Metal- and Phenol-Free Synthesis of Biaryl Ethers: Access to Dibenzobistriazolo-1,4,7-oxadiazonines and Vancomycin-Like Glyco-Macrocycles as Antibacterial Agents

Article abstract of DOI:10.1021/acs.joc.8b01631

An efficient synthesis of biaryl ethers, from electron-deficient aryl halides using NaH/DMSO under metal- and phenol-free conditions, has been achieved to access dibenzo-bistriazolo-1,4,7-oxadiazonines and vancomycin-like glyco-macrocycles. A 44-membered glyco-macrocycle showed promising activity against vancomycin-resistant Staphylococcus aureus (VRSA).

Full text of DOI:10.1021/acs.joc.8b01631

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Article
Metal and Phenol-Free Synthesis of Biaryl Ethers:
Access of Dibenzobistriazolo-1,4,7-oxadiazonines and
Vancomycin-like Glyco-Macrocycles as Antibacterial Agents
Kartikey Singh, Gaurav Sharma, MANJULIKA SHUKLA, Ruchir
Kant, Sidharth Chopra, Sanjeev K. Shukla, and Rama Pati Tripathi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01631 • Publication Date (Web): 20 Nov 2018
Downloaded from http://pubs.acs.org on November 21, 2018
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Metal and Phenol-Free Synthesis of Biaryl Ethers: Access of
Dibenzobistriazolo-1,4,7-oxadiazonines and Vancomycin-like Glyco-
Macrocycles as Antibacterial Agents
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Kartikey Singh,† Gaurav Sharma,‡,┴ Manjulika Shukla,§ Ruchir Kant,δ Sidharth Chopra,§ Sanjeev
K. Shukla,*,‡,┴ and Rama P. Tripathi*,†,┴,║
†Medicinal and Process Chemistry Division,
‡Sophisticated Analytical Instrument Facility,
§Microbiology Division,
δMolecular and Structural Biology Division,
CSIR-Central Drug Research Institute, BS-10/1, Sector 10, Jankipuram Extension, Sitapur Road,
Lucknow 226031, India.
┴Academy of Scientific and Innovative Research, Anusandhan Bhawan, New Delhi 110025, India
║Dean, National Institute of Pharmaceutical Education and Research Raebarely, New Transit
Campus, Bijnor Road, Sarojani Nagar Near CRPF Base Camp, Lucknow 226002, U.P., India
R1
R1
O
N
O
N
N
N
N
N
Metal free !
Phenol free !
X
O
O
O
NaH, 80 ºC
H2O-DMSO
O
R
R
R
O
O
N
N
N
N
O
O
O
O
N
N
O
X = F/Cl/ Br
R = Electron
R1 R1
Withdrawing
Group
N
N
N
N
N
N
O
R2
R2
ABSTRACT: An efficient synthesis of biaryl ethers, from electron-deficient aryl halides using
NaH/DMSO under metal and phenol free conditions, has been achieved to access dibenzo-
bistriazolo-1,4,7-oxadiazonines and vancomycin-like glyco-macrocycles. A 44-membered glyco-
macrocycle showed promising activity against vancomycin-resistant Staphylococcus aureus
(VRSA)
.
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INTRODUCTION
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Biaryl ethers constitute an important class of compounds owing a diverse range of
biological activities and also serve as a key intermediate for many drugs or drug-like
molecules.1-3 The biphenyl ether core is very common in a variety of naturally occurring
bioactive molecules such as cylindol A, B, piperazinomycin, marchantin C, bastadins, and
vancomycin (Figure 1).4,5 Consequently, a number of methods including classical
Ullmann reaction6-9, metal catalyzed reactions10-14, SNAr-based additions,15,16
intramolecular oxidative couplings17 and MW-assisted reactions18,19 have been used to
access these biaryl ethers. In spite of scanty reports for the synthesis of biphenyl ethers,
attempts are still being made to get them through economic and environment friendly
protocols. It is noteworthy that symmetrical and unsymmetrical biaryl ethers have their
own advantages either as materials or biologically active molecules.20,21 Although
synthesis of symmetrical biaryl ethers from phenol is well documented in the
literature22,23, yet their access from aromatic compounds other than phenol are rare.10,24
Biaryl ether formation has been observed during the reaction of 4-fluoro nitrobenzene and
p-methoxy anisidine in the presence of K2CO3/ DMSO under sonochemical or thermal
heating.25 However, access of biphenyl ethers from only one substrate are rare in
literature. Most of the methods to date advocate the use of a metal catalyst along with co-
catalyst during biphenyl ether synthesis.26,27 The use of metal catalyst has its limitation of
toxicity for the preparation of biologically active compounds. Herein, we report the
synthesis of a series of symmetrical biaryl ethers from activated halo benzenes in an
economically and precise way, few of the unsymmetrical biaryl ethers were also
synthesized where activated halo benzenes were used to get the desired product under
metal-free condition.
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Vancomycin and many other macrocyclic glycopeptides with biphenyl ether core in the
ring possess potent antibacterial activity.28 Out of curiosity, we were interested to see the
antibacterial activities of newly synthesized biphenyl ether-based macrocycles, where
triazole unit, a surrogate of the peptide bond is embedded in the ring. Triazole ring
provides a valuable replacement of peptide linkage in bioactive molecules because of its
physicochemical properties, in addition to their remarkable metabolic stability.29,30 Thus,
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we have developed a method for the synthesis of vancomycin-like macrocycle from the
azido functionalized biphenyls, and propargyloxy sugars using cyclodimerization via
Cu(I)-catalyzed 1,3-dipolar cycloaddition31 and evaluated their antibacterial activity. The
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1,2,3-triazole derivatives have potential utility in medicinal, chemistry32,33
,
supramolecular chemistry34 and synthetic chemistry.35-37 In this study biphenyl ethers
were synthesized from activated halo benzenes in one step under mild and economical
conditions. Synthesized biphenyl ethers were used as substrates for the access of biphenyl
ether incorporated dibenzo-1,4,7-oxadiazonines and 44-memebered glyco-macrocycles.
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OH
COOMe COOMe
COOMe COOMe
OH
O
HO
OH
NH2
O
O
H
N
H
O
H3C
N
OH
OH
OH
CH3
ii
O
i
OH
iii
O
Cylindol B
Cylindol A
O
Piperazinomycin
Cl OH
NOH
H
N
O
O
HO
OH
Br
O
OH
R4
Cl
O
O
O
O
H
H
N
H
N
N
O
O
O
Br
HO
N
H
N
N
OH
R3
R1
H
H
HO
R2
Br
O
O
NH
O
O
NH2
O
O
OH
N
OH
OH
H
NOH
HO
vi
Vancomycin
iv
v
Marchantin C
Bastadin 10 (R1, R3 = H; R2 =Br; R4 =OH)
Bastadin 5 (R1 = H; R2, R3 =Br; R4 =H)
Bastadin 6 (R1, R2, R3 = Br; R4 = H)
Figure 1. Selected examples of natural products with a biaryl and triaryl ether scaffold.
RESULTS AND DISCUSSION
During this work, 4-fluoronitrobenzene 1a was used as a model substrate to optimize the reaction
condition (Table 1). Treatment of 1a with NaH in DMSO as the solvent at ambient temperature
led to the formation of biphenyl ether (2a) in 6% yield (entry 6, Table 1). Interestingly, raising
the temperature to 80 ºC afforded the desired product (2a) in 72% yield (entry 8, Table 1).
Screening of other bases such as NaOH and KOH in the same solvent (DMSO), unfortunately,
gave the desired products (2a) and 4-nitrophenol (3a) (entries 8 and 9, Table 1) in of 40:56 and
45:52 ratio respectively. Use of other inorganic and organic bases such as NaHCO3, K2CO3,
Et3N and K3PO4 in DMSO led to the desired product (2a) in very low yields (entries 10-14,
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Table 1). However, use of KOBut /DMSO combination led to the formation of desired product
2a in 70% yield (entry 15, Table 1). Using acetonitrile as a solvent (entry 7, Table 1) generated
the desired product 2a only in 8% yield; it indicates the source of ether oxygen might be the
moisture. To justify the source of oxygen in the resulting biaryl ether, the reaction of 1a was
conducted on gram scale with an additional amount of 0.5 equiv. of water in the reaction mixture
under the above optimized condition to give the desired product 2a in 70% yield (entry 16, Table
1). Encouraged by the above initial success, we have investigated the scope of the methodology
using various halo benzenes.
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Table 1. Optimization conditions for synthesis of symmetrical biarylethersa
F
OH
O
Base
+
Solvent
Temp
O2N
NO2
NO2
NO2
1a
2a
3a
entry base solvent temp (ºC) time (h) yieldb (%)
(2a:3a)
water
toluene
DCE
80
80
80
rt
12
12
12
10
20
36
36
10
12
12
12
12
12
12
12
12
0:90
0:0
1
2
3
4
5
6
7
8
9
10
NaOH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaOH
KOH
0:0
THF
0:0
DMF
rt
0:0
DMSO
CH3CN
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
rt
6:0
80
80
80
80
80
80
80
80
80
80
8:0
72:0
40:56
45:52
10:0
20:0
0:0
11 NaHCO3
12 K2CO3
13
Et3N
2:0
14 K3PO4
15 KOBut
16c NaH
70:0
70:0
NaH &
17d
DMSO
80
16
68:08
NaOH
b
aReaction conditions: 1a (1.0 mmol), base (1.5 equiv.) heated in DMSO at 80 ºC, Isolated yield of pure
c
d
product, 1a (4.7 mmol), H2O (0.5 equiv), base (1.5 equiv.) heated in DMSO at 80 ºC, 1a (1.0 mmol),
NaH (0.75 equiv.), crushed NaOH (0.75 equiv.) heated in DMSO at 80 ºC.
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The reaction of the different nitro-substituted halo benzenes under the optimized reaction
condition NaH/DMSO at 80 ºC led to the formation of biaryl ethers (2a-2f) in good yield
(Scheme 1). The yields of the product in the reactions follows the order F> Br> Cl. The reaction
with 4-chloro-4’-fluorobutyrophenone (1e) in NaH/DMSO afforded cyclopropyl methanone
substituted symmetrical biaryl ether (2e) in 47% of yield, but 4-fluorophenol (1l), 1-(benzyloxy)-
4-fluorobenzene (1m), and fluorobenzene (1n) did not react to give any product in NaH in
DMSO, at 80 ºC (Scheme 1). It indicates the aromatic ring should be substituted with electron
withdrawing groups (EWG). The EWG of reactant also affect the yield of the reaction, as shown
in the Scheme 1, the reaction of 4-fluoronitrobenzene (1a) and 2-nitrofluorobenzene (1b) with
strong EWG in best optimized reaction condition led to the formation of symmetrical biaryl
ethers (2a and 2b) in good yields (72% and 76%) respectively. 2,4-Dinitrofluorobenzene (1c)
and 3,4-difluoronitrobenzene (1d) also reacted efficiently to form the corresponding symmetrical
biaryl ethers (2c and 2d) in (68% and 70%) yields respectively, the relatively low yield of the 2c
and 2d might be due to low reactivity of corresponding phenoxide intermediate for SNAr
reaction. The reaction with 4-chloro-4’-fluorobutyrophenone (1e) with relatively weak EWG led
to the formation of (2e) in only 47% of yield. 2-Chloro-4-fluoro-1-nitrobenzene (1i), 2-bromo-4-
fluoro-1-nitrobenzene (1j), 4-fluoro-2-methyl-1-nitrobenzene (1k) reacted smoothly to give the
respective biaryl ethers (2g, 2h, and 2i) in (74%, 68% and 54%) yields respectively, the yield of
the reaction follows the order Cl>Br>CH3.
Next, we turned our attention to access unsymmetrical biaryl ethers starting from differently
substituted aryl fluorides, and the results are shown in Scheme 2. The reaction of a mixture of 4-
fluoronitrobenzene (1a) and 2-nitrofluorobenzene (1b) in NaH/DMSO under the above
optimized reaction condition led to the formation of unsymmetrical biaryl ether (4a) as the major
product (35%) and the symmetrical biaryl ethers (2a and 2b) in low yields (10%, 14%).
Similarly, a mixture of 2,4-dinitrofluorobenzene (1c) and 3,4-difluoronitrobenzene (1d) led to
the formation of unsymmetrical biaryl ether (4b) in good yield (32%) compared to the
symmetrical biaryl ethers 2c and 2d (15%, 14%).
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Scheme 1. Synthesis of the various symmetrical biaryl ethers from aryl halides.
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X
O
product, yieldb (%)
H2O (0.5 equiv.)
aryl halide
R
DMSO,
1a, 1f, 1g
2a
2b
2c
4-NO2
, 72, 5, 50%
, 76%
R
R
R
NaH (1.5 equiv.),
80 °Ca
1b
1c
1d
1e
2-NO2
2a-2i
1a-1h
, 68%
2,4-dinitro
9
X
aryl halide
2d
2e
, 70%
2-F, 4-NO2
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1a-1e, 1h-1n
F
Cl
Br
, 47%
4-cyclopropanecarbonyl
2-NO2, 4,5-dichloro
2-Cl, 4-NO2
1f
1h
1i
2f
, 70%
1g
2g
, 74%
, 68%
, 54%
1j
2h
2-Br, 4-NO2
1k
1l
2i
2-CH3, 4-NO2
No reaction
No reaction
No reaction
4-OH
1m
1n
4-OCH2Ph
4-H
aReaction conditions: 1 Mmol of 1a-n 4 mL of DMSO was added 0.5 equiv. of H2O and 1.5 equiv of NaH
at 80 ºC and stirred the contents till completion (TLC). bIsolated yields
Scheme 2. Synthesis of the unsymmetrical biaryl ethers from different aryl fluorides.
F
F
H2O (0.5 equiv.),
NaH (1.5 equiv.)
O
O
O
+
+
+
DMSO, 80 °Ca
R1
R2
R2
R1
R1
R1
1a/1c
R2
R2
1b/1d
4ab
4bb
2ab
2bb
2db
, 35%
, 32%
, 10%
, 15%
, 14%
2cb
, 14%
comp.
no
1a, 2a
1b, 2b
1c, 2c
1d, 2d
R1
R2
-
2-NO2
4-NO2
-
2,4-NO2
-
-
2-F,4-NO2
2-NO2
4-NO2
2,4-NO2
4a
4b
2-F,4-NO2
aReaction conditions: 1 Mmol of 1a-c and 1b-d in 4 mL of DMSO was added 0.5 equiv. of H2O and 1.5
equiv of NaH at 80 ºC and stirred the contents till completion (TLC). bIsolated yields
A plausible reaction mechanism for the biphenyl ether formation is denoted in Scheme 3.
Reaction of 4-fluoronitrobenzene (1a) in situ led to the conversion of halo benzene into the
phenoxide anion (3a') in the presence of NaH. In situ generated phenoxide anion in reaction
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from halo benzene 1a further reacts with another mole of 4-fluoronitrobenzene (1a) lead to the
formation of respective biaryl ether 2a.
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Scheme 3. Plausible mechanism for the biaryl ether compounds
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NO2
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NaH + H2O*
H2
*
O
NaH
F
*OH
*
O2N
OH
O2N
O*
O2N
F
O2N
NO2
2a
3a
3a'
1a
Having the dinitro biaryl ethers (2a, 2b, and 2d) in our hand, the azide derivatives (6a,
6b, and 6c) were synthesized via the reduction of nitro groups followed by azidation.
Reduction was carried out by using Pd-C/H2 in methanol to give diamino biaryl ethers
(5a, 5b, and 5c), the latter on diazotization (NaNO2 in PTSA) and subsequent
nucleophilic substitution by azide using NaN3 to give the biazido derivatives 6a, 6b and
6c respectively with >90% yields (Scheme 4).
Finally to access the desired macrocycle from biphenyl ethers the preformed 1,2,5,6-di-O-
isopropylidene-3-O-propynyl-α-D-gluco-furanose 7a38 was reacted on CuAAC reactions
with the above synthesized diazidobiphenyl ether 6b to give a compound 8a with
bistriazole39,40 having 9-membered ring dibenzo-1,4,7-oxadiazonine scaffold as the major
product. The reactions were carried out at ambient temperature for 18 h in
water/acetonitrile (1:1,v/v) in presence of DIPEA and CuI (Scheme 5). Compound 8a has
axial chirality and results in a mixture of two diastereomers (8a and 8a') in 1:2 ratio
(HPLC). Both diastereomers 8a and 8a' were separated by HPLC and structure was
established by detail NMR study and ESI-MS analysis.
Scheme 4. Synthesis of the symmetrical biaryl ether azides from different biaryl ethers
p-TsOH (9 equiv.),
10% Pd/C
NaNO2 (9 equiv.),
(10 mol%),
O
O
O
NaN3 (3.2 equiv.)
H2, MeOH
N3
NO2
NH2
N3
6a
O2N
H2N
H2O,
2h, 96-98%
0.5h, 90-96%
2a/ 2b/ 2d
5a
5c
5b
(2-NH2)/
(4-NH2)/
(2-F, 4-NH2)
(4-NH2)/ 6b (2-NH2)/
(2-F, 4-NH2)
6c
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Scheme 5. Synthesis of the diastereomeric glycosyl dibenzo-bistriazolo-1,4,7-oxadiazonine.
5
6
7
8
9
O
O
(a)CuI (0.5 equiv.),
DIPEA (1 equiv.)
or
(b)CuI (1 equiv.),
DIPEA (2 equiv.)
O
O
N
O
N
O
N
O
N
O
O
N
N
N
N
O
N
O
O
O
N
N
N
O
O
O
O
O
O
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O
CH3CN-H2O
(1:1), rta
O
N3
N3
O
O
O
O
6b
7a
O
O
O
O
O
O
O
O
, 58 % (d.r. 1:2)c, (method a)
80 % (d.r. 1:2)c, (method b)
8ab
9b, 34 % (method a)
14 % (method b)
aReaction conditions: 0.5 or 1 equiv of CuI and 1 or 2 equiv of DIPEA was added to 6b (1 mmol)
and 7a (2 mmol) in 5 mL of CH3CN-H2O (1:1, v/v) and stirred the contents at rt. bIsolated yields.
cThe ratio was determined by HPLC.
Similarly, the reaction of 6b with another preformed glycosyl alkyne 7b under the
optimized condition led to afford 8b (Table 2, entry 2). The atropisomeric
stereochemistry of the bipentyl dibenzo-bistriazolo-1,4,7-oxadiazonine 8c was proven by
using single-crystal X-ray analysis (Figure 2). Rotation around the two rings of
bistriazole unit is highly hindered and fixed by cyclic structure hence the enantiomeric
forms do not interconvert at ambient temperature.
Finally, we attempted the synthesis of our planned macrocycle with well defined chiral
centers. Thus, preformed 1,2-O-isopropylidene-3,5-di-O-propynyl-α-D-xylo-furanose
7d38 was reacted with the above diazidobiphenyl ether 6b to give a polycyclic compound
8d (98 %, HPLC) having an 11-membered and 9-membered rings via (3+2) CuAAC in
oxidative cyclization with bistriazole axial chiral center (Scheme 6).
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Table 2. Syntheses of dibenzo-bistriazolo-1,4,7-oxadiazonines
5
6
7
8
9
O
CuI (1 equiv.),
DIPEA (2 equiv.)
R1
N
N
CH3CN-H2O
(1:1), rta
O
N
N
N3
N3
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R1 R1
7a-7c
6b
8
entry comp.
R1
O
yieldb (%)
80 (1:2)c
O
8a, 8a'
1
O
O
O
O
AcO
AcO
O
O
O
8b
8c
2
3
90
95
AcO
OAc
aReaction conditions: 1 equiv. of CuI and 2 equiv. of DIPEA was added to 6b (1 mmol) and 7a-c
b
c
(2 mmol) in 5 mL of CH3CN-H2O (1:1, v/v) and stirred the contents at rt. Isolated yields. The
ratio was determined by 1H NMR.
Figure 2. ORTEP diagram drawn with 10% ellipsoid probability for non-H atoms
determined at 293 K and representation from single-crystal X-ray analysis of 8c
Scheme 6. Synthesis of the polycyclic glyco-fused dibenzo-bistriazolo-1,4,7-
oxadiazonine
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2
3
4
O
5
6
7
8
N3
N3
N
O
N
O
O
O
CuI (1 equiv.),
DIPEA (2 equiv.)
N
N
O
O
N
N
O
CH3CN-H2O
(1:1)
O
7d
6b
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
26
27
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
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59
60
O
O
isolated 14%
O
8d
Reaction conditions: 1 equiv. of CuI and 2 equiv. of DIPEA was added to 6b (1 mmol) and 7d (1 mmol)
in 5 mL of CH3CN-H2O (1:1, v/v) and stirred the contents at rt.
Structure of compound 8d was confirmed by various 1D (1H, 13C, and DEPT), 2D (COSY,
TOCSY, NOESY, HSQC and HMBC) NMR experiments and ESI-MS analysis. H-3, H-4, H-5
& H-6 in ring A were forming one spin system and H-3′, H-4′, H-5′ & H-6′ in ring B forming
other spin system established with the help of COSY. NOESY helped in establishing spatial
correlation. As reported earlier, in 4,5-unsubstituted triazole derivatives C-4 and C-5 appeared at
~132 and ~123 ppm respectively, while in 4-substituted triazole derivatives C-4 appeared around
141-146 ppm.41 We have assigned the triazole carbons with the help of HMBC correlation.
HMBC correlation of H-9 with C-7 (124.9 ppm) & C-8 (146.8 ppm) and H-9′ with C-7′ (125.1
ppm) & C-8′ (147.7 ppm) and these chemical shift values are in good accordance with reported
values (Figure 3).41 Further DEPT analysis revealed that C-7 and C-7′ are quaternary carbons
and supported the bond formation between C-7 and C-7′.
5
6
6'
5'
O
4
B
4'
A
1
1'
2
3
2'
3'
N
N
N
7
7'
N
N
N
8
8'
9
9'
O
O
5''
4''
3''
2''
nOe correlation
O
HMBC correlation
O
1''
O
7''
8''
6''
8d
Figure 3. Key HMBC and NOESY correlations of 8d
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The reaction of 6a and 7d with CuAAC reaction condition gave an inseparable mixture of
two 44-membered regioisomeric macrocycles 10a and 11 in almost equal ratio as
1
13
evidenced by H & C-NMR spectroscopy and supported by ESI-HRMS data (Scheme
7).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 7. Synthesis of the regioisomeric glyco-macrocycle 10a and 11 (isomeric
mixture)
O
O
CuI (0.5 equiv.),
DIPEA (1 equiv.)
O
O
10a + 11
O
N3
N3
O
CH3CN-H2O
(1:1)
12%
7d
6a
O
N
O
N
N
N
N
O
N
O
N
N
N
N
N
O
O
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
O
N
N
N
N
N
N
N
N
N
N
N
O
O
10a
11
Reaction conditions: CuI (50 mol%) and 1 equiv. of DIPEA was added to 6a (1 mmol) and 7d (1 mmol)
in 5 mL of CH3CN-H2O (1:1, v/v) and stirred the contents at 30 ºC, 48 h.
Next, we turned out our attention towards the selective synthesis of 44-membered macrocycles
(10a, 10b) in a linear sequence. To get the desired linear intermediate 12a and 12b, 1,2,5,6-di-O-
isopropylidene-3-O-propynyl-α-D-gluco-furanose (7a) was used as the substrate. CuAAC
reactions in t-BuOH/H2O (1:1) were carried out with CuSO4.5H2O (10 mol%), and sodium
ascorbate (20 mol%) at ambient temperature to give the 12a and 12b. Cleavage of the acetonide
protecting group of 12a in 75% AcOH followed by oxidation with NaIO4 and reduction with
NaBH4 resulted in the intermediate 13. The latter (13) on reaction with propargyl bromide in the
presence of NaH in dry THF gave an intermediate 14 in of 84% yield. Having the biazide (6a
and 6c) and linear bialkyne intermediate 14 in our hands, we carried out the CuAAC reaction in
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water/acetonitrile (1:1, v/v) in the presence of DIPEA and CuI to get the respective 44-
5
6
membered macrocycle (10a, 10b) in good yields (16 and 18% respectively) (Scheme 8).
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Synthesis of the glyco-macrocycles 10a and 10b.
R1
R1
O
O
N
O
N
N
N
O
N
N
N
O
N
O
O
N
N
N
N
O
b
a
O
O
6a/ 6c
O
O
O
O
O
O
O
O
O
O
O
O
7a
O
HO
O
O
O
OH
13
(70 %)
O
O
O
12a (98 %)/ 12b (96 %)
N
N
O
N
N
N
O
N
N
O
N
N
N
N
N
R1
R1
O
O
O
O
O
O
c
d
O
O
O
O
N3
N3
O
O
O
O
6a/ 6c
O
O
O
O
O
N
N
N
N
N
N
R1
H
comp.
14
(84 %)
O
6a, 12a, 10a, 13
6c, 12b, 10b
R1
10b
R1
10a
F
(16 %)/
(18 %)
Reaction conditions: (a) CuSO4 (10 mol%), sodium ascorbate (20 mol%), tert-BuOH-H2O (1:1),
30 ºC, 3-4 h (b) (i) AcOH 75%, 10-12 h (ii) NaIO4, MeOH, 0 ºC-rt, 4 h (iii) NaBH4, MeOH, 0 ºC-
rt, 4 h (c) NaH, THF, propargyl bromide, TBAB, 0 ºC-rt, 6 h (d) CuI (50 mol%), DIPEA (1
equiv.), CH3CN-H2O (1:1), 30 ºC, 48 h
The chemical shift assignments of synthesized glyco-macrocycle 10b were carried out with the
help of 1D (1H, 13C, and DEPT), 2D (COSY, TOCSY, NOESY, HSQC and HMBC) NMR
experiments. COSY and TOCSY correlations established three coupled systems such as sugar
ring, H-2´, H-5´ & H-6´ in ring B and H-2´´,6´´ & H-3´´,5´´ in ring-D or half part of the
molecule, since it is C-2 symmetric. HMBC correlation of CH2-6 to C-5 and C-8 showed the
connectivity of triazole ring A with the sugar ring. While NOESY correlation of H-2´´ to H-11
showed proximity of these protons in the space and supported the linkage between triazole
moiety and ring-D and one more important NOESY correlation between H-6´ and H-8 suggested
the linkage between ring A and ring B (Figure 4). This molecule is C-2 symmetrical hence the
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9
1,4-regioselectivity during cycloaddition reaction was also evidenced on the basis of chemical
shifts of triazolyl H-8 (δ 8.06 ppm) and C-7 and C-8 (δ 145.9 and 121.2 ppm respectively) in
ring A and triazolyl H-11 (δ 7.99 ppm) and C-10 and C-11 (δ 145.2 and 121.4 ppm respectively)
in ring C.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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42
43
44
45
46
47
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50
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53
54
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57
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59
60
5''
5''
O
6''
6''
4''
3''
4''
3''
D
N
N
C
N
1''
N
1''
2''
N
2''
N
10
9
11
11
10
9
O
3
O
3
O
12
O
2
13
14
13
2
O
12
O
4
4
5
O
1
5
14
O
1
O
7
O
6
6
8
8
7
N
A
6'
6'
N
N
1'
2'
N
5'
4'
5'
N
N
1'
2'
B
4'
O
3'
3'
nOe correlation
HMBC correlation
F
F
Figure 4. Key HMBC and NOESY correlations of 10b
Dibenzo-bistriazolo-1,4,7-oxadiazonines (8a, 8a', 8b, 8c and 8d), biaryl ether triazole-
linked linear glycohybrids (9, 12a, 12b, 13 and 14) and macrocycles (10a, 10b) were
screened for the antibacterial activity against ESKAPE pathogen panel. Compounds
belongs to compound 8 and linear glycohybrids (9, 12a, 12b, 13 and 14) were found to be
inactive at 64 µg/mL while the 44-membered macrocycles (10a, 10b) displayed activity
against Staphylococcus aureus. Glyco-macrocycle 10a showed activity at higher
concentration (MIC = 64 µg/mL) while 10b showed promising activity (MIC =16 µg/mL)
against S. aureus. The MIC of 10b was determined against a clinical multi-drug resistant
MRSA and VRSA strain panel where 10b exhibited potent activity (MIC=8-16 μg/mL)
(Table 3). In addition, 10b was found to be non-cytotoxic (CC50=>160 µg/mL) against
Vero cells, with a selective index of >10. In comparison to 8, 9, 12, 13 and 14, 44-
membered macrocycle with two symmetrical biaryl ether motifs is active against S.
aureus while the macrocycle is having a fluoro substituent demonstrate promising activity
against MRSA and VRSA strains. It is very interesting to note that compound 10b
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exhibits activity against MDR strains and is able to escape currently existing drug-
resistance mechanisms, indicating a new mechanism of action.
7
8
Table 3. MIC values (μg/mL) of glyco-macrocycle 10b for various VRSA and MRSA
9
strains
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Van
No.
Strains
Met Van Lev 10b No.
Strains
Met
Lev 10b
S. aureus
ATCC 29213
1
1
1
<0.5
16
10
NR-119
>64
1
32
8
2
3
4
NR-129
NR-192
NR-198
>64
>64
>64
1
1
1
<0.5
8
16
8
11
12
13
VRSA-1
VRSA-4
VRSA-12
>64 >64 >64
>64 >64 >64
16
16
16
32
8
>64 >64
32
E. coli
ATCC 25922
5
6
7
NR-191
NR-193
NR-186
>64
>64
>64
1
1
1
32
32
8
16
8
14
15
16
17
-
-
-
-
-
-
-
-
<0.5 >64
K. pneumoniae
BAA-1705
64
8
>64
>64
>64
A. baumannii
BAA-1605
8
P. aeruginosa
ATCC 25923
8
9
NR-100
NR-194
>64
>64
1
1
<0.5
16
0.5
<0.5 >64
Van-Vancomycin, Met-Methicillin, Lev-Levofloxacin
CONCLUSIONS
In Summary, we have reported here a simple, metal and phenol free, mild and efficient method
for the synthesis of the symmetrical and unsymmetrical biaryl ethers. Synthetic application of
synthesized symmetrical biaryl ethers has been explored to access functionalized biaryl ether-
based small cyclic molecules with sugar as glyco-macrocycles. The synthesized 44-membered
vancomycin-like macrocycle showed potent antibacterial activity against MRSA and VRSA and
can escape currently existing drug-resistance mechanisms, indicating a new mechanism of
action. To overcome the challenge, simple accesses of biaryl ether incorporated glyco-
macrocycle with improved activity against VRSA are under progress.
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EXPERIMENTAL SECTION
General methods
7
8
9
Commercially available reagent grade chemicals were used as received. All reactions were
performed in oven-dried glassware. Thin layer chromatography (TLC) was carried out on
aluminium sheets coated with silica gel 60F254 (Merck, 1.05554) and the spots were visualized
with UV light at 254 nm or by staining with aqueous basic potassium permanganate. High-
performance liquid chromatography (HPLC) was carried out on the Agilent-1200 instrument
using X-BRIDGE C-18 150×4.6mm 5µ column. Gravity column chromatography was performed
using silica gel (Merck, 60A, 230-400 Mesh).1H and 13C NMR were recorded on Bruker 300 and
400 MHz spectrometers in CDCl3, CDCl3+CCl4, and DMSO-d6 as a solvent, using TMS or
residual solvent signal as an internal reference standard. Chemical shifts are given in ppm and
coupling constant (J) is measured in Hz. Abbreviation used to report multiplicities are as
follows: singlet (s), doublet (d), triplet (t), doublet of doublets (dd), triplet of doublets (td),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
28
29
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31
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
doublet of doublet of doublets (ddd) and multiplet (m). In cases of known compounds, their H
13
and C NMR values were compared with the literature values. The ESI-MS was recorded on
ION TRAP LCQ ADVANTAGE MAX mass spectrometer of Thermo Electron Corporation, and
HRMS spectra were performed using a mass spectrometer Q-TOF (Agilent 6520).
General procedure for preparation of symmetrical biaryl ethers (2a-2f):
To a stirring solution of NaH (1.5 equiv.) in DMSO (5 mL), substituted aryl halide (1 equiv.)
was slowly added at ambient temperature. After 10 min 0.5 equiv. H2O was added slowly in the
reaction mixture and temperature was raised to 80 ºC and stirring continued tills the
disappearance of the starting aryl halide. The reaction mixture was extracted with ethyl acetate
and washed with water, organic layer dried over Na2SO4 and solvent evaporated under reduced
pressure to give a crude mass, which was purified by column chromatography using SiO2 (60-
120 mesh) and gradient of EtOAc/hexane as eluent to give title compounds 2a-2f.
Bis(4-nitrophenyl)ether (2a).18 It was obtained by the reaction of 1a (0.2 mL, 1.88 mmol), NaH
1
(67 mg, 2.82 mmol) in DMSO in 72% yield (174 mg) as yellow solid; m. p. 140-142 ºC. H
NMR (400 MHz, CDCl3+CCl4) δ 8.32 (4H, d, J = 9.2 Hz, Ar-H), 7.18 (4H, d, J = 9.1 Hz, Ar-H);
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13C NMR (100 MHz, CDCl3+CCl4) δ 160.5 (Ar-C), 144.3 (Ar-C), 126.1 (Ar-C), 119.1 (Ar-C);
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H9N2O5 261.0506; Found 261.0536.
7
8
9
Bis(2-nitrophenyl)ether (2b).10 It was obtained by the reaction of 1b (0.2 mL, 1.89 mmol), NaH
(66 mg, 2.83 mmol) in DMSO in 72% yield (176 mg) as white solid; m. p. 112-114 ºC. 1H NMR
(400 MHz, CDCl3+CCl4) δ 8.04 (2H, dd, J1= 8.2, J2= 1.6 Hz, Ar-H), 7.58-7.56 (2H, m, Ar-H),
7.33-7.29 (2H,m, Ar-H), 7.06 (2H, dd, J1= 8.3, J2= 1.2 Hz, Ar-H); 13C NMR (100 MHz,
CDCl3+CCl4) δ 149.2 (Ar-C), 141.2 (Ar-C), 134.6 (Ar-C), 126.1 (Ar-C), 124.7 (Ar-C), 120.9
(Ar-C); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H9N2O5 261.0506; Found 261.0556.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Bis(2,4-dinitrophenyl)ether (2c).42 It was obtained by the reaction of 1c (0.2 mL, 1.57 mmol),
NaH (56 mg, 2.36 mmol) in DMSO in 68.8% yield (190 mg) as yellow solid; m. p. 192-194 ºC,
Lit. m. p. 194-195 ºC.43 1H NMR (400 MHz, CDCl3+CCl4+DMSO-d6) δ 8.96 (2H, d, J= 2.8 Hz,
13
Ar-H), 8.58 (2H, dd, J1= 9.1, J2= 2.8 Hz, Ar-H), 7.65 (2H, d, J= 9.2 Hz, Ar-H); C NMR (100
MHz, CDCl3+CCl4+DMSO-d6): δ 150.3 (Ar-C), 144.2 (Ar-C), 138.7 (Ar-C), 128.6 (Ar-C),
120.9 (Ar-C), 120.7 (Ar-C); HRMS (ESI-TOF) m/z: [M-H]- Calcd for C12H5N4O9 349.0062;
Found 348.9331.
Bis(2-fluoro-4-nitrophenyl)ether (2d).10 It was obtained by the reaction of 1d (0.2 mL, 1.80
mmol), NaH (65 mg, 2.70 mmol) in DMSO in 72.3% yield (194 mg) as yellow solid; m. p. 102-
104 ºC, Lit. m. p. 103-104 ºC.44 1H NMR (400 MHz, CDCl3) δ 8.15 (2H, dd, J1= 9.9, J2= 2.6 Hz,
13
Ar-H), 8.12-8.08 (2H, m, Ar-H), 7.19 (2H, t, J= 8.2 Hz, Ar-H); C NMR (75 MHz, CDCl3) δ
1
2
3
3
152.6 (d, JCF = 255.6 Hz), 148.4 (d, JCF = 11.3 Hz), 144.7 (d, JCF = 6.9 Hz), 121.0 (d, JCF
=
2
3.8 Hz), 120.2 (Ar-C), 113.9 (d, JCF = 22.8 Hz); HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C12H5F2N2O5 295.0172; Found 295.0055.
Bis(4-cyclopropylmethanonephenyl)ether (2e). It was obtained by the reaction of 1e (0.2 mL,
1.21 mmol) and NaH (73 mg, 3.04 mmol) in DMSO in 47% yield (87 mg) as white solid; m. p.
1
110-112 ºC. H NMR (400 MHz, CDCl3) δ 8.05 (4H, d, J= 8.8 Hz, Ar-H), 7.11 (4H, d, J= 8.8
Hz, Ar-H), 2.67-2.61 (2H, m), 1.26-1.23 (4H, m), 1.06-1.02 (4H, m); 13C NMR (100 MHz,
CDCl3): δ 199.1 (C=O), 160.0 (Ar-C), 133.8 (Ar-C), 130.3 (Ar-C), 118.7 (Ar-C), 16.9 (CH),
11.5 (CH2). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C20H19O3 307.1329; Found 307.1327.
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Bis(4,5-dichloro-2-nitrophenyl)ether (2f). It was obtained by the reaction of 1h (0.2 mL, 0.76
5
6
7
8
mmol), NaH (27 mg, 1.14 mmol) in DMSO (1 mL) in 70% yield (210 mg) as yellow solid; m. p.
1
13
172-174 ºC. H NMR (400 MHz, CDCl3) δ 8.23 (2H, s, Ar-H), 7.18 (2H, s, Ar-H); C NMR
(100 MHz, CDCl3) δ 147.3 (Ar-C), 139.8 (Ar-C), 139.4 (Ar-C), 129.9 (Ar-C), 127.9 (Ar-C);
HRMS (ESI-TOF) m/z: [M-H]- Calcd for C12H3Cl4N2O5 394.8802; Found 394.8020.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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Bis(2-chloro-4-nitrophenyl) (2g).10 It was obtained by the reaction of 1i (200 mg, 1.13 mmol),
NaH (41 mg, 1.70 mmol) in DMSO (1 mL) in 74% yield (138 mg) as white solid; m. p. 154-156
1
ºC. H NMR (400 MHz, CDCl3) δ 8.44 (2H, d, J= 2.6 Hz, Ar-H), 8.17 (2H, dd, J1= 9.0 Hz, J2=
13
2.7 Hz, Ar-H), 7.02 (2H, d, J= 9.0 Hz, Ar-H); C NMR (100 MHz, CDCl3) δ 155.9 (Ar-C),
144.6 (Ar-C), 127.0 (Ar-C), 126.3 (Ar-C), 123.9 (Ar-C), 119.3 (Ar-C); HRMS (ESI-TOF) m/z:
[M-H]- Calcd for C12H5Cl2N2O5 326.9581; Found 326.9574.
Bis(2-bromo-4-nitrophenyl) (2h).10 It was obtained by the reaction of 1j (200 mg, 0.90 mmol),
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NaH (21 mg, 1.36 mmol) in DMSO (1 mL) in 68% yield (128 mg) as yellow solid; H NMR
(400 MHz, CDCl3) δ 8.60 (2H, d, J= 2.4 Hz, Ar-H), 8.21 (2H, dd, J1= 8.9 Hz, J2= 2.5 Hz, Ar-H),
6.99 (2H, d, J= 8.9 Hz, Ar-H); 13C NMR (100 MHz, CDCl3) δ 157.1 (Ar-C), 144.8 (Ar-C), 130.1
(Ar-C), 124.6 (Ar-C), 119.2 (Ar-C), 114.8 (Ar-C); HRMS (ESI-TOF) m/z: [M-H]- Calcd for
C12H5Br2N2O5 414.8571; Found 414.8561.
Bis(2-methyl-4-nitrophenyl) (2i).45 It was obtained by the reaction of 1k (0.2 mL, 1.63 mmol),
NaH (40 mg, 1.66 mmol) in DMSO (1 mL) in 54% yield (125 mg) as yellow solid; m. p. 264-
266 ºC. 1H NMR (400 MHz, CDCl3) δ 8.09 (2H, d, J= 9.7 Hz, Ar-H), 6.97-6.95 (4H, m, Ar-H),
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2.63 (6H, s, CH3); C NMR (100 MHz, CDCl3) δ 159.1 (Ar-C), 145.0 (Ar-C), 137.3 (Ar-C),
127.5 (Ar-C), 122.4 (Ar-C), 116.9 (Ar-C), 21.1 (CH3); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H13N2O5 289.0819; Found 289.0844.
General procedure for preparation of unsymmetrical biaryl ethers (4a and 4b):
To a stirring solution of NaH (1.5 equiv.) in DMSO (5 mL), both substituted aryl halide (1 equiv.
each) was slowly added at ambient temperature. After 10 min, the temperature was raised to 80
ºC and stirring continued till the disappearance of the starting aryl halides. The reaction mixture
was extracted with ethyl acetate and washed with water, organic layer dried over Na2SO4 and
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solvent evaporated under reduced pressure to give a crude mass, which was purified by column
chromatography using SiO2 (60-120 mesh) and gradient of EtOAc/hexane as eluent to give title
compounds 4a and 4b.
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2,4'-oxybis(nitrobenzene) (4a).46 It was obtained by the reaction of 1a (0.2 mL, 1.88 mmol), 1b
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(0.2 mL, 1.89 mmol) and NaH (70 mg, 2.91 mmol) in DMSO (3 mL) in 35% yield (172.3 mg) as
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yellow solid; m. p. 104-106 ºC. H NMR (400 MHz, CDCl3) δ 8.24 (2H, d, J= 9.3 Hz, Ar-H),
8.07 (1H, dd, J1= 8.2, J2= 1.6 Hz, Ar-H), 7.70-7.66 (1H, m, Ar-H), 7.44-7.41 (1H, m, Ar-H),
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7.23 (1H, dd, J1= 8.2, J2= 1.2 Hz, Ar-H), 7.04 (2H, d, J= 9.3 Hz, Ar-H); C NMR (100 MHz,
CDCl3) δ 162.0 (Ar-C), 147.7 (Ar-C), 143.5 (Ar-C), 134.9 (Ar-C), 126.2 (Ar-C), 126.1 (Ar-C),
126.0 (Ar-C), 123.5 (Ar-C), 117.1 (Ar-C). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C12H9N2O5
261.0506; Found 261.0515.
1-(2,4-dinitrophenoxy)-2-fluoro-4-nitrobenzene (4b). It was obtained by the reaction of 1c (0.1
mL, 0.79 mmol), 1d (0.09 mL, 0.81.0 mmol) and NaH (30 mg, 1.25 mmol) in DMSO (2 mL) in
35% yield (47 mg) as yellow solid; m. p. 104-106 ºC. 1H NMR (400 MHz, CDCl3) δ 8.90 (1H, d,
J= 1.6 Hz, Ar-H), 8.42 (1H, dd, J1= 7.2 Hz, J2= 2.0 Hz, Ar-H), 8.17 (2H, dd, J1= 8.0 Hz, J2= 1.6
Hz, Ar-H), 7.34 (1H, t, J= 6.4 Hz, Ar-H), 7.12 (1H, d, J= 7.2, Ar-H); 13C NMR (100 MHz,
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CDCl3) δ 153.5 (Ar-C), 153.0 (d, JCF = 205 Hz), 146.7 (d, JCF = 9.0 Hz), 145.8 (d, JCF = 5.0
Hz), 143.4 (Ar-C), 140.1 (Ar-C), 129.4 (Ar-C), 122.6 (Ar-C), 121.4 (Ar-C), 119.5 (Ar-C), 114.2
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(d, JCF = 18 Hz); HRMS (ESI-TOF) m/z: [M-H]- Calcd for C12H5FN3O7) 322.0117; Found
322.0043.
General procedure for preparation of biamino biaryl ethers:
Bis(4-aminophenyl)ether (5a).47 To a methanolic solution (15 mL) of 4,4'-oxybis(nitrobenzene)
(2a) (0.40 g, 1.53 mmol), 10% Pd in charcoal (35 mg) was stirred under a hydrogen atmosphere
at room temperature for 2 h. The reaction mixture was filtered through a pad of celite. The pad
was washed with CH2Cl2 (20 mL). After evaporating the solvent, a white solid was obtained as
the product. Yield: 0.30 g, 98%. Their 1H and 13C NMR values are accordances to as reported in
the literature.
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Bis(2-aminophenyl)ether (5b).48 To a methanolic solution (15 mL) of 2,2'-oxybis(nitrobenzene)
(2b) (0.40 g, 1.53 mmol), 10% Pd in charcoal (35 mg) was stirred under a hydrogen atmosphere
at room temperature for 2 h. The reaction mixture was filtered through a pad of celite. The pad
was washed with CH2Cl2 (20 mL). After evaporating the solvent, an off-white solid was obtained
as the product. Yield: 0.30 g, 98%. Their 1H and 13C NMR values are accordances to as reported
in the literature.
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Bis(2-fluoro-4-aminophenyl)ether) (5c). To a methanolic solution (15 mL) of 2,2'-
oxybis(nitrobenzene) (2d) (0.45 g, 1.0 mmol), 10% Pd in charcoal (35 mg) was stirred under a
hydrogen atmosphere at room temperature for 2 h. The reaction mixture was filtered through a
pad of celite. The pad was washed with CH2Cl2 (20 mL). After evaporating the solvent, an
offwhite solid was obtained as the product. Yield: 0.34 g, 96%. 1H NMR (400 MHz, CDCl3): δ
6.79 (2H, t, J= 8.9 Hz, Ar-H), 6.48 (2H, dd, J1= 12.2, J2= 2.6 Hz, Ar-H), 6.35-6.32 (2H, m, Ar-
H), 3.60 (4H, bs, NH); 13C NMR (100 MHz, CDCl3): δ 154.0 (d, 1JCF = 244.9 Hz), 143.2 (d, 3JCF
= 9.3 Hz, Ar-C), 137.1 (d, 2JCF = 11.6 Hz, Ar-C), 120.8 (d, 3JCF = 2.5 Hz, Ar-C), 110.5 (d, 4JCF =
3.1 Hz, Ar-C), 103.9 (d, 2JCF = 21.3 Hz, Ar-C).
General procedure for preparation of diazide biaryl ethers:
To a solution of p-TsOH·H2O (1.62 g, 9.0 mmol) in H2O (9 mL) was added biamino biaryl ether
(5a, 5b, and 5c) (1.0 mmol). After stirring for 1 min, anhydrous NaNO2 (0.621 g, 9.0 mmol) was
added gradually during 5 min. The resulting solution was then stirred for 15– 30 min until the
starting disappeared as monitored by TLC (eluent: benzene–EtOH, 9:1). To the resulting
solution, anhydrous NaN3 (0.208 g, 3.2 mmol) was added. An immediate emission of N2 was
observed. Solid aryl azides 6a were filtered, washed with H2O (50 mL) and dried. Oily azides 6b
and 6c were extracted with EtOAc (3 × 10 mL), dried (Na2SO4), filtered, and the solvent was
removed in a rotary evaporator under reduced pressure.
Bis(4-azidophenyl)ether (6a).49 Azide was synthesized from 4,4'-oxydianiline (4a) (200 mg, 1.0
mmol) by the procedure described above Yield: 242 mg (96%); yellow solid; m. p. 68-70ºC. 1H
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NMR (400 MHz, CDCl3) δ 7.01 (8H, bs, Ar-H); C NMR (100 MHz, CDCl3) δ 154.3 (Ar-C),
135.1 (Ar-C), 120.3 (Ar-C), 120.0 (Ar-C).
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Bis(2-azidophenyl)ether (6b). Azide was synthesized from 4,4'-oxydianiline (4b) (200 mg, 1.0
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mmol) by the procedure described for the synthesis of 4a Yield: 226 mg, 90% brown oil. H
NMR (400 MHz, CDCl3) δ 7.17-7.13 (4H, m, Ar-H), 7.15-7.05 (2H, m, Ar-H), 6.84-6.81 (2H,
m, Ar-H); 13C NMR (100 MHz, CDCl3) δ 148.1 (Ar-C), 130.9 (Ar-C), 124.7 (Ar-C), 120.8 (Ar-
C), 119.4 (Ar-C).
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Bis(2-fluoro-4-azidoophenyl)ether) (6c). Azide synthesized from 4,4'-oxydianiline (4d) (240
mg, 1.0 mmol) by the procedure described for the synthesis of 4a Yield: 280 mg, 96%; brown
oil. 1H NMR (400 MHz, CDCl3): δ 6.96 (2H, t, J= 8.7 Hz, Ar-H), 6.86 (2H, dd, J1= 11.0, J2= 2.6
Hz, Ar-H), 6.78-6.75 (2H, m, Ar-H); 13C NMR (100 MHz, CDCl3): δ 155.0 (d, 1JCF = 249.8 Hz,
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C-F), 141.2 (d, JCF = 11.5 Hz, Ar-C), 136.7 (d, JCF = 8.6 Hz, Ar-C), 120.9 (Ar-C), 114.9 (d,
3JCF = 3.6 Hz, Ar-C), 108.4 (d, 2JCF = 21.68 Hz, Ar-C).
1,2,5,6-di-O-isopropylidene-3-O-propynyl-α-D-gluco-furanose (7a).38 To a stirring slurry of
NaH (0.37 g, 15.0 mmol) in anhydrous THF (20 mL), 1,2,5,6-di-O-isopropylidene-α-D-gluco-
furanose (2.0 g, 7.7 mmol) was added at 0 ºC and propargyl bromide (0.75 mL, 10.0 mmol) was
added to this stirring reaction mixture followed by the addition of TBAB (0.4 g, 1.24 mmol) and
stirring continued for further 12 hr at ambient temperature. The excess of NaH was quenched
with aq. NH4Cl solution and filtered on cellite and the filtrate was evaporated and the crude
product, thus obtained, was extracted with ethyl acetate and washed with water. The organic
layer was dried over Na2SO4, and the solvent was evaporated under reduced pressure to give the
crude product which was purified over SiO2 using hexane: ethyl acetate (5:1) as eluent to give
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compound 9 as color less liquid. (Yield 1.90 g, 82%). Their H and 13C NMR values are
accordances to as reported in the literature.
(E)-1-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-4-(4"-(prop-2-yn-1-yloxy)phenyl)but-3-
en-2-one (7b). To a stirring solution of β-glycosyl ketone ii (2.0 g, 5.15 mmol), 4-(prop-2-yn-1-
yloxy)benzaldehyde (5.66 mmol) in dry CH2Cl2 was added pyrrolidine (0.085 mL, 1.03 mmol).
After stirring at room temperature for 16 h, the reaction mixture was evaporated under reduced
pressure and extracted with ethyl acetate/ water. The ethyl acetate layer was dried over sodium
sulfate (Na2SO4) and concentrated. The product was purified by column chromatography on
silica gel (60-120 mesh) using ethyl acetate: hexane as eluent to give desired products (7b), m. p.
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104-106 ºC; yield 1.86 g, 68 %. 1H NMR (400 MHz, CDCl3+CCl4): δ 7.52-7.49 (3H, m, Ar-H),
7.00 (2H, d, J= 8.7 Hz, Ar-H), 6.63 (1H, d, J= 16.20 Hz), 5.22 (1H, t, J= 9.3 Hz), 5.07 (1H, t, J=
9.9 Hz), 4.98 (1H, t, J= 9.9 Hz), 4.73 (2H d, J= 2.4 Hz), 4.25 (1H, dd, J1= 12.4 Hz, J2= 4.9 Hz),
4.12 (1H, ddd, J1= 8.5 Hz, J2= 3.3 Hz, J3= 1.4 Hz), 4.01 (1H, dd, J1= 12.3 Hz, J2= 2.0 Hz), 3.71
(1H, ddd, J1=10.0 Hz, J2= 4.8 Hz, J3= 2.1 Hz), 3.00 (1H, dd, J1= 16.2 Hz, J2= 8.3 Hz), 2.66 (1H,
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dd, J1= 16.1 Hz J2= 3.3 Hz), 2.55 (1H, t, J= 2.4 Hz), 2.02, 2.01, 2.00 (12H, s, -OCOCH3 ); C
NMR (100 MHz, CDCl3+CCl4): δ 196.0 (C=O), 170.6, 170.2, 169.9, 169.5, (4 x -OCOCH3),
159.6 (Ar-C), 143.3, 130.1, 127.7, 124.5, 129.3, 115.4, 77.9 , 76.1, 75.7, 74.21, 71.7, 68.5, 62.0,
55.8, 42.5, 20.6-20.0 (4 x -OCOCH3); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C27H31O11:
531.1861; Found 531.1866.
3,5-di-O-propargyl-1,2-O-isopropylidene-α-D-xylo-furanose (7d).38 To a stirring slurry of NaH
(1.01 g, 40 mmol) in anhydrous THF (20 mL), 1,2,-O-isopropylidene-α-D-xylo-furanose (2.0 g,
10.5 mmol) was added at 0 ºC and propargyl bromide (1.7 mL, 22.0 mmol) was added to this
stirring reaction mixture followed by the addition of TBAB (0.4 g, 1.24 mmol) and stirring
continued for further 12 hr at ambient temperature. The excess of NaH was quenched with aq.
NH4Cl solution and filtered on cellite and the filtrate was evaporated and the crude product, thus
obtained, was extracted with ethyl acetate and washed with water. The organic layer was dried
over Na2SO4, and the solvent was evaporated under reduced pressure to give the crude product
which was purified over SiO2 using hexane: ethyl acetate (5:1) as eluent to give compound 6 as
color less liquid. (Yield 2.25 g, 80%). Their H and 13C NMR values are accordances to as
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reported in the literature.
General Procedures for synthesis of dibenzo[b,h]bis([1,2,3]triazolo)[1,5-d:5',1'-
f][1,4,7]oxadiazonine, dibenzo-bistriazolo-1,4,7-oxadiazonines:
All the reactions were carried out in CH3CN/H2O (1:1, v/v) at room temperature. The biazide
biarylether 6b (150 mg) and propargyl derivatives (7a-7c, 2 equiv.) first dissolved in acetonitrile
(4 mL). An equal volume of water was added followed by adding diisopropylethylamine
(DIPEA) (1 equiv), and the solution mixed for 5 min. Copper (I) iodide powder (0.5-1.0 equiv)
was added to the reaction mixture, and the solution stirred at room temperature for 20-24 h. The
reaction was monitored by TLC using chloroform: methanol (9:1) or ethyl acetate: hexane (4:1,
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v/v). The mixture was filtered over the celite pad and concentrated in vacuum. The residue was
purified over SiO2 using chloroform: methanol (9:1) or ethyl acetate: hexane (4:1, v/v). The
products were then characterized by 1H NMR, 13C NMR, and HRMS.
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Synthesis of compounds 8a, 8a' and 9
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It was obtained by the reaction of 6b (0.15 g, 0.6 mmol), 7a (0.36 g, 1.2 mmol) in the presence
of DIPEA (0.2 mL, 1.2 mmol) and CuI (0.113 g, 0.6 mmol) in 6 mL of CH3CN/H2O (1:1, v/v) to
give diastereomeric mixture of entitled compound 8a, 8a' in 80% of overall yield (0.40 g) and
linear glycohybrid 9 in 16% of yield (0.08 g).
3,4-bis-(1’,2’:5’,6’-di-O-isopropylidene-α-D-glucofuranos-3’a-
yloxy)methyl)dibenzo[b,h]bis([1,2,3]triazolo)[1,5-d:5',1'-f][1,4,7]oxadiazonine (8a and 8a').
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Major Isomer (8a): White solid, m. p. 98-100 ºC. H NMR (400 MHz, CDCl3) δ 7.79 (2H, dd,
J1= 10.6 Hz, J2= 1.8 Hz, Ar-H), 7.41 (2H, td, J1= 10.5 Hz, J2= 2.0 Hz, Ar-H), 7.33-7.30 (2H, m,
Ar-H), 7.23 (2H, dd, J1= 10.8 Hz, J2= 1.4 Hz, Ar-H), 5.69 (2H, d, J= 5.0 Hz), 4.75-4.67 (4H, m),
4.28 (2H, d, J= 5.0 Hz), 3.99-3.88 (10H, m), 1.48 (6H, s), 1.39 (6H, s), 1.31 (6H, s), 1.23 (6H ,
s); 13C NMR (100 MHz, CDCl3) δ 148.5, 131.6, 128.2, 127.6, 125.8, 121.6, 111.7, 109.2, 105.0,
82.5, 82.1, 81.1, 80.9, 71.7, 67.4, 63.4, 26.9, 26.6, 26.1, 25.3; HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C42H51N6O13 847.3509; Found 847.3504.
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Minor Isomer (8a'): White solid, m. p. 96-98 ºC. H NMR (400 MHz, CDCl3) δ 7.74 (2H, dd,
J1= 10.6 Hz, J2= 2.0 Hz, Ar-H), 7.44 (2H, td, J1= 10.4 Hz, J2= 1.9 Hz, Ar-H), 7.32-7.29 (2H, m,
Ar-H), 7.23 (2H, dd, J1= 10.8 Hz, J2= 1.4 Hz, Ar-H), 5.48 (2H, d, J= 4.8 Hz), 4.65 (4H, dd, J1=
22.8 Hz, J2= 15.8 Hz), 4.15 (2H, d, J= 4.80 Hz), 4.03-3.86 (8H, m), 3.55-3.48 (2H, m), 1.44 (6H,
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s), 1.38 (6H, s), 1.34 (6H, s), 1.23 (6H, s); C NMR (100 MHz, CDCl3) δ 148.6, 145.9, 131.7,
128.1, 127.6, 125.8, 121.6, 111.9, 109.2, 105.0, 82.7, 81.8, 80.8, 71.9, 67.3, 63.5, 27.0, 26.7,
26.2, 25.4; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C42H51N6O13: 847.3509; Found 847.3512.
1,1'-(oxybis(2,1-phenylene))bis(4-(1’,2’:5’,6’-di-O-isopropylidene-α-D-glucofuranos-3’a-
yloxy)methyl)-1H-1,2,3-triazole) (9). White solid, m. p. 76-78 ºC. 1H NMR (400 MHz, CDCl3) δ
8.02 (2H, s, triazole-H), 7.75 (2H, dd, J1= 8.0 Hz, J2= 1.6 Hz, Ar-H), 7.42 (2H, td, J1= 7.6 Hz,
J2= 1.6 Hz, Ar-H), 7.36 (2H, td, J1= 7.8 Hz, J2= 1.2 Hz, Ar-H), 7.04 (2H, dd, J1= 8.2 Hz, J2= 1.2
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Hz, Ar-H), 5.90 (2H, d, J= 3.7 Hz), 4.84-4.82 (4H, m), 4.66 (2H, d, J= 3.6 Hz), 4.33-4.28 (2H,
m), 4.14 (2H, d, J= 3.0 Hz), 4.08-4.04 (4H, m), 3.98 (2H, d, J = 5.5 Hz), 1.50 (6H, s), 1.40 (6H,
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s), 1.32 (6H, s), 1.29 (6H, s); C NMR (100 MHz, CDCl3) δ 147.8, 144.9, 130.7, 126.4, 125.2,
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124.4, 119.4, 111.8, 109.0, 105.3, 82.7, 82.0, 81.1, 72.4, 67.3, 63.9, 26.8, 26.2, 25.4; HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C42H53N6O13 849.3665; Found 849.3666.
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3,4-bis-((E)-1-(2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl)-4-phenyl-but-3-en-2-one-4"-
yloxy)methyl)dibenzo[b,h]bis([1,2,3]triazolo)[1,5-d:5',1'-f][1,4,7]oxadiazonine (8b). It was
obtained by the reaction of 6b (0.15 g, 0.6 mmol), 7b (0.63 g, 1.2 mmol) in the presence of
DIPEA (0.2 mL, 1.2 mmol) and CuI (113 mg, 0.6 mmol) in 6 mL of CH3CN/H2O (1:1, v/v) to
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give entitled compound 8b in 90% of yield (0.72 g) as white solid, m. p. 126-128 ºC. H NMR
(400 MHz, CDCl3) δ 7.58 (2H, dd, J1= 8.0 Hz, J2= 1.2 Hz, Ar-H), 7.47-7.41 (4H, m, Ar-H), 7.36
(4H, d, J= 8.2 Hz, Ar-H), 7.25-7.19 (2H, m, Ar-H), 7.18 (2H, d, J= 8.2 Hz), 6.72 (4H, d, J= 7.9
Hz), 6.59 (2H, d, J= 16.1 Hz), 5.28-5.23 (2H, m), 5.20-5.07 (6H, m), 5.00 (2H, t, J= 9.6 Hz),
4.28 (2H, dd, J1= 12.4 Hz, J2= 4.8 Hz), 4.17-4.12 (2H, m), 4.06-4.03 (2H, m), 3.76-3.72 (2H, m),
3.01 (2H, dd, J1= 16.2 Hz, J2= 8.4 Hz), 2.68 (2H, dd, J1= 16.1 Hz, J2= 2.7 Hz), 2.04-2.03 (24H,
s); 13C NMR (100 MHz, CDCl3) δ 195.9, 170.6, 170.2, 170.0, 169.6, 148.5, 145.0, 143.0, 131.7,
130.1, 128.0, 127.7, 127.3, 125.9, 124.9, 124.6, 121.6, 114.9, 75.7, 74.2, 71.7, 68.5, 62.0, 61.4,
42.5, 20.7, 20.7, 20.6, 20.6; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for (C66H67N6O23):
1311.4252. Found 1311.4250.
3,4-dipentyldibenzo[b,h]bis([1,2,3]triazolo)[1,5-d:5',1'-f][1,4,7]oxadiazonine (8c). It was
obtained by the reaction of 6b (150 mg, 0.6 mmol), 7c (0.083 mL, 1.2 mmol) in the presence of
DIPEA (0.2 mL, 1.2 mmol) and CuI (113 mg, 0.6 mmol) in 6 mL of CH3CN/H2O (1:1, v/v) to
give entitled compound 8c in 95% of yield (0.25 g) as white solid, m. p. 94-96 ºC. 1H NMR (400
MHz, CDCl3) δ 7.69 (2H, dd, J1= 7.96 Hz, J2= 1.56 Hz, Ar-H), 7.41 (2H, td, J1= 7.8 Hz, J2= 1.6
Hz, Ar-H), 7.27 (2H, td, J1= 7.8 Hz, J2= 1.3 Hz, Ar-H), 7.20 (2H, dd, J1= 8.1 Hz, J2= 1.2 Hz, Ar-
H), 2.62-2.55 (2H, m), 2.37 (2H, m), 1.55-1.42 (4H, m), 1.22-1.03 (8H, m), 0.74 (6H, t, J= 6.9
Hz); 13C NMR (100 MHz, CDCl3) δ 149.7, 148.8, 131.3, 128.6, 127.2, 125.7, 123.3, 121.6,
109.0, 31.1, 28.5, 24.9, 22.2, 13.8; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C26H31N6O
443.2554; Found 443.2559.
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Compound (8d). It was obtain by the reaction of 6b (150 mg, 0.6 mmol), 7d (158 mg, 0.6 mol),
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DIPEA (0.2 mL, 1.2 mmol) and CuI (113 mg, 0.6 mmol) in CH3CN/H2O (2:1, v/v) as white solid
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in 14 % yield (0.04 g), m. p. 124-126 ºC. H NMR (400 MHz, CDCl3) δ 7.70 (2H, ddd, J1= 7.7
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Hz, J2= 5.5 Hz, J3= 1.5 Hz, H-3′, H-3), 7.48-7.43 (2H, m, H-5′, H-5), 7.34-7.29 (2H, m, H-4′, H-
4), 7.24 (2H, ddd, J1= 8.1 Hz, J2= 3.7 Hz, J3= 1.3 Hz, H-6′, H-6), 5.93 (1H, d, J= 3.8 Hz, H-1′′),
4.99 (1H, d, J= 10.6 Hz, Ha-9), 4.84 (1H, d, J= 11.3 Hz, Ha-9′), 4.70 (1H, d, J= 3.8 Hz, H-2′′),
4.45-4.41 (1H, m, H-4′′), 4.02 (1H, dd, J1= 8.3 Hz, J2= 5.0 Hz, Ha-5′′), 3.97-3.94 (3H, m, Hb-9,
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Hb-9′, H-3′′), 3.48 (1H, t, J= 8.9 Hz, Hb-5′′), 1.46 (3H, s, H-8′′), 1.32 (3H, s, H-7′′); C NMR
(100 MHz, CDCl3) δ 148.8 (C-1′), 148.7 (C-1), 147.7 (C-8′), 146.8 (C-8), 131.94 (C-5′), 131.91
(C-5), 128.6 (C-2′), 128.5 (C-2), 127.7 (C-3′, C-3), 126.3 (C-4′, C-4), 125.1 (C-7′), 124.9 (C-7),
122.1 (C-6′), 121.9 (C-6), 112.0 (C-6′′), 105.7 (C-1′′), 85.6 (C-3′′), 83.6 (C-2′′), 78.5 (C-4′′), 69.5
(C-5′′), 64.7 (C-9′, C-9), 27.2 (C-8′′), 26.6 (C-7′′); HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C26H25N6O6 517.1830; Found 517.1824.
Regioisomeric macrocycles (10a, 11, mix.). It was obtained by the reaction of 5a (150 mg, 0.6
mmol), 6 (158 mg, 0.6 mmol), DIPEA (0.1 mL, 0.6 mmol) and CuI (57 mg, 0.3 mmol) in
CH3CN/H2O (1:1, v/v) in 12% of overall yield (1:1) as white solid. 1H NMR (400 MHz, CDCl3)
) δ 8.05 (2H, s, triazole-H), 8.00 (2H, s, triazole-H), 7.99 (2H, s, triazole-H), 7.94 (2H, s, triazole-
H), 7.72-7.59 (16H, m, Ar-H), 7.14-7.05 (16H, m, Ar-H), 5.95 (4H, bs), 4.95-4.90 (4H, m), 4.88-
4.82 (4H, m), 4.75-4.68 (12H, m), 4.43 (4H, bs), 4.10 (4H, bs), 3.90-3.87 (4H, m), 3.78-3.75
(4H, m), 1.50 (12H, s), 1.34 (12H, s), 13C NMR (100 MHz, CDCl3) δ 156.9, 156.8, 156.6, 156.5,
132.8, 132.7, 132.7, 132.6, 122.3, 122.3, 122.3, 122.2, 121.2, 121.1, 119.9, 119.8, 119.7, 119.7,
111.9, 105.0, 82.2, 82.1, 80.8, 80.6, 78.2, 78.2, 66.8, 66.6, 64.6, 64.6, 63.1, 63.0, 26.8, 26.3.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C52H53N12O12 1037.3900; Found 1037.3922.
8. General procedure for the synthesis of 12a and 12b:
Biazide 6a/ 6c (1 equiv.) and 1,2,5,6-di-O-isopropylidene-3-O-propynyl-α-D-gluco-furanose
(7a) (2 equiv.) were suspended in a mixture of 1:1 tert-butanol-water (20 mL) and kept for
stirring at room temperature. To the stirring reaction mixture freshly prepared solution of sodium
ascorbate (20 mol %) in 500 μL and freshly prepared solution of CuSO4.5H2O (10 mol%) in 200
μL water were sequentially added. The reaction mixture was stirred at ambient temperature for
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12-16 h. After completion of reaction (TLC), the reaction mixture was extracted with EtOAc and
water. The organic layer was dried (anhd. Na2SO4) and evaporated under reduced pressure to
give a crude mass. The latter was purified by silica gel (60-120 mesh) column chromatography
using ethyl acetate: hexane (1:1) as eluent to give the cycloaddition products 12a/ 12c
respectively.
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1,1'-(oxybis(4,1-phenylene))bis(4-(1’,2’:5’,6’-di-O-isopropylidene-α-D-glucofuranos-3’a-
yloxy)methyl)-1H-1,2,3-triazole) (12a). It was obtained by the reaction of 6a (0.84 g, 0.34 mol),
7a (2 g, 0.68 mol) in the presence of sodium ascorbate (20 mol %) and CuSO4.5H2O (10 mol%)
t
in 20 mL of BuOH/H2O (1:1, v/v) to give entitled compound 12a in 98% of yield (2.75 g) as
glassy solid. 1H NMR (400 MHz, CDCl3) δ 8.08 (2H, s, triazole-H), 7.74 (4H, d, J = 8.9 Hz, Ar-
H), 7.20 (4H, d, J = 8.9 Hz, Ar-H), 5.90 (2H, d, J= 3.6 Hz), 4.93 (4H, dd, J1= 27.3 Hz, J2= 13.0
Hz), 4.65 (2H, d, J= 3.7 Hz), 4.40-4.35 (2H, m), 4.13-4.10 (6H, m), 4.03 (2H, dd, J1= 8.6 Hz, J2=
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5.3 Hz), 1.50 (6H, s), 1.41 (6H, s), 1.35 (6H, s), 1.32 (6H, s); C NMR (100 MHz, CDCl3) δ
156.9, 145.8, 133.0, 129.0, 128.2, 125.3, 122.4, 120.8, 119.9, 111.9, 109.1, 110.2, 105.2, 82.6,
81.7, 81.1, 72.3, 67.5, 63.9, 26.9, 26.8, 26.2, 25.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C42H53N6O13 849.3665; Found 849.3665.
1,1'-(oxybis(3-fluoro-4,1-phenylene))bis(4-(1’,2’:5’,6’-di-O-isopropylidene-α-D-glucofuranos-
3’a-yloxy)methyl)-1H-1,2,3-triazole) (12b). It was obtained by the reaction of 6b (0.24 g, 8.5
mmol), 7a (0.5 g, 17 mmol) in the presence of sodium ascorbate (20 mol %) and CuSO4.5H2O
t
(10 mol%) in 20 mL of BuOH/H2O (1:1, v/v) to give entitled compound 12b in 96% of yield
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(0.70 g) as white solid, m.p. 78-80 ºC. H NMR (400 MHz, CDCl3) δ 8.13 (2H, s, triazole-H),
7.71 (2H, dd, J1= 10.7 Hz, J2= 3.9 Hz, Ar-H), 7.55-7.53 (2H, m, Ar-H), 7.22 (2H, t, J= 8.5 Hz,
Ar-H), 5.92 (2H, d, J= 3.7 Hz), 4.93 (4H, dd, J1= 28.5 Hz, J2= 13.1 Hz), 4.67 (2H, d, J= 3.7 Hz),
4.42-4.37 (2H, m), 4.16-4.12 (6H, m), 4.06 (2H, dd, J1= 8.7 Hz, J2= 5.2 Hz), 1.52 (6H, s), 1.44
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(6H, s), 1.38 (6H, s), 1.34 (6H, s); C NMR (100 MHz, CDCl3) δ 153.5 (d, JCF = 252.12 Hz),
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146.2, 143.8 (d, JCF = 11.34 Hz), 133.7, 130.1, 128.4, 120.9, 120.6, 116.5 (d, JCF = 2.6 Hz),
112.0, 110.3 (d, 2JCF = 22.5 Hz), 109.2, 82.6, 81.7, 81.0, 72.3, 67.5, 63.8, 26.9, 26.8, 26.2, 25.8.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C42H51F2N6O13 885.3477; Found 885.3514.
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1,1'-(oxybis(4,1-phenylene))bis(4-(1’,2’-O-isopropylidene-α-D-xylofuranos-3’a-yloxy)methyl)-
1H-1,2,3-triazole) (13). Compound 12a (2 g) was hydrolyzed in 70% glacial acetic acid for 14-
15 hr at ambient temperature. The excess of acetic acid was quenched with (NaHCO3) and
extracted with chloroform. The organic layer was dried over (Na2SO4) an evaporated to give the
crude product which was further subjected for the oxidation with NaIO4. To a methanolic
solution (25 mL) of crude, aqueous solution (2 mL) of NaIO4 (1.2 g, 5.60 mmol) was added at 0
ºC and stirring continued for further 4 hr at ambient temperature. The reaction mixture was
filtered through a pad of celite. After evaporating the solvent further subjected for the reduction
with NaBH4 (200 mg, 5.30 mmol) was added at 0 ºC in methanolic solution of oxidised crude
product stirred for 4 hr at ambient temperature. The reaction was quenched with sat. NH4Cl and
extracted with CHCl3 and washed with water. The organic layer was dried over (Na2SO4) an
evaporated to give the crude product which was purified by column chromatography over SiO2
using a gradient of chloroform: methanol (9:1) as eluent to give the title compound 11 as
colourless foam, yield (1.4 g, 70 %). 1H NMR (400 MHz, CDCl3) δ 7.97 (2H, s, triazole-H), 7.74
(4H, d, J= 9.0 Hz, Ar-H), 7.21 (4H, d, J= 9.0 Hz, Ar-H), 6.00 (2H, d, J= 3.8 Hz, CH), 4.97 (2H,
d, J= 13.0 Hz, CH), 4.78 (2H, d, J= 13.0 Hz, CH), 4.71 (2H, d, J= 3.8 Hz, CH), 4.38-4.36 (2H,
m, CH), 4.18 (2H, d, J= 3.4 Hz, CH), 3.94-3.92 (4H, m, CH), 1.52 (6H, s, CH3), 1.36 (6H, s,
CH3) 13C NMR (100 MHz, CDCl3) δ 157.0, 145.1, 132.8, 122.6, 120.6, 120.0, 111.9, 105.2,
82.8, 82.5, 80.0, 63.2, 60.0, 26.8, 26.3; HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C34H41N6O11
709.2828; Found 709.2828.
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1,1'-(oxybis(4,1-phenylene))bis(4-(1',2'-O-isopropylidene)-5-(prop-2-yn-1-yloxy)-α-D-
xylofuranos-3'a-yloxy)methyl)-1H-1,2,3-triazole) (14). To a stirring slurry of NaH (100 mg,
4.1.0 mmol) in anhydrous THF (20 mL), compound 13 (1.0 g, 1.41.0 mmol) was added at 0 ºC
and propargyl bromide (0.25 mL, 3.3 mmol) was added to this stirring reaction mixture followed
by the addition of TBAB (0.4 g) and stirring continued for further 12 hr at ambient temperature.
The excess of NaH was quenched with aq. NH4Cl solution and filtered on cellite and the filtrate
was evaporated and the crude product, thus obtained, was extracted with ethyl acetate and
washed with water. The organic layer was dried over Na2SO4 and the solvent was evaporated
under reduced pressure to give the crude product which was purified over SiO2 using hexane:
ethyl acetate (5:1) as eluent to give compound 14 as glassy solid. (Yield 0.94 g, 84%). 1H NMR
(400 MHz, CDCl3) δ 8.01 (2H, s, triazole-H), 7.76 (4H, d, J= 8.9 Hz, Ar-H), 7.21 (4H, d, J= 8.9
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Hz, Ar-H), 5.95 (2H, d, J= 3.8 Hz, CH), 4.91 (2H, d, J= 12.6 Hz, CH), 4.80 (2H, d, J= 12.6 Hz,
CH), 4.69 (2H, d, J= 3.8 Hz, CH), 4.44-4.40 (2H, m, CH), 4.28-4.15 (4H, m, CH), 4.10 (2H, d,
J= 3.1, CH), 3.88 (2H, dd, J1= 9.8, J2= 6.4, CH), 3.75 (2H, dd, J1= 9.7, J2= 6.0, CH), 2.42 (2H, t,
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J= 2.4, CH), 1.51 (6H, s, CH3), 1.34 (6H, s, CH3) C NMR (100 MHz, CDCl3) δ 156.9, 145.5,
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133.0, 122.5, 120.8, 120.0, 111.9, 105.0, 82.4, 82.0, 79.5, 78.6, 74.8, 67.0, 63.8, 58.7, 26.8, 26.3.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C40H45N6O11 785.3141; Found 785.3121.
Compound (10a). It was obtain by the reaction of 6a (60 mg, 0.23 mmol), 14 (186 mg, 0.23
mmol), DIPEA (0.041 mL, 0.23 mmol) and CuI (13 mg, 0.07 mmol) in CH3CN/H2O (2:1, v/v);
Yield: 42 mg, 16% as white solid, m. p. 184-186 ºC. 1H NMR (400 MHz, CDCl3): δ 8.01 (2H, s,
triazole-H), 8.00 (2H, s, triazole-H), 7.64-7.62 (8H, m, Ar-H), 7.11 (4H, d, J = 7.0 Hz, Ar-H),
7.07 (4H, d, J = 7.0 Hz, Ar-H), 5.95 (2H, d, J = 2.8 Hz, CH), 4.93 (2H, d, J = 9.9 Hz, CH), 4.80
(2H, d, J= 10.0 Hz, CH), 4.75-4.73 (4H, m), 4.71 (2H, d, J = 5.2 Hz, CH), 4.47-4.44 (2H, m,
CH), 4.11 (2H, d, J = 2.4, CH), 3.92-3.98 (2H, m, CH), 3.78-3.76 (2H, m, CH), 1.52 (6H, s,
CH3), 1.36 (6H, s, CH3), 13C NMR (100 MHz, CDCl3) δ 156.8, 156.7, 132.8, 132.74, 122.3,
122.2, 121.2, 119.6, 119.7, 111.9, 105.0, 82.2, 80.8, 78.3, 66.6, 64.6, 63.1, 26.8, 26.3. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C52H53N12O12 1037.3900; Found 1037.3921.
Compound (10b). It was obtain by the reaction of 6c (66 mg, 0.23 mmol), 14 (186 mg, 0.23
mmol), DIPEA (0.041 mL, 0.23 mmol) and CuI (13 mg, 0.07 mmol) in CH3CN/H2O (2:1, v/v);
Yield: 44 mg, 18 % as white solid, m. p. 294-296 ºC. 1H NMR (400 MHz, CDCl3): δ 8.06 (2H, s,
H-8), 7.99 (2H, s, H-11), 7.62-7.57 (6H, m, H-2'', H-6'', H-2'), 7.46-7.43 (2H, m, H-6'), 7.13 (2H,
t, J= 8.6 Hz, H-5'), 7.07 (4H, d, J= 9.0 Hz, H-3'', H-5''), 5.94 (2H, d, J= 3.7 Hz, H-1), 4.92 (2H,
d, J= 12.5 Hz, Hb-9), 4.86 (2H, d, J= 12.7 Hz, Hb-6), 4.74-4.67 (6H, m, Ha-9, Ha-6, H-2), 4.46-
4.42 (2H, m, H-4), 4.11 (2H, d, J= 3.1 Hz, H-3), 3.88 (2H, t, J= 8.6 Hz, Hb-5), 3.75 (2H, dd, J1=
9.0 Hz, J2= 5.3 Hz, Ha-5), 1.51 (6H, s, H-14), 1.35 (6H, s, H-13); 13C NMR (100 MHz, CDCl3) δ
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156.9 (C-4''), 153.5 (d, JCF = 251.8 Hz, C-3'), 145.9 (C-7), 145.2 (C-10), 144.0 (d, JCF = 10.9
Hz, C-4'), 133.6 (d, 3JCF= 8.8 Hz, C-1'), 132.8 (C-1''), 122.5 (C-2'', C-6''), 121.4 (C-11), 121.3 (d,
3JCF = 3.4 Hz, C-5'), 121.2 (C-8), 120.0 (C-3'', C-5''), 116.7 (d, 4JCF = 3.6 Hz, C-6'), 112.1 (C-12),
110.3 (d, 2JCF = 22.7 Hz, C-2'), 105.2 (C-1), 82.4 (C-2), 80.9 (C-3), 78.4 (C-4), 66.8 (C-5), 64.8
(C-6), 63.2 (C-9), 27.0 (C-14), 26.5 (C-13). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C52H51F2N12O12 1073.3712; Found 1073.3726.
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The bacterial panel consisted of ESKAPE pathogens namely Escherichia coli (ATCC 25922),
Klebsiella pneumoniae (BAA-1705), Acinetobacter baumannii (BAA-1605), Pseudomonas
aeruginosa (ATCC 27853), Staphylococcus aureus (ATCC 29213) and Enterococcus sp. This
panel was further expanded to include drug-resistant clinical S. aureus strains including resistant
to Vancomycin and other clinically utilized antibiotics. These strains were procured from
BEI/NARSA/ATCC (Biodefense and Emerging Infections Research Resources
Repository/Network on Antimicrobial Resistance in Staphylococcus aureus/American Type
Culture Collection, USA) and routinely cultivated on Mueller-Hinton Agar (MHA). Before
starting the experiment, a single colony was picked from MHA plate, inoculated in Mueller-
Hinton cation supplemented broth (MHB) and incubated overnight at 37 ºC with shaking for 18-
24 h to get the starter culture.50
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Minimal inhibitory concentration assays
Antibacterial susceptibility testing was carried out utilizing broth microdilution assay according
to CLSI guidelines. 10 mg/mL stock solutions of test and control compounds were prepared in
DMSO and stored in -20 ºC. Bacterial cultures were inoculated in appropriate media, and OD600
of the cultures was measured, followed by dilution to achieve ~105 CFU/mL. The compounds
were tested from 64-500 µg/L in two-fold serial diluted fashion with 2.5 μL of each
concentration added per well of a 96-well round bottom microtiter plate. Later, 97.5 μL of
bacterial suspension was added to each well containing the test compound along with appropriate
controls.
Cell Cytotoxicity Assay
Cell toxicity was performed against Vero cell using the MTT assay. ~103 cells/well were seeded
in 96 well plate and incubated at 37 ºC with a 5% CO2 atmosphere. After 24 h, the compound
was added and incubated for 72 h at 37 ºC with an 5% CO2 atmosphere. After the incubation was
over, MTT was added at 5 mg/L in each well, incubated at 37 ºC for further 4 hours, the residual
medium was discarded, 0.1 mL of DMSO was added to solubilize the formazan crystals, and OD
was taken at 540 nm for the calculation of CC50. CC50 is defined as the lowest concentration of
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compound which leads to a 50% reduction in cell viability. Doxorubicin was used as positive
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ASSOCIATED CONTENTS
Supporting Information
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60
X-Ray crystallographic data for compound 8c and copies of spectral data for all key compounds
are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rpt.cdri@gmail.com, rpt_tripathi@cdri.res.in
Notes
Authors declare no competing financial interest.
ACKNOWLEDGMENT
K.S, G.S., and M.S. are thankful to UGC, New Delhi for Fellowships. Financial assistance from
Indo-France project (CEFIPRA-5303-2) is also greatly acknowledged. We sincerely thank
SAIF div. for the analytical facilities and Dr. T. S. Thakur of MSB div., CSIR-CDRI for
supervising the X-ray data collection and structure determination. The following reagent was
provided by the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) for
distribution by BEI Resources, NIAID, NIH: NARSA 100, NARSA 119, NARSA 129, NARSA
198, NARSA 192, NARSA 191, NARSA 193, NARSA 186, NARSA 194, VRS 1, VRS 4, VRS
12.
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