Synthesis of glucosamine vinyl ether derivative and its deuterated analog

Article abstract of DOI:10.1007/s11172-020-2915-3

The use of calcium carbide (in the presence of H₂O) as a source of acetylene in the reaction with methyl 2-amino-4,6-O-benzylidene-2-deoxy-β-d-glucopyranoside under superbasic conditions (KF, KOH, DMSO, 130 °C, 3 h) led to the corresponding vin

Full text of DOI:10.1007/s11172-020-2915-3

Russian Chemical Bulletin, International Edition, Vol. 69, No. 7, pp. 1401—1404, July, 2020
1401
Brief Communications
Synthesis of glucosamine vinyl ether derivative and its deuterated analog*
K. S. Rodygin, V. V. Voronin, and M. S. Ledovskaya
St. Petersburg State University,
6 Universitetskii prosp., 198504 St. Petersburg, Russian Federation.
E-mail: k.rodygin@spbu.ru
2
The use of calcium carbide (in the presence of H O) as a source of acetylene in the reaction
2
with methyl 2-amino-4,6-O-benzylidene-2-deoxy-β-D-glucopyranoside under superbasic
conditions (KF, KOH, DMSO, 130 C, 3 h) led to the corresponding vinyl ether in 78% yield.
The vinylation does not affect other reaction centers. Replacement of water with deuterium
oxide in the reaction mixture gave a stable deuterated analog of this vinyl ether in 72% yield.
The one-step isotopic enrichment was practically quantitative (isotopic purity >96%). Introduced
deuterium atoms can be used as a convenient label in further transformations.
Key words: calcium carbide, vinyl ether, glucosamine, deuterium labeling, vinylation.
Glucosamine is a natural amino sugar that is part of
many natural glycoconjugates. In particular, glycosami-
noglycans of cartilage tissues contain glucosamine residues.
Glucosamine hydrochloride is widely used to treat degen-
of deuterium label into the composition of such objects
can significantly facilitate identification of intermediates
or final products. The problem of synthesis of deuterium-
labeled glycoconjugates can be solved by introducing
a vinyl group, including that labeled with deuterium, into
carbohydrate molecules with subsequent nucleophilic
addition to the double bond of, for example, mercapto
groups presented in many peptides.
1
erative diseases of cartilage, as well as plays an important
2
,3
role in processes of tissue healing. Reports on antican-
4
,5
6
cer and antiinflammatory activity of glucosamine and
its oligo- and polysaccharide derivatives allow them to be
classified as promising multifunctional therapeutic agents.
Of particular interest are polymers and glycoproteins with
glucosamine residues. About half of all natural proteins
The present work describes a pathway for selective
introduction of vinyl and trideuterovinyl group into
a glucosamine molecule. Vinylation of carbohydrate mol-
7
are glycosylated and belong to glycoconjugates, which
ecules with several hydroxy groups leads to the formation
are involved in key biological processes.8
—15
Introduction
of vinyl ethers with several vinyl groups,
16,17
the further
use of which in the synthesis can lead to complex mixtures
of products. Monovinylation requires one free hydroxy
group. The remaining hydroxy groups were preliminarily
protected according to the procedures described in the
*
Based on the materials of the XXI Mendeleev Congress
on General and Applied Chemistry (September 9—13, 2019,
St. Petersburg, Russia).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1401—1404, July, 2020.
066-5285/20/6907-1401 © 2020 Springer Science+Business Media LLC
1

1
402
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 7, July, 2020
Rodygin et al.
Scheme 1
Reagents and conditions: i. 1) MeONa, MeOH, 2) Ac O, MeOH, ~20 C, 1 h; ii. 1) FeCl in acetone, reflux 20 min, 2) Et N, 3) MeOH,
2
3
3
TsOH•H O, 4 h; iii. benzaldehyde, ZnCl , 20 C, 72 h; iv. 4 M aq. KOH, reflux, 24 h.
2
2
literature. At the first step, glucosamine hydrochloride was
Scheme 2
acylated to give N-acetylglucosamine (1) (see Ref. 18)
(
Scheme 1). Its reflux in acetone in the presence of anhy-
drous iron(III) chloride led to an intermediate oxazoline,
which without isolation was treated with p-toluenesulfonic
acid in methanol to form compound 2 (see Ref. 19). Then,
benzylidene protection20 was introduced to block two
hydroxy groups and allow further selective vinylation.
Immediately prior to vinylation, the N-acetyl protection
was removed by reflux of compound 3 in an aqueous alkali
solution2 to form compound 4 (see Ref. 22).
1
Calcium carbide was used as a source of acetylene,
which has successfully used in a wide range of organic
transformations.2
3,24
Procedures for a vinyl group intro-
duction using calcium carbide2
5,26
are convenient labora-
2
7
tory methods for the synthesis of O,S,N-vinyl derivatives.
The reaction requires superbasic conditions to achieve the
nucleophilic addition to the triple bond, which is charac-
teristic of acetylene and, in general, of alkynes.2
8,29
The
Reagents and conditions: i. CaC , DMSO, KOH, KF, H O,
2 2
benzylidene protection was stable under such harsh con-
ditions, and the final product 5 was isolated in 78% yield
130 C, 3 h; ii. CaC , DMSO-d , KOH, KF, D O, 130 C, 3 h.
2 6 2
(
Scheme 2).
sumed in the vinylation reaction, practically developing
no excessive pressure after the process. In general, a mix-
ture of calcium carbide and heavy water seems to be
a convenient reagent for the introduction of deuterium
into a wide variety of molecules, and the obtained deuter-
ated products can be used in further transformations with
retention of the isotopic label.
The use of heavy water D O and deuterated DMSO-d
2
6
3
0
as a solvent leads to perdeuterated vinyl derivatives. The
experiments showed that deuterovinylation proceeds quite
smoothly and does not affect any other groups, including
amino group. As a result, trideuterovinyl ether of glucos-
amine derivative 6 was isolated in 72% yield (Scheme 2).
The deuterium isotopic purity was more than 96%, and
the ether itself was stable and did not undergo H-D ex-
change.
Experimental
Direct introduction of deuterium using dideutero-
All reagents were commercially available (Acros Organics
and Sigma-Aldrich). Calcium carbide (97% purity) was purchased
from Acros. Potassium hydroxide of analytical grade (Vekton)
was pre-ground in a mortar. Solvents were dried and purified
according to standard procedures. NMR spectra were recorded on
a Bruker Avance III (400 MHz) spectrometer at 298 K using
acetylene in this reaction is extremely difficult. In addition
to the unsafe handling of gaseous acetylene,31 the synthe-
sis of significant amounts of dideuteroacetylene is very
expensive and the introduction of gases into the reaction
requires reactors and additional gas equipment.
The presented procedure is safer than that which uses
gaseous acetylene from an external source, since the
acetylene generated in situ from calcium carbide is con-
1
signals of residual protons of solvents as references in H NMR spec-
tra (δH 7.26, 2.50, and 4.79 for solutions in CDCl , DMSO-d ,
3
6
and D O, respectively) and signals of solvent carbon atoms in
2

Deuterated vinyl derivative of glucosamine
Russ. Chem. Bull., Int. Ed., Vol. 69, No. 7, July, 2020
1403
1
3
C NMR spectra (δ 77.16 and 39.52 for solutions in CDCl and
129.0, 128.3, 126.1, 105.5, 101.3, 89.6, 82.3, 80.8, 68.8, 66.6,
C
3
+
DMSO-d , respectively). Electrospray ionization high resolution
mass spectra (ESI HRMS) were recorded on a Bruker microTOF
mass spectrometer.
57.6, 57.0. HRMS ESI: found m/z 308.1492 [M+H] ; calcu-
6
+
lated for C16H21NO5 308.1491.
Methyl 2-amino-4,6-O-benzylidene-3-O-(trideuterovinyl)-
2-deoxy-β-D-glucopyranoside (6). The procedure was carried out
similarly to preparation of 5 with the only difference being that
DMSO-d and D O were used with the same amounts and con-
1
8
N-Acetyl-D-glucosamine (1), methyl 2-acetamido-2-de-
1
9
oxy-β-D-glucopyranoside (2), methyl 2-acetamido-4,6-O-
benzylidene-2-deoxy-β-D-glucopyranoside (3),2 and methyl
1
6
2
22,32
1
2
-amino-4,6-O-benzylidene-2-deoxy-β-D-glucopyranoside (4)
ditions. The yield was 223 mg (72%). H NMR (400 MHz,
were synthesized according to the previously described procedures
with slight modifications.
CDCl ), δ: 7.48—7.46 (m, 2 H, Ph); 7.39—7.32 (m, 3 H, Ph);
3
5.56 (s, 1 H, CHPh); 4.36 (dd, 1 H, C(6)H , J = 10.4 Hz,
2
Methyl 2-acetamido-2-deoxy-β-D-glucopyranoside (2). 1
H
J = 4.9 Hz); 4.26 (d, 1 H, C(1)H, J = 7.9 Hz); 3.81 (t, 1 H, C(6)H2,
NMR (400 MHz, D O), δ: 4.49 (d, 1 H, C(1)H, J = 8.5 Hz);
J = 10.4 Hz); 3.77 (t, 1 H, J = 9.2 Hz); 3.68 (t, 1 H, J = 9.2 Hz);
2
3
.98 (d, 1 H, C(6)H , J = 12.0 Hz); 3.79 (dd, 1 H, C(6)H ,
3.56 (s, 3 H, OCH ), 3.46 (td, 1 H, C(5)H, J = 10.4 Hz,
3
2
2
J = 12.0 Hz, J = 5.2 Hz); 3.75—3.71 (m, 1 H); 3.62—3.46 (m, 6 H);
J = 4.9 Hz); 2.98 (t, 1 H, C(2)H, J = 8.6 Hz); 1.60 (s, 2 H, NH ).
2
1
3
13
2
1
.08 (s, 3 H, CH CO). C NMR (101 MHz, DMSO-d ), δ:
69.1 (CO), 101.8, 77.0, 74.4, 70.7, 61.1 (CH ), 55.6, 55.2, 23.1
C NMR (101 MHz, CDCl ), δ: 152.7 (t, OCD=CD ,
3
6
3
2
J = 28.0 Hz); 137.3, 129.0, 128.3, 126.1, 105.5, 101.3, 88.9
2
(
CH CO).
(q, OCD=CD , J = 26.0 Hz); 82.2, 80.8, 68.8, 66.6, 57.6, 57.0.
3
2
+
Methyl 2-acetamido-4,6-O-benzylidene-2-deoxy-β-D-gluco-
HRMS ESI: found m/z 311.1682 [M+H] ; calculated for
1
+
pyranoside (3). H NMR (400 MHz, DMSO-d ), δ: 7.80 (d, 1 H,
C16H18D NO 311.1681.
6
3
5
NH, J = 8.7 Hz); 7.46—7.43 (m, 2 H, Ph); 7.39—7.36 (m, 3 H,
The isotopic purity of the obtained deuterated derivative was
1
Ph); 5.60 (s, 1 H, CHPh); 5.25 (d, 1 H, OH, J = 5.4 Hz); 4.39
determined by H NMR from the residual proton content of the
(
d, 1 H, C(1)H, J = 8.2 Hz); 4.21 (dd, 1 H, C(6)H , J = 10.1 Hz,
vinyl group with respect to the signal integrals of other protons.
The isotopic purity of the product was 96%.
2
J = 4.9 Hz); 3.73 (t, 1 H, J = 10.1 Hz); 3.62—3.49 (m, 2 H);
3
.42 (t, 1 H, J = 9.0 Hz); 3.37—3.29 (m, 1 H); 3.34 (s, 3 H,
13
OCH ); 1.82 (s, 3 H, CH CO). C NMR (101 MHz, DMSO-d ),
The team of authors thanks the Resource Centers
"Magnetic Resonance Methods of Research " and "Methods
of Analysis of Composition of Compounds" of St. Peters-
burg State University for the measurements.
This work was financially supported by the Russian
Science Foundation (Project No. 19-73-10032).
3
3
6
δ: 169.1 (CO), 137.7 (CPh), 128.8 (CPhH), 128.0 (2 CPhH), 126.3
(
2
2 CPhH), 102.5, 100.7, 81.3, 70.5, 67.9 (CH ), 66.0, 56.0, 55.9,
2
3.1 (CH CO).
3
Methyl 2-amino-4,6-O-benzylidene-2-deoxy-β-D-gluco-
1
pyranoside (4). H NMR (400 MHz, DMSO-d ), δ: 7.46—7.44
6
(
m, 2 H, Ph); 7.39—7.36 (m, 3 H, Ph); 5.59 (s, 1 H, CHPh);
5
3
.35 (s, 1 H, OH); 4.21—4.17 (m, 2 H); 3.72 (t, 1 H, J = 9.9 Hz);
.45—3.31 (m, 4 H); 3.40 (s, 3 H, OCH ); 1.54 (d, 2 H, NH ,
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8
2
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5
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