Synthesis of aminosterols and their derivatives

Synthesis of aminosterols and their derivatives ShaWlah,*

R. K. Singh,* Malik Jamaluddin,*H. Ogura,t and H. Takayanagit

*Steroid Research Laboratory. Department of Chemistry, Aligarh Muslim University, Aligarh, India; fSchoo1 of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo, Japan.

Reactions of steroidal epoxides such as 5,6ar-epoxyJa-cholestane (Z) and its 3@chloro (ZZ) and 3/?acetoxy (ZZZ)analogs with urea in dimethylformamide afforded 6/3-amino-Jar-cholestan-5-01 (IV-VI), 6P-amino-N-formyl-Sc-cholestan-5-01 along with the Sa-cholestaneJ,6@diol analog also afforded the N-carboxyl

(VII-IX), and 6j3-amino-N-amido-Sc-cholestan-5-01 (X-XZZ), (XZZZ-XV). In addition to these compounds, the 3/3-acetoxy derivative {XVZ). (Steroids 55:120-122, 1990)

Keywords: steroids; aminosterols; aminosterol derivatives

Introduction

The reports of the synthesis and nonhormonal biologic activities (such as tranquilizing, anticonvulsant, anesthetic, ant&rhythmic, and sedative) of aminosterols and their derivatives1-6 prompted us to synthesize these compounds. Different investigators use different routes to synthesize aminosterols. Most commonly, the oxirane ring is opened by sodium azide to give azido alcohols, which on reduction with lithium aluminum hydride produce aminosterols. In the present study, we attempted to synthesize these compounds by treating some of the steroidal epoxides in the cholestane series, such as 5,&-epoxySo-cholestane (I)7 and its 3p-chloro (ID8 and 3/3acetoxy (III)9 analogs, with urea and obtained some interesting compounds. The structures of the compounds obtained were established on the basis of their analytic and spectral data (Figures 1 and 2). Experimental Ail melting points are uncorrected. The infrared (IR) spectra were determined in Nujol with a Perkin-Elmer 237 spectrophotometer. Nuclear magnetic resonance (NMR) spectra were run in CDC& on a Varian A-60 D instrument with Me,$i as the internal standard. The mass spectra were measured on an AJMES-9 mass spectrometer. Thin-layer chromatography (TLC) Address reprint requests to Dr. Shaliullah, Steroid Research Laboratory, Department of Chemistry, Aligarh Muslim University, Aligarh 202 002, India. Received June 9, 1989; revised August 24, 1989.

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Steroids, 1990, vol. 55, March

plates were coated with silica gel (60 to 120 mesh). A 20% aqueous solution of perchloric acid was used as a spraying agent. Light petroleum refers to a fraction of boiling point (bp) 60 to 80 C. Anhydrous sodium sulfate was used as the drying agent. Nuclear magnetic resonance values are given in ppm (s, singlet; d, doublet; dd, double doublet; br, broad; m, multiplet centered. Reaction of 5,6mepoxy-5cu-cholestane with urea: general procedure:

(I)

A mixture of 5,&-epoxy-5ar-cholestane (I) (2.5 g, 6.5 mmol) and urea (2 g, 32.5 mmol) (1: 5 mol) was dissolved in dimethylformamide (100 ml) and the solution was heated under retlux for 8 hours. The progress of reaction was monitored with TLC until all the starting material was consumed. After the completion of the reaction, the reaction mixture was poured into water and extracted with ether. The ethereal layer was washed with water several times to remove unreacted urea and dried over anhydrous sodium sulfate. The solvent was evaporated in a water bath to yield a residue in the form of an oily mass which was chromatographed over silica gel (75 g). Elution with petroleum ether/ether (15 : 1) yielded 6@mino-5o-cholestan-5-01 (IV) (0.380 g, 0.94 mmol, 14.55%), mp 137 C, vmax 3,480 (NH, OH), 1,280, and 1,040 cm-r (C-O). The NMR spectrum showed peaks at 6 4.4 (m, NH& 4.1 (s, OH, exchangeable with deuterium oxide), 3.4 (m, 6-H, W1/2 = 6 Hz), 1.1 (s, 19-H), 0.65 (s, 18-H), 0.85, and 0.77 (other methyl protons). Analysis calculated for C27HdsNO (M+ 403): C, 80.39; H, 12.16; N, 3.45. Found: C, 80.37; H, 12.14; N, 3.43. 8

1990 Butterworth Publishers

Table 1

Physical and analytical data of the products

Product

mp (C) 173

V

151-153

VIII

175-177

XI

XIV Vl

ProdUCt

Infrared spectra (Nujol) vmax (cm-9

Molecular formula

Analysis calculated

Found (%I

13.32

C&H~NOCl (M’ 437/439)

C, 74.65 H, 10.97 N, 3.20

73.94 10.94 3.14

V

C&H,NO,Cl (M+ 465/467)

C, 72.18 H, 10.31 N, 3.00

72.05 10.27 3.01

VIII

C~HaN202Cl (M’ 4801482)

c, 69.92 H, 10.19 N, 5.82

69.99 10.20 5.73

c27H4YO&l

c, 73.86 H, 10.71

73.82 10.61

C,HnNOs (M+ 461)

c, 75.48 H, 11.06 N, 3.03

C&Hs,NO, (M+ 489)

7.21

10.84

7.35

226-228

13.26

256-258

XII

Spectral data of the products

Yield 4%)

1258

200-203

IX

Table 2

7.69

10.77

4.46 (m, NH,), 4.3 (m, 3-H, W?/2 = 17 Hz), 3.5 (m, 6-H W112 = 6 Hz), 2.75 (8, OH)” ?.2-0.70t 8.1 (s, CHO), 4.9 (M. ~~~~~~H~H), 1,700 -NH*-CHO), 4.2 k OH!‘, (-NH-I&O), 1,236, 3.48 (m, 3-H, 6-H)‘ 1,210, 1,035 (C-0). 730 ?.?5-0.70t

3,590.3,445 (NH. OH), 1,230 and 1,050 (C-O), 730 (C-Cl)

(C-c%

XI

3,646, 3,466 (-NH, OH), 1,696, 1,515 (NHCONH2), 1,020 (C-O), 725 (C-Cl)

75.41 11.05 3.05

VI

3,466 (NH,OH),1,730

c, 73.61 H, 10.42 N, 2.86

73.63 10.40 2.81

IX

C&HwN20, (M’ 504

C, 71.42 H, 10.31 N, 5.55

71.21 10.21 5.32

XV

208”

7.52

C~HsoO,

C, 75.32 H, 10.82

75.21 10.75

XVI

Oil

10.12

&Hs,NOs (M+ 461)

C, 71.28 H, 10.09 N, 2.77

71.26 10.07 2.42

Nuclear magnetic resonance spectra (CDCI,/TMS) 6 (ppm)

y..l)# ?.290,?,040

XII

XVI

3,500(-NH and OH), 1,740 (OAC). 1,680, 1,546 (NH, CHO), 1,286 (acetate) and 1,040 (C-0) 3,466 (-NH, OH), 1,730 lCH&OO). 1,680 and 1,520 (-NHCONH,), 1,270, 1,050 (C-O) 3,480 I-NH. OH), 1,736 ~OAc),l,72O, WOW, 1,296, 1,036 (C-0)

6.5 lm, -NH*-CONH2), 4.15 (d, -NH-CO-N/&, J = 8 Hz), 4.3 (m, 3-H, W?/2 = 17 Hz), 3.6 (m, 6-H), 2.75 (s, OH)*, ?.?5-0.70t 5.2 (m, 3-H), W?/2 = 18 Hz), 4.24 (m, NH,), 4.0 (m. 6-H). 2.80 (s, OH)“, 2.0 (s, OAc), I.?-0.65t 8.1 (s, CHO), 5.2 (m, 3-H), W112 = 18 Hz), 4.9 (m, -NH*CHO), 3.9 (m. 6-H), 2.75 (s, -OH)*, 2.0 (s, OAc1, ?.?3-0.70t 5.15 (m, 3-H, W112 = 18 Hz), 4.73 (d, -NH-CO-NH2, J i 7 Hz), 4.2 (m, -NH*CONH2), 4.1 (m, 6-H). 2.4 (s, OH)*, 2.0 (s, OAc), l.l-0.65t 9.35 ibr, s. COOH), 5.2 (m, -NH*COOH1,4.86 (m. 3-H. W112 = 18 Hz), 4.2 (m, 6-H), 3.0 (s, OH)*, 2.0 (s, OAc), ?.?3-0.70t

l Exchangeable with deuterium oxide. t Angular and side-chain methyl protons.

3

(I) (II) (III)

3

3

(IV)

H

(VII)

H

Cl

(v)

Cl

(VIII)

Cl

WC

(VI)

OAC

H

Agur8

1

(lx)

OAC

Further elution with light petroleum ether/ether (10 : 1) furnished 6jWunino-N-formyl-Sac-cholestan-501 (VII) (0.220 g, 0.5 1 mmol, 7.88%), as shining crystals, mp 121 C, vmax 3,500 (-NH, OH), 1,700 and 1,535 (NHCHO), and 1,230 and 1,030 cm-’ (C-O). The NMR spectrum showed bands at 6 8.03 (s, CHO), 4.73 (m, NB-CHO; exchangeable with deuterium oxide), 3.5 (m, 6-H), 2.85 (s, OH, exchangeable with deuterium oxide), 1.1 (s, 19-H), 0.7 (s, M-H), 0.91, and 0.83 (other methyl protons). Analysis calculated for C,&NOZ @I+ 431): C, 7;;5; H, 11.36;N, 3.28. Found: C, 78.00; 11,11.34; N, .

.

Elution with light petroleum ether/ether (5 : 1) afforded 6@amino-N-amido-Sa-cholestan-5-01 (X), recrystallized from light petroleum (0.315 g, 0.71 mmol, 10.33%), mp 148 C, ~max 3,450 (NH, OH), 1,690 and 1,510 (NHCONH& and 1,235 and 1,045 cm-’ (C-O). The NMR spectrum gave peaks at 6 4.63 (m, NHCONHd, 4.15 (m, dH), 3.1 (s, OH, exchangeable with deuterium oxide), 1.0 (s, 19-H), 0.73 (s, 18-H), 0.92, and 0.86 (other methyl protons). Analysis calculated for C&H&&& (W 446): C, Steroids, 1990, vol. 55, March

121

Papers on the epoxide ring from the /?-face followed by transdiaxial ring opening, were responsible for the formation of the rest of the products (Figure 3). Different modes of hydrolysis of the amide group in compounds (X-XII) resulted in aminosterols (IV-VI), its N-formy1 (VII-IX), and N-carboxyl derivatives (XVI). Formation of N-carboxyl derivatives with epoxides (I) and (II) in traces cannot be ruled out. Scheme 1 illustrates the formation of the products. Figure 3

Acknowledgments The authors are grateful to Professors M. S. Ahmad and S. M. Osman, Ohioan, ~p~rnent of Chemis-

try, for necessary facilities and useful discussion. Financial assistance from CSIR (New Delhi), is gratefully acknowledged. References 1.

2. 3. (XII)

w.Tf R = H,

Cl,

OAc

Scheme 1

75.33; H, 11.21; N, 6.27. Found: C, 74.34; H, 11.20; N, 6.30. Further elution with light petroleum ether/ether (1: 1) provided Sa-cholestane-5,6p-did (XIII) recrystallized from light petroleum (0.170 g, 0.42 mmol, 6.51%), mp 122 to 123 C (reported,rO mp 125 to 127 C). Reactions of epoxides (II and III) with urea were performed under identical conditions (the same counts of reactant and reagent were used). Physical, analytic, and spectral data are given in Tables 1 and 2. Results and discussion It was suggested that the 6-N-amido derivatives (X-

XIII), which were initially formed due to attack of urea

122

Steroids, 1990, vol. 55, March

4. 5. 6. 7, 8.

9.

10. 11.

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