Synthetic Study of Matrine-Type Alkaloids: Stereoselective Construction of the AB Rings of the Quinolizidine Skeleton

Abstract

A new method has been developed for the stereoselective construction of the AB rings of the quinolizidine skeleton of ­matrine-type alkaloids with a cis-cis stereochemistry. The key features of this method involve: (i) construction of the quinolizidine by reduction of an acylpyridinium cation; and (ii) late-stage introduction of methoxypyridine by sequential Stille coupling and diastereo­selective hydrogenation reactions.

Key words

quinolizidines - stereoselective synthesis - alkaloids - matrine - pyridines

• References and Notes

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• 18 Synthesis of 1,4-Dihydropyridine 6: To a solution of carboxylic acid 7 (2.20 g, 7.34 mmol) and MS (4 Å; ca. 5 g) in CH₂Cl₂ (50 mL) at 0 °C was added Ghosez reagent (1.00 mL, 7.41 mmol). The mixture was stirred at 0 °C for 30 min, then Hantzsch ester (5.58 g, 22.0 mmol) was added. After stirring at room temperature for 2 h, the mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Et₂O–toluene, 2–3%) to afford dihydropyridine 6 (1.28 g, 4.52 mmol, 61%) as a solid. IR (ATR): 2979, 2721, 1689, 1235, 1089, 893 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.35–7.25 (m, 5 H), 7.08 (dt, J = 8.0, 1.7 Hz, 1 H), 5.13 (dt, J = 8.3, 3.5 Hz, 1 H), 4.60–4.57 (m, 2 H), 4.49 (s, 2 H), 3.19–3.17 (m, 2 H), 2.74 (ddd, J = 8.3, 6.0, 1.5 Hz, 2 H), 2.67 (ddd, J = 8.3, 6.0, 1.5 Hz, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 192.3, 165.3, 138.1, 132.8, 128.9, 128.5, 127.8, 127.7, 122.7, 108.1, 73.0, 69.7, 35.9, 29.7, 25.9; MS (FAB): m/z = 284 [M + H]⁺. HRMS (FAB): m/z [M + H]⁺ calcd for C₁₇H₁₈NO₃: 284.1287; found: 284.1296.
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• 23 Synthesis of Quinolizidine 1: To a solution of alcohol 19 (11.3 mg, 0.0390 mmol) in THF (1 mL) was added dropwise a solution of LiAlH₄ (2.2 mg, 0.058 mmol, 1.5 equiv) in anhydrous THF (0.6 mL) at 0 °C under argon, and the resulting mixture was stirred at 50 °C for 30 min. After careful hydrolysis with 3 M aq NaOH (1 mL), EtOAc (1 mL) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 mL) and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated. The crude residue was purified by column chromatography (CHCl₃–MeOH, 20:1) to give alcohol 1 (10.8 mg, 0.035 mmol, 80%) as an oil. IR (ATR): 3356, 2928, 2857, 2754, 2683, 1578, 1466 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.47 (dd, J = 8.0, 7.4 Hz, 1 H), 7.00 (d, J = 7.4 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H), 3.91 (s, 3 H), 3.65–3.54 (m, 2 H), 3.46 (dd, J = 11.2, 3.0 Hz, 1 H), 3.20 (dd, J = 8.5, 6.3, 4.0 Hz, 1 H), 2.98 (br d, J = 11.7 Hz, 1 H), 2.87–2.83 (m, 2 H), 2.30–2.14 (m, 3 H), 2.10–2.02 (m, 2 H), 1.86–1.81 (m, 2 H), 1.59–1.43 (m, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 163.1, 160.8, 138.3, 116.2, 107.7, 67.2, 64.9, 57.7, 53.3, 45.2, 37.9, 31.9, 30.7, 29.6, 21.7, 21.6. MS (FAB): m/z = 277.2 [M + H]⁺. HRMS (FAB): m/z [M + H]⁺ calcd for C₁₆H₂₅N₂O₂: 277.1911; found: 277.1913.