Levoglucosenone-derived precursors for the stereoselective synthesis of methylene-expanded analogues of C-nucleosides

Article abstract of DOI:10.1016/j.mencom.2015.01.016

Simple chiral precursors for the preparation of methylene-expanded C-nucleosides were developed, using as key steps pyrolysis of cellulose to levoglucosenone followed by hydrogenation and introduction of vinyl and ethynyl fragments to the 2-position.

Full text of DOI:10.1016/j.mencom.2015.01.016

Mendeleev
Communications
Mendeleev Commun., 2015, 25, 44–46
Levoglucosenone-derived precursors for the stereoselective
synthesis of methylene-expanded analogues of C-nucleosides
Valery K. Brel,a,b Aleksandr V. Samet,c Leonid D. Konyushkin,c
Adam I. Stash,d Vitaly K. Belskyd and Victor V. Semenov*c
a Institute of Physiologically Active Compounds, Russian Academy of Sciences, 142432 Chernogolovka,
Moscow Region, Russian Federation
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
c N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian
Federation. Fax: + 7 499 135 5328; e-mail: vs@ioc.ac.ru
d L. Ya. Karpov Institute of Physical Chemistry, 105064 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2015.01.016
Simple chiral precursors for the preparation of methylene-expanded C-nucleosides were developed, using as key steps pyrolysis of
cellulose to levoglucosenone followed by hydrogenation and introduction of vinyl and ethynyl fragments to the 2-position.
H2,
2% Pd/C
(Sibunit)
Regioselective synthesis of sugar-connected heterocycles, such
6
O
O
as N- and C-nucleosides (A, Figure 1), is an important approach
to biomolecules.1 Nucleosides with heterocyclic base linked to
sugar through C–C bond attract much attention because of their
chemical and enzymatic stability.2
5
1
Cellulose
O
O
4
EtOAc,
40°C,
20 bar,
8 h
2
3
O
O
LG
DLG, 85%
H2C=CHMgBr
HC CMgBr
THF, 40 °C,
2 h
O
O
THF, room
temperature,
2 h
Het
X
2
Het
O
OH
1
X
6
O
RC N–O
HO
HO
3
4
O
O
O
5
O
Et2O,
–40 °C,
3 h
R
O
A
B
N
OH
OH
3 R = Ph
Nucleosides
Methylene-expanded
nucleosides
4 R = 4-MeC6H4
5 R = 4-FC6H4
6 R = Ac
CH2
CH
1a, 63%
+
X = N: N-nucleosides
X = C: C-nucleosides
2a, 42%
54–75%
PhCH2N3
Cu(OAc)2
+
Figure 1 Structure of nucleosides.
O
O
O
H2O,
O
O
O
Among the synthetic C-nucleosides, tiazofurin (2-b-d-ribo-
furanosylthiazole-4-carboxamide NSC-286193),3(a) selenazofurin
(2-b-d-ribofuranosylselenazole-4-carboxamide NSC-340847),3(b)
have gained significant recognition as potent antitumor agents.
When a methylene group is inserted between the ring oxygen
and the carbon atom linked to the base moiety, such compounds
are considered as ring-expanded (six-membered ring) analogues
of nucleosides (B, Figure 1). A number of six-membered ring
N-nucleoside derivatives (with pyranose,4(a) cyclohexane,4(b)
cyclohexene4(c) rings) as well as dideoxynucleosides containing
two heteroatoms within the carbohydrate moiety4(d) have been
prepared. Several of these compounds showed potent antiviral2,5
and antitumor2 activity.
An efficient synthesis of 1,6-anhydrohexitol N-nucleosides
(type B) allowing for introduction of alternative substituents at
the 2'-position of the sugar has been developed from levo-
glucosenone (LG).6 LG, a highly functionalized chiral synthon
with proper stereochemistry at the 5-position, is susceptible to
selective addition at the C=C bond on the side opposite to the
anhydro bridge,7 which opens an access to new enantiopure
compounds.8
CH
room
temperature,
1 h
OH
CH2
OH
1b, 5%
OH
2b, 4%
N
N
CH2Ph
N
7, 84%
Scheme 1
It is obtained by acid-catalyzed pyrolysis of cellulose9 and
available from Chemical Block Ltd.
D
ihydrolevoglucosenone (DLG) was synthesized by hydrogena-
tion of LG using 2%Pd catalyst on granulated graphite Sibunit10
in a specially designed stainless reactor ensuring contact between
a solution to be hydrogenated and a fixed layer of the catalyst.†
In the next step vinyl and ethynyl fragments were introduced to
†
Dihydrolevoglucosenone DLG (1,6-anhydro-3,4-dideoxy-b-d-glycero-
hexopyranos-2-ulose). Pd/Sibunit catalyst was prepared and regenerated
as described earlier.10 A stainless steel autoclave (650 ml)10 was charged
with LG (35 g, 0.273 mol) in EtOAc (400 ml). A gauze container with a
2%Pd/C catalyst (8 ml) was placed in the autoclave in such a way that
the catalyst was immersed in solution. LG was hydrogenated at 40°C
and a hydrogen pressure 20 atm for 48 h with stirring with a magnetic
bar. The autoclave was discharged, washed with EtOAc (2×20 ml), combined
We consider LG as an excellent starting material for the
synthesis of methylene-expanded C-nulceosides B (Scheme 1).
© 2015 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 44 –

Mendeleev Commun., 2015, 25, 44–46
O(1)
the 2-position of DLG via addition of the corresponding Gringard
reagents.‡ The presence of the 1,6-anhydro bridge provides high
stereoselectivity.6,8(b) Noteworthy, addition of MeMgI to DLG is
less stereoselective.11 The major isomers of target alcohols 1a
(92.9% in mixture) and 2a (91.7%) were easily separated by
column chromatography. The ethenyl and ethynyl substitutents in
such molecules can be transformed to various heterocyclic rings
via 3+2 dipolar cycloaddition reactions.12,§ We demonstrated such
transformation yielding isoxazoles 3–6 and 1,2,3-triazoles 7 with
1,5-anhydrohexitol moieties. 3-Acetylisoxazole 6 was synthesized
from alkyne 1a and acetone using ammonium cerium(iv) nitrate
in one-pot procedure13 (see Scheme 1).
O(2)
C(6)
O(3)
C(8)
C(7)
C(1)
C(2)
C(5)
C(3)
C(4)
Figure 2 Molecular structure of 1,6-anhydro-3,4-dideoxy-2-C-ethynyl-
b-d-threo-hexopyranose 1a.
N(1)
O(4)
Interesting biological properties have been reported for
1,2,3-triazole–carbohydrate conjugates.14 Isoxazoles and 4,5-di-
hydroisoxazoles are considered as useful intermediates in organic
synthesis.15 Furanose- and pyranose-containing C-nucleosides
with isoxazole group were reported previously.16 The opening
of 1,6-anhydrohexitol acetal ring, described earlier,6 can be used
for transformation of derivatives 3–7 into type B C-nucleosides.
The molecular structures of 1a and 3 and stereoselectivity were
unambiguously determined by X-ray crystal diffraction study
(Figures 2 and 3).¶
O(1)
C(15)
C(9)
C(10)
C(6)
O(3)
O(2)
C(14)
C(7)
C(1)
C(2)
C(8)
C(11)
C(13)
C(5)
C(12)
C(4)
C(3)
Figure 3 Molecular structure of 1,6-anhydro-3,4-dideoxy-2-C-(3-phenyl-
isoxazol-5-yl)-b-d-threo-hexopyranose 3.
In conclusion, we have developed the simple synthesis of C2
chiral derivatives of dihydrolevoglucosenone 1a, 2a and 3–7
as precursors for preparation of methylene-expanded C-nucleo-
sides (B).
EtOAc solution was evaporated. Residue was distilled to afford DLG,
30.2 g (85%), bp 52°C/2 Torr (lit.,17 104°C/16 Torr), [a]D20 –261.8 (c 1.0,
CHCl3) {lit.,17 [a]D25 –246 (CHCl3)}.
‡
1,6-Anhydro-3,4-dideoxy-2-C-ethynyl-b-d-hexopyranose 1a. Purified
anhydrous THF (100 ml) was placed in a 50 ml flask, acetylene was
introduced through a gas-inlet tube at the rate of 0.5–1.0 dm3 h–1, and
the stirrer was started. After 15 min, ethylmagnesium bromide (prepared
from 0.48 g, 0.02 g-atom of magnesium turnings, and 2.4 g, 0.022 mol of
bromoethane in the 25 ml of THF) was added over 2 h. The temperature
was raised to 5–10°C. The mixture was stirred at 30–35°C for 1 h, then
cooled in an ice bath and DLG (3.1 g, 0.024 mol) in tetrahydrofuran
(15 ml) was added over 15 min. The mixture was then stirred and heated
to 40–45 °C for a further 2 h, cooled and saturated aqueous NH4Cl was
added carefully to dissolve the solid components. The two layers were
separated and the aqueous phase was extracted with Et2O (3×15 ml). The
combined organic fractions were dried (K2CO3) and solvent was evaporated
in vacuo. The crude product (2.3 g) was purified by chromatography on
silica gel to afford 1a (1.95 g, 63%) and 1b (0.15 g, 5%) as white crystals.
1,6-Anhydro-3,4-dideoxy-2-C-ethenyl-b-d-hexopyranose 1b. A solution
of ethenylmagnesium bromide (prepared from 0.48 g, 0.02 g-atom of
magnesium turnings, and 2.4 g, 0.022 mol of bromoethene) in dry THF
(100 ml) was cooled to 5°C. Solution of DLG (3.12 g, 0.02 mol) in THF
(15 ml) was added. After stirring for 2 h at room temperature, the reaction
was cooled to 0°C and quenched with saturated NH4Cl. The organic layer
was separated and the aqueous layer was extracted with diethyl ether
(3×20 ml). The combined organic layers were dried over MgSO4, filtered
and concentrated in vacuo to afford a mixture of 2a and 2b. The crude
product was purified by flash chromatography to yield 2a (1.3 g, 42%)
and 2b (0.12 g, 4%) as white solid products.
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2015.01.016.
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§
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dissolved in Et2O (10 ml). PhCCl=NOH (0.47 g, 0.003 mol) in Et2O
(10 ml) was added at –40°C. Et3N (0.6 g, 0.006 mol) was added dropwise
over 2 h. Stirring was continued at –40°C until the reaction was complete
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benzene to yield 7 (241 mg, 84%) as a white solid.
For 1a: crystals of C8H10O3 (M = 154.16) are orthorombic, space group
P212121, at 293 K: a = 6.623(1), b = 9.427(2) and c = 12.076(2) Å, V =
= 754.0(3) Å3, Z = 4, dcalc = 1.358 g cm–3. 1061 reflections were collected,
from which 1395 unique (Rint = 0.0209), F(000) = 328. Refinement
converged to R1 = 0.0386, wR2 = 0.0848 (all data) and R1 = 0.0308,
wR2 = 0.0827 [I > 2s(I)], GOF = 1.103.
For 3: crystals of C15H15NO4 (M = 273.28) are hexagonal, space group
P31, at 293 K: a = 9.809(1), b = 9.809(1) and c = 11.856(2) Å, g = 120°,
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lected, from which 1288 unique (Rint = 0.0197), F(000) = 432. Refinement
converged to R1 = 0.0331, wR2 = 0.0612 (all data) and R1 = 0.0224,
wR2 = 0.0594 [I > 2s(I)], GOF = 1.033.
CCDC 961718 and 961719 contain the supplementary crystallographic data
forthispaper.ThesedatacanbeobtainedfreeofchargefromTheCambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
For more synthetic details and characteristics of compounds 1–7, see
Online Supplementary Materials.
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Mendeleev Commun., 2015, 25, 44–46
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Received: 19th March 2014; Com. 14/4327
– 46 –