Synthesis of sulfur-containing bis-terpenoids based on monoterpene oxides

Article abstract of DOI:10.1023/A:1017515825696

Ethanedithiol and di(mercaptoethyl)sulfide react regio- and stereoselectively with (+)-3-carene and α-hydroxy(-)-β-pinene β-oxides in the presence of sodium ethoxide to give the corresponding bis- and tris-sulfides with two terpene fragments.

Full text of DOI:10.1023/A:1017515825696

Chemistry of Natural Compounds, Vol. 36, No. 6, 2000
SYNTHESIS OF SULFUR-CONTAINING BIS-TERPENOIDS
BASED ON MONOTERPENE OXIDES
V. A. Startseva, L. E. Nikitina, N. P. Artemova,
S. A. Dieva, and V. V. Plemenkov
UDC 547.597
Ethanedithiol and di(mercaptoethyl)sulfide react regio- and stereoselectively with (+)-3-carene and
-
hydroxy(-)- -pinene -oxides in the presence of sodium ethoxide to give the corresponding bis- and tris-
sulfides with two terpene fragments.
Key words: monoterpene oxides, ethandithiol, di(mercaptoethyl)sulfide.
Natural monoterpenoids exhibit various biological activity, including antitumor [1]. Chemical modification of these
compounds can effectively increase the biological activity. On the other hand, various mono-, di-, and polysulfides exhibit
significant antitumor activity [2].
A series of terpenylsulfides synthesized by us was tested at the National Cancer Institute (NCI, USA) for antitumor
activity. These included 1, obtained from the reaction of (+)-3-carene -oxide (2) with thiourea in the presence of sodium
ethoxide [3]:
OH
OH
S
1
The antitumor effect was evaluated in percent effectiveness of inhibiting the growth of 60 cell lines for 8 tumor types
(
Leukemia, Non-Small Cell Lung Cancer, Small Cell Lung Cancer, Colon Cancer, CNS Cancer, Melanoma, Ovarian Cancer,
-9
-4
Renal Cancer). The experiment was carried out using a series of concentrations (from 10 to 10 mol/L) of the studied
-4
compound. Sulfide 1 acted as a growth inhibitor (34%) for leukemia and melanoma cell lines at 10 mol/L concentration.
The literature indicates that the biological activity tends to increase on going from mono- to bis- and polysulfides [2].
Thus, we hypothesized that increasing the number of sulfide groups in 1 could positively affect the biological activity of the
modified compound.
A synthetic approach to the new potentially biologically active terpenoids was developed by synthesizing bis- and tris-
sulfides using (+)-3-carene -oxide (2) and -pinene -oxide (3) as starting materials. The literature method was used to
synthesize 2 [4]. Reaction of (-)- -pinene and peroxybenzimidic acid using a method analogous to that in the literature [5] gave
-pinene -oxide (3).
Reaction of 2 and 3 with ethanedithiol and di(mercaptoethyl)sulfide in the presence of sodium ethoxide gives in each
instance a single product (4-7), which is isolated by column chromatography on silica gel. The purity of the compounds was
confirmed by GLC; the composition of 4 and 5, by elemental analysis; adducts 6 and 7, by mass spectrometry. The structure
1
was established using IR and H NMR spectroscopies. The reactions typically have good yields of the target compounds (62-
6
4%).
Apparently the reactions follow the general mechanism (described previously by us for reactions of 3-carene - and
S. V. Kurashov Kazan State Medical University, 420012 Kazan , ul. Butlerova 49, e-mail: nikit@mi.ru. Translated
from Khimiya Prirodnykh Soedinenii, No. 6, pp. 468-469, November-December, 2000. Original article submitted July 17, 2000.
©
0
009-3130/00/3606-0587$25.00 2001 Plenum Publishing Corporation
587

-oxides with thiourea in the presence of sodium ethoxide [3]). Thus, the thiol formed in the first step attacks a second oxide
molecule. This produces the corresponding bis- and tris-sulfides 4-7.
8
9
'
8
OH
7
SH
OH
'
9
O
H
S
5'
'
7
1
5
HS
C H ONa
H
S
H
S
3
OH
3
'
1
2
5
'
10
SH
2
11
12
10'
8
9
4
7
'
8
OH
S
1
5
'
9
HS
SH
5'
H
S
3
H
S
'
7
C H ONa
2
5
10
OH
3
'
1
14
S
'
11
12
13
'
0
1
5
8
9
7
5
SH
3
8'
'
7
9'
10'
SH C
HS
1
11
2
10
C H ONa
CH2S
HO
2
5
12
'
OH
3
'
1
5
'
O
3
6
8
9
7
S
HS
SH
3
5
C H ONa
'
2
5
1
8
'
'
9
'
0
7
'
1
1
0
SH C
2
CH S
2
S
OH
HO
'
3
'
1
5
7
EXPERIMENTAL
1
H NMR spectra of 4-7 in CDCl were measured on a Varian Unity-300 (300 MHz) spectrometer with TMS internal
3
standard; IR spectra, in mineral oil on a spectrometer-75 IR. Mass spectra of 6 and 7 were obtained on an Incos-50B mass
spectrometer in combination with a Varian-3400 gas chromatograph, capillary column, SE-30 phase, and 0.25 mm diameter.
o
o
The ionizing-electron energy was 70 eV. The injector temperature was 250 C; ion-source temperature, 150 C. Elemental
analyses of 4 and 5 correspond with those calculated.
Synthesis of 1,2-bis(4,4 -(3-Hydroxycaranyl))dithioethane (4), 2,2 -bis(4,4 -(3-Hydroxycaranyl))di(thioethyl)
sulfide (5), 1,2-bis(10,10 -(2-Hydroxypinanyl)dithioethane (6), and 2,2 bis(10,10 -(2-Hydroxypinanyl)di(thioethyl)sulfide
(
(
7). A solution of sodium ethoxide (0.76 g Na, 0.033 mol) in absolute C H OH (30 mL) was treated upon stirring with thiol
3.3 mmol) and oxide (2, 3, 6.6 mmol). The reaction mixture was heated at 90 C for 1.5-2.5 h. Water (100 mL) was added.
2 5
o
The mixture was extracted with ether. The ether was dried over MgSO . Solvent was distilled off. Products were separated
4
by column chromatography on silica gel (hexane—ether) as oily liquids. Yield, %: 4, 62; 5, 64; 6, 68; 7, 74.
1
Compound 4: H NMR ( , ppm, J, Hz): 0.44, 0.63 (m, m, H-1, H-1 , H-6, H-6 ), 0.84, 0.86 (s, s, 6H-7, 6H-7 ), 1.042,
1
.052 (s, s, 3H-10, H-10 ), 1.74, 1.92 (m, m, 2H-5, 2H-5 , 2H-2, 2H-2 ), 2.09, 2.22 (m, m, H-4, H-4 ), 2.70 (m, 2H-11, 2H-12).
-1
IR spectrum ( , cm ): 3500 (OH).
1
Compound 5: H NMR ( , ppm, J, Hz): 0.59, 0.78 (m, m, H-1, H-1 , H-6, H-6 ), 0.99, 1.02 (s, s, 6H-7, 6H-7 ), 1.20
(s, 3H-10, 3H-10 ), 1.89, 2.07 (m, m, 2H-5, 2H-5 , 2H-2, 2H-2 ), 2.22, 2.38 (dd, dd, J = 6.0, J = 10.0, H-4, H-4 ), 2.75 (m, 2H-
5
88

1
2, 2H-13), 2.86 (m, 2H-11, 2H-14).
-1
IR spectrum ( , cm ): 3520 (OH).
20
o
1
Compound 6: [ ]D -17.8 (0.16 M, ethanol), H NMR ( , ppm, J, Hz): 0.93, 1.24 (s, s, 6H-7, 6H-7 ), 1.53 (d, H-1,
H-1 ), 1.75-2.25 (m, 2H-3, 2H-3 , 2H-4, 2H-4 , 2H-6, 2H-6 ), 2.77, 2.86 (2H-10, 2H-10 , AB centers, J = 13.36), 2.02 (t,
J = 5.4, 2H-11, 2H-12).
-1
+
IR spectrum ( , cm ): 3500 (OH). Mass spectrum, m/z (I , %): [M ] 398 (0.2), 380 (1), 260 (8), 139 (90), 122 (100),
rel
6
9 (89), 55 (83), 41 (80).
Compound 7: [ ]D -10.3 (0.5 M, ethanol), H NMR ( , ppm, J, Hz): 0.94, 1.24 (s, s, 6H-7, 6H-7 ), 1.52 (d, H-1,
2
0
o
1
H-1 ), 1.75-2.25 (m, 2H-3, 2H-3 , 2H-4, 2H-4 , 2H-6, 2H-6 ), 2.76, 2.85 (2H-10, 2H-10 , AB centers, J = 13 Hz), 2.01 (t,
J = 5.4, 2H-11, 2H-12, 2H-13, 2H-14).
-1
+
IR spectrum ( , cm ): 3500 (OH). Mass spectrum, m/z (I , %): [M ] 458 (0.2), 440 (5), 320 (10), 182 (28), 167 (37),
rel
1
34 (79), 93 (62), 81 (27), 75 (59), 69 (100), 41 (83).
ACKNOWLEDGMENT
The work was supported by INCO-COPERNICUS (grant No. IC 15CT 98015015).
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