
Hz, 2H), 1.87−1.81 (m, 2H), 1.43 (s, 3H), 1.29 (s, 3H), 1.14 (t, J = 6.9
L
DOI: 10.1021/acs.joc.5b00179
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2002, 67, 3057. (c) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.;
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ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra for all the new compounds
and X-ray crystallographic data for 3a, 3b, 4b, and 6a (CIF) are
given. The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.joc.5b00179.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tiwari_chem@yahoo.co.in. Phone: +91-542-6702466.
Fax: +91-542-236817.
Notes
■
(15) (a) Beckmann, H. S. G.; Wittmann, V. In Organic Azides: Syntheses
and Applications; Brase, S., Banert, K., Eds.; John Wiley & Sons, 2010, p
̈
469. (b) Witczak, Z. J. Azides: Recent Advances in the Synthesis of
Functionalized Carbohydrate Azides. In Carbohydrate Chemistry; RSC
Publishing, 2010; Vol. 36, p 176
The authors declare no competing financial interest.
(16) Biffin, M. E. C., Miller, J., Paul, D. B., Patai, S., Eds.; The Chemistry
of the Azido Group; Interscience: London, 1971, p 57.
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Lett. 2004, 45, 1219.
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773.
ACKNOWLEDGMENTS
■
The authors thank CISC, Banaras Hindu University, and the
Central Drug Research Institute, Lucknow, for spectroscopic
studies and single crystal X-ray analysis. We thank the Council of
Scientific & Industrial Research, New Delhi (Grant No.
02(0173)/13/EMRII) for funding and Dr. R. P. Tripathi,
Scientist-G at CDRI, Lucknow, for help and suggestions during
preparation of the manuscript.
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DOI: 10.1021/acs.joc.5b00179
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