Synthesis of some novel steroidal 1,2,4,5-tetraoxanes

Abstract

A facile synthesis of A-ring manipulated C-20 methyl carboxylate steroid derivative with unsymmetrical dispiro 1,2,4,5-tetraoxanes has been focused herein via acid catalyzed cyclocondensation of bis-epidioxy ketone. Novel stable unsymmetrical steroidal based spirocycloalkane 1,2,4,5 tetraoxane 8 has been developed from 3β-acetoxy-pregn-5(6), 16(17)-diene-20-one (16-dehydropregnenolone acetate, i.e. 16-DPA) 1 via metal-mediated halogenation as a key reaction.

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1. Introduction

Tetroxanes are cyclic peroxides which have attracted considerable attention in clinical practice as antimalarial and antimicrobial drugs. Many studies reported that tetroxanes have similar antimalarial modes of action compared to the naturally occurring peroxides such as artemisinin and its derivatives.^1–3 In the past few decades, chemists and researchers put their attention to develop the organic peroxides in the field of drug design due to certain representatives of these compounds exhibiting antimalarial^4–9 and antitumor^10–14 activities. This has stimulated the development of several molecules of these types as depicted in various studies. It is pertinent to note that cyclic compounds such as tetraoxanes and trioxanes are considered as the most promising synthetic peroxides having antimalarial and antimicrobial activities. Some of these exhibit high antimalarial activity and antibacterial activity^15–18 compared to the natural peroxide artemisinin, a potent antimalarial drug.¹⁹ Nowadays, the design of explosives using cyclic peroxides is of particular interest. In addition to these, the synthesis of unsymmetrical tetroxane has become one of the promising areas towards the development of antimalarial drugs.²⁰ Syntheses of peroxides (tetroxanes) are mainly based on the cyclocondensation reaction of ketones/aldehydes with steroids and its intermediates^13,20 or alicyclic gem-bis-hydroperoxides,²¹ and aliphatic/alicyclic gem-bis-hydroperoxides.^15,22

Malaria has been considered as a serious threat to the health and economic prosperity of the human race in recent years. It is estimated that approximately 300 million clinical cases were observed and more than 2.5 million people die from this disease each year. Due to resistance of the vector (Anopheles mosquito) to insecticides and ongoing spread of the drug-resistant strains of Plasmodium falciparum against chloroquine and other clinically used drugs, there is considerable interest worldwide in new effective anti-malarial drug development.^23–25

Symmetric tetraoxanes are limited in number and non-symmetric tetraoxanes could offer more opportunity for the selective incorporation of various functional groups on the tetraoxane scaffold. Several factors, such as the structure of ketones, temperature, solvent, pH and the catalyst concentration of the substrate of the bis-peroxides, affect the synthesis of 1,2,4,5-tetroxanes.

In continuation to our work on steroid transformations,²⁶ we developed a potential method for the metal mediated halogenation of 16-DPA and its relatives using reagents such as MnO₂–TMSCl–AcOH. This reaction has been utilized to introduce C-20 methyl carboxylate group in a steroid molecule [Scheme 1].

Scheme 1 Synthetic route for the synthesis of 1,2,4,5-tetraoxane derivatives. Reagent and conditions used: (a) H₂, Pd/C; (b) TMSCL, MnO₂, acetic acid, r.t; (c) Favorskii rearrangement (3% KOH, r.t); (d) H₂, Pd/C; (e) PCC, CH₂Cl₂, r.t; (f) 30% H₂O₂, CH₃CN, 0 °C; (g) cyclohexanone, CH₃CN, H₂SO₄, 0 °C.

Our effort has been given to introduce spirocycloalkane 1,2,4,5-tetroxanes that possess significantly higher stability than that of their 1,2,4-trioxane or 1,2,4-trioxolane counterparts.^27,28 It is pertinent to note that to date, no reports on the tetroxane in pregnane-like structures are available except some reports on cholestane-like structure.¹⁴ In the synthetic route, we have utilized our metal mediated halogenation technique²⁶ to construct the C-20 methyl carboxylate side chain in D-ring and its derivatives, minimize the side effects associated with this class of compounds and make it a soft drug-like structure.

2. Results and discussion

As depicted in Scheme 1, 16-DPA was hydrogenated in presence of Pd/C to furnish the product 2, which was subjected to metal mediated halogenation reaction using MnO₂–TMSCl–AcOH system to furnish 17α,21-dichloro-20-oxopregnane 3 in high yield. The product was characterized by direct comparison with the authentic materials.^26,28,29 This compound 3 was reacted with alkaline methanolic solution to give the 3β-hydroxy Favorskii rearrangement product 4.^30,31 Catalytic hydrogenation of 4 in the presence of Pd/C provided the hydrogenated compound 5 in high yield. PCC oxidation of 5 in methylene chloride gave the corresponding 3-oxosteroid 6. Conversion of the compound 3-oxoandrostan 6 to bis-hydroperoxy androstan 7 was carried out by using 30% H₂O₂ in acetonitrile at 0 °C,¹⁴ and the reaction 7 was carried out with cyclohexanone/substituted cyclohexanone in the presence of conc. H₂SO₄ in CH₃CN to afford target compounds 8a–8i.

3. Conclusion

A facile and novel route towards the synthesis of 1,2,4,5-tetroxane 8a–8i from 16-dehydropregenolone acetate i.e., 16-DPA 1 using acid catalyzed cyclocondensation of bis-epidioxy tetraoxanes also with a C-20 methyl carboxylate side chain in ring D was developed. The method affords the target compounds with good yield (53–67%). Here also the acid acts both as catalyst and co-solvent, which influences both the formation of tetraoxanes and the stability of the peroxides during the experiment.

4. Experimental

4.1. General remarks

All the chemicals used were of the reagent grade of E. Merck and were used without further purification. The progress of each reaction was monitored using Merck thin layer chromatography silica gel 60 F254. Melting points were measured with a Buchi B-540 melting point apparatus and are uncorrected. IR spectra were recorded with a Perkin-Elmer model 2000 series FT-IR spectrometer for solutions in chloroform. Infrared absorbance is reported in reciprocal centimeters (cm⁻¹). ¹H and ¹³C NMR spectra were recorded using a Bruker DPX (300 MHz) spectrometer using CDCl₃ or DMSO-d₆ as solvent with tetramethylsilane (TMS) as internal standard on ppm scale (d). Multiplicity of the resonance peaks are indicated as singlet (s), broad singlet (bs), doublet (d), triplet (t), quartet (q) and multiplet (m). Mass spectrometric analysis was performed by positive mode electro spray ionization with Bruker Esquire 3000 LC-MS instrument. Elemental analysis was carried out using Varian CHN analyzer (Perkin-Elmer 2400 II).

4.2. Experimental methodology and chemistry

4.2.1. 3β-Acetoxy-5α-pregnan-20-one (2). 1 gm of 16-DPA (1) was dissolved in 50 mL of ethanol and hydrogenated at 45 psi using 200 mg of 5% Pd/C for a period of 12 h. The reaction mixture was filtered and alcohol was distilled under reduced pressure to get the crude hydrogenated product. The product was purified by column chromatography over silica gel using 1 : 10 ethyl acetate and hexane as eluent. The product obtained was pregnenolone acetate 2.

Yield: 950 mg (95%); melting point (mp.) 172 °C. The observed ¹H and ¹³C NMR data (300 MHz, CDCl₃) agree well with the previously reported values.²⁶ IR (CHCl₃): 1735, 1700, 1450, 1200 cm⁻¹; MS (ESI) m/z: 360 (M)⁺. Anal. calcd for C₂₃H₃₆O₃: C, 77.66; H, 10.00. Found: C, 77.49; H, 9.65.

4.2.2. 3β-Acetoxy-17α,21-dichloro-5α-pregnan-20-one (3). 450 mg of activated MnO₂ (5 mmol) and 4 mL of TMSCl (trimethyl chlorosilane) were added to a solution of 500 mg (1.4 mmol) of compound (2) dissolved in 10 mL of glacial acetic acid. The reaction mixture was maintained at room temperature for 24 hours, and then it was poured into 500 mL of water and extracted with chloroform (5 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the solid crude product. The product was purified by column chromatography to get the desired pure product 3 over silica gel using 1 : 40 ethyl acetate and hexane as eluent.

Yield: 405 mg (81%); mp. 160 °C. The observed ¹H and ¹³C NMR data (300 MHz, CDCl₃) agree well with the previously reported values.²⁶ IR (CHCl₃): 1730, 1710, 1445, 1200 cm⁻¹; MS (ESI) m/z: 428 (M)⁺. Anal. calcd for C₂₃H₃₄O₃Cl₂: C, 64.49; H, 7.94. Found: C, 64.46; H, 7.8; αD = +35° (CHCl₃, 22 °C and 0.1%).

4.2.3. Methyl (E)-3β-hydroxy-5α-pregn-17-ylideneacetate (4). 500 mg of substrate, 3β-acetoxy-17α, and 21-dichloro-5α-pregnan-20-one (3) was allowed to stir with 3% KOH in MeOH–H₂O (85 : 15) at room temperature for a period of 6 hours. The reaction was monitored using TLC. Then the reaction mixture was poured into cold water (300 mL), acidified with 30% citric acid solution and extracted with chloroform (5 × 100 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the solid crude product. The product was purified by column chromatography to get the desired pure product 4 over silica gel using 1 : 2 ethyl acetate and hexane as eluent.

Yield: 375 mg (75%); mp. 165 °C; IR (cm⁻¹): 3400, 1730, and 1250. The observed ¹H and ¹³C NMR data (300 MHz, CDCl₃) agree well with the previously reported values.²⁶ MS (ESI) m/z: 346 [M]⁺. Anal. calcd for C₂₂H₃₄O₃: C, 76.30; H, 9.83; found: C, 76.21; H, 9.76.

4.2.4. Methyl 3β-hydroxy-5α-pregnan-17β-acetate (5). 400 mg of compound (4) was dissolved in 20 mL of ethanol and hydrogenated at 45 psi using about 80 mg of 5% Pd/C for a period of 2 h. The reaction mixture was filtered and alcohol was distilled under reduced pressure to get the crude hydrogenated product. The product was purified by column chromatography to get the desired pure product 5 over silica gel using 1 : 3 ethyl acetate and hexane as eluent.

Yield: 284 mg (71%); mp. 172 °C; ¹H NMR (CDCl₃): 0.8 (s, 3H, Me), 1.2 (s, 3H, Me), 0.9–2.1 (m, 23H, –CH and –CH₂), 2.2 (m, 1H, 3-OH), 3.4 (s, 3H, OMe), 3.5 (m, 1H, H-3), 2.3 (s, 1H, H-20); ¹³C NMR: δ 15.2, 16.4, 21.4, 27.7, 29.7, 31.5, 32.0, 32.2, 36.6, 36.9, 37.8, 40.6, 46.3, 49.9, 56.8, 65.0, 73.8, 170.5; IR (cm⁻¹): 3400 (b), 1735, 1450, 1250; MS (ESI) m/z: 348 [M]⁺. Anal. calcd for C₂₂H₃₆O₃: C, 75.86; H, 10.34; found: C, 75.60; H, 10.18.

4.2.5. Methyl 3-oxo-5α-pregnan-17β-acetate (6). 200 mg of PCC was suspended in methylene chloride, and then, 200 mg of compound (5) was rapidly added to it at room temperature. The reaction mixture was allowed to stir at room temperature. The progress of the reaction was monitored by TLC using 1 : 5 ethyl acetate : hexane. After completion of the reaction (2 hours), the reaction mixture was diluted with 5 volumes of anhydrous ether and allowed to pass through neutral alumina. The ether was distilled under reduced pressure to get the crude product. The product was purified by column chromatography to get the desired pure product 6 over silica gel using 1 : 5 ethyl acetate and hexane as eluent.

Yield: 170 mg (85%); mp. 267 °C; IR (cm⁻¹): 1735, 1715, 1450, 1250; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me), 1.0 (s, 3H, Me), 0.9–2.1 (m, 23H and –CH₂), 3.4 (s, 3H, Me), 2.3 (s, 1H, H-20); ¹³C NMR: δ 13.4, 16.4, 18.8, 19.3, 20.6, 21.4, 27.7, 30.7, 31.5, 31.9, 32.1, 36.7, 36.9, 37.8, 38.0, 40.6, 46.3, 49.9, 56.9, 64.9, 170.6, 205.2; MS (ESI) m/z: 346 [M]⁺. Anal. calcd for C₂₂H₃₄O₃: C, 76.3; H, 9.82; found: C, 76.01; H, 9.79.

4.2.6. Methyl (3,3-bishydroperoxy)-5α-pregnan-17β-acetate (7). 100 mg of compound (6) was dissolved in acetonitrile, and 30% H₂O₂ was added at 0 °C. After completion of the reaction (4 hours), the reaction mixture was poured into cold water (300 mL) and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to get the crude product. The product was purified by column chromatography to get the desired pure product 7 over silica gel using 1 : 2 ethyl acetate and hexane as eluent.

Yield: 75 mg (75%); mp. 287 °C; IR (cm⁻¹): 1727.3, 1446.3, 1263, 754.6; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 1.0 (s, 3H, Me-18), 1.1–2.1 (m, 23H and –CH₂), 3.5 (s, 3H, Me), 3.7 (s, methyl ester), 9.6 (broad singlet, –OOH); ¹³C NMR: δ 12.5, 16.0, 24.4, 28.1, 12.5, 16.0, 24.4, 28.1, 28.8, 31.7, 32.1, 32.2, 35.8, 38.0, 42.1, 46.6, 51.4, 56.6, 110, 174.6; MS (ESI) m/z: 396 [M]⁺. Anal. calcd for C₂₂H₃₆O₆: C, 66.66; H, 9.09; found: C, 66.45; H, 9.03.

4.2.7. Methyl 3,3-(bis-epidioxycyclohexane)-5α-pregnan-17β-acetate (8a). 300 mg of compound (7) was dissolved in 10 mL CH₃CN, and then 7.5 mL cyclohexanone/substituted cyclohexanone was added at 0 °C. Conc. H₂SO₄ (0.5 mL) was then added dropwise to the reaction mixture and allowed to stir at 0 °C. After 24 hours, TLC indicated the completion of the reaction and neutralized the reaction mixture using base (1% NaOH) and after that acetonitrile was evaporated. The crude reaction mixture was added to 200 mL water and worked up with dichloromethane (300 mL). The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to get the product 8a.

Yield: 201 mg (67%); mp. 185 °C; IR (cm⁻¹): 2932, 1711, 1448.3, 1198, 773; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 1.2 (s, 3H, Me-18), 0.9–2.0 (m, 23H and –CH₂), 3.2 (s, 3H, Me), 3.6 (s, methyl ester); ¹³C NMR: δ 22.1, 22.3, 22.5, 22.7, 23.3, 24.0, 25.1, 26.0, 26.6, 27.1, 27.5, 31.7, 33.7, 37.7, 41.9, 42.1, 58.2, 58.6, 85.0, 97.7, 109.1, 174.0; MS (ESI) m/z: 476 [M]⁺. Anal. calcd for C₂₈H₄₄O₆: C, 70.59; H, 9.30; found: C, 70.32; H, 9.11.

4.2.8. Methyl 3,3-(1,1-epidioxy-4-methylcyclohexane)-5α-pregnan-17β-acetate (8b). Yield: 177 mg (59%); mp. 172 °C; IR (cm⁻¹): 2932, 1727, 1448.3, 1250, 773; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 1.0 (s, 3H, Me-18), 1.02 (s, 4-methyl), 1.03–2.2 (m, 23H and –CH₂), 3.2 (s, 3H, Me), 3.7 (s, methyl ester), 1.5–1.69 (m, CH₂-cyclic ring); ¹³C NMR: δ 15.2, 15.7, 16.4, 19.3, 20.6, 27.7, 29.7, 31.5, 32.1, 36.7, 36.9, 39.3, 40.6, 49.9, 56.8, 65.0, 89.8, 97.4, 109.2, 170.6; MS (ESI) m/z: 490 [M]⁺. Anal. calcd for C₂₉H₄₆O₆: C, 71.02; H, 9.38; found: C, 70.99; H, 9.02.

4.2.9. Methyl 3,3-(1,1-epidioxy-4-methoxycyclohexane)-5α-pregnan-17β-acetate (8c). Yield: 189 mg (63%); mp. 202 °C; IR (cm⁻¹): 2932, 2810, 1727, 1448.3, 1250, 773; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 1.0 (s, 3H, Me-18), 1.1–2.1 (m, 23H and –CH₂), 3.4 (s, 3H, Me), 3.6 (s, methyl ester), 3.3 (s, 4-methyl extended), 1.5–1.6 (m, CH₂-cyclic ring); ¹³C NMR: δ 15.2, 15.7, 16.4, 20.6, 27.7, 29.7, 31.5, 32.0, 32.2, 36.6, 39.3, 40.6, 46.3, 49.9, 56.8, 65.0, 89.8, 97.4, 109.2, 170.5; MS (ESI) m/z: 506 [M]⁺. Anal. calcd for C₂₉H₄₆O₇: C, 68.77; H, 9.09; found: C, 68.51; H, 9.03.

4.2.10. Methyl 3,3-(1,1-epidioxy-4-chlorocyclohexane)-5α-pregnan-17β-acetate (8d). Yield: 183 mg (61%); mp. 167 °C; IR (cm⁻¹): 2932, 1727, 1448.3, 1250, 773, 710; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 1.2 (s, 3H, Me-18), 1.25–2.1 (m, 23H and –CH₂), 3.4 (s, 3H, Me), 3.6 (s, methyl ester), 1.39–68 (m, CH₂-cyclic ring); ¹³C NMR: δ 15.2, 15.7, 16.4, 20.6, 27.7, 29.7, 31.5, 32.0, 32.2, 36.6, 39.3, 40.6, 46.3, 49.9, 56.8, 65.0, 89.8, 97.4, 109.2, 170.5; MS (ESI) m/z: 510 [M]⁺. Anal. calcd for C₂₈H₄₃O₆Cl: C, 65.89; H, 8.43; found: C, 65.52; H, 8.27.

4.2.11. Methyl 3,3-(1,1-epidioxy-4-bromocyclohexane)-5α-pregnan-17β-acetate (8e). Yield: 168 mg (56%); mp. 177 °C; IR (cm⁻¹): 2932, 1727, 1448.3, 1250, 773, 645; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 1.0 (s, 3H, Me-18), 1.1–2.2 (m, 23H and –CH₂), 3.6 (s, 3H, Me), 3.7 (s, methyl ester), 1.5–1.6 (m, CH₂-cyclic ring); ¹³C NMR: δ 15.2, 15.7, 16.4, 20.6, 27.7, 29.7, 31.5, 32.1, 36.7, 36.9, 39.3, 40.6, 49.9, 56.8, 65.0, 89.8, 97.4, 109.2, 170.6; MS (ESI) m/z: 554 [M]⁺. Anal. calcd for C₂₈H₄₃O₆Br: C, 60.65; H, 7.76; found: C, 60.29; H, 7.38.

4.2.12. Methyl 3,3-(1,1-epidioxy-4-nitrocyclohexane)-5α-pregnan-17β-acetate (8f). Yield: 186 mg (62%); mp. 205 °C; IR (cm⁻¹): 2932, 1727, 1448.3, 1250, 1190, 773; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 1.0 (s, 3H, Me-18), 1.1–2.1 (m, 23H and –CH₂), 3.2 (s, 3H, Me), 3.4 (s, methyl ester), 3.1 (m, 1H-extended ring); ¹³C NMR: δ 15.2, 15.7, 16.4, 20.6, 27.7, 29.7, 31.5, 32.1, 36.7, 36.9, 39.3, 40.6, 49.9, 56.8, 65.0, 89.8, 90.0, 109.7, 170.6; MS (ESI) m/z: 521 [M]⁺. Anal. calcd for C₂₈H₄₃O₈N: C, 64.49; H, 8.25, N, 2.69; found: C, 64.15; H, 7.98, N, 2.44.

4.2.13. Methyl 3,3-(1,1-epidioxy-4-acetylcyclohexane)-5α-pregnan-17β-acetate (8g). Yield: 198 mg (66%); mp. 185 °C; IR (cm⁻¹): 2932, 1727, 1745, 1448.3, 1250, 773; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 1.0 (s, 3H, Me-18), 1.1–2.1 (m, 23H, –CH₂, –COCH₃), 3.2 (s, 3H, Me), 3.6 (s, methyl ester); ¹³C NMR: δ 15.2, 15.7, 16.4, 20.6, 29.7, 31.5, 32.1, 36.7, 36.9, 37.8, 38.0, 39.3, 40.6, 49.9, 56.8, 65.0, 89.8, 97.4, 109.6, 170.6, 209.6; MS (ESI) m/z: 518 [M]⁺. Anal. calcd for C₃₀H₄₆O₇: C, 69.5; H, 8.88; found: C, 69.35; H, 8.65.

4.2.14. Methyl 3,3-(1,1-epidioxy-4-hexanecyclohexane)-5α-pregnan-17β-acetate (8h). Yield: 159 mg (53%); mp. 173 °C; IR (cm⁻¹): 2932, 1727, 1745, 1448.3, 1250, 773; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 1.0 (s, 3H, Me-18), 1.1–2.1 (m, 23H, –CH₂, –COCH₃), 3.4 (s, 3H, Me), 3.6 (s, methyl ester), 5.2 (m, –CH–); ¹³C NMR: δ 13.8, 14.5, 16.2, 20.7, 27.7, 28.7, 30.2, 31.3, 31.8, 32.0, 36.7, 36.9, 39.7, 40.2, 41.5, 49.9, 56.4, 62.0, 80.8, 97.4, 109.2, 120.7, 170.5; MS (ESI) m/z: 558 [M]⁺; anal. calcd for C₃₄H₅₄O₆: C, 73.10; H, 9.67; found: C, 72.87; H, 9.38.

4.2.15. Methyl 3,3-(1,1-epidioxy-4-butanecyclohexane)-5α-pregnan-17β-acetate (8i). Yield: 192 mg (64%); mp. 155 °C; IR (cm⁻¹): 2932, 1727, 1745, 1448.3, 1250, 773; ¹H NMR (CDCl₃): δ 0.8 (s, 3H, Me-19), 0.9 (s, 3H, Me-18), 1.2–2.1 (m, 23H, –CH₂, –COCH₃), 3.2 (s, 3H, Me), 3.4 (s, methyl ester), 5.5 (m, –CH–); ¹³C NMR: δ 13.8, 14.5, 16.2, 20.7, 27.7, 28.7, 30.2, 31.3, 31.8, 32.0, 36.7, 36.9, 39.7, 40.2, 41.5, 49.9, 56.4, 62.0, 80.8, 97.4, 170.5; MS (ESI) m/z: 532 [M]⁺. Anal. calcd for C₃₂H₅₂O₆: C, 72.18; H, 9.77; found: C, 71.91; H, 9.45.

Acknowledgements

The authors thank the Director of CSIR-North East Institute of Science & Technology, Jorhat, Assam for providing facilities and valuable advice and also gratefully acknowledge the financial assistance supported by DST, New Delhi, for awarding Fast Track Young Scientist Award, EEOES and CSIR, New Delhi, India.

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