Synlett 2014; 25(5): 653-656
DOI: 10.1055/s-0033-1340179
letter
© Georg Thieme Verlag Stuttgart · New York

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

Chihiro Tsukano
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan   Fax: +81(75)7534569   Email: [email protected]
,
Atsuko Oimura
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan   Fax: +81(75)7534569   Email: [email protected]
,
Iderbat Enkhtaivan
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan   Fax: +81(75)7534569   Email: [email protected]
,
Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto, 606-8501, Japan   Fax: +81(75)7534569   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 12 December 2013

Accepted after revision: 06 January 2014

Publication Date:
10 February 2014 (online)


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.

Supporting Information

 
  • 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.