Synthesis of polyfunctional glycosyl derivatives of 2,7-dioxabicyclo[3.2.1]octane

Full text of DOI:10.1134/S107042801608025X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 8, pp. 1220–1222. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © M.Yu. Ievlev, O.V. Ershov, A.G. Milovidova, M.Yu. Belikov, O.E. Nasakin, 2016, published in Zhurnal Organicheskoi Khimii, 2016,
Vol. 52, No. 8, pp. 1226–1228.
SHORT
COMMUNICATIONS
Synthesis of Polyfunctional Glycosyl Derivatives
of 2,7-Dioxabicyclo[3.2.1]octane
M. Yu. Ievlev*, O. V. Ershov, A. G. Milovidova, M. Yu. Belikov, and O. E. Nasakin
I.N. Ul’yanov Chuvash State University, Moskovskii pr. 15, Cheboksary, 428015 Russia
*e-mail: hiliam@bk.ru
Received April 6, 2016
DOI: 10.1134/S107042801608025X
Oxabicyclo[3.2.1]octane framework is
a
key
interaction with galactins which are often
overexpressed on the surface of cancerous cells [10].
Besides the carbohydrates possess a pronounced
antitoxic action against cyanides that can provide a
positive influence by decreasing the unwanted toxic
effect of cyano derivatives.
structural element of many biologically important
compounds, in particular, naturally occurring ones. It
is encountered in insect pheromones [1], plant growth
regulators [2], as well as in compounds of carbo-
hydrate series [3]. Many oxabicyclo[3.2.1]octanes may
be utilized as convenient initial compounds for the
synthesis of oxygen heterocyclic natural molecules, for
instance, of pyran or furan series [4, 5].
Aiming at targeted synthesis of compounds from
the 2,7-dioxabicyclo[3.2.1]octane series
1
with
carbohydrate fragment we prepared glycosides 3
having an aldehyde group in the molecule. Their
synthesis was performed in keeping with published
procedures using commercially available pentaacetyl-
β-D-glucose 4, and also vanillin and 4-hydroxy-
benzaldehyde as aglycones (Scheme 1) [11, 12].
We reported on several efficient procedures of the
targeted synthesis of functionalized derivatives of 2,7-
dioxabicyclo[3.2.1]octane, 6-imino-2,7-dioxabicyclo-
[3.2.1]octane-4,4,5-tricarbonitriles 1, proceeding from
available and highly reactive adducts of ketones and
tetracyanoethylene (4-oxoalkane-1,1,2,2-tetracarbonit-
riles) 2 [6–8]. A special interest to framework
compounds 1 is caused by the antitumor activity
exhibited by them towards some cell strains of cancer
[9].
In the course of the synthesis of glycosides 3 we
have found that it is possible to use the
bromoderivative of tetraacetylglucose 5 in the reaction
with hydroxybenzaldehydes without its additional
purification and crystallization, just after its isolation
as a gel mass resulting from distilling off the solvent.
This procedure considerably increased the overall
conversion of the initial pentaacetylglucose 4 in the
corresponding glycoside, resulted in virtually 100%
The introduction in the structure of a molecule of
mono-, di-, and oligosaccharide fragments not only
supplies it with the amphiphilic character but may also
ensure its directional transport into a tumor due to the
Scheme 1.
O
O
OAc
OAc
OAc
O
O
O
P, Br2, AcOH
HO
R, NaOH
AcO
AcO
AcO
AcO
AcO
AcO
OAc
O
R
OAc
OAc
OAc
Br
4
5
3a, 3b
R = H (a), OMe (b).
1220

SYNTHESIS OF POLYFUNCTIONAL GLYCOSYL DERIVATIVES OF 2,7-DIOXABICYCLO...
1221
Scheme 2.
NH
NC
R3
O
NC CN
NC
NC
O
O
NC
R2
R2
OAc
OAc
O
CN
R3
O
O
2
AcO
AcO
AcO
AcO
i-PrOH, CH3CN
O
R1
O
OAc
OAc
R1
3a, 3b
1a, 1b
R1 = H (a), OMe (b); R2 + R3 = (CH2)4.
yield at the bromination stage (84% [11]), and did not
propanol–water, 1 : 1, and dried in a vacuum-
desiccator over CaCl2 till constant weight.
spoil the purity of the final compound 3.
Glycosides 3 were brought into the reaction with
tetracyanoethylated ketone 2 (Scheme 2). The optimum
condition for the reaction was stirring at room
temperature of equimolar amounts of initial com-
pounds in a mixture of 2-propanol–acetonitrile, 4 : 1.
12-Imino-9-[4-(2,3,4,6-tetra-O-acetyl-β-D-gluco-
pyranosyloxy)phenyl]-10,11-dioxatricyclo[5.3.2.01,6]-
dodecane-7,8,8-tricarbonitrile (1a). Yield 67%,
colorless crystals, mp 96–98°C. IR spectrum, ν, cm–1:
3298 (N–H), 2231 (C≡N), 1752 (С=O), 1698 (С=N).
1Н NMR spectrum, δ, ppm: 1.08–1.14 m (1H, CH2),
1.27–1.35 m (1H, CH2), 1.51–1.55 m (1H, CH2), 1.73–
1.80 m (2H, CH2), 1.84–1.92 m (1H, CH2), 1.97 s (3H,
CH3CO), 2.01 s (3H, CH3CO), 2.02 s (3H, CH3CO),
2.03 s (3H, CH3CO), 2.06–2.15 m (2H, CH2), 3.03 d.d
(1H, CH, J 11.5, 5.6 Hz), 4.07–4.11 m (1H, OCH),
4.17–4.23 m (1H, OCH2), 4.26–4.31 m (1H, OCH2),
5.01 d.t (1H, OCH, J 9.7, 2.5 Hz), 5.06–5.12 m (1H,
OCH), 5.40 d.t (1H, OCH, J 9.5, 2.3 Hz), 5.65 s (1H,
OCHAr), 5.69 d.d (1H, OCH, J 12.6, 8.0 Hz), 7.14 d
(2Harom, J 8.6 Hz), 7.62 d (2Harom, J 7.7 Hz), 9.86 s
(1H, NH). 13C NMR spectrum, δ, ppm: 20.74, 20.77,
20.85, 20.92, 21.25, 22.85, 25.71, 30.78, 37.97, 46.35,
62.00, 68.44, 71.01, 71.08, 71.48, 72.31, 72.42, 96.78,
107.32, 116.74, 116.94 (2C), 117.02, 117.42, 129.82,
132.20 (2C), 152.83, 161.24, 169.57, 169.78, 170.07,
170.43. Mass spectrum, m/z (Irel, %): 332 [M – 346]+
(9.7), 43 (100). High resolution mass spectrum (ESI-
TOF), m/z: [M + Na]+ 701.2077. C33H34N4O12.
Calculated M 678.2173.
The structure of compounds 1 was confirmed by
IR, 1H, and 13C NMR, and high resolution mass
spectra. In the IR spectra of compounds 1 strong
absorption bands are present of the stretching
vibrations of the imino group N–H bond in the region
3298–3270 cm–1, of unconjugated cyano groups (2245–
2231 cm–1), and also wide absorption bands of acetyl
С=O groups at 1751 cm–1, partially overlapping with
the absorption band of the imino group C=N bond at
1698–1701 cm–1. 1H NMR spectra contain
a
characteristic downfield singlet of the imino group
proton at 9.9 ppm, proton signals of the glucopyranose
ring in the region 4.0–5.5 ppm, and also proton signals
of alkyl and aryl fragments of the molecule in the
corresponding spectral range. In the mass spectra
molecular ions of compounds 1a and 1b were absent
because of a strong fragmentation.
Polyfunctional derivatives of 2,7-dioxabicyclo-
[3.2.1]octane 1 containing a glycoside fragment are
synthesized for estimating their antitumor activity.
12-Imino-9-[3-methoxy-4-(2,3,4,6-tetra-O-acetyl-
β-D-glucopyranosyloxy)phenyl]-10,11-dioxatricy-
clo[5.3.2.01,6]dodecane-7,8,8-tricarbonitrile (1b).
Yield 72%, colorless crystals, mp 109–111°C. IR
spectrum, ν, cm–1: 3270 (N–H), 2245 (C≡N), 1751
(С=O), 1701 (С=N). 1Н NMR spectrum, δ, ppm: 1.06–
1.13 m (1H, CH2), 1.25–1.38 m (1H, CH2), 1.48–1.58
m (1H, CH2), 1.72–1.81 m (2H, CH2), 1.85–1.94 m
(1H, CH2), 1.97 s (3H, CH3CO), 2.00 s (3H, CH3CO),
Glycosyl derivatives of 2,7-dioxabicyclo[3.2.1]oc-
tane (1) (general procedure). To a slurry of 0.0003 mol
of 4-oxoalkane-1,1,2,2-tetracarbonitrile 2 in 2 mL of 2-
propanol was added at stirring 0.0003 mol of glycoside
3 in 0.5 mL of acetonitrile. The reaction mixture was
stirred at room temperature till the disappearance of
initial compounds (TLC monitoring). The precipitate
was filtered off, washed with a cooled mixture 2-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 8 2016

IEVLEV et al.
1222
2.01 s (3H, CH3CO), 2.02 s (3H, CH3CO), 2.03–2.15
m (2H, CH2), 3.05 d.d (1H, CH, J 11.6, 5.7 Hz), 3.78 s
(3H, CH3O), 4.06–4.10 m (1H, OCH), 4.19–4.24 m
(2H, OCH2), 5.00 t (1H, OCH, J 9.5 Hz), 5.08 d.d (1H,
OCH, J 9.8, 8.0 Hz), 5.38 t (1H, OCH, J 9.5 Hz), 5.52
t (1H, OCH, J 7.9 Hz), 5.61 s (1H, OCHAr), 7.19–7.24
m (2Harom), 7.33–7.36 m (1Harom), 9.86 s (1H, NH). 13C
NMR spectrum, δ, ppm: 20.67, 20.70, 20.76, 20.83,
21.17, 22.29, 25.69, 30.01, 46.27, 46.98, 53.54, 56.56,
62.01, 68.44, 71.06, 71.26, 72.24, 74.87, 98.42,
108.12, 110.52, 111.11, 112.92, 113.19, 117.76,
120.61, 127.84, 147.48, 149.76, 156.14, 169.37,
169.70, 169.94, 170.32. Mass spectrum, m/z (Irel, %):
331 [M – 377]+ (10.5), 43 (100). High resolution mass
spectrum (ESI-TOF), m/z: [M + Na]+ 731.2179.
C34H36N4O13. Calculated M 708.2273.
the Russian Federation (stipends for young scientists
and postgraduate students SP-127.2016.4).
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