New 9,11-ethano-7-oxo-13-thia prostanoids

Article abstract of DOI:10.1023/A:1022559428435

New 9,11-ethano analogs of prostaglandin endoperoxides containing a sulfur atom in position 13 were synthesized by nucleophilic addition of thiols at the polarized double bond of 2-acylbicyclo[2.2.1]hept-2-enes. Physicochemical properties and biological a

Full text of DOI:10.1023/A:1022559428435

Russian Journal of Organic Chemistry, Vol. 38, No. 12, 2002, pp. 1749 1754. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 12, 2002,
pp. 1810 1815.
Original Russian Text Copyright
2002 by Bondar’, Isaenya, Skupskaya, Lakhvich.
New 9,11-Ethano-7-oxo-13-thia Prostanoids
N. F. Bondar’, L. P. Isaenya, R. V. Skupskaya, and F. A. Lakhvich
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus,
ul. Kuprevicha 5/2, Minsk, 220141 Belarus
e-mail: prostan@iboch.bas-net.by
Received April 5, 2002
Abstract New 9,11-ethano analogs of prostaglandin endoperoxides containing a sulfur atom in position 13
were synthesized by nucleophilic addition of thiols at the polarized double bond of 2-acylbicyclo[2.2.1]hept-
2-enes. Physicochemical properties and biological activity of the products were studied.
Prostaglandin endoperoxides (PGG2, PGH2) are
key intermediates in the biosynthesis of primary
prostaglandins (PGE2, PGD2, PGF2, etc.), throm-
boxans (TXA2, TXB2), and prostacyclin (PGI2) from
arachidonic acid. TXA2 and PGI2 are cellular bio-
regulators which exhibit opposite physiological
effects. TXA2 is a powerful vasoconstrictor which
induces thrombocyte aggregation, whereas PGI2
posseses a high vasodilating and antiaggregation
activity. In the absence of pathologies, the action of
TXA2 is counterpoised by the action of PGI2. Im-
balance of these bioregulators induces serious damage
of the cardiovascular and other systems [1, 2]. Native
TXA2 and PGI2 are local hormones which are formed
in cells at a very low concentrations, and they act
instantaneously. Therefore, from the viewpoint of
practical medicine it is important to have a chance
of controlling the TXA2/PGI2 ratio with the aid of
more stable mimetics or antagonists, as well as of
inhibitors of biosynthesis of these bioregulators. In
this connection, of particular interest are 9,11-ethano-
prostanoids, i.e., carbacyclic analogs of PGH [3].
Studies of the structure activity relations in the
series of PGH carbacyclic analogs have shown [4] that
structural variations in the prostanoid -chain, includ-
ing introduction of a heteroatom thereinto, strongly
affects the kind of biological activity. We made
an attempt to synthesize 9,11-ethano-7-oxo-13-thia
prostanoids starting from 2-acylbicyclo[2.2.1]hept-
2-enes II V which were reported by us previously
[5]. The transformation of II V into the target
9,11-ethano prostanoids includes the stage of forma-
tion of a native or modified -chain via conjugate
1,4-addition at the activated double bond.
13-Thia prostanoids were synthesized by nucleo-
philic addition of thiols at the polarized double bond
of acylbicycloheptenes II V. The reaction occurs
readily, and the sulfur atom adds to the electron-
deficient carbon atom at the double bond in a stereo-
selective fashion, in the exo position with respect to
the methylene bridge. All the thiols used turned out
to be active nucleophiles in the Michael addition to
acylbicycloheptenes II V. 1,4-Addition of thiols
VI XIII to enones II V smoothly proceeds at room
Scheme 1.
II, IV, XIV, XV, XVII, XIX, XXI XXIV, n = 4; III, XVI, XVIII, XX, n = 5; V, XXV, n = 6; VI, XIV, R = C4H9; VII,
XV, XVI, R = C6H13; VIII, XVII, XVIII, R = C8H17; IX, XIX, XX, R = C6H5; X, XXI, R = C6H4NH2-4; XI, XXII, R =
CH2COOH; XII, XXIII, XXIV, R = CH(CH3)COOH; XIII, XXV, R = (CH2)2CO2C2H5; II, III, XIV XXII, XXIV, R =
COOCH3; IV, XXIII, R = COOCH3; V, XXV, R = CH3.
1070-4280/02/3812-1749$27.00 2002 MAIK Nauka/Interperiodica

1750
BONDAR’ et al.
Table 1. Spectral parameters of compounds XIV XXV
Comp.
no.
1
1H NMR spectrum, , ppm (J, Hz)
IR spectrum, , cm
[M]+
XIV
0.92 t (3H, CH3, 3J16, 17 = 7.0), 1.06 m (1H, endo-11 -H), 1.17 1.46 m (5H, 760, 890, 961, 1015, 326
2
1H, exo-9 -H; 1H, endo-9 -H; 1H, anti-10-H, J10, 10 = 10.0; 2H, CH2),
1045, 1068, 1110,
1179, 1207, 1265,
1305, 1370, 1445,
1470, 1715 s (C O),
1.46 1.70 m (7H: 6H, 3CH2; 1H, exo-11 -H), 1.84 d.m (1H, syn-10-H,
3
2J10, 10 = 10.0), 2.22 br.d (1H, 11-H, J11, 11 = 4.1), 2.31 t (2H,
3
3
CH2CO2CH3, J3, 4 = 7.0), 2.36 2.51 m [4H, 2H, CH2C(O), J5, 6 = 6.0;
3
4
2H, SCH2, J14, 15 = 7.2], 2.60 br.d (2H: 1H, exo-8-H, J8, 10 = 2.1; 1H,
1748, 2879, 2963
3
4
9-H), 3.12 d.d (1H, endo-12-H, J8, 12 = 4.2, J10, 12 = 2.1), 3.66 s (3H,
CH3O)
XV
0.88 t (3H, CH3, 3J18, 19 = 6.4), 1.00 1.15 m (1H, endo-11 -H), 1.15 1.47 m 824, 850, 890, 918, 960, 354
[9H: 1H, exo-9 -H; 1H, endo-9 -H; 1.36 d.m, 1H, anti-10-H, 2J10, 10 = 9.6;
6H, CH2], 1.47 1.64 m (7H, 3CH2; 1H, exo-11 -H), 1.86 d.m (1H, syn-
1009, 1031, 1077,
1108, 1178, 1205,
1257, 1289, 1300,
1370, 1442, 1459,
1710 s (C O), 1740,
2878, 2955
2
3
10-H, J10, 10 = 9.6), 2.24 br.d (1H, 11-H, J11, 11 = 4.4), 2.33 t (2H,
CH2CO2CH3, 3J3, 4 = 6.9), 2.39 2.57 m [4H; 2.45 t, 2H, CH2C(O), 3J5, 6
7.0; 2.50 t, 2H, SCH2, J14, 15 = 7.2], 2.64 br.s (1H, 9-H), 2.69 t.d (1H,
exo-8-H, 3.18 d.d (1H, endo-12-H, 3J8, 12 = 4.2, 4J10, 12 = 1.9), 3.67 s (3H,
CO2CH3)
=
3
XVI
0.89 t (3H, CH3, 3J18, 19 = 6.8), 1.02 m (1H, endo-11 -H), 1.21 1.41 m (11H: 740, 850, 880, 927, 975, 368
2
1H, exo-9 -H; 1H, endo-9 -H; 1.35 d.m, 1H, anti-10-H, J10, 10 = 9.9; 8H,
4CH2), 1.56 1.70 m (7H: 1H, exo-11 -H; 6H, 3CH2), 1.84 d.m (1H, syn-
1003, 1070, 1081,
1102, 1170, 1200,
1256, 1283, 1294,
1312, 1360, 1432,
2
3
10-H, J10, 10 = 9.8), 2.24 d (1H, 11-H, J11, 11 = 4.4), 2.31 t (2H,
3
3
CH2CO2CH3, J2, 3 = 7.0), 2.42 t [2H, CH2C(O), J5, 6 = 6.5], 2.48 d.t
(2H, SCH2, 3J14, 15 = 7.2, 2J14, 14 = 1.2), 2.63 br.s (1H, 9-H), 2.66 t.d (1H,
1455, 1709 s (C O),
3
3
4
exo-8-H, J8, 12 = 5.0, J8, 9 = 4.9, J8, 9 = 1.8), 3.16 d.d (1H, endo-12-H,
1740, 2865, 2870,
2926, 2950
3J8, 12 = 5.0, J10, 12 = 1.8), 3.66 s (3H, CH3O)
4
XVII 0.89 t (3H, CH3, 3J20, 21 = 6.6), 1.00 1.09 m (1H, endo-11 -H), 1.18 1.43 m 740, 850, 890, 925, 960, 382
2
(13H: 1H, exo-9 -H; 1H, endo-9 -H; 1.35 d.m, 1H, anti-10-H, J10, 10
=
975, 1006, 1075,
9.8; 10H, 5CH2), 1.51 1.65 m (7H: 6H, 3CH2; 1H, exo-11 -H; 1.85 d.m
(1H, syn-10-H, J10, 10 = 9.8), 2.23 br.d (1H, 11-H, J11, 11 = 4.2), 2.32 t
1102, 1170, 1200,
2
3
1258, 1296, 1302,
1365, 1433, 1455,
3
3
(2H, CH2CO2CH3, J3, 4 = 6.9), 2.43 t [2H, CH2C(O), J5, 6 = 6.2],
3
2
2.48 t.d (2H, SCH2, J14, 15 = 7.8, J14, 14 = 1.3), 2.61 m (1H, 9-H),
2.65 t.d (1H, exo-8-H, 3J8, 12 = 4.6, 4J8, 9 = 1.5), 3.17 d.d (1H, endo-12-H,
1709 s (C O), 1740,
2860, 2870, 2926,
2950
3J8, 12 = 4.6, J10, 12 = 1.5), 3.66 s (3H, CH3O)
4
XVIII 0.89 t (3H, CH3, 3J20, 21 = 6.9), 1.04 m (1H, endo-11 -H), 1.22 1.41 m (15H: 745, 850, 880, 927, 955, 396
1H, exo-9 -H; 1H, endo-9 -H; 1H, anti-10-H; 12H, 6CH2), 1.53 1.69 m
(7H, 6H, 3CH2; 1H, exo-11 -H), 1.84 d.m (1H, syn-10-H, J10, 10 = 9.6),
2.24 br.d (1H, 11-H, 3J11, 11 = 4.2), 2.31 t (2H, CH2CO2CH3, 3J2, 3 = 7.4),
1006, 1105, 1175,
1200, 1258, 1295,
2
1365, 1435, 1454,
3
3
2.41 t [2H, CH2C(O), J5, 6 = 7.4], 2.48 t.d (2H, SCH2, J14, 15 = 7.8,
1710 s (C O), 1740,
2860, 2878, 2930,
2960
2J14, 14 = 1.3), 2.61 br.s (1H, 9-H), 2.65 t.d (1H, exo-8-H, J8, 12 = 4.6,
3
4J8, 9 = 1.5), 3.17 d.d (1H, endo-12-H, J8, 12 = 4.6, J10, 12 = 1.5), 3.68 s
3
4
(3H, CH3O)
XIX
1.02 1.19 m (1H, endo-11 -H), 1.19 1.48 m (3H: 1H, exo-9 -H; 1H, endo- 906, 917, 944, 992, 346
2
9 -H; 1.41 d.m, 1H, anti-10-H, J10, 10 = 9.8), 1.48 1.68 m (5H, 4H,
1015, 1033, 1060,
1090, 1094, 1165,
1200, 1245, 1278,
1290, 1360, 1406,
1432, 1449, 1477,
2CH2; 1H, exo-11 -H), 1.94 d.m (1H, syn-10-H, 2J10, 10 = 9.8), 2.29 t (2H,
3
3
CH2CO2CH3, J3, 4 = 6.8), 2.33 m [3H, 2H, CH2C(O), J5, 6 = 6.9; 1H,
3
4
11-H], 2.64 br.s (1H, 9-H), 2.76 t.d (1H, exo-8-H, J8, 12 = 4.6, J8, 9
1.8), 3.67 s (3H, CO2CH3), 3.75 d.d (1H, endo-12-H, J8, 12 = 4.6,
=
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

NEW 9,11-ETHANO-7-OXO-13-THIA PROSTANOIDS
1751
Table 1. (Contd.)
Comp.
no.
1
1H NMR spectrum, , ppm (J, Hz)
IR spectrum, , cm
[M]+
XIX
4J10, 12 = 2.0), 7.16 t (1H, 4 -H, C6H5), 7.25 d.d (2H, 3 -H, 5 -H, C6H5),
7.32 d (2H, 2 -H, 6 -H, C6H5)
1584, 1712 s (C O),
1742, 2861, 2842,
3048, 3067
XX
1.09 m (1H, endo-11 -H), 1.20 1.45 m (5H: 1H, exo-9 -H; 1H, endo-9 -H; 955, 1029, 1070,1090, 360
2
1.40 d.m, 1H, anti-10-H, J10,10 10.5; 2H, CH2), 1.48 1.67 m (5H: 4H,
1108, 1175, 1200,
1253, 1260, 1300,
1365, 1410, 1440,
1455, 1480, 1585,
1710, 1740, 2878,
2965, 3062, 3080
2
2CH2; 1H, exo-11 -H), 1.95 d.m (1H, syn-10-H, J10, 10 = 10.5), 2.23
3
2.40 m [5H: 2.28 t, 2H, CH2CO2CH3, J3, 4 = 7.4; 2H, CH2C(O); 1H,
3
3
11-H], 2.63 br.s (1H, 9-H), 2.76 t.d (1H, exo-8-H, J8, 12 = 4.8, J8, 9
=
=
4.8, J8, 9 = 1.8), 3.68 s (3H, CO2CH3), 3.74 d.d (1H, endo-12-H, 3J8, 12
4.8, J10, 12 = 1.8), 7.16 t (1H, 4 -H, C6H5), 7.25 d.d (2H, 3 -H, 5 -H,
4
4
C6H5), 7.32 d (2H, 2 -H, 6 -H, C6H5)
XXI
1.00 1.14 m (1H, endo-11 -H), 1.17 1.43 m (3H: 1H, exo-9 -H; 1H, endo- 960, 1018, 1110, 1182, 361
2
4
9 -H; 1.36 d.m, 1H, anti-10-H, J10, 10 = 10.0, J10, 12 = 1.9), 1.43 1.67 m
1205, 1220, 1269,
1300, 1372, 1442,
1463, 1506, 1609,
1635 m ( NH), 1715,
1740, 2372, 2880,
2960, 3242, 3382,
3475
2
(5H, 4H, 2CH2; 1H, exo-11 -H), 1.94 d.m (1H, syn-10-H, J10, 10 = 10.0),
2.11 2.42 m [5H, 2H, CH2COOCH3; 2H, CH2C(O); 1H, 11-H], 2.58 br.s
3
4
(1H, 9-H), 2.70 t.d (1H, exo-8-H, J8, 12 = 4.1, J8, 9 = 1.9), 3.48 d.d (1H,
3
4
endo-12-H, J8, 12 = 4.1, J10, 12 = 2.0), 3.66 s (3H, COOCH3), 6.55 d
(2H, 2 -H, 6 -H, C6H5), 7.18 d (2H, 3 -H, 5 -H, C6H5)
XXII 0.98 1.13 m (1H, endo-11 -H), 1.16 1.49 m (3H: 1H, exo-9 -H; 1H, endo- 912, 962, 1015, 1050, 328
2
4
9 -H; 1H, anti-10-H, J10, 10 = 10.0, J10, 12 = 1.9), 1.62 m (5H: 4H,
1068, 1023, 1155,
1188, 1209, 1270,
1300, 1379, 1415,
1447, 1718 s (C O),
1739, 2882, 2964,
2382 3550
2
2CH2; 1H, exo-11 -H), 1.84 d.m (1H, syn-10-H, J10, 10 = 10.0), 2.26
3
2.40 m (3H, 2.34 t, 2H, CH2COOCH3, J3, 4 = 7.0; 2.30 d.m, 1H, 11-H),
2.45 t [2H, CH2C(O), 3J5, 6 = 6.0], 2.66 br.s (1H, 9-H), 2.76 t.d (1H, exo-
3
4
8-H, J8, 12 = 4.5, J8, 9 = 1.5), 3.31 m (3H: 1H, endo-12-H; 2H, SCH2),
3.68 s (3H, COOCH3), 10.74 br.s (1H, COOH)
XXIII 1.05 m (1H, endo-11 -H), 1.25 m (3H: 1H, exo-11 -H; 1H, exo-9 -H; 1H, 930, 956, 995, 1043, 328
endo-9 -H), 1.36 d.m (1H, anti-10-H, 2J10, 10 = 10.0, 4J10, 12 = 1.6), 1.48 d
1065, 1077, 1108,
1159, 1181, 1209,
1239, 1261, 1294,
1317, 1378, 1511,
3
(3H, CH3, J14, 15 = 7.2), 1.56 m (4H, 2CH2), 1.76 d.m (1H, syn-10-H,
3
2J10, 10 = 10.0), 2.28 d (1H, 11-H, J11, 11 = 4.2), 2.32 2.54 m (4H,
3
3
2CH2), 2.61 br.s (1H, 9-H), 2.76 t.d (1H, 8-H, J8, 12 = 4.3, J8, 9 = 4.3,
4J8, 9 = 1.6), 3.37 d.d (1H, exo-12-H, J8, 12 = 4.3, J10, 12 = 1.6), 3.41 q
(1H, CHS, J14, 15 = 7.2), 10.08 br.s (2H, COOH)
1554, 1708 s (C O),
2880, 2400 3460
3
4
3
XXIV 1.04 m (1H, endo-11 -H), 1.17 1.70 m (13H: 1H, exo-11 -H; 1H, exo-9 -H; 959, 1004, 1047, 1064, 342
2
4
1H, endo-9 -H; 1.36 d.m, 1H, anti-10-H, J10, 10 = 10.0, J10, 12 = 1.6;
1080, 1108, 1176,
1208, 1241, 1260,
1291, 1316, 1371,
1412, 1440, 1452,
1707, 1736, 2878,
2959,2350 3400
1.45 d, 3H, CH3, 3J14, 15 = 7.2), 1.78 d.m (1H, syn-10-H, J10, 10 = 10.0),
2.27 d (1H, 11-H, J11, 11 = 4.2), 2.32 2.48 m (4H, 2CH2), 2.62 br.s (1H,
9-H), 2.71 t.d (1H, 8-H, J8, 12 = 4.3, J8, 9 = 4.3, J8, 9 = 1.6), 3.32
3.54 m (2H: 1H, 12-H; 3.44 q, 1H, CHS, J14, 15 = 7.3), 3.68 s (3H,
2
3
3
3
4
3
CH3O), 10.40 br.s (1H, COOH)
3
XXV 0.89 t (3H, CH3, J1, 2 = 6.6), 1.04 m (1H, endo-11 -H), 1.21 1.46 m (14H, 935, 954, 1000, 1076, 354
8H, 4CH2; 3H, OCH2CH3; 1H, exo-9 -H; 1H, endo-9 -H), 1.38 d.m (1H,
1115, 1180, 1215,
1242, 1282, 1315,
1345, 1370, 1408,
1455, 1710 s (C O),
1738, 2865, 2879,
2938, 2962
2
anti-10-H, J10, 10 = 9.9), 1.52 1.66 m (3H: 2H, CH2; 1H, exo-11 -H),
2
3
1.84 d.m (1H, syn-10-H, J10, 10 = 9.9), 2.26 br.d (1H, 11-H, J11, 11
=
4.2), 2.41 t [2H, CH2C(O), 3J5, 6 = 7.2], 2.57 2.69 m (4H: 2H, 8-H, 9-H;
3
2H, CH2COOC2H5), 2.75 m (2H, CH2S), 3.21 d.d (1H, 12-H, J8, 12
=
4.3, J10, 12 = 1.9), 4.14 q (2H, CH3CH2O, 3J = 7.2)
4
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

1752
BONDAR’ et al.
temperature in 1 2 h even in the absence of a catalyst
and in such a weakly polar aprotic solvent as benzene.
Products XIV XXV were formed in high yields
(Scheme 1). When the reaction was carried out in the
presence of triethylamine or tetramethylguanidine as
catalyst, the reaction time shortened to 20 and 10 min,
respectively. In all cases, the 1,4-addition products
were isolated in 95 98% yield.
Compounds XIV XXV were purified by column
chromatography or preparative thin-layer chromatog-
raphy on silica gel. They were isolated as oily sub-
stances. Comparison of the spectral data of the reac-
tion mixtures with those of the idividual compounds
showed that the addition yields only products with
trans arrangement of the side chains.
siderable deshielding of 12-H ( 3.76 ppm) in the
spectra of XIX, XX, and XXI is explained by the
effect of the benzene ring (phenylthio group).
Signals in the 13C NMR spectra of compounds
XIV XXI and XXV were assigned using the data
of [6, 7] for substituted bicycloheptanes, taking into
account the known general relations holding in the
spectra of norbornane derivatives [8]. The side-chain
configuration in prostaglandin endoperoxides and their
carbacyclic analogs is established on the basis of the
chemical shift of the bridging carbon atom (C10) [6].
endo-Substitution in bicyclo[2.2.1]heptane derivatives
almost does not affect the position of the C10 signal,
whereas exo-substitution should lead to an upfield
shift of 3 ppm per substituent. The chemical shifts of
C10 in the compounds under study fall into the range
from 38.05 to 38.31 ppm (Table 2), which is consist-
The structure of 13-thia prostanoids is unambigu-
ously confirmed by their spectral data in comparison
with those of initial enones. The IR spectra of XIV
ent with
38 ppm calculated from the data for
C
1
bicycloheptane. Therefore, the substituents are charac-
terized by endo,exo-orientation, i.e., the side chains
are arranged trans. The chemical shift of C7 is
XXV lack absorption bands at 1660 and 1580 cm ,
typical of carbonyl group conjugated with double
1
bond, but a band at 1710 1715 cm appears due to
209 ppm, indicating endo-orientation of the C1 C7
saturated ketone moiety. Doublet signal of the olefinic
C
1
side chain. The signals at
46 and 63 ppm in the
proton ( 6.85 ppm, Table 1) disappears from the H
C
monoresonance spectra are doublets, which suggests
that they belong to carbon atoms attached to the endo-
and exo-substituents in the bicycloheptane system.
The other signals were assigned on the basis of data
for substituted bicycloheptanes [8].
The chemical shifts of carbon atoms of the -chain
containing a carbonyl group in position 7 coincide
with those calculated previously by Kwiatkowski and
co-workers [7] in two independent ways: from the
spectra of methyl heptanoate or 2-heptanone and with
the aid of increments for acetyl and methoxycarbonyl
groups, respectively. The chemical shift of the car-
NMR spectra of the thia analogs, while signals from
8-H ( 2.65 2.76 ppm, t.d) and 12-H ( 3.16
3.74 ppm, d.d, J = 4.8, 1.8 Hz) are present together
with proton signals from the other structural frag-
ments. Among the latter, a characteristic triplet of the
CH2 group at the sulfur atom at 2.48 ppm should
be noted (when R is an alkyl group); in the case of
compounds XXIII and XXIV, the corresponding
signal is a quartet from the CH proton, which is
located at
3.41 and 3.44 ppm, respectively. The
1H NMR signals were assigned on the basis of the
data obtained by the double resonance technique.
bonyl carbon atom,
208.7 209.4 ppm, is very
The trans arrangement of the - and -chains was
derived from the orientation of 8-H and 12-H. The
relative configuration of the latter was established
on the basis of the multiplicities of the corresponding
signals and the coupling constants J8, 12 which were
C
consistent with both Kwiatkowski’s results and the
data for acetone ( 209.6 ppm [8]). Alkyl substitu-
tion at the -carbonCatom induces an additional down-
field shift by 2 3 to 13 ppm, depending on the degree
of branching.
compared with those reported in [5]. Unlike exo-
oriented protons, endo-protons in the bicycloheptane
ring are involved in a limited number of couplings:
The signals from the -chain were identified on the
basis of published data for the corresponding alkanes,
acids, and esters. Undoubtedly, the doublet signal at
1
They show in the H NMR spectra vicinal couplings
32.0 ppm belongs to C14 in the -position with
with J = 4 6 Hz and, in some cases, long-range
W-coupling (J = 1 2 Hz) with the anti-proton of the
methylene bridge. In fact, in the spectra of all com-
pounds XIV XXV, the signal assigned to 8-H is
a triplet of doublets with a vicinal coupling constant
of 4.6 5.0 Hz, located at 2.60 to 2.76 ppm. The
signal from endo-12-H is a doublet of doublets
located in a weaker field, 3.12 3.76 ppm. A con-
C
respect to sulfur. Its chemical shift can be compared
with those found in [4] for thia analogs of prosta-
glandin endoperoxides having a sulfur atom in posi-
tion 14 of the prostanoid chain [9].
Study of biological activity of the compounds
prepared showed that some of them exhibit immuno-
stimulating effect.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

NEW 9,11-ETHANO-7-OXO-13-THIA PROSTANOIDS
1753
Table 2. 13C NMR spectra of compounds XIV XXI and XXV, C, ppm
Atom no.
XIV
XV
XVI
XVII
XVIII
XIX
XX
XXI
XXV
C1
C2
C3
173.54 s 173.77 s 173.81 s
173.80 s
33.90 t
24.57 t
173.96 s
33.90 t
24.77 t
173.66 s
33.85 t
24.50 t
173.64 s
33.84 t
24.65 t
173.50 s
33.73 t
24.37 t
14.05 q
22.63 t
31.72 t,
29.12 t
28.54 t
23.89 t
42.16 s
33.76 t
24.96 t
33.92 t
24.62 t
33.94 t
24.69 t
C4
28.80 t
23.26 t
41.89 t
28.81 t
23.29 t
41.91 t
209.41 s
63.58 d
40.71 d
38.21 t
43.77 d
46.53 d
32.56 t
28.58 t
29.04 t
29.21 t
29.21 t
31.85 t
22.67 t
14.06 q
29.78 t,
23.89 t
51.39 q
28.79 t
23.15 t
41.82 t
208.98 s
62.27 d
40.97 d
38.36 t
C5
23.78 t
41.59 t
23.15 t
41.75 t
23.09 t
41.69 t
209.20 s
63.44 d
40.68 d
38.16 t
43.67 d
46.36 d
32.52 t
28.51 t
29.05 t
29.21 t
29.21 t
31.85 t
22.68 t
14.11 q
29.73 t,
23.86 t
51.51 q
23.05 t
41.76 t
208.91 s
62.16 d
40.98 d
38.31 t
23.72 t
41.61 t
208.72 s 209.65 s
61.94 d 63.40 d
41.06 d 40.74 d
38.05 t
42.86 d 43.74 d
50.44 d 46.30 d
C6
C7
208.86 s 209.14 s 209.30 s
63.29 d 63.58 d 63.54 d
40.57 d 40.72 d 40.70 d
C8
C9
C10
38.10 t
38.21 t
38.19 d
38.21 t
C11
43.54 d 43.77 d 43.75 d
46.20 d 46.53 d 46.49 d
43.37 t
43.43 t
C12
48.28 d
136.29 s
126.18 d
128.82 d
130.24 d
128.82 d
126.18 d
48.41 d
136.27 s
126.13 d
128.80 d
130.21 d
128.80 d
126.13 d
C14
32.08 t
31.68 t
22.01 t
13.64 q 31.47 t
22.56 t
32.58 t
28.58 t
28.70 t
32.60 t
28.56 t
28.69 t
31.46 t
22.55 t
122.67 s
27.33 t
C15
134.78 d 34.98 t
115.28 d 171.95 s
146.13 t
115.28 d
134.78 d
C16
C17
C18
C19
13.99 q 13.99 q
C20
C21
CH2CH2 28.43 t,
22.98 t
CH3O
29.74 t,
23.89 t
51.38 q 51.43 q
28.37 t,
23.82 t
51.46 q
28.37 t,
23.82 t
51.46 q
28.40 t,
22.87 t
51.30 q
29.31 t,
23.72 t
a
a
C2H5O: 14.24 q (CH3), 60.57 t (OCH2).
EXPERIMENTAL
of dry benzene or chloroform, and the mixture was
stirred for 1 2 h at room temperature until the initial
enone disappeared. The solvent was removed under
reduced pressure, and the residue was subjected to
column chromatography on silica gel using hexane
ether as eluent (gradient elution).
Methyl 6-(3-butylthiobicyclo[2.2.1]hept-2-yl)-6-
oxohexanoate (XIV) was synthesized from 0.07 g of
enone II and 0.034 ml of 1-butanethiol (VI). Yield
0.092 g 98%. Oily substance.
Methyl 6-(3-hexylthiobicyclo[2.2.1]hept-2-yl)-6-
oxohexanoate (XV) was synthesized from 0.11 g of
enone II and 0.072 ml of 1-hexanethiol (VII). Yield
0.161 g (97%). Oily substance.
Methyl 7-(3-hexylthiobicyclo[2.2.1]hept-2-yl)-7-
oxoheptanoate (XVI) was synthesized from 0.09 g of
enone III and 0.06 ml of 1-hexanethiol (VII). Yield
0.129 g (97%). Oily substance.
The H and 13C NMR spectra were recorded on
1
a Bruker AC-200 spectrometer (200 MHz) at 25 C
using CDCl3 as solvent and TMS as internal reference.
The IR spectra were obtained on a UR-20 instrument
from samples prepared as thin films. The mass spectra
were run on a Varian-MAT-311A mass spectrometer
(emission current 1000 mA, energy of ionizing elec-
trons 70 eV, vaporizer temperature 120 150 C, ion
source temperature 200 C). The progress of reactions
and the purity of products were monitored by TLC
on Silufol UV-254 plates using ether hexane (1:1)
as eluent. The products were isolated by column
chromatography on Kieselgel 600 silica gel with
ether hexane as eluent (gradient elution). The NMR,
IR, and mass spectral data are given in Tables 1 and 2.
General procedure for the synthesis of 7-oxo-
9,11-ethano-13-thia prostanoids XIV XXV. Thiol
VI XIII, 1.1 mmol, was added to a solution of
1 mmol of 2-acylbicyclo[2.2.1]heptene II V in 10 ml
Methyl 6-(3-octylthiobicyclo[2.2.1]hept-2-yl)-6-
oxohexanoate (XVI) was synthesized from 0.09 g of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002

1754
BONDAR’ et al.
enone II and 0.07 ml of 1-octanethiol (VIII). Yield
REFERENCES
0.143 g (98%). Oily substance.
1. Nugteren, D.H. and Haselhof, E., Biochim. Biophys.
Acta, 1973, vol. 326, no. 3, pp. 399 403.
2. Hamberg, M. and Samuelsson, B., Proc. Natl. Acad.
Sci. USA, 1973, vol. 70, pp. 899 903; Hamberg, M.,
Svensson, J., and Samuelsson, B., Proc. Natl. Acad.
Sci. USA, 1975, vol. 72, no. 8, pp. 2994 2998.
3. Narisada, M., Ohtani, M., Watanabe, F., Uchida, K.,
Arita, H., Doteuchi, M., Hanasaki, K., Kakushi, H.,
Otani, K., and Hara, S., J. Med. Chem., 1988, vol. 31,
pp. 1847 1854; Hagishita, S. and Seno, K., Chem.
Pharm. Bull., 1989, vol. 37, no. 2, p. 327; Seno, K.
and Hagishita, S., Chem. Pharm. Bull., 1989, vol. 37,
no. 4, pp. 948 954.
Methyl 7-(3-octylthiobicyclo[2.2.1]hept-2-yl)-7-
oxoheptanoate (XVIII) was synthesized from 0.06 g
of enone III and 0.05 ml of 1-octanethiol (VIII).
Yield 0.093 g (98%). Oily substance.
Methyl 6-(3-phenylthiobicyclo[2.2.1]hept-2-yl)-6-
oxohexanoate (XIX) was synthesized from 0.08 g of
enone II and 0.04 ml of benzenethiol (IX). Yield
0.114 g (97%). Oily substance.
Methyl 7-(3-phenylthiobicyclo[2.2.1]hept-2-yl)-7-
oxoheptanoate (XX) was synthesized from 0.08 g of
enone III and 0.04 ml of benzenethiol (IX). Yield
0.112 g (97%). Oily substance.
4. Bondar’, N.F., Kuz’mitskii, B.B., and Malaeva, L.P.,
Vestsi Akad. Navuk BSSR, Ser. Khim. Navuk, 1991,
no. 3, pp. 52 57; Bondar’, N.F., Kuz’mitskii, B.B.,
Mizulo, N.A., Skupskaya, R.V., and Shulyak, V.N.,
Vestsi Akad. Navuk BSSR, Ser. Khim. Navuk, 1999,
no. 3, pp. 89 91.
5. Bondar’, N.F., Skupskaya, R.V., Kozinets, V.A., and
Lakhvich, F.A., Zh. Org. Khim., 1989, vol. 25, no. 3,
pp. 656 657; Bondar’, N.F., Skupskaya, R.V., Lev-
chenko, V.K., and Lakhvich, F.A., Vestsi Akad. Navuk
BSSR, Ser. Khim. Navuk, 1991, no. 3, pp. 48 52;
Bondar’, N.F., Skupskaya, R.V., and Lakhvich, F.A.,
Vestsi Akad. Navuk Belarusi, Ser. Khim. Navuk, 1995,
no. 1, pp. 65 68.
6. Pekhk, T., Vyalimyae, T., Samel’, N., Lopp, M.,
Lille, Yu., and Lippmaa, E., Izv. Akad. Nauk Est. SSR,
Khim., 1982, vol. 31, no. 2, pp. 85 90.
7. Danikiewicz, W., Jaworski, T., and Kwiatkowski, S.,
Monatsh. Chem., 1986, vol. 117, no. 11, pp. 1279
1286.
Methyl 6-[3-(4-aminophenylthio)bicyclo[2.2.1]-
hept-2-yl]-6-oxohexanoate (XXI) was synthesized
from 0.05 g of enone II and 0.029 g of 4-aminoben-
zenethiol (X). Yield 0.074 g (96%). Oily substance.
Methyl 6-(3-carboxymethylthiobicyclo[2.2.1]-
hept-2-yl)-6-oxohexanoate (XXII) was synthesized
from 0.07 g of enone II and 0.023 ml of mercapto-
acetic acid (XI). Yield 0.093 g (96%). Crystallizable
viscous liquid.
6-[3-(1-Carboxyethylthio)bicyclo[2.2.1]hept-2-
yl]-6-oxohexanoic acid (XXIII) was synthesized
from 0.075 g of enone IV and 0.033 ml of 2-mer-
captopropionic acid (XII). Yield 0.105 g (95%). Crys-
tallizable viscous liquid.
Methyl 6-[3-(1-carboxyethylthio)bicyclo[2.2.1]-
hept-2-yl]-6-oxohexanoate (XXIV) was synthesized
from 0.105 g of enone II and 0.043 ml of 2-mercapto-
propionic acid (XII). Yield 0.145 g (95%). Crystal-
lizable viscous liquid.
8. Levy, G.C. and Nelson, G.L., Carbon-13 Nuclear
Magnetic Resonance for Organic Chemists, New
York: Wiley, 1972.
9. Hall, S.E., Han, W.-C., Harris, D.N., Hedberg, A., and
Ogletree, M.L., J. Med. Chem., 1989, vol. 32, no. 5,
pp. 974 983.
Ethyl 3-(3-octanoylbicyclo[2.2.1]hept-2-ylthio)-
propionate (XXV) was synthesized from 0.08 g of
enone V and 0.05 ml of 3-mercaptopropionic acid
(XIII). Yield 0.124 g (96%). Crystallizable viscous
liquid.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 12 2002