C-Glycosyl 1,2,4-triazoles: Synthesis of the 3-β-D-glucopyranosyl-1,5-disubstituted and 5-β-D-glucopyranosyl-1,3-disubstituted variants

Article abstract of DOI:10.1016/j.tet.2017.05.014

Highly variable synthetic routes were elaborated toward trisubstituted C-glycopyranosyl 1,2,4-triazoles. N-Acyl-thioamide derivatives were obtained by acylation of O-perbenzoylated 2,6-anhydro-D-glycero-D-gulo-heptonothioamide by acid chlorides and of thioamides by O-perbenzoylated 2,6-anhydro-D-glycero-D-gulo-heptonoyl chloride. These precursors reacted with substituted hydrazines in a regioselective manner to yield 3-β-D-glucopyranosyl-1,5-disubstituted- and 5-β-D-glucopyranosyl-1,3-disubstituted-1,2,4-triazoles, respectively. Analogous N-acyl-2,6-anhydro-heptonamides failed to give the above triazoles with hydrazines. O-Deprotection of the C-glucosyl 1,2,4-triazoles by the Zemplén method furnished test compounds which showed no inhibition against rabbit muscle glycogen phosphorylase b.

Full text of DOI:10.1016/j.tet.2017.05.014

Accepted Manuscript
C-Glycosyl 1,2,4-triazoles: Synthesis of the 3-β-D-glucopyranosyl-1,5-disubstituted
and 5-β-D-glucopyranosyl-1,3-disubstituted variants
Katalin E. Szabó, András Páhi, László Somsák
PII:
S0040-4020(17)30479-9
10.1016/j.tet.2017.05.014
TET 28680
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 February 2017
Revised Date: 18 April 2017
Accepted Date: 3 May 2017
Please cite this article as: Szabó KE, Páhi Andrá, Somsák Láó, C-Glycosyl 1,2,4-triazoles: Synthesis
of the 3-β-D-glucopyranosyl-1,5-disubstituted and 5-β-D-glucopyranosyl-1,3-disubstituted variants,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.014.
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ACCEPTED MANUSCRIPT
R'
N
OBz
O
OR''
O
S
O
S
N
O
NH2NHR'
BzO
BzO
R
R''O
R''O
RCOCl
N
N
H
R
NH2
OBz
OBz
OR''
9 examples R'' = Bz (65-90 %) R'' = H (45-84 %)
R'
N
OBz
O
O
S
N
O
R''O
R''O
R''O
O
O
R'NHNH2
RCSNH2
R
BzO
BzO
N
N
H
R
Cl
OBz
OR''
OBz
5 examples R'' = Bz (60-90 %) R'' = H (83-99 %)

ACCEPTED MANUSCRIPT
C-Glycosyl 1,2,4-triazoles: synthesis of the 3-β- -glucopyranosyl-
D
1,5-disubstituted and 5-β- -glucopyranosyl-1,3-disubstituted
D
variants
Katalin E. Szabó, András Páhi, László Somsák
Department of Organic Chemistry, University of Debrecen, PO Box 400, H-4002 Debrecen,
Hungary
Abstract
Highly variable synthetic routes were elaborated toward trisubstituted C-glycopyranosyl
1,2,4-triazoles. N-Acyl-thioamide derivatives were obtained by acylation of O-perbenzoylated
2,6-anhydro-
perbenzoylated 2,6-anhydro-
with substituted hydrazines in a regioselective manner to yield 3-β-
disubstituted- and 5-β- -glucopyranosyl-1,3-disubstituted-1,2,4-triazoles, respectively.
D
-glycero-
D
-gulo-heptonothioamide by acid chlorides and of thioamides by O-
-glycero- -gulo-heptonoyl chloride. These precursors reacted
-glucopyranosyl-1,5-
D
D
D
D
Analogous N-acyl-2,6-anhydro-heptonamides failed to give the above triazoles with
hydrazines. O-Deprotection of the C-glucosyl 1,2,4-triazoles by the Zemplén method
furnished test compounds which showed no inhibition against rabbit muscle glycogen
phosphorylase b.
Keywords
C-Glycosyl heterocycle; 1,2,4-triazole; 2,6-anhydro-aldonamide; 2,6-anhydro-
aldonothioamide
Corresponding author ‒ Tel: +3652512900 ext 22348; Fax: +3652512744; E-mail:
somsak.laszlo@science.unideb.hu
1

ACCEPTED MANUSCRIPT
Introduction
Although 1,2,4-triazoles have not been found as constituents of natural compounds, this
heterocycle is frequently part of biologically active synthetic molecules, among them a wide
range of marketed drugs and agricultural chemicals, and finds various applications in many
other fields, e.g. in synthetic and analytical chemistry, uses as corrosion inhibitors, ligands of
metal complexes, and functional materials. As a consequence of this broad utility and interest,
a large variety of synthetic methods have been elaborated to get this heteroring and its
derivatives resulting in miriads of 1,2,4-triazole containing compounds.1-8
Carbohydrate derivatives of this heterocycle are much less available. Direct conjugation of the
1,2,4-triazole ring with sugars may occur by a C-N or a C-C bond. From the former class
several examples of bioactive nucleoside analogues9 and N1-10-13 as well as N4-
glycopyranosides14 have been known. C-Glycosyl 1,2,4-triazoles are an even more
uncommon type15-18 and only in recent years has progress been made in this field with the
syntheses of 3-glycopyranosyl-5-substituted-1,2,4-triazoles as glycogen phosphorylase
inhibitors for potential antidiabetic use.19-24
As a continuation of our efforts in the above syntheses, the preparation of trisubstituted C-
glycopyranosyl 1,2,4-triazoles was envisaged to generate molecules for structure‒activity
relationships of glycogen phosphorylase inhibitors and also for other potential biological
applications. From the three possible isomeric structures (Scheme 1) some examples of the 3-
glycosyl-4,5-disubstituted-1,2,4-triazoles (I) were already described,21 therefore, this work
has focused on the 3-β-D-glucopyranosyl-1,5-disubstituted (II) and 5-β-D-glucopyranosyl-1,3-
disubstituted (III) counterparts.
2

ACCEPTED MANUSCRIPT
Results and Discussion
A retrosynthetic analysis of the target compounds (Scheme 1) revealed two types of synthetic
possibilities. Type A syntheses would require a 1,3-dipolar cycloaddition of nitriles with
nitrilimines. Toward triazoles II route A would require a series of nitriles IV which
themselves may also have to be prepared from other kinds of starting materials and C-
glycosyl nitrilimine precursors with appropriate substituents like 5-glycosyl-2-substituted-
tetrazoles V or hydrazonoyl halide derivatives of anhydro-aldonic acids VI which are also not
readily available. Toward triazoles III route A would need well known glycosyl cyanides X
and nitrilimine precursors such as 2,5-disubstituted-tetrazoles XI or hydrazonoyl halides XII.
Actually, the latter type reaction (X + XII) was studied to some extent, and a few 3-β-D-
glycopyranosyl-1,5-disubstituted-1,2,4-triazoles were described.16,17 However, for getting a
large series of compounds, multistep synthesis of each hydrazonoyl halide and/or 2,5-
disubstituted-tetrazole would be necessary. These requirements adumbrate rather labour
intensive preparative work to get the precursors for both route A type syntheses. Therefore we
turned to type B synthetic pathways which would need various hydrazines VII and acylation
of easily available C-glycosyl formamides (anhydro-aldonamides) to get precursors VIII. In
these cases the regioselectivity may be a challenge due to the possibly similar reactivity of the
two electrophilic centres of VIII, therefore, the related acyl-thioamides IX and XIII were also
taken into consideration.
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ACCEPTED MANUSCRIPT
Synthesis realized by the transformation
of O-peracylated 5-glycosyl tetrazoles
with imidoyl chlorides.21
R'
N
N
R'
Gly C N N R'
H
N N
or Gly C N N R'
N
+
N
Gly
Hlg
R
Gly
N
N C R
V
VI
route A
route B
IV
1 R'
N N
2
O
O
5
3
R
Gly
N
H
4
Gly
Gly
N
R
R
H2N N R'
H
II
1 R'
N N
2
VII
VIII
+
5
S
O
3
R
Gly
N
4
N
H
Gly
N
R
H
IX
Scheme 1. Isomers of trisubstituted C-glycopyranosyl 1,2,4-triazoles (I-III) and retrosynthetic analysis
of the target compounds II and III.
4

ACCEPTED MANUSCRIPT
To get precursors of type VIII, the acylation of O-perbenzoylated 2,6-anhydro-heptonamide
(C-β-D
-glucopyranosyl formamide) 125 was studied (Scheme 1). Under some conditions (1.5-
15 equiv. of Ac2O in the presence of N-bases,26,27 or 1-2 equiv. of AcCl the presence of 1.2
equiv of NaH in THF,28,29 2.5 equiv. of Bz2O with catalytic H2SO4 in CHCl3 at reflux
temperature30) incomplete conversion of the starting 1 was observed. Full transformation of 1
was achieved however, by using 5 equiv. of both an acid chloride and pyridine in CHCl3 at r.
t. (Table 1), but the products 2-4 were accompanied by significant amounts of diacylated
derivatives 5-7, respectively, and in the cases of aromatic acid chlorides, the dehydration31 of
1 to give glucosyl cyanide 825 (cf also Scheme 3) was the main reaction pathway.
Table 1. Experiments towards acylation of 2,6-anhydro-heptonamide 1
i) 5 equiv. RCOCl, 5 equiv. pyridine, dry CHCl3, rt
R
Yield (%)
5 (34)
Me
2 (51)
3 (26)
4 (16)
-
Ph
6 (8)
8 (67)
8 (39)
1-Naphthyl
7 (15)
5

ACCEPTED MANUSCRIPT
An initial experiment towards the formation of a 1,2,4-triazole was carried out by reacting 2
with hydrazine hydrate or hydrazinium acetate. Surprisingly, the products of this
transformation, obtained after column chromatography with an acetone-hexane eluent, proved
to be amide 1 and acylhydrazone 10 (Scheme 2). This experiment proved the similar
reactivity of the two N-carbonyls in 2 (the appearance of 10 can be explained by the formation
of 9 which was condensed with acetone during the purification). Under the same conditions
monoacyl-amides 3 and 4 gave only 10 as the final product in 74 and 72 % yields,
respectively. These observations indicated that N-acyl-amides 2-4 could not serve as starting
materials for the planned 1,2,4-triazole syntheses.
Scheme 2.
After this failure we turned to the preparation of precursors IX and XIII (Scheme 3). Towards
IX, the N-acylation of 2,6-anhydro-aldonothioamide (C-β-D-glucopyranosyl thioformamide)
1132 was smoothly carried out by several aliphatic acid chlorides to give excellent yields of
12-15. Unexpectedly, attempts to acylate 11 by aromatic acid chlorides (PhCOCl, 1-
naphthoylchloride) gave glucosyl cyanide 825 as the main product. Each reaction mixture
contained a second product, probably the N-aroyl-thioamide, however, this could not be
isolated in a pure state. This observation turned out to have a literature precedent,33 and thus,
6

ACCEPTED MANUSCRIPT
the formation of 8 as the primary product could be explained by an S-aroylation of the CSNH2
moiety to give 16 (X = S) which then underwent a spontaneous loss of ArCOSH. Formation
of 8 in N-aroylations of 1 (Table 1) can be explained in an analogous manner via 16 (X = O).
Precursors of type XIII were obtained by glycosylcarbonylation of thioacetamide and
thiobenzamide with 2,6-anhydro-aldonoyl chloride (C-β-D-glucopyranosylformyl chloride)
1720,34 and the expected 18 and 19, respectively, could be isolated in acceptable yields
(Scheme 3).
Scheme 3. Reagents and conditions: i) 1.5 equiv. RCOCl, 1.5 equiv. pyridine, dry CHCl3, rt;
ii) 2 equiv. RCSNH2, 2 equiv. pyridine, dry CH3CN, rt.
With the N-acyl-thioamide precursors in hand, the syntheses of the target 1,2,4-triazoles were
carried out. Compounds 12-15 were reacted with hydrazinium acetate in pyridine at r. t.
(Table 2) to give 20, 24, 27 and 30, respectively, from which the first three were identical,
when compared, with previously prepared compounds,20 thereby proving the suitability of
these precursors for the triazole synthesis. Reactions of 12-15 with substituted hydrazines
7

ACCEPTED MANUSCRIPT
(phenylhydrazine, 2-hydroxyethyl-hydrazine and tosylhydrazine) gave the corresponding 21-
23, 25, 26, 28, 29, 31, and 32, respectively, in good yields. O-Debenzoylation of 21, 22, 24,
25, 27-31 by the Zemplén method gave 3-β-D-glucopyranosyl-1,5-disubstituted-1,2,4-
triazoles 33-41, respectively, in good yields.
Reactions of N-acyl-thioamides 18 and 19 with hydrazinium acetate gave the known 3-β-
D-
glucopyranosyl-5-substituted-1,2,4-triazoles20 20 and 43, respectively (Table 3). With
substituted hydrazines the expected 1,2,4-triazoles 42, 44-47 were obtained in varying yields,
which were O-deprotected by the Zemplén protocol to give 5-β- -glucopyranosyl-1,3-
D
disubstituted-1,2,4-triazoles 48-52, respectively, in excellent yields. When 19 was
transformed with tosylhydrazine, triazole 43 was isolated indicating spontaneous loss of the
tosyl moiety under the applied conditions similarly to the observations made in reactions of
N1-tosyl-C-(2,3,4,6-tetra-O-benzoyl-β-
D
-glucopyranosyl)formamidrazone and acid
chlorides.20
8

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Table 2. Synthesis of 3-β-
D
-glucopyranosyl-1,5-disubstituted-1,2,4-triazoles
Starting
compound
Yield (%)
R
R’
R’’ = Bz
20a (55)
21 (67)
22 (70)
23a (63)
24a (92)
R’’ = H
Me
H
-
12
Ph
33 (70)
C2H4OH
34 (72)
Ts
H
-
-
AcOCH2
13
35 (84)
Ph
25 (70)
R = CH2OH
26 (65)
36 (62)
C2H4OH
R = CH2OH
27a (79)
28 (66)
R = CH2OH
tBu
H
-
14
Ph
37 (50)
38 (65)
39 (45)
40 (70)
41 (51)
C2H4OH
H
29 (65)
Bn
30 (75)
15
Ph
31 (71)
C2H4OH
32 (90)
a The compound was identical with the one obtained from N1-tosyl-C-(2,3,4,6-tetra-O-benzoyl-β-
D-
glucopyranosyl)formamidrazone and the corresponding acid chloride.20
9

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Table 3. Synthesis of 5-β-
D
-glucopyranosyl-1,3-disubstituted-1,2,4-triazoles
Starting
compound
Yield (%)
R
R’
R’’ = Bz
20a (57)
42 (65)
43a (35)
44 (90)
45 (90)
46 (60)
47 (72)
R’’ = H
-
Me
H
18
Ph
48 (96)
-
Ph
H
19
Ph
49 (83)
50 (98)
51 (99)
52 (99)
C2H4OH
tBu
3-Cl-C6H4
43a (62)
Ts (in the hydrazine)
-
(R’=H)
a The compound was identical with the one obtained from N1-tosyl-C-(2,3,4,6-tetra-O-benzoyl-β-
D-
glucopyranosyl)formamidrazone and the corresponding acid chloride.20
The different reactivity of the C=O and C=S moieties in the N-acyl-thioamides leaves not
much doubt about the regioselectivity of the above ring closing reactions, i. e. the more
nucleophilic terminal nitrogen of the substituted hydrazine reagent reacts with the more
electrophilic C=S group, it was found appropriate to prove this at least in one case. Thus,
nuclear Overhauser effects (NOE) were measured in isomeric triazoles 33 and 48 (Figure 1)
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ACCEPTED MANUSCRIPT
to show the vicinity of the Me and Ph groups in the former and that of the H-1 and Ph in the
latter.
CH3
OH
N
NOE
O
HO
HO
N
33
N
HO
CH3
OH
O
N
HO
HO
N
48
N
O
H
H
NOE
Figure 1. Evidence of the isomeric structures for 1,2,4-triazoles 33 and 48
The unprotected compounds 33-41 and 48-52 were assayed against rabbit muscle glycogen
phosphorylase b (RMGPb) as described before,35 however, none of them showed inhibition in
625 µM concentration. In our previous studies19,21 several 3-glucopyranosyl-5-substituted-
1,2,4-triazoles were found active against RMGPb in the submicromolar range. The good
inhibitory effect of those compounds was attributed to the hydrogen bond donor ability of the
heterocycle, a feature discussed in a recent review.18 In the context of structure-activity
relationships of GP inhibitors, the present results underline the importance of the H-bridge
formation since this possibility is absent in the trisubtituted 1,2,4-triazoles. Furthermore, the
additional substituent of the triazole ring may also impede binding of these molecules to the
active site of the enzyme.
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In conclusion, reactions of substituted hydrazines and sugar derived N-acyl-thioamide type
precursors facilitate versatile syntheses of 3-β-
glucopyranosyl-1,3-disubstituted-1,2,4-triazoles. The only limitation of the method is that in
the 3-β- -glucopyranosyl-1,5-disubstituted isomers no aromatic substituent can be introduced
D-glucopyranosyl-1,5-disubstituted- and 5-β-D-
D
in the 5-position due to facile desulfuration of the corresponding 2,6-anhydro-
aldonothioamide by aromatic acid chlorides.
Experimental
General Methods
Melting points were measured on a Kofler hot-stage and are uncorrected. Optical rotations
were determined with a Perkin-Elmer 241 polarimeter at rt. NMR spectra were recorded with
Bruker 360 (360/90 MHz for 1H/13C) or Bruker 400 (400/100 MHz for 1H/13C) spectrometers.
Chemical shifts are referenced to the internal TMS (1H), or to the residual solvent signals
(13C). Mass spectra were obtained by a Thermo Scientific LTQ XL instrument or by a Bruker
micrOTOF-Q instrument. TLC was performed on DC-Alurolle Kieselgel 60 F254 (Merck), and
the plates were visualised under UV light and by gentle heating (generally no spray reagent
was used but, if more intense charring was necessary, the plate was sprayed with the
following solution: abs. EtOH (95 mL), ccH2SO4 (5 mL) anisaldehyde (1 mL)). For column
chromatography Kieselgel 60 (Merck, particle size 0.063-0.200 mm) was used. MeCN and
CHCl3 were distilled from P4O10 and stored over 4 Å molecular sieves. Pyridine was distilled
from KOH and stored over KOH pellets. MeOH was purified by distillation after refluxing for
a couple of hours with magnesium turnings and iodine. Organic solutions were dried over
anhydrous MgSO4 and concentrated under diminished pressure at 40 ºC (water bath). Acid
chlorides, thioamides, hydrazine hydrate and hydrazinium acetate, substituted hydrazines
were purchased from Sigma-Aldrich. C-(2,3,4,6-tetra-O-benzoyl-β-D-
12

ACCEPTED MANUSCRIPT
glucopyranosyl)formamide25 (1) and C-(2,3,4,6-tetra-O-benzoyl-β-
D-
glucopyranosyl)thioformamide32 (11) were synthesized according to published procedures.
General procedure I for the acylation of C-(2,3,4,6-tetra-O-benzoyl-β-D-
glucopyranosyl)formamide.
To a solution of C-(2,3,4,6-tetra-O-benzoyl-β-D
-glucopyranosyl)formamide25 (1) in
anhydrous CHCl3 (10 mL/mmol) the corresponding acid chloride (5.0 equiv.) and pyridine
(5.0 equiv.) were added. The reaction mixture was stirred at rt and monitored by TLC (1:8
EtOAc/toluene). After complete conversion of 1 the mixture was diluted with CHCl3 (30 mL)
and extracted with NaHCO3 (2 × 10 mL) then with water (1 × 10 mL). The organic phase was
dried over MgSO4, concentrated under diminished pressure, and the crude product was
purified by column chromatography.
General procedure II for the preparation of N-acyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-
glucopyranosyl)thioformamides.
To a solution of the C-(2,3,4,6-tetra-O-benzoyl-β-D
-glucopyranosyl)thioformamide32 (11) in
anhydrous CHCl3 (10 mL/mmol) the corresponding acid chloride (1.5 equiv.) and pyridine
(1.5 equiv.) were added. The reaction mixture was stirred at rt and monitored by TLC (1:8
EtOAc/toluene). After complete conversion of 11 the mixture was diluted with CHCl3 (30
mL) and extracted with NaHCO3 (2 × 10 mL) then with water (1 × 10 mL). The organic phase
was dried over MgSO4, concentrated under diminished pressure, and the crude product was
purified by column chromatography.
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General procedure III for the preparation of N-(2,3,4,6-tetra-O-benzoyl-β-D-
glucopyranosylcarbonyl) thioamides.
C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)formic acid was boiled in SOCl2 (10
mL/mmol) for 2 hours, then the excess of SOCl2 was evaporated under reduced pressure.
Traces of the reagents were removed by repeated co-evaporations with anhydorus toluene.
The resulting acid chloride 1720 was dissolved in anhydrous CH3CN (15 mL/mmol), and the
solution of the corresponding thioamide (2.0 equiv.) and pyridine (2.0 equiv.) in anhydrous
CH3CN (15 mL/mmol) were added dropwise over 20 minutes. The reaction mixture was
stirred at rt. After complete conversion of 17 (monitored by TLC, 1:1 EtOAc/hexane, 12 h)
the solvent was removed and the residue was purified by column chromatography.
General procedure IV for the preparation of 1,5-disubstituted-3-(2’,3’,4’,6’-tetra-O-
benzoyl-β-
D
D
-glucopyranosyl)-1,2,4-triazoles and 1,3-disubstituted-5-(2’,3’,4’,6’-tetra-O-
benzoyl-β-
-glucopyranosyl)-1,2,4-triazoles.
To a solution of an N-acyl-thioamide 12-15, 18, or 19 in anhydrous pyridine (10 mL/mmol)
the corresponding hydrazine (1.2 equiv.) was added, and the reaction mixture was stirred at rt
for 2 h. After complete conversion of the starting material (monitored by TLC, 2:1
EtOAc/hexane) the solvent was removed and the residue was purified by column
chromatography.
General procedure V for the removal of O-acyl protecting groups by the Zemplén
protocol.
An O-acylated compound was dissolved in dry MeOH (5 mL/ 100 mg) and 1-2 drops of a 1
M methanolic NaOMe solution were added. The mixture was kept at rt and monitored by
TLC (3:7 MeOH/CHCl3). When the starting material was consumed the mixture was
14

ACCEPTED MANUSCRIPT
neutralised with a cation exchange resin Amberlyst 15 (H+ form) or with acetic acid, then the
resin was filtered off and the solvent removed. The residue was purified by column
chromatography.
Synthesis and characterization of the compounds
N-Acetyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)formamide (2)
Prepared from compound 1 (0.25 g, 0.40 mmol) and acetyl chloride (0.14 mL, 2.00 mmol)
according to general procedure I (reaction time: 12 h). Purified by column chromatography
(1:4 EtOAc/hexane) to give 0.14 g (51 %) white amorphous solid. Rf = 0.27 (1:2
1
EtOAc/hexane); [α]D ‒2 (c 0.58, CHCl3); H NMR (400 MHz, CDCl3) δ (ppm): 8.99 (1H, s,
NH), 8.06 (2H, dd, J = 8.2, 1.1 Hz, aromatics), 7.97–7.91 (4H, m, aromatics), 7.83 (2H, dd, J
= 8.2, 1.1 Hz, aromatics), 7.58–7.25 (12H, m, aromatics), 5.99 (1H, pseudo t, J = 9.2 Hz, H-2’
or H-3’ or H-4’), 5.75–5.66 (2H, m, H-2’ and/or H-3’ and/or H-4’), 4.72 (1H, dd, J = 12.5, 2.6
Hz, H-6’a ), 4.55 (1H, dd, J = 12.5, 5.3 Hz, H-6’b), 4.37 (1H, d, J = 9.5 Hz, H-1’), 4.27 (1H,
13
ddd, J = 9.6, 5.2, 2.7 Hz, H-5’), 2.37 (3H, s, CH3); C NMR (100 MHz, CDCl3) δ (ppm):
171.9, 166.4, 166.0, 165.7, 165.4, 165.2 (C=O), 133.7–128.5 (aromatics), 76.8, 76.5, 73.2,
69.8, 68.9 (C-1’–C-5’), 62.8 (C-6’), 25.4 (CH3). ESI-MS positive mode (m/z): [M+Na]+,
found 688.18; C37H31NNaO11 requires 688.180. Anal. Calcd for C37H31NO11: C, 66.76; H,
4.69; N, 2.10. Found: C, 66.88; H, 4.75; N, 2.08.
N-Benzoyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)formamide (3)
Prepared from compound 1 (0.25 g, 0.40 mmol) and benzoyl chloride (0.23 mL, 2.00 mmol)
according to general procedure I (reaction time: 3 d). Purified by column chromatography
(1:3 EtOAc/hexane) to give 0.08 g (26 %) white amorphous solid. Rf = 0.38 (1:1
15

ACCEPTED MANUSCRIPT
EtOAc/hexane); [α]D ‒1 (c 0.51, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 9.47 (1H, s,
NH), 8.01 (2H, dd, J = 8.2, 1.1 Hz, aromatics), 7.96–7.93 (3H, m, aromatics), 7.83 (3H, d, J =
8.1 Hz, aromatics), 7.56–7.26 (17H, m, aromatics), 6.00 (1H, pseudo t, J = 9.2 Hz, H-2’ or H-
3’ or H-4’), 5.84 (1H, pseudo t, J = 9.4 Hz, H-2’ or H-3’ or H-4’), 5.76 (1H, pseudo t, J = 9.5
Hz, H-2’ or H-3’ or H-4’), 4.78 (1H, dd, J = 12.5, 2.5 Hz, H-6’a ), 4.69 (1H, d, J = 9.5 Hz, H-
13
1’), 4.58 (1H, dd, J = 12.5, 5.3 Hz, H-6’b), 4.32 (1H, ddd, J = 10.0, 5.3, 2.5 Hz, H-5’); C
NMR (100 MHz, CDCl3) δ (ppm): 166.4, 165.8, 165.5, 165.3, 165.3, 164.7 (C=O), 133.8–
128.0 (aromatics), 76.9, 76.7, 73.6, 69.5, 68.9 (C-1’–C-5’), 62.5 (C-6’). ESI-MS positive
mode (m/z): calcd for C42H33NNaO11 ([M+Na]+): 750.195. Found: 750.19. Anal. Calcd for
C42H33NO11: C, 69.32; H, 4.57; N, 1.92. Found: C, 69.46; H, 4.47; N, 1.90.
N-(1-Naphthoyl)-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)formamide (4)
Prepared from compound 1 (0.20 g, 0.32 mmol) and naphthoyl chloride (0.24 mL, 1.6 mmol)
according to general procedure I (reaction time: 1 d). Purified by column chromatography
(1:1:3 EtOAc/toluene/hexane) to give 0.04 g (16 %) white amorphous solid. Rf = 0.42 (1:3:1
EtOAc/toluene/hexane); [α]D ‒4 (c 0.53, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29
(1H, s, NH), 8.33 (1H, d, J = 7.3 Hz, aromatics), 7.98–7.79 (9H, m, aromatics), 7.72 (1H, d, J
= 6.8 Hz, aromatics), 7.57–7.20 (16H, m, aromatics), 5.98 (1H, pseudo t, J = 9.2 Hz, H-2’ or
H-3’ or H-4’), 5.84 (1H, pseudo t, J = 9.4 Hz, H-2’ or H-3’ or H-4’), 5.71 (1H, pseudo t, J =
9.5 Hz, H-2’ or H-3’ or H-4’), 4.67 (2H, m, H-6’and H-1’), 4.52 (1H, dd, J = 12.4, 5.4 Hz, H-
6’b), 4.28 (1H, ddd, J = 10.1, 5.5, 2.6 Hz, H-5’); 13C NMR (90 MHz, CDCl3) δ (ppm): 166.8,
166.3, 165.8, 165.5, 165.3, 165.3 (C=O), 133.8–124.6 (aromatics), 76.9, 76.6, 73.6, 69.5, 68.9
(C-1’–C-5’), 62.6 (C-6’). ESI-MS positive mode (m/z): calcd for C46H35NNaO11 ([M+Na]+):
800.211. Found: 800.21. Anal. Calcd for C46H35NO11: C, 71.04; H, 4.54; N, 1.80. Found: C,
71.28; H, 4.60; N, 1.82.
16

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N,N-Diacetyl-C-(2,3,4,6-tetra-O-benzoyl-β-
D
-glucopyranosyl)formamide (5)
Prepared from compound 1 (0.25 g, 0.40 mmol) and acetyl chloride (0.14 mL, 2.00 mmol)
according to general procedure I (reaction time: 12 h). Purified by column chromatography
(1:4 EtOAc/hexane) to give 0.10 g (34 %) white amorphous solid. Rf = 0.33 (1:2
EtOAc/hexane); [α]D +80 (c 0.51, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 8.09 (2H, d,
J = 8.3 Hz, aromatics), 7.96–7.90 (4H, m, aromatics), 7.84 (2H, d, J = 8.4 Hz, aromatics),
7.60–7.25 (12H, m, aromatics), 6.00 (1H, pseudo t, J = 9.5 Hz, H-2’ or H-3’ or H-4’), 5.92
(1H, pseudo t, J = 9.3 Hz, H-2’ or H-3’ or H-4’), 5.69 (1H, pseudo t, J = 9.6 Hz, H-2’ or H-3’
or H-4’), 4.84 (1H, d, J = 9.6 Hz, H-1’), 4.67 (1H, dd, J = 12.6, 2.4 Hz, H-6’a ), 4.42 (1H, dd,
J = 12.6, 5.1 Hz, H-6’b), 4.16 (1H, ddd, J = 9.6, 5.1, 2.4 Hz, H-5’), 2.33 (6H, s, 2 × CH3); 13C
NMR (90 MHz, CDCl3) δ (ppm): 174.2, 174.2, 170.5, 166.1, 165.9, 165.2, 165.1 (C=O),
133.7–128.4 (aromatics), 77.1, 76.4, 74.2, 69.2, 68.7 (C-1’–C-5’), 62.7 (C-6’), 26.3 (2 ×
CH3). ESI-MS positive mode (m/z): calcd for C39H33NNaO12 ([M+Na]+): 730.190. Found:
730.19. Anal. Calcd for C39H33NO12: C, 66.19; H, 4.70; N, 1.98. Found: C, 66.32; H, 4.76; N,
1.93.
N,N-Dibenzoyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)formamide (6)
Prepared from compound 1 (0.25 g, 0.40 mmol) and benzoyl chloride (0.23 mL, 2.00 mmol)
according to general procedure I (reaction time: 3 d). Purified by column chromatography
(1:3 EtOAc/hexane) to give 0.01 g (26 %) white amorphous solid. Rf = 0.48 (1:1
EtOAc/hexane); [α]D +88 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 8.12 (1H, d,
J = 7.4 Hz, aromatics), 7.92–7.84 (7H, m, aromatics), 7.75 (3H, d, J = 7.5 Hz, aromatics),
7.48–7.24 (19H, m, aromatics), 6.13 (1H, pseudo t, J = 9.6 Hz, H-2’ or H-3’ or H-4’), 5.94
(1H, pseudo t, J = 9.4 Hz, H-2’ or H-3’ or H-4’), 5.76 (1H, pseudo t, J = 9.5 Hz, H-2’ or H-3’
17

ACCEPTED MANUSCRIPT
or H-4’), 5.11 (1H, d, J = 9.9 Hz, H-1’), 4.35 (1H, dd, J = 12.5, 2.3 Hz, H-6’b), 4.26–4.19
(2H, m, H-6’a and H-5’); 13C NMR (100 MHz, CDCl3) δ (ppm): 172.1, 1 72.1, 171.6, 166.0,
165.9, 165.2, 164.9 (C=O), 133.9–128.4 (aromatics), 77.1, 76.3, 74.5, 69.4, 68.6 (C-1’–C-5’),
62.6 (C-6’). ESI-MS positive mode (m/z): calcd for C49H37NNaO12 ([M+Na]+): 854.221.
Found: 854.22. Anal. Calcd for C49H37NO12: C, 70.75; H, 4.48; N, 1.68. Found: C, 70.99; H,
4.53; N, 1.61.
N,N-Bis-(1-naphthoyl)-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)formamide (7)
Prepared from compound 1 (0.20 g, 0.32 mmol) and naphthoyl chloride (0.24 mL, 1.6 mmol)
according to general procedure I (reaction time: 1 d). Purified by column chromatography
(1:1:3 Toluene/EtOAc/hexane) to give 0.05 g (15 %) white amorphous solid. Rf = 0.28 (3:1:1
1
Toluene/EtOAc/hexane); [α]D +44 (c 0.61, CHCl3); H NMR (400 MHz, CDCl3) δ (ppm):
8.14 (2H, d, J = 8.2 Hz, aromatics), 7.98–7.85 (8H, m, aromatics), 7.65 (2H, d, J = 7.7 Hz,
aromatics), 7.56–7.22 (18H, m, aromatics), 7.13 (2H, t, J = 7.7 Hz, aromatics), 6.97 (2H, t, J
= 7.7 Hz, aromatics), 6.28 (1H, pseudo t, J = 9.6 Hz, H-2’ or H-3’ or H-4’), 5.99 (1H, pseudo
t, J = 9.5 Hz, H-2’ or H-3’ or H-4’), 5.76 (1H, pseudo t, J = 9.7 Hz, H-2’ or H-3’ or H-4’),
5.19 (1H, d, J = 9.8 Hz, H-1’), 4.50 (1H, dd, J = 12.5, 2.0 Hz, H-6’a ), 4.35 (1H, dd, J = 12.5,
13
5.2 Hz, H-6’b), 4.25 (1H, ddd, J = 10.0, 5.3, 2.0 Hz, H-5’); C NMR (100 MHz, CDCl3) δ
(ppm): 171.7, 171.7, 171.7, 166.0, 166.0, 165.2, 165.0, (C=O), 133.7–124.2 (aromatics), 77.1,
77.0, 74.5, 69.7, 68.5 (C-1’–C-5’), 62.8 (C-6’). ESI-MS positive mode (m/z): calcd for
C57H41NNaO12 ([M+Na]+): 954.253. Found: 954.25. Anal. Calcd for C57H41NO12: C, 73.46;
H, 4.43; N, 1.50. Found: C, 73.60; H, 4.59; N, 1.45.
Acetone N2-(2,3,4,6-tetra-O-benzoyl-β-
D-glucopyranosylcarbonyl)hydrazone (10)
To a solution of imide 2 (0.10 g, 0.15 mmol) in pyridine was added hydrazine hydrate (9 µL,
18

ACCEPTED MANUSCRIPT
1.2 equiv., 0.18 mmol) and the reaction mixture was stirred at room temperature. After
disappearance of the starting material (3h, TLC, 1:1 Acetone/hexane) the solvent was
removed and the purification by column chromatography (1:3 Acetone/hexane) yielded 0.04 g
1
(39 %) yellow syrup. Rf = 0.26 (1:1 Acetone/hexane); [α]D ‒24 (c 0.29, CHCl3); H NMR
(400 MHz, CDCl3) δ (ppm): 8.07 (2H, dd, J = 8.2, 1.1 Hz, aromatics), 7.97–7.94 (4H, m,
aromatics), 7.83 (2H, dd, J = 8.2, 1.1 Hz, aromatics), 7.62–7.26 (12H, m, aromatics), 5.96
(1H, pseudo t, J = 9.2 Hz, H-2’ or H-3’ or H-4’), 5.74 (1H, pseudo t, J = 9.5 Hz, H-2’ or H-3’
or H-4’), 5.71 (1H, pseudo t, J = 9.5 Hz, H-2’ or H-3’ or H-4’), 4.83 (1H, dd, J = 12.5, 2.4 Hz,
H-6’a ), 4.53 (1H, dd, J = 12.5, 4.9 Hz, H-6’b), 4.44 (1H, d, J = 9.5 Hz, H-1’), 4.21 (1H, ddd,
J = 9.9, 4.9, 2.4 Hz, H-5’), 2.05 (3H, s, CH3), 1.85 (3H, s, CH3); 13C NMR (100 MHz, CDCl3)
δ (ppm): 166.3, 165.8, 165.5, 165.3, 162.4 (C=O), 157.3 (C=N), 133.8–128.3 (aromatics),
76.7, 76.3, 73.5, 70.2, 68.8 (C-1’–C-5’), 62.1 (C-6’), 25.6, 16.6 (2 × CH3). ESI-MS positive
mode (m/z): calcd for C38H34N2NaO10 ([M+Na]+): 701.211. Found: 701.21. Anal. Calcd for
C38H34N2O10: C, 67.25; H, 5.05; N, 4.13. Found: C, 67.54; H, 5.18; N, 4.05.
N-Acetyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)thioformamide (12)
Prepared from compound 11 (1.00 g, 1.56 mmol) and acetyl chloride (168 µL, 2.35 mmol)
according to general procedure II (reaction time: 1 h). Purified by column chromatography
(1:3 EtOAc/hexane) to give 0.96 g (91 %) red foam. Rf = 0.50 (1:1 EtOAc/hexane); [α]D =
+20 (c 0.53, CHCl3); 1H NMR (360 MHz, CDCl3) δ (ppm): 9.97 (1H, s, NH), 8.07 (2H, dd, J
= 8.2, 1.1 Hz, aromatics), 7.94–7.90 (4H, m, aromatics), 7.81 (2H, dd, J = 8.2, 1.1 Hz,
aromatics), 7.59–7.24 (12H, m, aromatics), 5.99 (1H, pseudo t, J = 9.3 Hz, H-2’ or H-3’ or H-
4’), 5.76 (1H, pseudo t, J = 9.6 Hz, H-2’ or H-3’ or H-4’), 5.68 (1H, pseudo t, J = 9.3 Hz, H-
2’ or H-3’ or H-4’), 4.88 (1H, d, J = 9.0 Hz, H-1’), 4.72 (1H, dd, J = 12.4, 2.6 Hz, H-6’a),
4.57 (1H, dd, J = 12.5, 5.3 Hz, H-6’b), 4.30 (1H, ddd, J = 9.8, 5.2, 2.7 Hz, H-5’), 2.42 (3H, s,
19

ACCEPTED MANUSCRIPT
13
CH3); C NMR (90 MHz, CDCl3) δ (ppm): 197.3 (C=S), 170.5, 166.4, 165.7, 165.3, 165.2
(C=O), 133.6–128.2 (aromatics), 84.9, 76.2, 73.4, 71.2, 69.0 (C-1’–C-5’), 62.9 (C-6’), 26.3
(CH3). ESI-MS negative mode (m/z): calcd for C37H30NO10S ([M-H]-): 680.159. Found:
680.08. Anal. Calcd for C37H31NO10S: C, 65.19; H, 4.58; N, 2.05; S, 4.70. Found: C, 65.33;
H, 4.77; N, 2.09; S, 4.81.
N-Acetoxyacetyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)thioformamide (13)
Prepared from compound 11 (1.20 g, 1.87 mmol) and acetoxyacetyl chloride (303 µL, 2.81
mmol) according to general procedure II (reaction time: 6 h). Purified by column
chromatography (1:3 EtOAc/hexane) to give 1.18 g (85 %) red foam. Rf = 0.25 (1:2
EtOAc/hexane); [α]D = +60 (c 0.45, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 10.22 (1H,
s, NH), 8.06 (2H, d, J = 7.2 Hz, aromatics), 7.93–7.90 (4H, m, aromatics), 7.81 (2H, d, J = 7.2
Hz, aromatics), 7.60–7.25 (12H, m, aromatics), 5.99 (1H, pseudo t, J = 9.3 Hz, H-2’ or H-3’
or H-4’), 5.74 (1H, pseudo t, J = 9.6 Hz, H-2’ or H-3’ or H-4’), 5.69 (1H, pseudo t, J = 9.3
Hz, H-2’ or H-3’ or H-4’), 5.04 (1H, d, J = 16.8 Hz, CH2 ), 4.89 (1H, d, J = 9.3 Hz, H-1’),
4.84 (1H, d, J = 16.8 Hz, CH2), 4.67 (1H, dd, J = 12.6, 2.6 Hz, H-6’a), 4.58 (1H, dd, J = 12.5,
13
5.6 Hz, H-6’b), 4.30 (1H, ddd, J = 9.6, 5.5, 2.5 Hz, H-5’), 2.15 (3H, s, CH3); C NMR (100
MHz, CDCl3) δ (ppm): 197.0 (C=S), 169.9, 167.3, 166.4, 165.7, 165.3, 165.2 (C=O), 133.8–
128.5 (aromatics), 84.6, 76.4, 73.4, 71.2, 69.0 (C-1’–C-5’), 64.4 (CH2), 63.0 (C-6’) 20.6
(CH3). ESI-MS negative mode (m/z): calcd for C39H32NO12S ([M-H]-): 738.165. Found:
738.18. Anal. Calcd for C39H33NO12S: C, 63.32; H, 4.50; N, 1.89; S, 4.33. Found: C, 63.67;
H, 4.74; N, 1.87; S, 4.41.
N-Pivaloyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)thioformamide (14)
Prepared from compound 11 (1.10 g, 1.72 mmol) and pivaloyl chloride (317 µL, 2.58 mmol)
20

ACCEPTED MANUSCRIPT
according to general procedure II (reaction time: 1 h). Purified by column chromatography
(1:4 Acetone/hexane) to give 1.11 g (90 %) red foam. Rf = 0.50 (1:2 Acetone/hexane); [α]D =
+42 (c 0.53, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 10.10 (1H, s, NH), 8.06 (2H, d, J
= 8.2 Hz, aromatics), 7.95–7.88 (4H, m, aromatics), 7.82 (2H, d, J = 8.2 Hz, aromatics), 7.62–
7.24 (12H, m, aromatics), 5.99 (1H, pseudo t, J = 9.3 Hz, H-2’ or H-3’ or H-4’), 5.80 (1H,
pseudo t, J = 9.6 Hz, H-2’ or H-3’ or H-4’), 5.71 (1H, pseudo t, J = 9.4 Hz, H-2’ or H-3’ or H-
4’), 5.04 (1H, d, J = 9.0 Hz, H-1’), 4.75 (1H, dd, J = 12.5, 2.4 Hz, H-6’a), 4.54 (1H, dd, J =
13
12.5, 4.7 Hz, H-6’b), 4.31 (1H, ddd, J = 9.8, 4.5, 2.5 Hz, H-5’), 1.20 (9H, s, C(CH3)3; C
NMR (100 MHz, CDCl3) δ (ppm): 196.8 (C=S), 175.1, 166.1, 165.7, 165.2, 165.1 (C=O),
133.8–128.4 (aromatics), 84.2, 76.2, 73.7, 71.3, 68.9 (C-1’–C-5’), 62.4 (C-6’), 40.9
(C(CH3)3), 26.9 (C(CH3)3). ESI-MS positive mode (m/z): calcd for C40H38NO10S ([M+H]+):
724.222. Found: 724.33. Anal. Calcd for C40H37NO10S: C, 66.38; H, 5.15; N, 1.94; S, 4.43.
Found: C, 66.52; H, 5.20; N, 1.90; S, 4.53.
N-Phenylacetyl-C-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)thioformamide (15)
Prepared from compound 11 (1.10 g, 1.72 mmol) and 2-phenylacetyl chloride (341 µL, 2.58
mmol) according to general procedure II (reaction time: 1d). Purified by column
chromatography (1:5 EtOAc/hexane) to give 0.90 g (69 %) red foam. Rf = 0.52 (1:1
EtOAc/hexane); [α]D = +15 (c 0.51, CHCl3); 1H NMR (360 MHz, CDCl3) δ (ppm): 9.88 (1H,
s, NH), 8.04 (2H, d, J = 7.9 Hz, aromatics), 7.92–7.89 (4H, m, aromatics), 7.80 (2H, d, J = 7.9
Hz, aromatics), 7.59–7.26 (17H, m, aromatics), 5.92 (1H, pseudo t, J = 9.3 Hz, H-2’ or H-3’
or H-4’), 5.57 (2H, pseudo t, J = 9.6 Hz, H-2’ and/or H-3’ and/or H-4’), 4.85 (1H, d, J = 8.6
Hz, H-1’), 4.55 (1H, dd, J = 12.3, 2.5 Hz, H-6’a), 4.37 (1H, dd, J = 12.4, 5.8 Hz, H-6’b), 4.22
(1H, ddd, J = 9.1, 5.6, 2.5 Hz, H-5’), 3.90 (2H, s, PhCH2); 13C NMR (90 MHz, CDCl3) δ
(ppm): 196.6 (C=S), 169.3, 166.4, 165.7, 165.3, 165.2 (C=O), 133.8–128.2 (aromatics), 84.4,
21

ACCEPTED MANUSCRIPT
76.2, 73.5, 71.2, 69.2 (C-1’–C-5’), 63.3 (C-6’) 45.3 (PhCH2). ESI-MS positive mode (m/z):
calcd for C43H36NO10S ([M+H]+): 758.206. Found: 758.25. Anal. Calcd for C43H35NO10S: C,
68.15; H, 4.66; N, 1.85; S, 4.23. Found: C, 68.33; H, 4.80; N, 1.90; S, 4.39.
N-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosylcarbonyl) thioacetamide (18)
Prepared from compound 17 (0.21 g, 0.32 mmol) and thioacetamide (0.02 g, 0.64 mmol)
according to general procedure III. Purified by column chromatography (1:3 EtOAc/hexane)
to give 0.12 g (58 %) yellow amorphous solid. Rf = 0.46 (1:2 EtOAc/hexane); [α]D ‒146 (c
0.38, CHCl3); 1H NMR (360 MHz, CDCl3) δ (ppm): 10.17 (1H, s, NH), 8.09–7.25 (20H, m,
aromatics), 6.00 (1H, pseudo t, J = 9.3 Hz, H-2’ or H-3’ or H-4’), 5.72 (1H, pseudo t, J = 9.3
Hz, H-2’ or H-3’ or H-4’), 5.70 (1H, pseudo t, J = 9.3 Hz, H-2’ or H-3’ or H-4’), 4.76 (1H,
dd, J = 12.5, 2.7 Hz, H-6’a), 4.57 (1H, dd, J = 12.5, 5.1 Hz, H-6’b), 4.37 (1H, d, J = 9.3 Hz,
H-1’), 4.28 (1H, ddd, J = 9.8, 5.1, 2.7 Hz, H-5’), 2.88 (3H, s, CH3); 13C NMR (90 MHz,
CDCl3) δ (ppm): 210.6 (C=S), 166.3, 165.7, 165.4, 165.2, 163.4 (C=O), 133.8–128.5
(aromatics), 76.6, 76.6, 73.0, 69.8, 68.8 (C-1’–C-5’), 62.5 (C-6’), 35.0 (CH3);. ESI-MS
positive mode (m/z): calcd for C37H31NNaO10S ([M+Na]+): 704.157. Found: 704.15. Anal.
Calcd for C37H31NO10S: C, 65.19; H, 4.58; N, 2.05; S, 4.70. Found: C, 65.41; H, 4.60; N,
2.03; S, 4.78.
N-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosylcarbonyl) thiobenzamide (19)
Prepared from compound 17 (0.21 g, 0.32 mmol) and thiobenzamide (0.04 g, 0.64 mmol)
according to general procedure III. Purified by column chromatography (1:3 EtOAc/hexane)
to give 0.17 g (71 %) red solid. Mp: 124–127 °C; Rf = 0.54 (1:2 EtOAc/hexane); [α]D ‒204 (c
0.36, CHCl3); 1H NMR (360 MHz, CDCl3) δ (ppm): 10.38 (1H, s, NH), 8.04–7.23 (25H, m,
aromatics), 6.00 (1H, pseudo t, J = 9.3 Hz, H-2’ or H-3’ or H-4’), 5.84 (1H, pseudo t, J = 9.3
22

ACCEPTED MANUSCRIPT
Hz, H-2’ or H-3’ or H-4’), 5.78 (1H, pseudo t, J = 9.3 Hz, H-2’ or H-3’ or H-4’), 4.78 (1H,
dd, J = 12.3, 1.8 Hz, H-6’a), 4.59 (1H, dd, J = 12.3, 5.0 Hz, H-6’b), 4.51 (1H, d, J = 9.3 Hz,
H-1’), 4.31 (1H, ddd, J = 9.6, 5.0, 1.8 Hz, H-5’); 13C NMR (90 MHz, CDCl3) δ (ppm): 202.2
(C=S), 166.3, 165.7, 165.3, 165.2, 163.5 (C=O), 141.9–127.5 (aromatics), 76.7, 76.6, 73.2,
69.6, 68.7 (C-1’–C-5’), 62.4 (C-6’). ESI-MS positive mode (m/z): calcd for C42H33NNaO10S
([M+Na]+): 766.172. Found: 766.17. Anal. Calcd for C42H33NO10S: C, 67.82; H, 4.47; N, 1.88
S, 4.31. Found: C, 67.98; H, 4.56; N, 1.90; S, 4.30.
3-(2′,3′,4′,6′-Tetra-O-benzoyl-β-D-glucopyranosyl)-5-methyl-1,2,4-triazole (20)
Prepared from compound 12 (0.10 g, 0.15 mmol) and hydrazinium acetate (16 mg, 0.18
mmol) according to general procedure IV. Purification by column chromatography (3:2
EtOAc/hexane) yielded 0.06 g (55 %) pale yellow amorphous solid.
Prepared from compound 18 (0.12 g, 0.18 mmol) and hydrazinium acetate (19 mg, 0.21
mmol) according to general procedure IV. Purification by column chromatography (3:2
EtOAc/hexane) yielded 0.07 g (57 %) pale yellow amorphous solid.
The compound characterization data are identical with those reported 20.
3-(2′,3′,4′,6′-Tetra-O-benzoyl-β-D-glucopyranosyl)-5-methyl-1-phenyl-1,2,4-triazole (21)
Prepared from compound 12 (0.35 g, 0.51 mmol) and phenylhydrazine (61 µL, 0.62 mmol)
according to general procedure IV. Purified by column chromatography (1:2 Acetone/hexane)
to give 0.27 g (71 %) pale yellow amorphous solid. Rf = 0.42 (1:1 Acetone/hexane); [α]D =
+12 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 8.00 (2H, dd, J = 8.3, 1.2 Hz,
aromatics), 7.92 (2H, dd, J = 8.3, 1.1 Hz, aromatics), 7.88–7.85 (4H, m, aromatics), 7.51–7.21
(17H, m, aromatics), 6.17 (1H, pseudo t, J = 9.7 Hz, H-2’ or H-3’ or H-4’), 6.07 (1H, pseudo
t, J = 9.5 Hz, H-2’ or H-3’ or H-4’), 5.88 (1H, pseudo t, J = 9.7 Hz, H-2’ or H-3’ or H-4’),
23

ACCEPTED MANUSCRIPT
5.08 (1H, d, J = 9.8 Hz, H-1’), 4.66 (1H, dd, J = 12.3, 3.1 Hz, H-6’a), 4.59 (1H, dd, J = 12.3,
13
5.0 Hz, H-6’b), 4.38 (1H, ddd, J = 9.7, 4.9, 3.2 Hz, H-5’), 2.46 (3H, s, CH3); C NMR (100
MHz, CDCl3) δ (ppm): 166.3, 165.9, 165.2, 164.7 (C=O), 158.5, 153.4 (triazole C-3, C-5),
137.1 (q, Ph), 133.4–124.5 (aromatics), 76.8, 74.7, 74.6, 71.5, 69.8 (C-1’–C-5’), 63.7 (C-6’),
13.3 (CH3). ESI-MS positive mode (m/z): calcd for C43H36N3O9 ([M+H]+): 738.245. Found:
738.25. Anal. Calcd for C43H35N3O9: C, 70.01; H, 4.78; N, 5.70. Found: C, 70.27; H, 4.90; N,
5.65.
3-(2′,3′,4′,6′-Tetra-O-benzoyl-β-D-glucopyranosyl)-1-(2-hydroxyethyl)-5-methyl-1,2,4-
triazole (22)
Prepared from compound 12 (0.33 g, 0.49 mmol) and 2-hydroxyethylhydrazine (40 µL, 0.58
mmol) according to general procedure IV. Purified by column chromatography (1:2
Acetone/hexane) to give 0.24 g (70 %) pale yellow amorphous solid. Rf = 0.15 (4:1
EtOAc/hexane); [α]D = +21 (c 0.55, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 8.00 (2H,
dd, J = 8.2, 1.0 Hz, aromatics), 7.92 (2H, dd, J = 8.2, 1.1 Hz, aromatics), 7.82–7.85 (4H, m,
aromatics), 7.51–7.23 (12H, m, aromatics), 6.09–5.99 (2H, m, H-2’ and/or H-3’ and/or H-4’),
5.85 (1H, pseudo t, J = 9.5 Hz, H-2’ or H-3’ or H-4’), 4.96 (1H, d, J = 9.3 Hz, H-1’), 4.65
(1H, dd, J = 12.3 3.0 Hz, H-6’a), 4.57 (1H, dd, J = 12.3, 5.1 Hz, H-6’b), 4.35 (1H, ddd, J =
9.6, 5.0, 3.2 Hz, H-5’), 4.00 (2H, t, J = 4.7 Hz, CH2), 3.95–3.90 (1H, m, CH2), 3.75–3.71 (1H,
m, CH2), 3.13 (1H, br s, OH), 2.34 (3H, s, CH3); 13C NMR (100 MHz, CDCl3) δ (ppm):
166.2, 165.9, 165.3, 165.2 (C=O), 158.0, 154.1 (triazole C-3, C-5), 133.4–128.3 (aromatics),
76.7, 74.7, 74.3, 72.1, 69.7 (C-1’–C-5’), 63.6 (C-6’), 60.6, 50.5 (2 × CH2), 11.9 (CH3). ESI-
MS positive mode (m/z): calcd for C39H36N3O10 ([M+H]+): 706.240. Found: 706.28. Anal.
Calcd for C39H35N3O10: C, 66.38; H, 5.00; N, 5.95. Found: C, 66.40; H, 5.09; N, 6.03.
24

ACCEPTED MANUSCRIPT
3-(2′,3′,4′,6′-Tetra-O-benzoyl-β-D-glucopyranosyl)-5-methyl-1-tosyl-1,2,4-triazole (23)
Prepared from compound 12 (0.10 g, 0.15 mmol) and tosylhydrazine (34 mg, 0.18 mmol)
according to general procedure IV. Purification by column chromatography (1:2
EtOAc/hexane) yielded 0.08 g (63%) pale yellow amorphous solid. The compound
characterization data are identical with those reported.20
5-(Acetoxymethyl)-3-(2′,3′,4′,6′-tetra-O-benzoyl-β-D-glucopyranosyl)-1,2,4-triazole (24)
Prepared from compound 13 (0.10 g, 0.14 mmol) hydrazinium acetate (15 mg, 0.16 mmol)
according to general procedure IV. Purification by column chromatography (1:2
EtOAc/hexane) yielded 0.09 g (92 %) pale yellow amorphous solid. The compound
characterization data are identical with those reported.20
5-(Acetoxymethyl)-3-(2′,3′,4′,6′-tetra-O-benzoyl-β-D-glucopyranosyl)-1-phenyl-1,2,4-
triazole (25)
Prepared from compound 13 (0.30 g, 0.41 mmol) and phenylhydrazine (48 µL, 0.49 mmol)
according to general procedure IV. Purified by column chromatography (1:2 EtOAc/hexane)
to give 0.22 g (70 %) pale yellow amorphous solid. Rf = 0.28 (1:1 EtOAc/hexane); [α]D = +4
1
(c 0.48, CHCl3); H NMR (400 MHz, CDCl3) δ (ppm): 8.01 (2H, dd, J = 8.2, 1.1 Hz,
aromatics), 7.92 (2H, dd, J = 8.2, 1.0, aromatics), 7.88–7.84 (4H, m, aromatics), 7.51–7.23
(17H, m, aromatics), 6.20 (1H, pseudo t, J = 9.7 Hz, H-2’ or H-3’ or H-4’), 6.09 (1H, pseudo
t, J = 9.5 Hz, H-2’ or H-3’ or H-4’), 5.90 (1H, pseudo t, J = 9.7 Hz, H-2’ or H-3’ or H-4’),
5.15 (1H, d, J = 9.8 Hz, H-1’), 5.12 (2H, s, CH2), 4.68 (1H, dd, J = 12.3, 3.0 Hz, H-6’a), 4.59
(1H, dd, J = 12.3, 5.0 Hz, H-6’b), 4.40 (1H, ddd, J = 9.7, 4.8, 3.1 Hz, H-5’), 1.96 (3H, s,
CH3); 13C NMR (100 MHz, CDCl3) δ (ppm): 169.8, 166.2, 165.9, 165.2, 164.6 (C=O), 159.2,
151.2 (triazole C-3, C-5), 136.5 (q, Ph), 133.4–124.6 (aromatics), 76.8, 74.5, 74.5, 71.5, 69.7
25

ACCEPTED MANUSCRIPT
(C-1’–C-5’), 63.5 (C-6’), 56.3 (CH2), 20.3 (CH3). ESI-MS positive mode (m/z): calcd for
C45H38N3O11 ([M+H]+): 796.251. Found: 796.25. Anal. Calcd for C45H37N3O11: C, 67.92; H,
4.69; N, 5.28. Found: C, 68.11; H, 4.82; N, 5.22.
3-(2′,3′,4′,6′-Tetra-O-benzoyl-β-D-glucopyranosyl)-1-(2-hydroxyethyl)-5-
(hydroxymethyl)-1,2,4-triazole (26)
Prepared from compound 13 (0.30 g, 0.41 mmol) and 2-hydroxyethylhydrazine (33 µL, 0.49
mmol) according to general procedure IV. Purified by column chromatography (1:2
EtOAc/hexane) to give 0.19 g (65 %) pale yellow amorphous solid. Rf = 0.45 (2:1
Acetone/hexane); [α]D = +6 (c 0.47, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 7.98 (2H,
dd, J = 8.2, 1.2 Hz, aromatics), 7.91 (2H, dd, J = 8.2, 1.2, aromatics), 7.84–7.79 (4H, m,
aromatics), 7.51–7.23 (12H , m, aromatics), 6.05 (1H, pseudo t, J = 9.5 Hz, H-2’ or H-3’ or
H-4’), 5.96 (1H, pseudo t, J = 9.6 Hz, H-2’ or H-3’ or H-4’), 5.85 (1H, pseudo t, J = 9.6 Hz,
H-2’ or H-3’ or H-4’), 4.98 (1H, d, J = 9.6 Hz, H-1’), 4.67–4.62 (1H, m, H-6’a), 4.62 (2H, s,
CH2), 4.53 (1H, dd, J = 12.3, 5.0 Hz, H-6’b), 4.34 (1H, ddd, J = 9.7, 4.8, 3.1 Hz, H-5’), 4.13
13
(2H, t, J = 4.6 Hz, CH2), 3.82–3.77 (1H, m, CH2), 3.71–3.65 (1H, m, CH2); C NMR (100
MHz, CDCl3) δ (ppm): 166.3, 165.9, 165.3, 165.3 (C=O), 158.0, 156.5 (triazole C-3, C-5),
133.5–128.3 (aromatics), 76.7, 74.4, 74.3, 71.9, 69.7 (C-1’–C-5’), 63.5 (C-6’), 60.6, 55.0,
51.1 (3 × CH2). ESI-MS negative mode (m/z): calcd for C41H38N3O13 ([M+OAc]-): 780.240.
Found: 780.27. Anal. Calcd for C39H35N3O11: C, 64.90; H, 4.89; N, 5.82. Found: C, 65.22; H,
4.99; N, 5.93.
3-(2′,3′,4′,6′-Tetra-O-benzoyl-β-D-glucopyranosyl)-5-(tert-butyl)-1,2,4-triazole (27)
Prepared from compound 14 (0.10 g, 0.14 mmol) hydrazinium acetate (15 mg, 0.17 mmol)
according to general procedure IV. Purification by column chromatography (1:2
26

ACCEPTED MANUSCRIPT
EtOAc/hexane) yielded 0.08g (79 %) pale yellow amorphous solid. The compound
characterization data are identical with those reported.20
3-(2′,3′,4′,6′-Tetra-O-benzoyl-β-D-glucopyranosyl)-5-(tert-butyl)-1-phenyl-1,2,4-triazole
(28)
Prepared from compound 14 (0.30 g, 0.41 mmol) and phenylhydrazine (48 µL, 0.49 mmol)
according to general procedure IV. Purified by column chromatography (1:4 EtOAc/hexane)
to give 0.21 g (66 %) pale yellow amorphous solid. Rf = 0.55 (1:1 EtOAc/hexane); [α]D = +9
1
(c 0.49, CHCl3); H NMR (400 MHz, CDCl3) δ (ppm): 8.01 (2H, dd, J = 8.2, 1.2 Hz,
aromatics), 7.94–7.85 (6H, m, aromatics), 7.51–7.25 (15H , m, aromatics), 7.15–7.13 (2H, m,
aromatics), 6.13 (1H, pseudo t, J = 9.7 Hz, H-2’ or H-3’ or H-4’), 6.05 (1H, pseudo t, J = 9.5
Hz, H-2’ or H-3’ or H-4’), 5.89 (1H, pseudo t, J = 9.6 Hz, H-2’ or H-3’ or H-4’), 5.05 (1H, d,
J = 9.7 Hz, H-1’), 4.66 (1H, dd, J = 12.3, 3.1 Hz,H-6’a), 4.59 (1H, dd, J = 12.3, 5.0 Hz, H-
13
6’b), 4.36 (1H, ddd, J = 9.6, 4.7, 3.3 Hz, H-5’), 1.09 (9H, s, C(CH3)3); C NMR (100 MHz,
CDCl3) δ (ppm): 166.3, 165.9, 165.3, 164.7 (C=O), 164.1, 157.1 (triazole C-3, C-5), 139.5 (q,
Ph), 133.4–127.9 (aromatics), 77.0, 74.9, 74.5, 72.1, 69.9 (C-1’–C-5’), 63.7 (C-6’), 33.5
(C(CH3)3), 29.7(C(CH3)3). ESI-MS positive mode (m/z): calcd for C46H42N3O9 ([M+H]+):
780.292. Found: 780.30. Anal. Calcd for C46H41N3O9: C, 70.85; H, 5.30; N, 5.39. Found: C,
70.91; H, 5.42; N, 5.34.
3-(2′,3′,4′,6′-Tetra-O-benzoyl-β-D-glucopyranosyl)-5-(tert-butyl)-1-(2-hydroxyethyl)-
1,2,4-triazole (29)
Prepared from compound 14 (0.30 g, 0.41 mmol) and 2-hydroxyethylhydrazine (33 µL, 0.49
mmol) according to general procedure IV. Purified by column chromatography (1:1
EtOAc/hexane) to give 0.21 g (66 %) white amorphous solid. Rf = 0.20 (1:1 EtOAc/hexane);
27

ACCEPTED MANUSCRIPT
[α]D = +29 (c 0.56, CHCl3); 1H NMR (400 MHz, CDCl3) δ (ppm): 8.01 (2H, dd, J = 8.2, 1.1
Hz, aromatics), 7.93 (2H, dd, J = 8.2, 1.0, aromatics), 7.88–7.80 (4H, m, aromatics), 7.52–
7.22 (12H, m, aromatics), 6.11 (1H, pseudo t, J = 9.6 Hz, H-2’ or H-3’ or H-4’), 6.06 (1H,
pseudo t, J = 9.6 Hz, H-2’ or H-3’ or H-4’), 5.87 (1H, pseudo t, J = 9.5 Hz, H-2’ or H-3’ or H-
4’), 5.00 (1H, d, J = 9.4 Hz, H-1’), 4.66 (1H, dd, J = 12.3, 2.9 Hz, H-6’a), 4.57 (1H, dd, J =
12.3, 5.1 Hz, H-6’b), 4.35 (1H, ddd, J = 9.6, 5.0, 3.2 Hz, H-5’), 4.32–4.27 (1H, m, CH2),
4.22–4.14 (2H, m, CH2), 3.91–3.85 (1H, m, CH2), 1.25 (9H, s, C(CH3)3 ); 13C NMR (100
MHz, CDCl3) δ (ppm): 166.2, 165.8, 165.4, 165.2 (C=O), 163.3, 156.7 (triazole C-3, C-5),
133.4–128.3 (aromatics), 76.8, 74.8, 74.2, 72.2, 69.8 (C-1’–C-5’), 63.6 (C-6’), 60.8, 52.6 (2 ×
CH2), 32.4 (C(CH3)3), 29.1 (C(CH3)3). ESI-MS positive mode (m/z): calcd for C42H42N3O10
([M+H]+): 748.287. Found: 748.35. Anal. Calcd for C42H41N3O10: C, 67.46; H, 5.53; N, 5.62.
Found: C, 67.78; H, 5.80; N, 5.79.
3-(2′,3′,4′,6′-Tetra-O-benzoyl-β-D-glucopyranosyl)-5-benzyl-1,2,4-triazole (30)
Prepared from compound 15 (0.30 g, 0.39 mmol) and hydrazinium acetate (44 mg, 0.48
mmol) according to general procedure IV. Purified by column chromatography (1:2
EtOAc/hexane) to give 0.22 g (75 %) white amorphous solid. Rf = 0.45 (2:1 Acetone/hexane);
1
[α]D = +15 (c 0.54, CHCl3); H NMR (360 MHz, CDCl3) δ (ppm): 7.94–7.90 (4H, m,
aromatics), 7.79–7.77 (4H, m, aromatics), 7.50–7.07 (17H, m, aromatics), 6.19 (1H, pseudo t,
J = 9.7 Hz, H-2’ or H-3’ or H-4’), 6.05 (1H, pseudo t, J = 9.5 Hz, H-2’ or H-3’ or H-4’), 5.91
(1H, pseudo t, J = 9.7 Hz, H-2’ or H-3’ or H-4’), 5.12 (1H, d, J = 9.9 Hz, H-1’), 4.56–4.54
(2H, m, H-6’a, H-6’b), 4.59 (1H, dd, J = 12.3, 5.0 Hz, H-6’b), 4.38–4.33 (1H, m, H-5’), 4.02
(2H, s, PhCH2); 13C NMR (90 MHz, CDCl3) δ (ppm): 166.4, 166.1, 165.3, 165.1 (C=O),
158.4, 157.8 (triazole C-3, C-5), 135.7 (q, Ph), 133.5–127.2 (aromatics), 76.9, 74.6, 74.4,
71.5, 69.8 (C-1’–C-5’), 63.6 (C-6’), 33.2 (PhCH2). ESI-MS negative mode (m/z): calcd for
28