Prostanoids: LXXXVIII. Chlorocyclopentenone building blocks in the synthesis of marine prostanoids

Article abstract of DOI:10.1023/B:RUJO.0000019734.67980.35

Starting from 2,3-dichloro-4,4-ethylenedioxy-2-cyclopentenone, a practical procedure has been developed for the synthesis of a series of 4-substituted 2-chloro-4-hydroxycyclopentenones.

Full text of DOI:10.1023/B:RUJO.0000019734.67980.35

Russian Journal of Organic Chemistry, Vol. 39, No. 12, 2003, pp. 1719 1723. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 12, 2003,
pp. 1791 1795.
Original Russian Text Copyright
2003 by Akhmetvaleev, Karimova, Akbutina, Shavaleeva, Belogaeva, Miftakhov.
Prostanoids: LXXXVIII.* Chlorocyclopentenone Building
Blocks in the Synthesis of Marine Prostanoids
R. R. Akhmetvaleev, A. M. Karimova, F. A. Akbutina, G. A. Shavaleeva,
T. A. Belogaeva, 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 19, 2002
Abstract Starting from 2,3-dichloro-4,4-ethylenedioxy-2-cyclopentenone, a practical procedure has been
developed for the synthesis of a series of 4-substituted 2-chloro-4-hydroxycyclopentenones.
In the preceding paper [2] we have described an ef-
ficient procedure for the transformation of previously
reported dichlorocyclopentenone I [3] into a chloro-
vulone II analog, 11-chloro-substituted chlorovulone
II (II), and substantiated its pharmacological potential.
were prepared by condensation of the corresponding
Grignard and Reformatsky compounds with cyclo-
pentenone I, followed by acid hydrolysis of ethylene
acetals V thus formed (Scheme 2).
Scheme 1.
Special comments should be given to the trans-
formation of I into compounds IVa IVd. Some ap-
prehensions were concerned with the condensation of
I with 2-octynyl bromide (which is a disubstituted
acetylene derivative) under the Reformatsky reaction
conditions [8, 9] and subsequent hydrolysis of acetal
Vd. Our experiments showed that the use of such
a reactive electrophile as compound I ensures prepara-
tion of acetal Vd (as precursor of IVd) in a good
yield. The hydrolysis of Vd was also successful. Here,
it should be noted that we previously failed to effect
acid hydrolysis of analogous acetal VI [9] to the cor-
responding ketone even under fairly severe conditions
[2]. This was explained by the presence in molecule
VI of a side-chain double (Z)-C C bond which
creates steric hindrances to hydrolysis. Acetal Vd
has a linear side-chain acetylenic moiety, so that steric
hindrances are lacking, and the hydrolysis occurs
The present communication deals with possible
applications of compound I in the synthesis of cyclo-
pentenone building blocks for natural chlorine-con-
taining prostanoids, chlorovulones and punaglandins,
which exhibit a strong antiviral and anticarcinogenic
activity [4 7]. Most syntheses of chlorovulones and
punaglandins are based on the use of 4-substituted
2-chloro-4-hydroxy-2-cyclopentenones III as starting
compounds (Scheme 1). Compounds III were syn-
thesized by selective reductive monodechlorination of
2,3-dichloro-4-hydroxy-2-cyclopentenones IV which
____________
*
For communication LXXXVII, see [1].
1070-4280/03/3912-1719$25.00 2003 MAIK Nauka/Interperiodica

1720
AKHMETVALEEV et al.
Scheme 2.
IVa IVd, X = O; Va Vd, X = OCH2CH2O; H+/H2O stands for Me2CO 10% hydrochloric acid, 56 C, 1 h.
relatively smoothly. Presumably, the above stated also
applies to the hydrolysis of compounds Va Vc,
where the side-chain double and triple bonds occupy
terminal position.
pounds VIIa and VIIb, respectively (Scheme 3).
Monodechlorinated products VIIc and VIId obtained
from acetylenic enones IVc and IVd were subjected
to exhaustive dechlorination to obtain chlorine-free
enones VIIIc and VIIId. Prolonged reduction of
enone IVc with increased amount of the reducing
agent (12 equiv of Zn) at elevated temperature (under
reflux) led to conjugated dienone VIIIe (Scheme 4).
Scheme 3.
Compounds IVa IVd were smoothly dechlorinated
with the system Zn NH4Cl MeOH under controlled
conditions. The reactions were fast and selective.
Dechlorination of vinyl and allyl derivatives IVa and
IVb occurred exclusively at the C3 atom to give com-
R = CH2 CH (a), CH2 CHCH2 (b), CH CCH2 (c),
Me(CH2)4C CCH2 (d).
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PROSTANOIDS: LXXXVIII.
1721
Presumably, the reaction involves intermediate forma-
tion of -hydroxycyclopentenone IX via saturation of
the endocyclic double bond. Compound IX undergoes
acetylene allene rearrangement with simultaneous
elimination of water and subsequent reduction of the
terminal double bond in the allene fragment.
(1H, CH ). 13C NMR spectrum (CDCl3), C, ppm:
49.16 (C5), 77.43 (C4), 116.98 (CH2 ), 133.34 (C2),
137.25 (CH ), 164.78 (C3), 193.95 (C O).
4-Allyl-2,3-dichloro-4-hydroxy-2-cyclopentenone
(IVb). Yield 84%, oily substance. IR spectrum,
,
1
1
cm : 850, 1615, 1680, 1740, 3100, 3450. H NMR
spectrum (CDCl3), , ppm: 2.46 d.d (1H, CH2, J =
13.6, 7.1 Hz), 2.52 d.d (1H, CH2, J = 13.6, 7.1 Hz),
2.58 d (1H, 5-H, J = 18.5, 7.1 Hz), 2.80 d (1H, CH2,
J = 18.5, 7.1 Hz), 4.30 br.s (1H, OH), 5.05 5.17 m
(2H, CH2 ), 5.60 5.75 m (1H, CH ). 13C NMR
spectrum (CDCl3), C, ppm: 42.09 (CH2), 46.80 (C5),
77.04 (C4), 120.97 (CH2 ), 130.22 (CH ), 132.73
(C2), 165.83 (C3), 194.43 (C O).
Scheme 4.
2,3-Dichloro-4-hydroxy-4-(2-propynyl)-2-cyclo-
pentenone (IVc). Yield 85%, oily substance. IR spec-
1
trum, , cm : 850, 1615, 1680, 1740, 3100, 3450.
1H NMR spectrum (CDCl3), , ppm: 2.50 2.90 m
(5H, 2CH2, CH), 3.16 br.s (1H, OH). 13C NMR spec-
trum (CDCl3), C, ppm: 29.13 (CH2), 47.22 (C5), 72.8
(CH ), 93.97 (C ), 77.04 (C4), 163.55 (C2), 134.08
(C3), 193.65 (C O).
Thus we have developed a practical and efficient
procedure for the transformation of readily accessible
compound I into key chlorocyclopentenone building
blocks VIIa VIId.
2,3-Dichloro-4-hydroxy-4-(2-octynyl)-2-cyclo-
pentenone (IVd). Yield 50%, oily substance. IR spec-
1
1
trum, , cm : 1614, 1740, 3480. H NMR spectrum
(CDCl3), , ppm: 0.90 t (3H, CH3), 1.20 1.55 m (6H,
3CH2), 2.15 m (2H, CH2), 2.55 2.90 m (5H, 2CH2,
EXPERIMENTAL
OH), 7.39 s (1H, CH). 13C NMR spectrum (CDCl3),
C, ppm: 13.89 (CH3), 18.42 (C4 ), 22.08 (C7 ), 28.17
(C1 ), 29.86 (C5 ), 30.87 (C6 ), 47.79 (C5), 72.52 (C2 ),
The IR spectra were recorded on UR-20 and
Specord M-80 spectrometers from samples prepared
1
as thin films or dispersed in mineral oil. The H and
13C NMR spectra were obtained on a Bruker AM-300
instrument at 300 and 75.47 MHz, respectively, using
tetramethylsilane as internal reference and CDCl3 and
(CD3)2CO as solvents.
77.40 (C4), 85.46 (C3 ), 133.84 (C2), 163.42 (C3),
193.26 (C O).
6,7-Dichloro-8-hydroxy-8-vinyl-1,4-dioxaspiro-
[4.4]non-6-ene (Va). A 0.5 N solution of vinylmagne-
sium bromide in THF, 8 ml, was added dropwise
under argon to a solution of 0.42 g (2.0 mmol) of
ketone I in 10 ml of anhydrous THF, stirred at 20 C.
The mixture was allowed to warm up to 0 C and was
stirred for 0.5 h at that temperature. A saturated solu-
tion of ammonium chloride, 10 ml, was added, and
the product was extracted into chloroform (3 30 ml).
The combined extracts were dried over MgSO4 and
evaporated, and the residue was purified by column
chromatography on silica gel using ethyl acetate
petroleum ether (1:1) as eluent. Yield 45%, oily sub-
4-Alken(yn)yl-2,3-dichloro-4-hydroxy-2-cyclo-
pentenones IVa IVd. Acetal Va Vd, 2 mmol, was
dissolved in a mixture of 20 ml of acetone and 4 ml
of 15% hydrochloric acid. The mixture was heated
for 1 h under reflux and cooled to 20 C, 4 ml of
a saturated aqueous solution of sodium chloride was
added, and the product was extracted into ethyl acetate
(3 20 ml). The combined extracts were washed with
an aqueous solution of sodium chloride until neutral
reaction, dried over MgSO4, filtered, and evaporated.
The residue was purified by column chromatography
on silica gel using ethyl acetate petroleum ether
(3:7) as eluent.
1
1
stance. IR spectrum, , cm : 1610, 3450. H NMR
spectrum (CDCl3), , ppm: 2.35 d.d (1H, 9-H, J =
6.1 Hz), 2.49 d.d (1H, 9-H, J = 6.1 Hz), 3.28 br.s
(1H, OH), 3.80 4.20 m (4H, 2CH2), 5.15 5.45 m
2,3-Dichloro-4-hydroxy-4-vinyl-2-cyclopente-
none (IVa). Yield 50%, oily substance. IR spectrum,
1
, cm : 1610, 1730, 3450. 1H NMR spectrum
(2H, CH ), 5.70 5.90 m (1H, CH ). 13C NMR spec-
trum (CDCl3), C, ppm: 50.09 (C9), 65.80 (CH2O),
(CDCl3), , ppm: 2.80 2.98 m (2H, CH2), 3.30 br.s
(1H, OH), 5.35 5.55 m (2H, CH2), 5.80 6.00 m
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 12 2003

1722
AKHMETVALEEV et al.
66.04 (CH2O), 79.03 (C8), 112.07 (C5), 115.18
(CH2 ), 132.28 (C6), 132.28 (C7), 138.67 (CH ).
of dichlorocyclopentenone IVa IVd in 7 ml of
methanol. The mixture was stirred at 20 C, and the
progress of the reaction was monitored by TLC. When
the initial compound disappeared ( 15 min), the mix-
ture was filtered, 5 ml of a saturated aqueous solution
of ammonium chloride was added to the filtrate,
and the product was extracted into ethyl acetate
(3 20 ml). The combined extracts were dried over
MgSO4, filtered, and evaporated, and the residue was
purified by chromatography on silica gel using ethyl
acetate petroleum ether (1:4) as eluent.
8-Alken(yn)yl-6,7-dichloro-8-hydroxy-1,4-dioxa-
spiro[4.4]non-6-enes Vb Vd. Zinc dust, 15.0 mmol,
was added under vigorous stirring to a solution of
5 mmol of ketone I and 7 mmol of allyl bromide,
2-propynyl bromide, or 6-octynyl bromide in 15 ml of
DMF. The reaction was fairly vigorous and was ac-
companied by heat evolution. After 30 min, the mix-
ture was acidified with a saturated aqueous solution
of ammonium chloride, and the product was extracted
into diethyl ether (3 30 ml). The combined extracts
were dried over MgSO4 and evaporated, and the
residue was purified by chromatography on silica gel
using ethyl acetate petroleum ether (1:1) as eluent.
2-Chloro-4-hydroxy-4-vinyl-2-cyclopentenone
(VIIa). Yield 53%, oily substance. IR spectrum,
,
1
1
cm : 1420, 1720, 3500. H NMR spectrum (CDCl3),
, ppm: 2.70 2.78 m (2H, CH2), 3.29 br.s (1H, OH),
5.20 5.41 m (2H, CH2), 5.90 6,09 m (1H, CH ),
8-Allyl-6,7-dichloro-8-hydroxy-1,4-dioxaspiro-
7.31 br.s (1H, CH). 13C NMR spectrum (CDCl3),
,
[4.4]non-6-ene (Vb). Yield 87%, oily substance. IR
C
1
spectrum, , cm : 1615, 3100, 3450. 1H NMR
ppm: 48.76 (C5), 75.80 (C4), 115.23 (CH2 ), 125.86
(C2), 139.57 (CH ), 157.57 (C3), 198.53 (C O).
spectrum (CDCl3), , ppm: 2.17 d (1H, 0.5CH2, J =
14.2 Hz), 2.32 d.d (1H, CH2, J = 13.7, 7.3 Hz),
2.46 d (1H, 9-H, J = 14.2, 7.3 Hz), 2.48 d (1H,
CH2, J = 13.7 Hz), 3.32 br.s (1H, OH), 3.85 4.20 m
(4H, 2CH2O), 5.05 5.17 5 m (2H, CH2 ), 5.60
5.75 m (1H, CH ). 13C (CDCl3), C, ppm: 42.36
(CH2), 47.82 (C9), 65.92 (C2, C3), 78.69 (C8), 112.22
(C5), 119.62 (CH2 ), 131.82 (CH ), 132.18 (C7),
139.58 (C6).
4-Allyl-2-chloro-4-hydroxy-2-cyclopentenone
(VIIb). Yield 80%, oily substance. IR spectrum,
,
1
1
cm : 850, 1615, 1680, 1740, 3100, 3250. H NMR
spectrum (CDCl3), , ppm: 2.39 d.d (1H, 0.5CH2, J =
15.1, 7.0 Hz), 2.44 d.d (1H, 0.5CH2, J 15.1, 7.0 Hz),
2.57 d (1H, 5-H, J = 18.7 Hz), 2.70 d (1H, 5-H, J =
18.7 Hz), 3.70 3.90 br.s (1H, OH), 4.90 5.10 m (2H,
CH2 ), 5.50 5.70 m (1H, CH ), 7.3 s (1H, OH).
13C NMR spectrum (CDCl3), C, ppm: 44.46 (CH2),
47.21 (C5), 75.23 (C4), 120.33 (CH2 ), 131.37
(CH ), 135.59 (C2), 158.88 (C3), 198.64 (C O).
6,7-Dichloro-8-hydroxy-8-(2-propynyl)-1,4-di-
oxaspiro[4.4]non-6-ene (Vc). Yield 69%, oily sub-
1
stance. IR spectrum, , cm : 1650, 2150, 3320, 3450.
1H NMR spectrum (CDCl3), , ppm: 2.08 t (1H, CH,
J = 2.7 Hz), 2.33 d (1H, 9-H, J = 14.3 Hz), 2.55 d.d
(1H, CH2, J = 15.7, 2.7 Hz), 2.70 d.d (1H, CH2, J =
15.7, 2.7 Hz), 2.72 d (1H, 9-H, J = 14.3 Hz), 3.25 s
(1H, OH), 4.00 m (2H, CH2O), 4.20 m (2H, CH2O).
2-Chloro-4-hydroxy-4-(2-propynyl)-2-cyclopen-
tenone (VIIc). Yield 60%, oily substance. IR spec-
1
trum, , cm : 850, 1615, 1680, 1740, 3100, 3450.
1H NMR spectrum (CDCl3), , ppm: 2.50 2.90 m
(5H, 2CH2, CH), 3.16 br.s (1H, OH), 7.42 s (1H, CH).
13C NMR spectrum (CDCl3), C, ppm: 29.03 (CH2),
48.36 (C9), 78.36 (C8), 78.57 (C ), 112.21 (C5),
133.30 (C6), 138.30 (C7).
13C NMR spectrum (CDCl3), C, ppm: 31.23 (CH2),
47.53 (C5), 72.63 ( CH), 74.94 (C ), 78.29 (C4),
137.18 (C2), 156.73 (C3), 197.41 (C O).
6,7-Dichloro-8-hydroxy-8-(2-octynyl)-1,4-dioxa-
2-Chloro-4-hydroxy-4-(2-octynyl)-2-cyclopente-
spiro[4.4]non-6-ene (Vd). Yield 81%, oily substance.
none (VIId). Yield 76%, oily substance. IR spectrum,
1
1
IR spectrum, , cm : 1610, 3450. H NMR spectrum
(CDCl3), , ppm: 0.86 m (3H, CH3), 2.13 m (2H2),
2.4 3.0 m (5H, 2CH2, OH), 3.80 4.20 m (4H, 2CH2).
13C NMR spectrum (CDCl3), C, ppm: 13.83 (CH3),
1
, cm : 1614, 1740, 3480. 1H NMR spectrum
(CDCl3), , ppm: 0.90 t (3H, CH3), 1.20 1.55 m
(6H, 3CH2), 2.15 m (2H, CH2), 2.55 2.90 m (5H,
2CH2, OH), 7.39 s (1H, CH). 13C NMR spectrum
(CDCl3), C, ppm: 13.99 (CH3), 18.63 (C4 ), 22.19
(C7 ), 28.44 (C6 ), 31.08 (C5 ), 31.80 (C1 ), 47.53 (C5),
73.59 (C2 ), 75.24 (C4), 85.51 (C3 ), 136.84 (C2),
157.23 (C3), 197.61 (C O).
18.51 (C7 ), 22.06 (C4 ), 28.28 (C6 ), 29.40 (C5 ), 30.81
(C1 ), 73.76 (C2 ), 84.05 (C3 ), 48.30 (C9), 78.47 (C8),
112.203 (C5), 132.83 (C6), 138.47 (C7).
4-Alken(yn)yl-2-chloro-4-hydroxy-2-cyclopente-
nones VIIa VIId (general procedure). Zinc dust,
1 g (15.3 mmol), and ammonium chloride, 0.1 g
(1.87 mmol), were added to a solution of 2.5 mmol
Compounds VIIIc and VIIId were synthesized by
subsequent reduction of compounds VIIc and VIId,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 12 2003

PROSTANOIDS: LXXXVIII.
1723
following the procedure described above for the
reduction of IVa IVd.
26.88 (C4), 34.52 (C5), 127.75 (C2), 128.49 (CH ),
136.02 (CH ), 172.86 (C3), 209.76 (C O).
4-Hydroxy-4-(2-propynyl)-2-cycopentenone
This study was financially supported by the Rus-
sian Foundation for Basic Research (project no. 02-
03-32594a).
(VIIIc). Yield 57%, oily substance. IR spectrum, ,
1
1
cm : 850, 1615, 1680, 1740, 3100, 3450. H NMR
spectrum (CDCl3), , ppm: 2.50 2.70 m (5H, 2CH2,
CH), 2.90 br.s (1H, OH), 6.20 d (1H, CH, J = 5.7 Hz),
7.50 d (1H, CH, J = 5.7 Hz). 13C NMR spectrum
(CDCl3), C, ppm: 30.90 (CH2), 48.24 (C5), 72.11
( CH), 77.64 (C ), 78.65 (C4), 134.34 (C2), 163.72
(C3), 205.94 (C O).
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(VIIId). Yield 74%, oily substance. IR spectrum, ,
1
1
cm : 1614, 1740, 3480. H NMR spectrum (CDCl3),
, ppm: 0.90 t (3H, CH3), 1.20 1.70 m (8H, 4CH2),
2.10 2.25 m (2H, CH2), 2.50 2.70 m (5H, 2CH2,
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1
, cm : 1576, 1644, 1676, 1688, 1712, 1744, 3032.
1H NMR spectrum (CDCl3), , ppm: 1.85 d.d (3H,
CH3, J = 6.7, 1.3 Hz), 2.30 2.50 m (2H, 4-H), 2.60
2.70 m (2H, 5-H), 5.87 s (1H, 2-H), 6.48 d (1H, 1 -H,
J = 16.1 Hz), 6.28 d.q (1H, 2 -H, J = 6.7, 1.3 Hz).
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 12 2003