Efficient synthesis, structural characterization and anti-microbial activity of chiral aryl boronate esters of 1,2-O-isopropylidene-α-D- xylofuranose

Article abstract of DOI:10.1016/j.bmcl.2011.05.036

A simple and efficient synthetic approach toward a series of chiral aryl boronate esters, starting from d-xylose, as anti-microbial agents, is described herein. Minimum inhibitory concentration and zone of inhibition revealed that these derivatives exhibit potent anti-bacterial and anti-fungal properties. Herein, we report the first anti-microbial activity of this class of compounds. All products have been characterized by NMR (¹H, ¹³C and ¹¹B), IR, elemental and mass spectral study.

Full text of DOI:10.1016/j.bmcl.2011.05.036

Bioorganic & Medicinal Chemistry Letters 21 (2011) 3890–3893
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Efficient synthesis, structural characterization and anti-microbial activity
of chiral aryl boronate esters of 1,2-O-isopropylidene-a-D-xylofuranose
Rajiv Trivedi a, , E. Rami Reddy a, Ch. Kiran Kumar a, B. Sridhar b, K. Pranay Kumar c, M. Srinivasa Rao c
⇑
a Organometallic Group, I & P C Division, Discovery Lab D-214, Indian Institute of Chemical Technology, Hyderabad, Uppal Road, Tarnaka, Hyderabad 500007, India
b Center for X-ray Crystallography, Indian Institute of Chemical Technology, Hyderabad 500 007, India
c Chemical Biology Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient synthetic approach toward a series of chiral aryl boronate esters, starting from
Received 14 March 2011
Revised 27 April 2011
Accepted 10 May 2011
Available online 18 May 2011
D
-xylose, as anti-microbial agents, is described herein. Minimum inhibitory concentration and zone of
inhibition revealed that these derivatives exhibit potent anti-bacterial and anti-fungal properties. Herein,
we report the first anti-microbial activity of this class of compounds. All products have been character-
ized by NMR (1H, 13C and 11B), IR, elemental and mass spectral study.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Chiral boronate esters
1,2-O-isopropylidene-
-Xylose
a-D-xylofuranose
D
Anti-bacterial activity
Anti-fungal activity
Carbohydrates are ubiquitous in nature, readily available,
cheap, biodegradable and non-toxic materials.1,2 Presence of sev-
eral functional groups and stereogenic centers in carbohydrates
permit stereochemical differentiations, enantiopure compounds
synthesis,3–5 and their use as chiral templates,6 biosensors7 and
as precursors for several biological active products.8 Besides their
crucial role, carbohydrates possess a unique set of chemical and
structural features that make them particularly attractive as
molecular scaffolds.
It is well documented that boron, as an essential trace element,
has demonstrated significant relevance in a series of biochemical
and biological processes such as protecting groups, enzyme inhib-
itors, affinity purification agents, receptors for saccharide sensing,
neutron capturing agents for cancer therapy, bio-conjugates and
protein lables.9–17 Among the natural and synthetic boron
compounds, several have displayed anti-bacterial, anti-fungal or
anti-viral activities.11–20 During the recent times, reports have de-
scribed interesting activities of organoboron compounds such as:
anti-HIV,21 bacterial anti-inducer involved in quorum sensing,22,23
and as therapeutics.24,25
and make them more lipophilic and also increases transport through
liquid organic membranes.36 Klüfers and co-workers have tested the
suitability of carbohydrate boronate esters as linear linkers for the
formation of intrinsically chiral covalent organic frameworks
(COF).37 Nevertheless, taking into account the vast possibilities of
carbohydrate structures incorporating boron, no reports on the use
of carbohydrate based boronate esters in medicine is available.
Based on our ongoing research interest in organoboron and
carbohydrate chemistry, we intend to investigate the mutual
interactions of boron and carbohydrates to produce a new class of
anti-microbial agents. We hereby report a feasible and efficient
synthesis, characterization and anti-microbial screening of carbo-
hydrate based boronate esters. These compounds can be conve-
niently prepared in good yields and in a modular fashion, which
leads to a better understanding of the structure–activity relation-
ship. In the present study, we used gram-positive and gram-
negative bacteria and fungi as representative microorganisms.
For the introduction of the boron moiety in carbohydrate frame
work, we intended to use the known protected pentose sugar,
1,2-O-isopropylidene-a-D
-xylofuranose 1,38 as the precursor
Boronic esters of monosaccharides were first reported five dec-
ades ago.26,27 The boronic esters of carbohydrates have essentially
demonstrated their role as fluorescence sensors,28–31 and as protect-
inggroups.26,27,32–35 Furthermore, itis wellknownthatthediol func-
tionalities of the carbohydrates form cyclic esters with boronic acids
because of its utility as a key intermediate in synthesis of antibiot-
ics,39 nucleosides,40 herbicides,41 anti-HIV agents,42 and other
biologically active compounds.43 Thus, this compound was straight-
forwardly obtained from D
-xylose as described by Moravcova et al.38
With protected diol 1 in hands, we turned our attention to the
incorporation of the boron moiety in the furanoside back bone as
shown in Scheme 1. A thorough literature search resulted in three
reports for the synthesis of 1,2-O-isopropylidene-
a-D-xylofura-
⇑
Corresponding author. Tel.: +91 40 2719 1667; fax: +91 40 2716 0921.
E-mail address: trivedi@iict.res.in (R. Trivedi).
nose-3,5-phenylboronate 3a.44–46 However, these methods suffer
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.05.036

R. Trivedi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3890–3893
3891
Scheme 1. Synthesis of 1,2-O-isopropylidine-
a-
D-xylofuranose-3,5-phenyl boronate 3a from D-xylose.
from various drawbacks such as use of toxic pyridine45 as solvent,
very low yields,46 long reaction time and the removal of by prod-
ucts.44 This motivated us to undertake the challenge to carryout es-
ter formation reaction in a convenient way. The screening of
solvents and reaction conditions were conducted for the formation
of ester 3a by the reaction of protected diol 1 (3 mmol) with phen-
ylboronic acid 2a (3 mmol). After screening the solvents and tem-
perature parameters, we found that the best results were achieved
by using Et2O as solvent at room temperature. Under these condi-
tions, diol 1 was cleanly converted into chiral aryl boronate ester
3a and the product was isolated in 92% yield. Experiments con-
ducted using toluene,47 THF and EtOAc did not result in good yields
of the desired product. The boronic esters were synthesised using
the optimized condition48 and different aryl boronic acids 2b–2j
as starting materials, as shown in Table 1. Electron donating and
electron withdrawing groups attached at the para position were
efficiently used to prepare boronate esters 3b–3c and 3e–3g in
the range of 87–97% yield (Table 1, entries b–c and e–g). Aryl boro-
nic acid carrying electron withdrawing substituent at the meta
position was also prepared in good yield 95% (Table 1, entry h).
3-Thiophenyl, 2-thiophenyl and 2-naphthyl boronate esters 3d,
3i and 3j, respectively, were also prepared in the range of 75–
83% yield (Table 1, entries d, i and j). All the products described
in the Table 1 were characterized by 1H, 13C, 11B NMR, IR, elemental
analysis and EI-MS (see Supplementary Data).
Table 1
Efficient synthesis of chiral aryl boronate esters 3a–3j
Entry Aryl bronicacid (2)
Producta (3)
Yieldb
(%)
a
92
b
90
c
93
78
d
The IR spectra of all the cyclic boronate derivatives 3a–3j exhib-
ited three characteristic bands B–O, B–C and C–O absorption in the
regions 1380–1305 cmÀ1, 1081–1012 cmÀ1 and 1145–1167 cmÀ1
,
respectively. The other bands were well matched with the other
characteristic functional groups.
1H NMR and 13C NMR values were well assigned to all boronate
esters.49 The NMR signals of the aromatic ipso carbon atoms were
not detectable may be due to fast relaxation caused by the mag-
netic interaction with the boron nuclei.37 Thus, the 1H NMR and
13C NMR spectra did not yield a final proof for the existence of a
cyclic system, such as a six-membered ring.47 The 11B NMR spectral
data shows only one broad singlet peak in the region of d
24.6–26.9 ppm, discloses that the boron atom remains three co-
ordinate.19,49,50 All the six-membered cyclic boronates 3a–3j,
showed the characteristic fragmentation structures51 in mass spec-
tral study (see Supplementary Data).
e
87
88
f
To obtain the precise three-dimensional structural information,
the compound 3a was characterized by single crystal X-ray
diffraction studies, which confirms the six-membered boronate ring
existence.37,49,50 ORTEP diagram of 3a was shown in Figure 1. The
g
97
a
-furanose ring adopts an envelope conformation on C4 being the
extraplanar atom (puckering parameters52: Q2 = 0.362(2) Å and
2 = 317.5(4)°). The crystallographic data53 were listed in
u
Supplementary Data.
The minimum inhibitory concentrations (MIC) of various syn-
thetic compounds were screened against three representative
gram-positive microorganisms viz. Bacillus subtilis (MTCC 441),
Staphylococcus aureus (MTCC 96), Staphylococcus epidermidis (MTCC
2639) and gram-negative organisms viz. Escherichia coli (MTCC
443), Pseudomonas aeruginosa (MTCC 741) and Klebsiella pneumo-
niae (MTCC 618). The assays were performed by broth dilution
h
95
(continued on next page)

3892
R. Trivedi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3890–3893
techniques according to National Committee for Clinical Labora-
Table 1 (continued)
tory (NCCL) standards (1).54 Standard anti-bacterial agents like
Penicillin and Streptomycin were also screened under identical
conditions for comparison. The minimum inhibitory concentration
(MIC) values are presented in Table 2.
Entry Aryl bronicacid (2)
Producta (3)
Yieldb
(%)
These results clearly indicate that compounds 3a–3j displayed
significant activity with a high degree of variation. The results also
demonstrated that the activity of these compounds is influenced
by their structures, the most effective (lower MIC values) being
boronate esters 3g and 3h (Table 2). Moderate activity was shown
by the compounds 3a, 3b and 3d against all the tested organisms.
Compound 3c showed some activity against P. aeruginosa. Com-
pound 3i is active against S. epidermidis to some extent. The com-
pounds 3e, 3f and 3j have not shown any appreciable activity
compared to other compounds.
i
75
83
j
In vitro anti-fungal activity of the synthesized boronate esters
was studied against the fungal strains, Candida albicans (MTCC
227), Candida rugosa (NCIM 3462), Saccharomyces cerevisiae (MTCC
36) and Aspergillus niger (MTCC 282) by Agar Well Diffusion Meth-
od (2). The ready-made Potato Dextrose Agar (PDA) medium (Hi-
media, 39 g) was suspended in distilled water (1000 ml) and
heated to boiling until it dissolved completely, the medium and
Petri dishes were autoclaved at pressure of 15 lb/inc55 for 20 min.
Agar well bioassay was employed for testing anti-fungal activity
and the results were shown in Table 3.
a
All compounds were characterized by NMR (1H,13C and 11B), IR, elemental and
mass spectroscopy.
b
Yields refer to pure products after column chromatography.
The medium was poured into sterile Petri dishes under aseptic
conditions in a laminar air flow chamber. When the medium in the
plates solidified, 0.5 ml of (week old) culture of test organism was
inoculated and uniformly spread over the agar surface with a ster-
ile L-shaped rod. Solutions were prepared by dissolving the com-
pound in DMSO and different concentrations were made. After
inoculation, wells were scooped out with 6 mm sterile cork borer
and the lids of the dishes were replaced. To each well different con-
centrations of test solutions were added. Controls were main-
tained. The treated and the controls were kept at 27 °C for 48 h.
Inhibition zones were measured and the diameter was calculated
in millimetre (mm). Three to four replicates were maintained for
each treatment.
The anti-fungal screening data of compounds 3a–3j revealed
that all the tested compounds showed moderate to good anti-fun-
gal activities against the tested fungal strains. Standard anti-fungal
drug, amphotericin-B was also screened under identical conditions
for comparison. Zone of inhibition (in mm) values indicates that
the compounds 3g and 3h (Table 3) showed better anti-fungal
activity against all fungal strains. The compounds 3b and 3j
showed appreciable activity against all the tested fungal strains ex-
cept A. niger. The compound 3a showed only active against A. niger.
The compound 3c displayed activity except C. rugosa. The com-
pound 3d showed better activity against all strains except
Figure 1. ORTEP diagram of compound 3a (30% probability ellipsoids, hydrogen
atoms with arbitrary radii).
Table 2
Anti-bacterial activity of compounds 3a–3j
MIC (lg/ml)
Compd code
B. Subtilis
S. aureus
S. epidermidis
E. coli
P. aeruginosa
K. pneumoniae
3a
3b
3c
3d
3e
3f
3g
3h
37.5
75
75
75
18.75
75
37.5
150
150
9.375
4.68
150
150
1.562
6.25
18.75
75
75
18.75
150
150
18.75
9.375
37.5
75
3.125
3.125
18.75
37.5
150
4.68
150
37.5
75
37.5
18.75
150
75
37.5
150
75
75
150
150
18.75
2.34
75
150
1.562
6.25
75
150
150
150
4.68
4.68
150
150
6.25
3.125
4.68
9.375
150
150
12.5
6.25
37.5
18.75
75
150
12.5
1.562
3i
3j
Penicillin
Streptomycin

R. Trivedi et al. / Bioorg. Med. Chem. Lett. 21 (2011) 3890–3893
3893
Table 3
Anti-fungal activity of compounds 3a–3j
Zone of Inhibition (mm)
Compd code
C.albicans
C.rugosa
S.cerevisiae
A. niger
100
l
g
150
lg
100
lg
150
lg
100
lg
150
lg
100
l
g
150 lg
3a
3b
3c
3d
3e
3f
0
6
6
0
0
0
6
8
9
7
0
0
0
11
0
14
7
0
0
14
0
20
10
6
0
7
6
10
0
0
10
8
14
0
0
8
0
9
12
0
12
6
14
16
0
0
0
0
3g
3h
3i
3j
12
13
0
6
23.5
14
18
6
13
16
9
13
21
17
20
13
16
14
11
12
7
19
16
17
11
6
14
9
0
25
8
18
11
4
9
Amphotericin B
22
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This work was financially supported by the project fund DST
Fast-TrackProject, GAP-0131. E.R.R and Ch.K.K are grateful to CSIR,
New Delhi for the award of a fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.05.036.
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