Syntheses and biologic studies of steroidal methyl sulfides and sulfones

Syntheses and biologic studies of steroidal methyl sulfides and sulfones Shafiullah,” P. R. Dua,‘f R. C. Srimal,? and Shahid A. Ansari” “Steroid Research Laboratory, Department Aligarh, India; tDivision of Pharmacology, Lucknow, India

of Chemistry, Aligarh Muslim University, Central Drug Research Institute,

Reactions of cholest-5-ene (I) and its 3/3-chloro (II) and3/3-acetoxy (III) analogs with trimethylchlorosilane-dimethyl sulfoxide in dry acetonitrile furnish cholest4-en-6P-yl methyl sulfide (IV) and its 3P-chloro (V) and 3/3-acetoxy (VZ) analogs. Oxidation of (IV) with m-chloroperbenzoic acid affords cholest4-en6/3-yl methyl sulfone (VIZ) and 4a,.5-epoxy-5a-cholestan-6fi-yl methyl sulfone (VZZI). Under similar reaction conditions, V furnishes 3/3-chlorocholest4-en-6/3-yl methyl sulfone (IX), while VI gives 3pacetoxycholest4-en-6fl-yl methyl s&one (X) and 3~-acetoxy4~,5-epoxy-5a-cholestan-6~-yl methyl sulfone (XZ). The structures of these compounds were established on the basis of analytic and spectral data. Some of these compounds have been evaluated for their possible biologic activities. (Steroids 56:562-565, 1991)

Keywords:

thiosteroids;

biologic studies; trimethylchlorosilane-dimethyl

Introduction A survey of the literature’s’ reveals that trimethylchlorosilane-dimethyl sulfoxide (TMCS-DMSO) is one of the commonly used reagents and solvents for specific organic reactions, and it has been recently selectively used for the preparation of halogen-containing methyl sulfides.3 We have carried out the reaction of easily accessible steroidal olefins (I to III)e with TMCSDMSO to afford steroidal methyl sulfides (IV to VI). Oxidation of compounds IV to VI with m-chloroperbenzoic acid gave steroidal sulfones (VII to XI). The structures of these compounds were established on the basis of their elemental and spectral data (Figure 1). Some of these compounds were tested for their anticonvulsant, antireserpine, anorexigenic, analgesic, antiinflammatory, and diuretic activities. The compounds were evaluated for different central nervous system (CNS) activities in groups of five mice each at a fixed dose of 10 mg/kg intraperitoneally, since most of the known CNS active agents exhibit significant activity at this dose level. The methods described by Dua7 were used for evaluation of different CNS activities of these compounds. The cardiovascular ef-

Address reprint requests to Dr. Shafiullah, at the Steroid Research Laboratory, Department of Chemistry, Aligarh Muslim University, Aligarh, India. Received September 8, 1990; accepted May 8. 1991.

562

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1991, vol. 56, November

sulfoxide; acetonitrile

fects of the compounds were evaluated at a dose of 1 mg/kg intravenously (IV) in pentabarbitone-anesthetized cats by studying the effects on blood pressure and autonomic responses. In pentabarbitone-anesthetized cats, the steroidal methyl sulfide (IV) and steroidal sulfone (VII) at a dose of 1 mg/kg IV produced a transient fall in blood pressure of 16 and 30 mm Hg, respectively. Compound IV showed slightly modified isoprenaline and nictitating membrane responses. Compound VII also potentiated acetylcholine (45%), histamine (77%), isoprenaline (71%), and adrenaline (16%) responses. The chloroderivative of steroidal methyl sulfide (V) has been observed to possess a peculiar feature in that at a dose of 1 mg/kg IV it produces no change in blood pressure but potentiates the adrenaline response (16%). However, when a higher dose of 5 mg/kg IV was used, it was observed that it causes a rise in blood pressure (10 mm Hg) for 2 minutes; adrenaline response was also potentiated by 11%. None of the compounds evaluated at 10 mg/kg intraperitoneally exhibited any significant effect on gross behavior, spontaneous motor activity, electroconvulsions, or reserpine-induced syndrome effects, nor did any compound exhibit analgesic, anorexigenie, anti-inflammatory, or diuretic activities in mice.

Experimental All reported melting points are uncorrected. The infrared spectra were recorded in Nujol with a Pye-Unicam 0

1991 Butterworth-Heinemann

Steroidal methyl sulfides and sulfones:

t

::,

(III)

F1 OAc

(VI)

F1 OAc

Figure 1 Reaction of cholest-5-ene silane-dimethyl sulfoxide.

L

L

ii

R

VII) IX) X)

H Cl OAc

VIII) XI)

H OAc

(I) with trimethylchloro-

SP3-100 spectrometer. Nuclear magnetic resonance spectra were obtained in CDCl, on a Varian A-60D instrument with Me,Si as the internal standard. Light petroleum refers to a fraction of (bp) 60 to 80 C. Thinlayer chromatography (TLC) plates were coated with silica gel (60 to 120 mesh). A 20% aqueous solution of perchloric acid was used as a spraying agent. Anhydrous sodium sulfate was used as the drying agent. Nuclear magnetic resonance values are given in ppm (s, singlet; d, doublet; br, broad; m, multiplet centered at).

Shafiullah et al.

lane (5.0 ml) and dimethyl sulfoxide (5.0 ml) were added slowly. The temperature of the reaction mixture was maintained at 50 to 60 C. The stirring was continued for 6 hours. After completion of reaction, the reaction mixture was poured into cold water (100 ml) and extracted with ether. The ethereal solution was washed with water and sodium bicarbonate solution (10%) and again with water, and was then dried over anhydrous sodium sulfate. Removal of the solvent gave an oily residue that was chromatographed over silica gel (20.0 g). Elution with petroleum ether/ether (20: 1) yielded cholest-4-en-6/3-yl methyl sulfide (IV; 0.785 g, 1.88 mmol, 70.02%), mp 111 C. v,,, : 1,650 (C=C), 765 cm-’ (C-S). The NMR spectrum showed peaks at S 5.33 (m, 4-H), 2.50 (m, 6-H, W1/2 = 8 Hz, equatorial),’ 2.20 (s, 6-S-CH3), 1.12 (s, 19-H), 0.68 (s, 18-H), 0.85, and 0.77 (other methyl protons). Analysis calculated for C,H,,S: C, 80.69; H, 11.60. Found: C, 80.65; H, 11.58. Reactions of steroidal olefins (II and III) with trimethylchlorosilane-dimethyl sulfoxide in dry acetonitrile were carried out under similar reaction conditions (same amount of reactant and reagent were used). Physical, analytic, and spectral data are given in Table 1.

General procedure

m-Chloroperbenzoic acid oxidation of cholest4 en-@-y1 methyl sulfide (IV)

To a stirred solution of steroidal olefin (I; 1.0 g, 2.69 mmol) in dry acetonitrile (10.0 ml), trimethylchlorosi-

Cholest-4-en-BP-y1 methyl sulfide (IV) (1.0 g, 2.39 mmol) was dissolved in chloroform (20 ml); to this was

Table 1

Product

Physical, analytic, and spectral data of the products Solvent of elution (petroleum ether/ether)

Nuclear magnetic resonance spectra Analysis calculated

Found (%I

Infrared spectra (Nujol) urnax.(cm-‘)

52.25

c, 74.54 H, 10.50

74.50 10.50

1,640 (C=C), 770 K-S), 750 K-Cl)

mp ICI

Yield (%.) (mmol)

145

Molecular formula

V

14: 1

VI

1O:l

158-160

68.18

C, 75.89 H, 10.61

75.85 10.56

1,730 (OAc), 1,640 K=CL 1,260, 1,045 (C-O), 765 K-S)

IX

8:l

Oil

46.72

C, 69.59 H, 9.80

69.55 9.75

1,310, 1,140 (-SOJ, 770 (C-S), 750 (C-Cl)

X

3:l

179-182

42.45

c, 71.09 H, 9.94

71.00 9.90

XI

1:l

137-140

36.36

C, 68.92 H, 9.64

68.90 9.60

1,740 1,140 1,045 K-S) 1,735 1 ,130 1,260 (C-O),

d Angular and side-chain

(OAc), 1,330, (--SO2). (C-O), 770 (OAc), 1,310, f-SOJ, (A\), 1,040 765 (C-S)

5.52 (brs, 4-H), 4.10 (m, 3-H, WI/2 = 18 Hz), 2.65 (m, 6-H, W1/2 = 8 Hz), 2.1 (s, 6-S-CH,), 1.22-0.72’ 5.60 (brs, 4-H), 4.20 (m, 3-H. W1/2 = 17 Hz), 2.70 (m, 6-H, Wl, W1/2 = 8 HZ), 2.15 (S, 6-SCH3), 2.0 (s, OAc), 1.18-0.76’ 5.54 (brs, 4-H), 4.2 (m, 3-H, W1/2 = 17 Hz), 3.30 (m, 6-H, W1/2 = 8 Hz), 2.95 (S, 6-O+-CH3), 1 .20-0.68a 5.62 (brs, 4-H). 4.1 (m, 3H, W1/2 = 18 Hz). 3.26 (m, 6-H, W1/2 = 8 Hz), 3.10 (s,6-O+-CH3) 4.2 (m, 3-H, W1/2 = 18 Hz), 3.5 (m, 6-H, W1/2 = 8 Hz), 3.15 (s, 6-02S-CH3), 2.9 (brs, 4-H). 2.0 (s, OAc), 1.22-0.68’

methyl protons.

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1991, vol. 56, November

563

Papers

Cl Q CH3 \

CH3 s=

0

+

t-y-

\

Si -

b

CL

/

/ CH3

CH3

-

CI +

Ot Si Me3)2

+

H3C-S:

-

I

(I-III)

-Y R q?

-HCl

6 Gs+ c’

Sulf

S-CH3

d”3

onium

(A)

ion

Scheme

added m-chloroperbenzoic acid (1.24 g, 7.18 mmol) at 0 C. The reaction mixture was kept at room temperature for 30 hours to complete the conversion of starting material. The progress of reaction was monitored by TLC. The reaction mixture was worked up in chloroform and washed successively with water, sodium bicarbonate solution (lo%), and further with water, and was then dried over anhydrous sodium sulfate. Removal of the solvent gave an oily residue (1.1 g) that was chromatographed over silica gel (20 g). Elution with light petroleum ether/ether (10 : 1) afforded cholest-4-en-6/3-yl methyl sulfone (VII)(0.410 g, 0.91 mmol, 38.23%), mp 131 C. ZJ,,,: 1,300, 1,140 (-SO,),9 1,640 (C=C), 770 cm-’ (C-S). The NMR spectrum gave peaks at 6 5.4 (m, 4-H), 2.95 (m, 6-H, W1/2 = 7 Hz, equatorial), 2.80 (s, 6-O,S-CH,), 1.1 (s, 19-H), 0.7 (s, l&H), 0.90, and 0.82 (other methyl protons). Analysis calculated for C,,H,,SO,: C, 74.94; H, 10.78. Found: C, 74.93; H, 10.77. 564

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1991, vol. 56, November

(IV - VI) 1

Further elution with light petroleum ether/ether (4-l) furnished 4a,5-epoxy-5a-cholestan-6P-yl methyl sulfone (VIII) (0.350 g, 0.75 mmol, 3 1.5 l%), mp 150 C. v,,,: 1,320, 1,190 (-SO,), 1,240 (epoxy ring), 765 cm-’ (C-S). The NMR spectrum exhibited peaks at 6 3.6 (m, 4-H, axial),9 3.30 (m, 6-H, W1/2 = 8 Hz, equatorial), 2.95 (s, 6-OS-CH,), 1.1 (s, 19-H), 0.7 (s, 18H), 0.91, and 0.84 (other methyl protons). Analysis calculated for C,sH,,SO,: C, 72.36; H, 10.41. Found: C, 72.34; H, 10.40. Oxidations of steroidal methyl sulfides (II and III) with m-chloroperbenzoic acid at 0 C furnished products IX to XI. Physical, analytic, and spectral data are summarized in Table 1.

Results and discussion The formation of steroidal methyl sulfides basically involves the generation of a sulfonium ion intermediate

Steroidal methyl sulfides and sulfones:

that is formed due to the reaction of dimethyl sulfoxide with trimethylchlorosilane. The sulfonium ion intermediate is converted into methanesulfenyl chloride due to attack of nucleophile. The latter attacks at olefinic bond of steroidal compounds I to III, giving rise to a cyclized sulfonium ion, which affords 5-chloro intermediate (A). This intermediate suffers elimination to give 6P-methyl sulfides (IV to VI) (Scheme 1). Steroidal sulfones (VII, IX, and X) and epoxy sulfones (VIII and XI) were obtained simply by treating the methyl sulfides (IV to VI) with m-chloroperbenzoic acid.

Shafiullah

et al.

References 1.

2.

3.

4.

Bellesia F, Ghelfi F, Grandi R, Pagnoni UM (1986). Reactions of the trimethylchlorosilane-dimethyl sulphoxide reagent with carbonyl compounds. J Chem Res 426-427. Bellesia F, Ghelfi F, Pagnoni UM, Pinetti A (1989). The treatment of indoles with trimethylhalogenosilanes and sulphoxides. J Chem Res 182-183. Bellesia F, Ghelfi F, Pagnoni UM, Pinetti A (1987). The reaction of trimethylchloro- and trimethylbromosilane-dimethyl sulphoxide reagent systems on alkenes. Synthesis of 2-chloroalkyl and 2chlorocycloalkyl methyl sulphides. .I Chem Res 238-239. Dauben WG, Takemura KH (1953). A study of the mechanism of conversion of acetate to cholesterol via squalene. JAm Chem Sot 75x6302-6304.

5. 6.

Acknowledgments The authors are thankful to Professor S. A. A. Zaidi, Chairman, Department of Chemistry, for providing research facilities. The technical help of V. N. Bhalla and R. M. Saxena (CDRI-Lucknow) is acknowledged. Financial support from the UGC (New Delhi) is gratefully acknowledged.

7.

8. 9.

Fieser LF, Fieser M (1959). Investigation of cholesterol. In: Steroids. Reinhold Publishing Co., New York, pp. 26-52. Roberts G, Shoppee CW, Stephenson JR (1954). Steroids and Walden inversion. The epimeric cholest-5-ene-3-carboxylic acids and the epimeric cholestane-3-carboxylic acids. J Chem Sot 2705-2715. Dua PR (1984). The use of pharmacological techniques for the evaluation of natural products. Dhawan BN, Srimaf RC (eds). Lucknow Publishing House, Lucknow, India. Bhacca NS, Williams DH (1964). Application of NMR spectroscopy in organic chemistry. Holden-Day, San Francisco. Bellamy LJ (1958). Infrared spectra of complex organic molecules. Wiley, New York.

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