Synthesis of C-ring hydrogenated sinomenine cinnamate derivatives via Heck reactions

Abstract

The synthesis of C-ring hydrogenated sinomenine derivatives is accomplished from sinomenine by treatment with Zn-Hg/HCl, halogenation with NIS, and Heck reactions with various acrylates. A total of nine novel sinomenine cinnamate derivatives are obtained in 84%–93% yields. The structures of all the derivatives are characterized by ¹H NMR, ¹³C NMR, and MS spectroscopy.

Many natural products and their derivatives are Food and Drug Administration (FDA)–approved drugs. ¹ Sinomenine is a natural product isolated from the stems and roots of the plant Sinomenium acutum, native to China and Japan. ² It contains a morphinan skeleton, and some derivatives demonstrate anti-inflammatory, anti-arrhythmic, anti-oxidant, and immunosuppressive activities, especially in treatment of rheumatoid arthritis in Asia;^3–7 it can also lower blood pressure. ⁴ In recent years, it has been reported that sinomenine can be used in the treatment of chronic pneumonia, cancer, and drug addiction. ³

However, some side effects, for example, hydrophilic–lipophilic balance (HLB), large dose requirements and the induction of hypersusceptibility,^8–13 prevent it from becoming a drug directly. In order to obtain sinomenine analogues with better therapeutic effects and less side effects, structural modifications of sinomenine have attracted significant research to improve its further applications,^14–16 and many of its derivatives show comprehensive immune-regulatory and anti-inflammatory functions.^17,18

Structurally, sinomenine is a very suitable starting natural product for new derivatives since it possesses four fused rings and a number of chemically active groups; however, most of the structural modifications are concentrated on only one active site. Meanwhile, a few reports have focused on simultaneous modifications of two or more active sites. ¹⁹ Consequently, as a continuation of our previous efforts on the synthesis of sinomenine derivatives, ²⁰ herein, we report the synthesis of a class of novel C-ring hydrogenated sinomenine cinnamate derivatives. These sinomenine derivatives are obtained in good yields following simultaneous modifications at the C- and A-ring.

Results and discussion

The synthetic route toward the target compounds is outlined in Scheme 1 and requires five steps. Treatment of commercial sinomenine hydrochloride (1) with concentrated hydrochloric acid produced diketone scaffold 2, which was converted into C-ring hydrogenated sinomenine 3 in situ upon Clemmensen reduction. Halogenation of the C-1 position on the A-ring of 3 by NIS generated the key intermediate, 1-iodo-C-ring hydrogenated sinomenine 4. Finally, Heck reactions of 4 with different acrylates 5 yielded various C-ring hydrogenated sinomenine cinnamate derivatives substituted at the C-1 position.

Scheme 1.

Synthesis of C-ring hydrogenated sinomenine cinnamate derivatives.

The C-ring of (1) consists of an α,β-unsaturated ketone scaffold, which forms a stable diketone motif at the C-6 and C-7 positions when refluxed in the presence of concentrated hydrochloric acid. The diketone scaffold is prone to benzilic rearrangement under alkaline conditions; however, in our experiment, we did not observe any rearrangement product after NH₃·H₂O was added (Scheme 2), and this might be due to only weakly alkaline conditions or the twisted chair configuration of the C-ring. Zinc amalgam and hydrochloric acid reduce the carbonyl groups to methylene groups, and the C-ring becomes a saturated cycloalkane to give C-ring hydrogenated sinomenine 3 after the pH was adjusted to 9–10 with NH₃·H₂O. ¹⁸ Organic compounds are usually difficult to dissolve in concentrated hydrochloric acid, and the Clemmensen reduction is often carried out in the presence of a co-solvent, such as acetic acid, ethanol, dioxane, and so on, to prevent the reactants and products from enveloping the zinc amalgam and making the reaction difficult to proceed. In our reaction, since sinomenine hydrochloride was well dissolved in concentrated hydrochloric acid, it was not necessary to add an organic co-solvent. We also found that the higher the concentration of hydrochloric acid, the better the purity of the product, so concentrated additional hydrochloric acid was added to increase the purity of the product when the reaction had proceeded halfway. Interestingly, we also found a small amount of two incomplete reduction by-products of molecular weights 3a 301 and 3b 303 (Scheme 2). The by-product of molecular weight 3a 301 might possess one carbonyl on the C-ring, while that of 3b 303 might contain one hydroxy group. However, the position of these hydroxy or carbonyl groups was not determined and we did not conduct further research on these two possible by-products.

Scheme 2.

Synthesis of C-ring hydrogenated sinomenine.

According to the results reported in the literature, ²¹ we used NIS to carry out the halogenation reaction of C-ring hydrogenated sinomenine 3. NIS and C-ring hydrogenated sinomenine were added to a flask and reacted for 2 h, but some by-products were found by TLC (thin-layer chromatography). Thus, we improved the reaction conditions. NIS was added slowly to a dichloromethane solution of C-ring hydrogenated sinomenine over 5 min with stirring. Stirring was then continued for 5 min, and gratifyingly, no by-product was found and the product, 1-iodo-C-ring hydrogenated sinomenine 4, could be used directly in the next step without further purification.

There are two methods for the synthesis of cinnamate structural units starting from 4. The first method requires a two-step reaction, preparing a cinnamic acid derivative first, and then reacting it with various alcohols to form cinnamate structural units; this method will purify the sinomenine twice by column chromatography and result in a loss of the total isolated yield. The second method, reacting 4 with various acrylates 5 directly, requires only one step, a Heck reaction, and purification to give the cinnamate derivatives. Hence, we chose the second method and obtained nine target compounds with 84%–93% yields. We used Pd(OAc)₂ as the catalyst for Heck reaction, Ph₃P as the ligand, Et₃N as the base, and the products 6a–i were successfully formed at 85 °C with DMF as solvent (Figure 1).

Figure 1.

C-ring hydrogenated sinomenine cinnamate derivatives.

Conclusion

In summary, we have developed a practical approach to synthesize novel C-ring hydrogenated sinomenine cinnamate derivatives with excellent yields via Heck reactions. This approach has several merits including no by-products, easy purification, and high yields. All compounds were characterized by ¹H NMR, ¹³C NMR, and ESI-MS (nuclear magnetic resonance (NMR) spectra for all new compounds are in the Supporting Information). These new compounds may be beneficially used in future drug development.

Experimental

All regents, including sinomenine, were purchased from Macklin and China National Pharmaceutical Group Corporation, and all commercial reagents were used directly without further purification. All reactions were monitored by TLC with GF₂₅₄ silica gel plates under a UV lamp (254 nm) or with I₂ detection. Column chromatography purifications were performed on silica gel (300–400 mesh) with CH₂Cl₂/CH₃OH/NH₃·H₂O (200:10:1–400:10:1, v/v) as eluents. Melting points were measured with a Jinke SGWX-4B melting point apparatus and are uncorrected. All NMR spectra were recorded on a Bruker AV-II 300 MHz NMR spectrometer using tetramethylsilane as an internal standard, operating at 300 MHz for ¹H NMR, and 75 MHz for ¹³C NMR. CDCl₃ was used as the solvent, and chemical shifts (δ) are reported in parts per million (ppm). Mass spectra were obtained on an Agilent 6100 mass spectrometer.

Synthesis of C-ring hydrogenated sinomenine 3

Concentrated HCl (3 mL) was diluted to 60 mL; HgCl₂ (4 g, 14.7 mmol) was added; and the mixture poured into a 500 mL round-bottom flask containing Zn (60 g, 0.92 mol). After shaking for 5 min, water was decanted and the solid washed once with concentrated HCl to give zinc amalgam. Sinomenine hydrochloride (1) (16 g, 44 mmol) was dissolved in 120 mL HCl solution (40 mL water + 80 mL concentrated HCl), added to the zinc amalgam, refluxed for 5 h, and then 40 mL concentrated HCl was added and reflux was continued for 5 h. After the reaction was complete (monitored by TLC), the reaction solution was cooled to room temperature and the pH adjusted to 9–10 with NH₃·H₂O. The solution was extracted with dichloromethane (3 × 100 mL), and the combined organic layers were dried over anhydrous sodium sulfate and evaporated to give crude product. ¹⁸ Purification by column chromatography gave the main product 3 in CH₂Cl₂/CH₃OH/NH₃•H₂O (200:10:1, v/v).

(9α,13α,14α)-4-Hydroxy-3-methoxy-17-methyl morphinan (3): Brown powder; yield 81%; m.p.: 78–80 °C; ESI-MS m/z: 286 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 6.69 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 6.03 (brs, 1H), 3.86 (s, 3H), 3.38–3.33 (m, 1H), 2.94 (d, J = 18.1 Hz, 1H), 2.78–2.74 (m, 1H), 2.69–2.61 (m, 1H), 2.48–2.42 (m, 1H), 2.38 (s, 3H), 2.12–2.02 (m, 1H), 1.75–1.54 (m, 5H), 1.45–1.07 (m, 5H); ¹³C NMR (75 MHz; CDCl₃) δ: 144.4, 144.3, 132.1, 125.8, 118.2, 107.9, 57.8, 56.0, 47.6, 46.7, 42.7, 38.3, 37.9, 36.9, 27.2, 26.7, 24.0, 23.1.

Synthesis of 1-iodo-C-ring hydrogenated sinomenine 4

C-ring hydrogenated sinomenine 3 (5.74 g, 20 mmol) was dissolved in 160-mL dichloromethane at room temperature, and NIS (4.7 g, 21 mmol) was slowly added over 5 min with stirring. Stirring was continued for 5 min, after which 120-mL saturated solution of Na₂S₂O₃ was added and the mixture stirred for 5 min. The dichloromethane layer was separated and washed with 50-mL water and 50-mL brine 3 times, respectively, then dried over anhydrous Na₂SO₄, and evaporated to give a brown powder. The product was further purified by column chromatography in CH₂Cl₂/CH₃OH/NH₃•H₂O (200:10:1 v/v) as eluents to give 1-iodo-C-ring hydrogenated sinomenine 4.

(9α,13α,14α)-1-Iodo-4-hydroxy-3-methoxy-17-methyl morphinan (4): Brown powder; yield 84%; m.p.: 143–145 °C; ESI-MS m/z: 414 [M+H]⁺; ¹H NMR (300 MHz; CDCl₃) δ: 7.24 (s, 1H), 3.86 (s, 3H), 3.39 (d, J = 12.2 Hz, 1H), 3.29 (brs, 1H), 2.94 (dd, J₁ = 12.2 Hz, J₂ = 2.9 Hz, 1H), 2.79 (m, 2H), 2.63 (s, 3H), 2.36-2.28 (m, 1H), 2.21–2.16 (m, 1H), 2.05–1.96 (m, 1H), 1.90–1.85 (m, 1H), 1.63–1.37 (m, 4H), 1.25–1.05 (m, 3H); ¹³C NMR (75 MHz; CDCl₃) δ: 146.1, 144.9, 129.1, 125.2, 119.6, 87.9, 60.5, 56.4, 48.1, 42.9, 41.5, 37.3, 35.2, 34.9, 32.5, 26.0, 25.5, 22.3.

Synthesis of C-ring hydrogenated sinomenine cinnamate derivatives 6a-i; general procedure

1-Iodo-C-ring hydrogenated sinomenine 4 (413 mg, 1 mmol), acrylate 5 (1 mmol), Pd(OAc)₂ (11.2 mg, 0.05 mmol), and Ph₃P (26.2 mg, 0.1 mmol) were mixed in DMF/Et₃N (5 mL, 5:1 v/v). The solution was heated at 85 °C for 2 h and then quenched with water (5 mL). The organic solvent and water were evaporated, and ethyl acetate (10 mL) was added to dissolve the crude product. The organic fraction was washed with brine (3 × 5 mL), dried over anhydrous sodium sulfate, and evaporated. Then the residue was purified by column chromatographed in CH₂Cl₂/CH₃OH/NH₃•H₂O (400:10:1 v/v) on silica gel. The C-ring hydrogenated sinomenine cinnamate derivative 6a-i was obtained. All compounds were brown powders.

(9α,13α,14α)-1-Methylacrylate-4-hydroxy-3-methoxy-17-methyl morphinan (6a): Yield 93%; m.p. 230–231 °C; ESI-MS m/z: 370 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 8.04 (d, J = 15.6 Hz, 1H), 6.96 (s, 1H), 6.23 (d, J = 15.6 Hz, 1H), 3.89 (s, 3H), 3.80 (s, 3H), 3.36 (m, 1H), 3.01–2.91 (m, 2H), 2.75–2.67 (m, 1H), 2.55–2.49 (m, 1H), 2.39 (s, 3H), 2.10–2.01 (m, 1H), 1.83–1.09 (m, 10H); ¹³C NMR (75 MHz; CDCl₃) δ: 167.7, 146.9, 144.9, 142.3, 132.1, 126.0, 123.1, 116.1, 106.0, 57.6, 56.0, 51.6, 47.5, 45.6, 42.5, 37.8, 37.4, 36.5, 26.9, 26.3, 22.9, 22.0.

(9α,13α,14α)-1-Ethylacrylate-4-hydroxy-3-methoxy-17-methyl morphinan (6b): Yield 91%; m.p. 173–175 °C; ESI-MS m/z: 384 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 8.02 (d, J = 15.6 Hz, 1H), 6.96 (s, 1H), 6.23 (d, J = 15.6 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 3.36 (m, 1H), 3.00–2.92 (m, 2H), 2.75–2.67 (m, 1H), 2.55–2.50 (m, 1H), 2.39 (s, 3H), 2.10–2.01 (m, 1H), 1.84–1.07 (m, 10H), 1.32 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz; CDCl₃) δ: 167.3, 146.9, 145.0, 142.0, 131.9, 125.9, 123.1, 116.5, 106.0, 60.3, 57.7, 55.9, 47.6, 45.5, 42.5, 37.7, 37.3, 36.5, 26.9, 26.3, 22.9, 22.0, 14.3.

(9α,13α,14α)-1-Butylacrylate-4-hydroxy-3-methoxy-17-methyl morphinan (6c): Yield 92%; m.p.: 142–144 °C; ESI-MS m/z: 412 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 8.02 (d, J = 15.6 Hz, 1H), 6.96 (s, 1H), 6.23 (d, J = 15.6 Hz, 1H), 4.19 (t, J = 6.6 Hz, 2H), 3.88 (s, 3H), 3.38 (m, 1H), 3.00–2.90 (m, 2H), 2.74–2.66 (m, 1H), 2.54–2.49 (m, 1H), 2.38 (s, 3H), 2.10–2.00 (m, 1H), 1.82–1.07 (m, 14H), 0.95 (t, J = 7.3 Hz, 3H); ¹³C NMR (75 MHz; CDCl₃) δ: 167.4, 146.9, 145.0, 142.0, 131.9, 125.9, 123.1, 116.5, 106.0, 64.3, 57.6, 55.9, 47.5, 45.5, 42.4, 37.7, 37.3, 36.5, 30.7, 26.8, 26.3, 22.9, 22.0, 19.1, 13.7.

(9α,13α,14α)-1-Isobutylacrylate-4-hydroxy-3-methoxy-17-methyl morphinan (6d): Yield 89%; m.p.: 169–171 °C; ESI-MS m/z: 412 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 8.03 (d, J = 15.6 Hz, 1H), 6.96 (s, 1H), 6.22 (d, J = 15.6 Hz, 1H), 3.97 (d, J = 6.6 Hz, 2H), 3.88 (s, 3H), 3.36 (m, 1H), 2.99–2.87 (m, 2H), 2.72–2.64 (m, 1H), 2.54–2.41 (m, 2H), 2.36 (s, 3H), 2.07–0.89 (m, 11H), 0.96 (d, J = 6.6 Hz, 6H); ¹³C NMR (75 MHz; CDCl₃) δ: 167.4, 146.9, 145.0, 142.1, 132.2, 126.1, 123.1, 116.4, 106.0, 70.4, 57.6, 55.9, 47.5, 45.6, 42.5, 37.8, 37.4, 36.6, 27.8, 26.9, 26.4, 22.9, 22.0, 19.1.

(9α,13α,14α)-1-(tert-Butylacrylate)-4-hydroxy-3-methoxy-17-methyl morphinan (6e): Yield 84%; m.p.: 176–178 °C; ESI-MS m/z: 412 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 7.95 (d, J = 15.6 Hz, 1H), 6.94 (s, 1H), 6.15 (d, J = 15.6 Hz, 1H), 3.86 (s, 3H), 3.35 (m, 1H), 2.96 (d, J = 18.4 Hz, 1H), 2.85 (m, 1H), 2.68–2.60 (m, 1H), 2.48–2.43 (m, 1H), 2.34 (s, 3H), 2.05–0.90 (m, 11H), 1.51 (m, 9H); ¹³C NMR (75 MHz; CDCl₃) δ: 166.8, 146.7, 144.9, 141.2, 132.1, 126.0, 123.1, 118.1, 105.9, 80.2, 57.5, 55.9, 47.5, 45.8, 42.6, 37.8, 37.5, 36.6, 28.2, 26.9, 26.4, 22.9, 21.9.

(9α,13α,14α)-1-(2-Methoxyethylacrylate)-4-hydroxy-3-methoxy-17-methyl morphinan (6f): Yield 87%; m.p.: 151–153 °C; ESI-MS m/z: 414 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 8.05 (d, J = 15.6 Hz, 1H), 6.95 (s, 1H), 6.28 (d, J = 15.6 Hz, 1H), 4.34 (t, J = 4.5 Hz, 2H), 3.85 (s, 3H), 3.65 (t, J = 4.5 Hz, 2H), 3.40 (s, 3H), 3.34 (m, 1H), 2.96 (d, J = 18.4 Hz, 1H), 2.87 (m, 1H), 2.71–2.63 (m, 1H), 2.50–2.45 (m, 1H), 2.35 (s, 3H), 2.06–1.06 (m, 11H); ¹³C NMR (75 MHz; CDCl₃) δ: 167.3, 147.1, 145.0, 142.6, 132.3, 126.1, 122.9, 115.8, 106.0, 70.5, 63.3, 58.9, 57.6, 55.9, 47.5, 45.7, 42.5, 37.8, 37.4, 36.6, 26.9, 26.4, 22.9, 22.0.

(9α,13α,14α)-1-Hexylacrylate-4-hydroxy-3-methoxy-17-methyl morphinan (6g): Yield 90%; m.p.: 148–150 °C; ESI-MS m/z: 440 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 8.03 (d, J = 15.6 Hz, 1H), 6.96 (s, 1H), 6.21 (d, J = 15.6 Hz, 1H), 4.19 (t, J = 6.6 Hz, 2H), 3.89 (s, 3H), 3.36 (m, 1H), 3.00–2.89 (m, 2H), 2.73–2.65 (m, 1H), 2.54–2.47 (m, 1H), 2.38 (s, 3H), 2.10–0.85 (m, 22H); ¹³C NMR (75 MHz; CDCl₃) δ: 167.4, 146.8, 144.9, 142.1, 132.2, 126.0, 123.1, 116.5, 106.0, 64.5, 57.6, 55.9, 47.5, 45.8, 42.6, 37.8, 37.5, 36.6, 31.4, 28.6, 26.9, 26.4, 25.6, 22.9, 22.5, 22.0, 13.9.

(9α,13α,14α)-1-Cyclohexylacrylate-4-hydroxy-3-methoxy-17-methyl morphinan (6h): Yield 86%; m.p.: 159–161 °C; ESI-MS m/z: 440 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 7.99 (d, J = 15.6 Hz, 1H), 6.95 (s, 1H), 6.19 (d, J = 15.6 Hz, 1H), 4.85 (m, 1H), 3.86 (s, 3H), 3.35 (m, 1H), 2.98–2.89 (m, 2H), 2.73–2.65 (m, 1H), 2.52–2.47 (m, 1H), 2.37 (s, 3H), 2.06–0.96 (m, 21H); ¹³C NMR (75 MHz; CDCl₃) δ: 166.8, 146.8, 145.0, 141.8, 132.0, 126.0, 123.1, 117.0, 106.0, 72.6, 57.6, 55.9, 47.5, 45.7, 42.5, 37.7, 37.4, 36.6, 31.7, 26.9, 26.4, 25.3, 23.7, 22.9, 22.0.

(9α,13α,14α)-1-(2-Ethyl-hexylacrylate)-4-hydroxy-3-methoxy-17-methyl morphinan (6i): Yield 87%; m.p.: 125–127 °C; ESI-MS m/z: 468 [M-H]^–; ¹H NMR (300 MHz; CDCl₃) δ: 7.86 (d, J = 15.6 Hz, 1H), 7.01 (s, 1H), 6.25 (d, J = 15.6 Hz, 1H), 4.10 (d, J = 5.7 Hz, 2H), 3.89 (s, 3H), 3.59 (m, 1H), 3.42–2.93 (m, 4H), 2.75 (s, 3H), 2.54–0.85 (m, 26H); ¹³C NMR (75 MHz; CDCl3) δ: 167.0, 146.7, 145.7, 140.5, 132.0, 126.7, 124.1, 118.4, 107.1, 67.1, 60.0, 56.2, 48.6, 42.4, 41.4, 38.8, 36.3, 35.0, 34.8, 30.3, 28.8, 26.0, 25.4, 23.7, 22.9, 22.4, 22.3, 14.0, 10.9.

Supplemental Material

3.Supplementary_information-2 – Supplemental material for Synthesis of C-ring hydrogenated sinomenine cinnamate derivatives via Heck reactions

Supplemental material, 3.Supplementary_information-2 for Synthesis of C-ring hydrogenated sinomenine cinnamate derivatives via Heck reactions by Hongmei Pan, Tong Lu, Xuedan Wu, Chuan Jiang, Chengwen Gu, Kehua Zhang and Jie Jin in Journal of Chemical Research