Highly Diastereoselective 1,6-Conjugate Addition of Arylboronic Acids to Securinine

Abstract

The asymmetric 1,6-conjugate addition of arylboronic acids to natural securinine under rhodium(I) catalysis displays a very high regioselectivity, along with a remarkable diastereoselectivity (>99:1) and high yields. The in vitro cytotoxicity of the resulting securinine analogues was assayed against HCT-116 colon cancer cells, giving a new insight into the structure–activity relationship of securinine.

Key words

catalysis - rhodium - securinine - arylboronic acids - conjugate addition - medicinal chemistry

• References and Notes

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2-Hetarylboronic acids are known to undergo rapid degradation by protodeboronation or oxidation processes. For examples, see:
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• 11 Crystallographic data for compound 2e have been deposited with the accession number CCDC 1439457, and can be obtained free of charge from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: [phone]; E-mail: [e-mail]; Web site: www.ccdc.cam.ac.uk/conts/retrieving.html.
• 12 Under similar experimental conditions, securinine (1) was found to inhibit the proliferation by 90% at 20 µM.
• 13 Synthesis of Arylsecurine Derivatives 2 from Securinine (1); General Procedure A 10 mL glass screw-cap tube, capped with a rubber septum, was charged with securinine (1; 108 mg, 0.5 mmol), [Rh(C₂H₄)₂Cl]₂ (5 mol%, corresponding to 10 mol% Rh), and the appropriate arylboronic acid (3 equiv) under argon. DCE (2 mL), H₂O (0.2 mL), and Et₃N (0.5 equiv) were then added under argon. The septum was replaced by a screw cap, and the mixture was stirred at 110 °C in an oil bath. After 24 h, the mixture was treated with 0.5 M aq NaOH (5 mL) and diluted with CH₂Cl₂ (5 mL). The aqueous layer was extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layers were dried (MgSO₄), filtered, and concentrated to dryness. Purification by flash column chromatography on silica gel gave the addition product 2. Compound 2a White solid; yield: 107 mg (73%); mp 126 °C; R_f = 0.83 (PE–EtOAc, 50:50); [α]_D ²⁰ +131 (c 0.10, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.28–7.16 (m, 5 H), 5.59 (d, J = 2.2 Hz, 1 H), 3.20 (d, J = 6.2 Hz, 1 H), 3.11–2.99 (m, 2 H), 2.91–2.73 (m, 4 H), 2.47–2.41 (m, 1 H), 1.79–1.75 (m, 1 H), 1.60–1.53 (m, 2 H), 1.39–1.14 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.6, 173.3, 142.7, 128.4, 127.6, 126.9, 110.0, 91.1, 66.0, 61.0, 50.6, 50.1, 39.3, 29.8, 26.1, 24.1, 21.6. MS (CI, NH₃): m/z = 296 [M + H]⁺. Compound 2b Brown solid; yield: 130 mg (80%); mp 132 °C; R_f = 0.30 (PE–EtOAc, 75:25); [α]_D ²⁰ +128 (c 0.10, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.21 (t, J = 7.9 Hz, 1 H), 6.93–6.86 (m, 2 H), 6.81 (ddd, J = 8.2, 2.6, 0.9 Hz, 1 H), 5.64 (d, J = 2.2 Hz, 1 H), 3.80 (s, 3 H), 3.27 (d, J = 6.2 Hz, 1 H), 3.17–3.11 (m, 1 H), 3.09–2.98 (m, 1 H), 2.97–2.86 (m, 2 H), 2.84–2.77 (m, 2 H), 2.62–2.54 (m, 1 H), 1.87–1.80 (m, 1 H), 1.65–1.58 (m, 2 H), 1.46–1.19 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.5, 173.2, 159.6, 144.4, 129.2, 120.0, 113.3, 112.0, 109.9, 91.1, 65.8, 60.9, 55.1, 50.6, 50.1, 39.3, 29.9, 26.1, 24.1, 21.6. MS (CI, NH₃): m/z = 326 [M + H]⁺, 343 [M + NH₄]⁺. Compound 2c Beige solid; yield: 111.5 mg (69%); mp 225 °C; R_f = 0.41 (PE–EtOAc, 75:25); [α]_D ²⁰ +200 (c 0.10, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 6.94 (s, 2 H), 6.89 (s, 1 H), 5.65 (d, J = 2.2 Hz, 1 H), 3.26 (d, J = 6.2 Hz, 1 H), 3.18–3.04 (m, 2 H), 3.00–2.90 (m, 2 H), 2.88–2.72 (m, 2 H), 2.61–2.53 (m, 1 H), 2.31 (s, 6 H), 1.89–1.83 (m, 1 H), 1.66–1.57 (m, 2 H), 1.44–1.17 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.8, 173.3, 142.6, 137.7, 128.4, 125.4, 109.8, 91.1, 65.9, 60.9, 50.6, 50.1, 39.4, 29.9, 26.2, 24.2, 21.8, 21.3. MS (CI, NH₃): m/z = 324 [M + H]⁺, 341 [M + NH₄]⁺. Compound 2e Orange solid; yield: 123 mg (80%); mp 175 °C; R_f = 0.26 (PE–EtOAc, 65:35); [α]_D ²⁰ +110 (c 0.15, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.95 (t, J = 1.6 Hz, 1 H), 7.82 (dt, J = 7.7, 1.5 Hz, 1 H), 7.53 (dt, J = 7.7, 1.5 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 1 H), 5.65 (d, J = 2.2 Hz, 1 H), 3.25 (d, J = 6.2 Hz, 1 H), 3.19–3.05 (m, 2 H), 2.97–2.88 (m, 3 H), 2.81 (dd, J = 10.6, 6.3 Hz, 1 H), 2.59 (s, 3 H), 2.51–2.44 (m, 1 H), 1.87–1.79 (m, 1 H), 1.66–1.58 (m, 2 H), 1.44–1.18 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 198.0, 174.0, 173.0, 143.3, 137.2, 132.4, 128.6, 127.3, 127.0, 110.1, 91.0, 65.9, 60.9, 50.2, 50.1, 39.1, 29.8, 26.6, 26.0, 24.0, 21.4. MS (CI, NH₃): m/z = 338 [M + H]⁺. Compound 2f Orange solid; yield: 108 mg (67%); mp 144 °C; R_f = 0.48 (PE–EtOAc, 50:50); [α]_D ²⁰ +91 (c 0.11, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 9.95 (s, 1 H), 7.80 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 8.2 Hz, 2 H), 5.66 (d, J = 1.8 Hz, 1 H), 3.26 (d, J = 6.1 Hz, 1 H), 3.17–3.04 (m, 2 H), 2.98–2.88 (m, 3 H), 2.86–2.78 (m, 1 H), 2.48–2.41 (m, 1 H), 1.85–1.77 (m, 1 H), 1.67–1.55 (m, 2 H), 1.42–1.14 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 191.8, 173.7, 172.9, 149.8, 135.2, 129.8, 128.2, 110.2, 90.9, 65.9, 60.9, 50.6, 50.1, 39.1, 29.4, 25.9, 23.9, 21.4. MS (CI, NH₃): m/z = 324 [M + H]⁺, 341 [M + NH₄]⁺. Compound 2g Yellow solid; yield: 125.4 mg (71%); mp 181 °C; R_f = 0.32 (PE–EtOAc, 75:25); [α]_D ²⁰ +199 (c 0.14, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.97 (d, J = 8.4 Hz, 2 H), 7.40 (d, J = 8.4 Hz, 2 H), 5.67 (d, J = 2.2 Hz, 1 H), 3.90 (s, 3 H), 3.26 (d, J = 6.2 Hz, 1 H), 3.19–3.06 (m, 2 H), 2.96–2.80 (m, 4 H), 2.50–2.42 (m, 1 H), 1.87–1.80 (m, 1 H), 1.67–1.59 (m, 2 H), 1.44–1.20 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.0, 173.1, 166.9, 148.0, 129.7, 128.8, 127.6, 110.3, 91.0, 66.0, 61.0, 52.0, 50.6, 50.1, 39.2, 29.5, 26.1, 24.0, 21.5. MS (CI, NH₃): m/z = 354 [M + H]⁺, 371 [M + NH₄]⁺. Compound 2h Orange solid; yield: 106.5 mg (68%); mp 137 °C; R_f = 0.41 (PE–EtOAc, 75:25); [α]_D ²⁰ +148 (c 0.12, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.23–7.15 (m, 1 H), 7.04–6.99 (m, 2 H), 6.86 (tdd, J = 8.5, 2.5, 1.0 Hz, 1 H), 5.59 (d, J = 2.1 Hz, 1 H), 3.19 (d, J = 6.3 Hz, 1 H), 3.11–3.05 (m, 1 H), 2.99–2.81 (m, 3 H), 2.80–2.71 (m, 2 H), 2.50–2.42 (m, 1 H), 1.80–1.74 (m, 1 H), 1.59–1.51 (m, 2 H), 1.39–1.13 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.0, 173.1, 162.8 (d, J = 245.4 Hz), 145.4 (d, J = 7.1 Hz), 129.7 (d, J = 8.3 Hz), 123.3 (d, J = 2.0 Hz), 114.3 (d, J = 21.7 Hz), 113.7 (d, J = 21.1 Hz), 110.1, 91.0, 65.9, 60.9, 50.2, 50.0, 39.1, 29.7, 26.0, 24.0, 21.5. MS (CI, NH₃): m/z = 314 [M + H]⁺, 331 [M + NH₄]⁺. Compound 2i Orange solid; yield: 130 mg (79%); mp 208 °C; R_f = 0.43 (PE–EtOAc, 75:25); [α]_D ²⁰ +181 (c 0.14, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.20 (br s, 4 H), 5.59 (d, J = 2.1 Hz, 1 H), 3.15 (d, J = 6.2 Hz, 1 H), 3.10–3.04 (m, 1 H), 3.02–2.90 (m, 2 H), 2.89–2.72 (m, 3 H), 2.44 (dt, J = 13.5, 3.7 Hz, 1 H), 1.81–1.74 (m, 1 H), 1.58–1.52 (m, 2 H), 1.38–1.15 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.1, 173.1, 141.2, 132.6, 128.9, 128.5, 110.1, 91.0, 65.9, 60.9, 50.1, 49.9, 39.1, 29.8, 26.0, 24.0, 21.5. MS (CI, NH₃): m/z = 330 [M + H]⁺, 347 [M + NH₄]⁺. Compound 2j Brown solid; yield: 127 mg (70%); mp 224 °C; R_f = 0.53 (PE–EtOAc, 70:30); [α]_D ²⁰ +115 (c 0.10, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.57 (d, J = 8.1 Hz, 2 H), 7.45 (d, J = 8.1 Hz, 2 H), 5.68 (d, J = 2.2 Hz, 1 H), 3.26 (d, J = 6.2 Hz, 1 H), 3.20–3.05 (m, 2 H), 2.98–2.81 (m, 4 H), 2.50 (dd, J = 13.3, 3.8, 2.5 Hz, 1 H), 1.88–1.81 (m, 1 H), 1.69–1.60 (m, 2 H), 1.47–1.22 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 173.7, 172.9, 146.8, 129.3 (q, J = 32.4 Hz), 128.0, 125.3 (q, J = 3.5 Hz), 124.2 (q, J = 271.8 Hz), 110.4, 91.0, 65.9, 61.0, 50.4, 50.2, 39.2, 29.7, 26.0, 24.0, 21.4. MS (CI, NH₃): m/z = 364 [M + H]⁺, 381 [M + NH₄]⁺. Compound 2k Yield: 127.3 mg (74%); mp 182 °C; R_f = 0.30 (PE–EtOAc, 75:25); [α]_D ²⁰ +182 (c 0.10, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ =7.84–7.79 (m, 3 H), 7.74 (br s, 1 H), 7.52–7.45 (m, 3 H), 5.68 (d, J = 2.2 Hz, 1 H), 3.33 (d, J = 6.2 Hz, 1 H), 3.24–3.17 (m, 2 H), 3.03–2.93 (m, 3 H), 2.91–2.82 (m, 1 H), 2.47 (dd, J = 13.6, 3.3 Hz, 1 H), 1.88–1.80 (m, 1 H), 1.70–1.61 (m, 2 H), 1.46–1.20 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 174.5, 173.2, 140.1, 133.3, 132.5, 127.9, 127.6, 127.5, 126.2, 126.0, 125.9, 125.6, 110.0, 91.1, 65.9, 61.0, 50.7, 50.1, 39.3, 29.7, 26.2, 24.1, 21.6. MS (CI, NH₃): m/z = 346 [M + H]⁺, 363 [M + NH₄]⁺. Compound 2l Yield: 35.6 mg (25%); mp 141 °C; R_f = 0.27 (PE–EtOAc, 75:25); [α]_D ²⁰ +186 (c 0.14, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 7.32 (dd, J = 1.8, 0.8 Hz, 1 H), 6.30 (dd, J = 3.2, 1.8 Hz, 1 H), 6.07 (d, J = 3.2 Hz, 1 H), 5.65 (d, J = 1.6 Hz, 1 H), 3.54 (d, J = 6.2 Hz, 1 H), 3.04–2.90 (m, 4 H), 2.86–2.74 (m, 2 H), 2.54–2.47 (m, 1 H), 1.86–1.80 (m, 1 H), 1.59–1.53 (m, 2 H), 1.38–1.18 (m, 4 H). ¹³C NMR (75 MHz, CDCl₃): δ = 173.4, 167.4, 149.4, 142.6, 132.9, 124.3, 111.6, 107.8, 106.5, 90.0, 62.7, 58.2, 48.8, 42.3, 27.3, 25.9, 24.5. MS (CI, NH₃): m/z = 286 [M + H]⁺, 303 [M + NH₄]⁺.