Stereospecific synthesis of a new N-tosyl bromo-aminocyclitol

Article abstract of DOI:10.1007/s13738-016-0961-4

Abstract: Aminocyclitols are cyclic polyhydroxylated amines formally derived from cyclitols, and they constitute an important class of biologically active compounds. In the current research, the synthesis and characterization of a new N-tosyl bromo-aminoc

Full text of DOI:10.1007/s13738-016-0961-4

J IRAN CHEM SOC
DOI 10.1007/s13738-016-0961-4
ORIGINAL PAPER
Stereospecific synthesis of a new N‑tosyl bromo‑aminocyclitol
1
˙
Namudar Izzet Kurbanog˘lu
Received: 29 January 2016 / Accepted: 11 August 2016
© Iranian Chemical Society 2016
Abstract Aminocyclitols are cyclic polyhydroxylated
amines formally derived from cyclitols, and they constitute
an important class of biologically active compounds. In the
current research, the synthesis and characterization of a new
N-tosyl bromo-aminocyclitol 8 starting from cyclohexadi-
ene were carried out. In accordance with this purpose, the
oxazolidinone 13 was prepared by the palladium-catalyzed
reaction of bis-carbamate 12, synthesized from cyclohexen-
ediol, derived in two steps from cyclohexadiene. Hydroly-
sis of 13 was achieved with methanolic potassium carbon-
ate to afford 14 and ketalization gave 18 with good yield.
Allylic bromination of 18 gave compound 19. Bromination
was conducted with N-bromosuccinimide in the presence
of a catalytic amount of benzoyl peroxide. Osmylation of
the double bond and acid-mediated acetonide removal of
19 gave N-((1S,2R,3R,4S,6S)-4-bromo-2,3,6-trihydroxycy-
clohexyl)-4-methylbenzenesulfonamide 8. This molecule
may also be evaluated for its biological activity.
Introduction
The cyclitols (1, 3) are polyhydroxy cyclic compounds
[1–5], and the biological activity of these compounds, as
well as their role in intracellular communication, has been
extensively studied and summarized [6]. Aminocyclitols
(2, 4) are cyclic polyhydroxylated amines formally derived
from cyclitols, in which one of the hydroxyl groups is
exchanged with an amino group. They constitute a con-
tinuing and growing class of important compounds with
often interesting biological activities [7–14]. Moreover,
some aminocyclitols have significant glycosidase inhibi-
tory effects [15]. There are also applications of these com-
pounds as substrates for mutasynthesis of new antibiotics
[16]. The development of synthesis methods and the syn-
thesis of these compounds contribute significantly to the
biological and pharmaceutical industries (Fig. 1).
Numerous research groups [1–36] have reported fas-
cinating syntheses of cyclitols, aminocyclitols, and their
derivatives. In recent years, new synthetic methodologies
for various polyhydroxylated aminocyclitol compounds
and their analogues have also been developed [9–14,
37–39].
Graphical abstract
OH
OH
Br
In our early studies, were reported the first synthesis and
characterization of some aminocyclitol derivatives, such as
N-tosyl derivatives of dihydroconduramine E-2 5 and ent-
dihydroconduramine F-2 6 [40], and the gala-aminocyclitol
7 [5] starting from 1,3-cyclohexadine and 1,4-cyclohexa-
dine, respectively (Fig. 2).
To the best of our knowledge, there is no previous report
on the synthesis and characterization of N-tosyl bromo-ami-
nocyclitol 8, although the synthesis of the cyclitols (1, 3)
and related structures (2, 4–7) has been reported. Therefore,
in the current research, starting from 1,3-cyclohexadine, a
NHTs
OH
8
Keywords Aminocyclitols · Bromo-aminocyclitols ·
Cyclitols · Dihydroconduramines
* Namudar İzzet Kurbanoğlu
kurbanoglu@sakarya.edu.tr
1
Department of Science Education, Faculty of Education,
Sakarya University, 54300 Hendek, Sakarya, Turkey
1 3

J IRAN CHEM SOC
Experimental
OH
OH
OH
OH
OH
General procedures
NH2
Solvents were purified and dried by the standard procedures
before used. Melting points were determined on Electro-
thermal BI-9100 capillary melting apparatus and uncor-
OH
1
OH
2
1
rected. The H and 13C NMR spectra were recorded on a
300 (75) MHz Varian spectrometer. Infrared spectra were
obtained from Shimadzu Fourier transform infrared spec-
trophotometer (IR Prestige-21, 200 VCE). Column chro-
matography was performed on silica gel 60 (70–230 mesh).
Thin layer chromatography was carried out on Merck
0.2 mm silica gel, 60 F254 analytical aluminum plates.
OH
OH
OH
OH
OH
HO
HO
NH2
OH
OH
3
4
The endoperoxide (10) and the cyclohexenediol (11)
These compounds were synthesized by the photooxygena-
tion reaction of cyclohexadiene and subsequent the reduc-
tion of the endoperoxide with thiourea under mild condi-
tions in quantitative yield as reported by Balci [41].
Fig. 1 Various types of cyclitols, aminocyclitols
OH
OH
OH
OH
NHTs
Meso‑2‑ene‑1,4‑diol diester (12)
NHTs
Bis-carbamate 12 was prepared with ene-diol as described
by Trost et al. [42].
OH
OH
6
5
(3aR,7aS)‑3‑Tosyl‑3,3a,7,7a‑tetrahydrobenzo[d]ox‑
azol‑2(6H)‑one (13)
N-tosyl derivative of ent-
N-tosyl derivative of
dihydroconduramine F-2
dihydroconduramine E-2
The oxazolidin-2-one 13 was prepared with bis-carbamate
according to the procedure reported by Trost and Patterson
[43, 44].
OH
OH
OH
Br
OH
(3aR,7aS)‑2,2‑Dimethyl‑3‑tosyl‑2,3,3a,6,7,7a‑hexa‑
hydrobenzo[d]oxazole (18)
HO
NHTs
NHTs
OH
OH
7
8
Hydrolysis of carbamate 13 was achieved with methanolic
potassium carbonate to afford 14, and subsequent the ketal-
ization gave 18 with good yield as reported by Kurbanoglu
et al. [40].
N-tosyl derivative of the
N-tosyl derivative of the
gala-aminocyclitol
bromo-aminocyclitol
Fig. 2 N-tosyl derivatives of aminocyclitols
(3aR,6S,7aS)‑6‑Bromo‑2,
2‑dimethyl‑3‑tosyl‑2,3,3a,6,7,7a‑
hexa‑hydrobenzo[d]oxazole (19)
new N-tosyl bromo-aminocyclitol [N-((1S,2R,3R,4S,6S)-
4-bromo-2,3,6-trihydroxycyclohexyl)-4-methylbenzenesul-
fonamide] 8 was synthesized by following the procedure
described below. Cyclitols, aminocyclitols, and structurally
related compounds belong to an important class of glycosi-
dase inhibitors which are essential elements of many bio-
logically active compounds [1–40]. Compound 8 may also
be evaluated for biological activity.
A mixture of oxazolidine 18 (2 g, 6.5 mmol) and N-brom-
osuccinimide (NBS) (1.4 g, 7.8 mmol) in the presence of
catalytic amounts of benzoyl peroxide (1.5 g, 6.2 mmol) in
methylene chloride (40 mL) was stirred under argon atmos-
phere. The allylic bromination reaction was carried out at
85 °C for 4 h. After the completion of the reaction (4 h), the
1 3

J IRAN CHEM SOC
hot reaction mixture was filtered, water (100 mL) was added
and the organic layer was extracted with CH2Cl2. The phases
were separated and the organic layer was dried with MgSO4.
After removal of CH2Cl2 by using a rotary evaporator was
obtained the crude product, which was separated by crystal-
lization from reaction mixture (CCl4-hexane) to give 19 as
137.20, 129.78, 128.14, 109.01, 97.98, 78.36, 75.76, 73.95,
59.48, 42.56, 31.39, 29.27, 27.07, 25.23, 24.88, 21.80. IR
(ART) 3501, 3232, 2980, 2924, 2302, 1597, 1490, 1454,
1373, 1342, 1236, 1213, 1154, 1092, 878, 811, 744, 676,
594 cm−1. Anal. calcd for C19H26BrNO5S (460.38): C,
49.57; H, 5.69; N, 3.04; S, 6.96; Found: C, 49.40; H, 5.48;
N, 3.31; S, 7.03.
1
a single-isomer solid (0.70 g, 35 %), mp.: 127–128 °C. H
NMR (300 MHz, CDCl3) δ 7.96 (A part of AA′ BB′ sys-
tem, d, 2H, J = 8.5 Hz, aromatic), 7.38 (B part of AA′ BB′
system, d, 2H, JAB = 8.3 Hz, aromatic), 6.01–5.97 (dd, 1H,
J = 10.60, 10.55 Hz), 5.64-5.60 (dd, 1H, J = 10.8 Hz), 4.64–
4.62 (m, 1H, J = 10.55, 10.25 Hz), 4.21–4.18 (m, 1H, N–
CH, J = 4.10 Hz), 4.17–4.13 (m, 1H, O–CH, J = 6.40 Hz),
2.44–2.27 (m, 2H, J = 10.25 Hz), 2.40 (s, 3H, –CH3), 1.62–
1.56 (s, 6H, 2x–CH3); 13C NMR (75 MHz, CDCl3) δ 143.86,
138.53, 13.62, 129.97, 127.55, 127.42, 97.58, 72.70, 55.24,
41.85, 36.34, 30.11, 25.85, 21.79.
The following magnetically stirred solution of com-
pound 20 (0.245 g, 0.54 mmol) in a 1:1 mixture of 10 %
AcOH (15 mL) and THF (15 mL) was heated under reflux
for 7 h. Removal of the solvent gave N-((1S,2R,3R,4S,6S)-
4-bromo-2,3,6-trihydroxycyclohexyl)-4-methylbenzene-
sulfonamide 8 (0.18 g, 90 %), which was crystallized from
MeOH-hexane (4:1) as a white solid, mp.: 217–219 °C. 1H
NMR (300 MHz, CD3OD) δ 7.80 (A part of AA′ BB′ sys-
tem, d, 2H, J = 8.5 Hz, aromatic), 7.33 (B part of AA′ BB′
system, d, 2H, JAB = 8.3 Hz, aromatic), 3.72–3.68 (d, 1H,
–NH), 3.67 (s, 3H, –OH), 3.15–3.08 (dt, 1H, J = 12.88 Hz,
J = 2.30 Hz), 2.78 (m, 1H, J = 4.40 Hz), 2.43–2.42 (dd,
1H, J = 2.90 Hz), 2.40–2.39 (t, 1H, J = 10.55 Hz), 2.13–
2.08 (dd, 1H, J = 12.30 Hz), 2.02 (s, 3H, –CH3), 0.92–0.87
(m, 2H); 13C NMR (75 MHz, CD3OD) δ 143.30, 138.86,
129.43, 126.97, 73.93, 69.06, 55.94, 48.70, 47.00, 37.12,
20.32. IR (ART) 3551, 3333, 2922, 2624, 2522, 2479,1598,
1496, 1439, 1383, 1321, 1152, 1090, 1064, 949, 859, 819,
N‑((1S,2R,3R,4S,6S)‑4‑bromo‑2,3,6‑
trihydroxycyclohexyl)‑4‑methylbenzenesulfonamide (8)
The compound 19 (0.52 g, 1.34 mmol) was dissolved in
THF–H2O (10:5 mL), and then, NMO: H2O (0.197 g,
1.47 mmol) and a 0.5 M solution of OsO4 in THF (2 mL,
0.1 mmol) was successively added. The reaction mix-
ture was rapidly stirred for 36 h at room temperature and
was quenched with a 10 % solution of Na2SO3. Follow-
ing removal of solvent in vacuo, the mixture was chroma-
tographed on a column of silica gel with 5 % methanol/
ethyl acetate, and the solvents were evaporated in vacuo
to give the crude diol. The osmylation of 19 and for puri-
fication of the product was carried out the ketalization of
reaction mixture. Thus, the crude diol was dissolved in
dry benzene (30 mL) and dimethoxypropane (20 mL),
and then, p-TsOH (50 mg, 0.26 mmol) were added. The
reaction mixture was heated under reflux for 4 h, cooled
to room temperature, and washed with the saturated solu-
tion of Na2CO3. The organic layer was decanted and the
aqueous layer was extracted with CH2Cl2. The combined
extracts were washed with brine and dried over MgSO4,
and the solvents were evaporated in vacuum. The crude
product was purified by chromatography through silica
gel (CH2Cl2-hexane, 3:7). Removal of the solvent gave the
crude product, which was crystallized from CH2Cl2-hex-
ane (3:2) to give 20 as a white solid (0.245 g, 40 %), mp.:
779, 665, 634 cm−1
.
Results and discussion
For the synthesis of oxazolidinone 13, the starting mate-
rial cyclohexene endoperoxide 10 was first prepared from
the photooxygenation reaction of 1,3-cyclohexadiene 9 as
reported by Balci [41]. The endoperoxide 10 was reacted
with thiourea under mild conditions to give diol 11 in quan-
titative yield. The reaction of diol 11 with 2 equivalents of
toluenesulfonyl isocyanate yielded bis-carbamate 12 [42].
The palladium-catalyzed desymmetrization of bis-carba-
mate 12 was confirmed to give the monosubstitution prod-
uct oxazolidin-2-one 13 (Scheme 1) [40, 43, 44].
As a first strategy, cis-aminoalcohol 14 was prepared by
the hydrolysis of 13 with methanolic potassium carbonate.
Compound 14 was converted into acetate 15 by treatment
with AcCl in methylene chloride. The allylic bromination
of 15 was achieved with a mixture of 16 and 17 isomers
1
1
183–185 °C. H NMR (300 MHz, CDCl3) δ 7.80 (A part
(Scheme 2). The results of H and 13C NMR showed that
of AA′ BB′ system, d, 2H, J = 8.5 Hz, aromatic), 7.30 (B
part of AA′ BB′ system, d, 2H, JAB = 8.3 Hz, aromatic),
4.40–4.38 (m, 1H, J = 6.45 Hz, J = 6.15 Hz), 4.37–4.35
(dt, 1H), 4.23–4.20 (dd, 1H, J = 7.03 Hz), 4.19–4.17 (dd,
1H, J = 6.7 Hz), 3.67–3.64 (dt, 1H, J = 9.6 Hz), 2.40–
2.10 (m, 2H, J = 8.8 Hz), 2.42 (s, 3H, –CH3), 1.80–1.30
(s, 12H, 4x–CH3); 13C NMR (75 MHz, CDCl3) δ 144.12,
16 was the main product of the first reaction.
Since the aim of this research was the stereospecific syn-
thesis of the N-tosyl derivative of bromo-aminocyclitol 8, we
followed the second strategy for the synthesis of 8. In order
to decrease the conformational flexibility of the cyclohexene
skeleton and to influence the further stereoselective transfor-
mations, the ketalization of 14 was conducted. The bicyclic
1 3

J IRAN CHEM SOC
O
OCNHTs
OH
2 eq. Ts-N=C=O
1O2, TPP, hv
Thiourea
O
O
OCNHTs
O
12
OH
11
9
10
(dba)3Pd2 CHCl3,
P(O i Pr)3
O
O
O
O
OCNHTs
O
TsHN
TsN
L
Pd
L
L
L
PdL2
_ OCONHTs
Pd
13
OCNHTs
O
Scheme 1 Synthesis of oxazolidinone 13
OAc
OAc
OAc
TsHN
TsHN
TsHN
+
NBS
peroxides
Br
Br
15
16
17
CH Cl
AcCl
2
2
O
O
TsN
O
OH
TsN
TsHN
OsO4/NMO,THF-H2O
K2CO3
Me2C(OMe)2
6
43
5
and
10% AcOH-THF;
m - CPBA;
MeOH
p-TsOH
13
18
14
10% AcOH-THF
peroxides
NBS
OH
O
O
O
OsO4/NMO,
OH
NHTs
OsO4/NMO,
Br
TsN
O
TsN
TsN
O
6
THF-H2O
THF-H2O
5
4
1
+
2
Me2C(OMe)2,
p-TsOH
10% AcOH
3
Br
Br
Br
THF
OH
( )8
O
O
19
21
20
Me2C(OMe)2, p-TsOH
10% AcOH-THF
Scheme 2 Synthesis of a new N-tosyl bromo-aminocyclitol 8
1 3

J IRAN CHEM SOC
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(NBS) as a brominating agent in the presence of a catalytic
amount of benzoyl peroxide [(C6H5CO)2O2] under heat [46].
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in the reaction, which was separated by column chromatog-
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ochemistry was determined when was obtained the 20. The
structure of single product 20 was established for this product
on the grounds of 1H and 13C NMR spectroscopy (Scheme 2).
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atom (H-4) with H-3 is measured to be J3,4 = 6.15 Hz. This
value is consistent with a typical axial/equatorial coupling
constant in the cyclohexene ring, indicating the cis-configu-
ration as well as the equatorial/axial position of the bromine
atom. Furthermore, the coupling constant between protons
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confirms the trans-configuration as well as the axial/axial
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In conclusion, we have reported the synthesis of a new
N-tosyl bromo-aminocyclitol that can be used for various
biological studies.
Acknowledgments The authors greatly acknowledge the Scientific
and Technological Research Council of Turkey (TUBITAK) for its
financial support (Project No: 106T374).
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