Prostanoids: LXXXV. Synthesis 9-Oxo Derivatives of 9-LO Thromboxans

Article abstract of DOI:10.1023/A:1026053111451

Starting from levoglucosan, 1,6-anhydro-2,4-dideoxy-4-C-(2Z-octenyl)- β-D-arabino-hexopyranose was synthesized and converted into 9-oxo-9-LO thromboxan δ-lactone.

Full text of DOI:10.1023/A:1026053111451

Russian Journal of Organic Chemistry, Vol. 39, No. 5, 2003, pp. 658 662. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 5, 2003,
pp. 703 707.
Original Russian Text Copyright
2003 by Akhmetvaleev, Bikbulatov, Belogaeva, Akbutina, Miftakhov.
Prostanoids: LXXXV.* Synthesis 9-Oxo Derivatives
of 9-LO Thromboxans
R. R. Akhmetvaleev, R. V. Bikbulatov, T. A. Belogaeva,
F. A. Akbutina, and M. S. Miftakhov
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: bioreg@anrb.ru
Received July 24, 2001
Abstract Starting from levoglucosan, 1,6-anhydro-2,4-dideoxy-4-C-(2Z-octenyl)- -D-arabino-hexopyranose
was synthesized and converted into 9-oxo-9-LO thromboxan -lactone.
In the recent publication [2] we described the
transformation sequence I IV and planned to con-
vert compound IV into V [3] (Scheme 1). The latter
may be a useful model for studying the structure
activity relations in the series of 9-LO thromboxans
(for 9-LO prostaglandins, see [4 6]).
cases, unusual fragmentation of molecule IV occurred
[8]. We also tried to approach compound V through
9-hydroxy derivatives (thromban nomenclature) which
could be prepared from bis(triethylsilyl) ether VI.
By analogy with the data of [9, 10], we used the
system oxalyl chloride DMSO (Swern’s reagent [11])
to effect direct oxidation of the primary triethylsiloxy
group in VI. Unfortunately, ether VI failed to react
for unknown reason (Scheme 2).
It was more promising to use protected derivatives
of alcohol I. We examined methanolysis of the corre-
sponding acetate, methoxymethyl ether, and benzoate
VII. Under these conditions, the acetate and methoxy-
methyl ether of III readily underwent hydrolysis to
diol II, whereas the benzoate protection turned out
The optimal version of the transformation IV
V
seemed to be that involving regioselective reduction
of the side-chain keto group in IV. However, our
attempt to use for this purpose (i-Bu)3Al (CH2Cl2,
78 C), which showed good results in the chemo-
selective reduction of the 15-keto group in 9,15-di-
ketoprostenoic acid esters [7], was unsuccessful.
We also failed to reduce both ketone groups in IV
using L-Selectride, NaBH4, and Zn(BH4)2. In all
Scheme 1.
____________
*
For communication LXXXIV, see [1].
1070-4280/03/3905-0658$25.00 2003 MAIK Nauka/Interperiodica

PROSTANOIDS: LXXXV.
659
Scheme 2.
to be resistant to the system 10% HCl MeOH (20 C,
0.5 h), and -anomer VIII was obtained in a high
yield. The corresponding -glycoside was formed in
phosphonate IX [5] gave enone X in a good yield.
Compound X was reduced with sodium tetrahydrido-
borate in EtOH at 0 C to obtain a mixture of dia-
stereoisomeric diols XI ( 1:1, according to the HLPC
data) which could not be separated by chromatography
on silica gel. Exhaustive alkaline hydrolysis of both
ester groups (ethoxycarbonyl and benzoyloxy) in XI
afforded the corresponding hydroxy acid which was
converted into lactone XII during purification on
silica gel. Lactone XII was oxidized with pyridinium
chlorochromate on Al2O3 [12] to 9-oxo derivative
1
an amount not exceeding 2 3% (according to the H
NMR data). It should be noted that prolonged keeping
of compound VII in the system 1% HCl MeOH
(20 C, 10 h) leads to formation of an equilibrium
( 1:1) mixture of the - and -anomers of VIII.
Oxidation of the hydroxy group in VIII with
Swern’s reagent, followed by Emmons Horner
olefination of unstable intermediate aldehyde with
Scheme 3.
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660
AKHMETVALEEV et al.
XIII (Scheme 3). The latter is a bioisoster of target
compound V, which is suitable for biological testing
both per se and as sodium salt readily obtainable via
opening of the lactone ring.
under reduced pressure, and the residue was subjected
to column chromatography on silica gel to isolate
1.25 g (87%) of compound VII as an oily substance.
Rf 0.34 (heptane ethyl acetate, 4:1); [ ]D20
=
39
1
(c = 1.0, CHCl3). IR spectrum, , cm : 3040, 1760,
1
EXPERIMENTAL
1690, 1684, 1568. H NMR spectrum, , ppm: 0.65 t
(3H, CH3, J = 7.4 Hz), 1.00 1.30 m (6H, 3CH2),
1.60 2.40 m (7H, 4-H, 3CH2), 3.75 d.d (1H, exo-6-H,
J = 5.2, 6.8 Hz), 4.10 d (1H, endo-6-H, J = 6.8 Hz),
4.20 d (1H, 5-H, J = 5.2 Hz), 4.87 d (1H, 3-H, J =
5.2 Hz), 5.30 5.60 m (2H, CH CH), 5.54 s (1H,
1-H), 7.30 7.65 m (3H) and 7.95 8.20 m (2H)
(Harom). 13C NMR spectrum, C, ppm: 14.08 (CH3),
22.61 (C7 ), 27.39 (C5 ), 28.67 (C4 ), 29.33 (C1 ), 31.58
(C6 ), 33.67 (C2), 43.46 (C4), 67.90 (C6), 70.03 (C3),
74.17 (C5), 100.22 (C1), 126.26 (C3 ), 128.93, 129.05,
130.62 (Carom), 133.18 (C2 ), 165.93 (CO2).
The IR spectra were recorded on UR-20 and
Specord M-80 spectrometers from samples prepared
as thin films or dispersed in mineral oil. The H and
1
13C NMR spectra were obtained on a Bruker AM-300
instrument at 300 and 75.47 MHz, respectively, using
CDCl3 as solvent, and TMS as internal reference.
HPLC analysis was performed with a Du Pont-8800
liquid chromatograph; 3 150-mm column packed
with Separon SGX NH2 (5 m); eluent hexane
i-PrOH H2O (90:9.5:0.5, by volume), flow rate
0.5 ml/min; pressure 5 MPa; UV detector ( 254 nm).
Thin-layer chromatography was performed on Silufol
UV 254:366 plates; spots were visualized by treat-
ment with iodine vapor, calcination, or spraying with
a solution of p-methoxybenzaldehyde and sulfuric
acid in ethanol (1:0.5:10) with subsequent heating
at 120 150 C. The optical rotations were measured
on a Perkin Elmer 141 polarimeter.
Methyl 2,4-dideoxy-3-O-benzoyl-4-C-(2Z-oc-
tenyl)- -D-arabino-hexopyranoside (VIII). A solu-
tion of 0.4 g (1.16 mmol) of benzoate VII in 5 ml
of a 10% solution of HCl in methanol was stirred for
1 h, neutralized with NaHCO3, and filtered, and the
filtrate was evaporated to obtain 0.35 g (0.93 mmol,
80%) of compound VIII containing 3% of the cor-
responding -anomer. Oily substance, [ ]2D0 = +16
1
Methyl 2,4-dideoxy-3,6-di-O-triethylsilyl-4-C-
(2Z-octenyl)- -D-arabino-hexopiranoside (VI).
Chlorotriethylsilane, 1.37 g (9.1 mmol), was added
dropwise with stirring to a solution of 1 g (3.6 mmol)
of diol II in 20 ml of anhydrous pyridine. The mixture
was kept for 1 h at room temperature, diluted with
100 ml of ethyl acetate, and washed with a saturated
solution of sodium chloride (3 30 ml). The organic
phase was dried over MgSO4 and evaporated to obtain
1.27 g (92%) of bis-silyl ether IV as an oily sub-
(c = 1.0, CHCl3). IR spectrum, , cm : 1600, 1620,
1
1740, 3500. H NMR spectrum, , ppm: 0.80 t (3H,
CH3, J = 8.0 Hz), 1.05 1.35 m (6H), 1.70 2.40 m
(8H), 3.35 s (3H, OCH3), 3.60 3.90 m (3H, CH2O,
5-H), 4.90 br.s (1H, 1-H), 5.30 5.50 m (3H, CH CH,
3-H), 7.45 m (2H), 7.55 m (1H), 8.05 m (2H) (Harom).
13C NMR spectrum, C, ppm: 14.05 (CH3), 22.50
(C7 ), 24.72 (C5 ), 27.38 (C4 ), 29.17 (C1 ), 31.54 (C6 ),
35.95 (C2), 41.40 (C4), 54.85 (OCH3), 63.32 (CH2O),
69.89 (C3), 71.44 (C5), 98.61 (C1), 124.98 and 132.48
(CH CH), 128.40, 128.55, 129.66, 130.25 (Carom),
165.60 (CO2).
Methyl (2R,3S,4R,6S)-7-[3-(2Z-octenyl)-4-ben-
zoyloxy-6-methoxytetrahydropyran-2-yl]-5-oxo-6E-
heptenoate (X). A solution of 2.59 g (33.11 mmol)
of DMSO in 5 ml of dry methylene chloride was
added dropwise under argon to a solution of 1.19 g
(15.05 mmol) of oxalyl chloride in 20 ml of dry
methylene chloride on stirring at 60 C. The mixture
was stirred for 30 min at 70 C, and a solution of
1.13 g (3.01 mmol) of methyl pyranoside VIII in 5 ml
of methylene chloride was added, maintaining the
temperature below 60 C. The mixture was stirred
for 30 min at 70 C, and 3.76 g (63.67 mmol, 5.6 ml)
of triethylamine was added. The mixture was allowed
to warm up to room temperature, diluted with 15 ml
of water, and stirred for 10 min. The organic phase
was separated, the aqueous phase was extracted with
1
stance. IR spectrum, , cm : 1460, 1410, 1240.
13C NMR spectrum, C, ppm: 4.97 t (SiCH2), 6.39 t
(SiCH2), 6.76 (SiCH2CH3), 14.03 (CH3), 22.62 (C7 ),
27.53 (C5 ), 29.74 (C1 ), 31.64 (C6 ), 39.69 (C2), 44.36
(C4), 54.30 (OCH3), 63.74 (CH2), 66.97 (C3), 72.45
(C5), 98.58 (C1), 126.62 and 130.85 (CH CH).
1,6-Anhydro-3-O-benzoyl-2,4-dideoxy-4-C-(2Z-
octenyl)- -D-arabino-hexopyranose (VII). Freshly
distilled benzoyl chloride, 0.68 g (4.79 mmol), was
added dropwise over a period of 5 min to a solution
of 1 g (4.17 mmol) of alcohol I in 10 ml of anhydrous
pyridine under stirring at 0 C. The mixture was stirred
for about 30 min at room temperature, treated with
30 ml of a saturated solution of NaHCO3, and ex-
tracted with chloroform (3 10 ml). The combined
extracts were washed with several portions of water
and with a saturated solution of sodium chloride and
dried over Na2SO4. The solvent was distilled off
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PROSTANOIDS: LXXXV.
661
CH2Cl2 (2 15 ml), and the extracts were combined
with the organic phase and dried over Na2SO4. The
solvent was distilled off under reduced pressure, a 1-g
portion of the oily residue was dissolved in 20 ml
of CH2Cl2 containing 0.93 g (3.67 mmol) of phos-
phonate IX and 3.5 mg of benzyltriethylammonium
chloride, and 0.3 ml of 50% aqueous NaOH was
added under vigorous stirring. When the reaction was
complete (15 20 min, TLC), the mixture was diluted
with 50 ml of CH2Cl2, acidified with 1 N hydro-
chloric acid to pH 5, and washed with a saturated
aqueous solution of sodium chloride (3 15 ml). The
organic phase was dried over MgSO4 and evaporated
under reduced pressure at room temperature, and the
residue was subjected to chromatography on silica
gel using ethyl acetate hexane (2:1) as eluent to
isolate 0.98 g of enone X (Rf 0.28). Yield 65% (cal-
culated on compound VIII). [ ]2D0 = +44 (c = 1.0,
and 9.3 min (for conditions, see above). IR spectrum,
1
1
, cm : 3500, 1740, 1720. H NMR spectrum,
,
ppm: 0.75 t (3H, CH3, J = 7.0 Hz), 1.00 1.30 m (8H),
1.25 t (3H, CH3, J = 7.0 Hz), 1.50 2.30 (10H), 2.35 t
(2H, CH2), 3.33 s (3H, OCH3), 4.12 q (2H, OCH2,
J = 6.8 Hz), 4.10 4.20 m (1H), 4.85 br.s (1H, 6 -H),
5.32 m (3H, CH CH, 4 -H), 6.70 6.90 m (2H,
CH CH), 7.40 m (2H), 7.55 m (1H), 8.00 m (2H,
Harom). 13C NMR spectrum, C, ppm: 13.93 (CH3),
14.18 (CH3), 20.79 and 20.81 (C3), 22.37 (C7 ), 25.09
and 25.16 (C5 ), 27.28 (C4 ), 29.07 (C1 ), 31.41 (C6 ),
33.96 (C2), 35.80 (C5 ), 36.28 and 36.32 (C4), 45.43
and 45.57 (C2 ), 54.77 (OCH3), 60.27 (OCH2), 69.79
and 69.87 (C5), 71.40 (C1 ), 71.67 (C4 ), 98.57 (C6 ),
124.87 and 125.15 (C3 ), 128.24 (Co), 128.80 and
129.04 (C2 ), 129.54 (Cm), 130.35 (Ci), 131.89 and
131.98 (C7), 132.82 (Cp), 137.06 and 137.16 (C6),
165.58 (CO2), 173.49 and 173.53 (C1).
1
CHCl3). IR spectrum, , cm : 1600, 1620, 1660,
1
1690, 1720, 1750, 3040. H NMR spectrum, , ppm:
(2 R,3 S,6 S,5RS)-7-[6-Methoxy-4-oxo-3-(2Z-oc-
tenyl)tetrahydropyran-2-yl]-6E-hepten-5-olide
(XIII). A solution of 30 mg (0.6 mmol) of sodium
methoxide in 1 ml of methanol was added under
stirring at room temperature to a solution of 0.2 g
(0.4 mmol) of benzoate XI in 2 ml of methanol.
When the reaction was complete (TLC), the mixture
was diluted with 5 ml of water and extracted with
chloroform (3 5 ml). The combined extracts were
washed with water and a saturated aqueous solution of
sodium chloride, dried over MgSO4, and evaporated.
The residue was subjected to chromatography on silica
0.78 t (3H, CH3, J = 7 Hz), 1.00 1.40 m (6H, 3CH2),
1.70 2.35 m (9H, 4CH2, CH), 2.37 t (2H, CH2, J =
7.1 Hz), 2.65 t (2H, CH2, J = 7 Hz), 3.33 s (3H,
OCH3), 3.66 s (3H, OCH3), 4.29 d.d (1H, 2 -H, J =
10.1, 6.1 Hz), 4.89 s (1H, 6 -H), 5.30 5.50 m (3H,
4 -H, CH CH), 6.38 d (1H, 6-H, J = 15.8 Hz),
6.86 d.d (1H, 7-H, J = 15.8, 6.1 Hz), 7.38 7.50 m
(2H, o-H), 7.50 7.60 m (1H, p-H), 7.95 8.10 m (2H,
m-H). 13C NMR spectrum (CDCl3), C, ppm: 13.87
(CH3), 18.97 (C3), 22.33 (C7 ), 24.89 (C5 ), 27.30
(C4 ), 28.99 (C1 ), 31.37 (C6 ), 32.98 (C2), 35.70 (C5 ),
39.28 (C4), 45.72 (C3 ), 51.44 (OCH3), 69.54 (C4 ),
70.37 (C2 ), 98.60 (C6 ), 124.69 (C2 ), 128.27 (Co),
129.50 (C3 ), 129.52 (Cm), 130.38 (Cp), 132.41 (Ci),
gel to isolate 0.11 g (72%) of lactone XII. Rf 0.1
1
(ethyl acetate hexane, 1:1). H NMR spectrum,
,
ppm: 0.86 t (3H, CH3, J = 7 Hz), 3.30 s (3H, OCH3),
3.90 m (2H, 5-H, 4 -H), 4.80 m (2H, 6 -H, 5-H),
5.45 m (2H, CH CH), 5.80 m (2H, CH CH).
A mixture of 0.1 g (0.27 mmol) of lactone XII and
0.8 g ( 0.82 mmol) of pyridinium chlorochromate on
aluminum oxide in 2 ml of methylene chloride was
stirred for 12 h at room temperature. The mixture was
filtered, the precipitate was washed with methylene
chloride (5 2 ml) on a filter, and the filtrate was
combined with the washings and evaporated to obtain
75 mg (76%) of compound XII as a 3:2 mixture of
132.69 (C6), 142.89 (C7), 165.51 (CO2), 173.45
(CO2), 199.07 (C O).
Ethyl (2 R,3 S,4 R,6 S,5RS)-7-[4-benzoyloxy-6-
methoxy-3-(2Z-octenyl)tetrahydropyran-2-yl]-5-
hydroxy-6E-heptenoate (XI). A freshly prepared
solution of 3.5 mg (0.94 mmol) of NaBH4 in 1 ml of
EtOH was added with stirring at 0 C to a solution of
0.2 g (0.4 mmol) of enone X in 3 ml of EtOH. The
mixture was stirred for 30 min, acidified with 3% hy-
drochloric acid to pH 5, and extracted with ethyl
acetate (3 5 ml). The extract was washed with
an aqueous solution of sodium chloride (2 3 ml),
dried over MgSO4, and evaporated under reduced
pressure. The residue was subjected to chromatog-
raphy on silica gel using ethyl acetate hexane (1:1)
as eluent to isolate 0.19 g (95%) of compound XI
(Rf 0.39) as a mixture of epimers (1:1, HPLC);
oily substance. The HPLC retention times were 8.7
1
epimers at C5. Oily substance. H NMR spectrum, ,
ppm: 0.87 t (3H, CH3, J = 7 Hz), 1.19 1.40 m (6H,
3CH2), 1.60 2.70 m (13H), 3.33 s (3H, OCH3),
4.22 m (1H, 2 -H), 4.86 m (1H, 5-H), 5.10 br.s (1H,
6 -H), 5.20 5.30 m (2H, CH CH), 5.80 5.90 m
(2H, CH CH). 13C NMR spectrum, C, ppm: 14.10
(CH3), 18.29 (C3), 22.46 (C7 ), 22.59 (C5 ), 27.42
(C4 ), 28.12 (C1 ), 29.19 (C4), 29.58 (C6 ), 31.59 (C2),
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AKHMETVALEEV et al.
46.78 (C4 ), 54.99 (OCH3), 55.05 (C3 ), 72.89 and
73.05 (C2 ), 79.23 (C5), 99.89 (C6), 126.15 and 126.23
(C3 ), 130.29 and 130.55 (C6), 131.48 and 131.63
(C2 ), 131.86 (C7), 170.74 (CO2), 204.44 (C O).
5. Miftakhov, M.S., Imaeva, L.R., Fatykhov, A.A., and
Akhmetvaleev, R.R., Russ. J. Org. Chem., 1997,
vol. 33, p. 47.
6. Miftakhov, M.S., Akhmetvaleev, R.R., Imaeva, L.R.,
Vostrikov, N.S., Saitova, M.Yu., Zarudii, F.S., and
Tolstikov, G.A., Khim.-Farm. Zh., 1996, vol. 30,
p. 22.
7. Tolstikov, G.A., Akbutina, F.A., Adler, M.E.,
Sidorov, N.N., Kuchin, A.V., and Miftakhov, M.S.,
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This study was financially supported by the Rus-
sian Foundation for Basic Research (project no. 99-
03-32916).
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