Total Synthesis of ent-Sedridine Using Proline-Catalyzed Asymmetric ­Addition as a Key Step

Takashi Itoh; Kosuke Nishimura; Kazuhiro Nagata; Masashi Yokoya

doi:10.1055/s-2006-948203

LETTER

Total Synthesis of ent-Sedridine Using Proline-Catalyzed Asymmetric Addition as a Key Step

Takashi Itoh*, Kosuke Nishimura, Kazuhiro Nagata, Masashi Yokoya
School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan
Fax: +81(3)37845982; e-Mail: itoh-t@pharm.showa-u.ac.jp;

Abstract

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Abstract

A total synthesis of ent-sedridine is described. The development of a new method for the construction of the C-2 chiral center of the piperidine ring was achieved using a proline-catalyzed Mannich reaction. Reaction of 4-hydroxybutanal and p-anisidine to form an imine and subsequent addition of acetone gave the key chiral aliphatic precursor with high enantioselectivity.

Key words

asymmetric catalysis - nucleophilic additions - total synthesis - alkaloids - piperidine

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References

References and Notes

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8-Hydroxy-4-[(4-methoxyphenyl)amino]octan-2-one ( 2). l-Proline (80 mg, 30 mol%) was added to a solution of 5-hydroxypentanal (750 µL, 6.95 mmol) and p-anisidine (286 mg, 2.32 mmol) in 2-propanol (10 mL) at -10 °C under an Ar atmosphere. After acetone (2.5 mL) was added, the reaction mixture was stirred at -10 °C for 185 h. Then EtOAc was added and the mixture was extracted with 1 N HCl aqueous solution. The combined aqueous layer was neutralized with NaHCO₃ and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄ and evaporated off to give crude 2. ¹H NMR (CDCl₃): δ = 1.39-1.63 (m, 6 H), 2.13 (s, 3 H), 2.60 (dd, J = 16.6, 6.4 Hz, 1 H), 2.71 (dd, J = 16.6, 5.2 Hz, 1 H), 2.85 (br s, 1 H), 3.62 (t, J = 6.1 Hz, 2 H), 3.74 (s, 3 H), 6.65 (d, J = 8.8 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 2 H); ¹³C NMR (CDCl₃): δ = 22.4, 30.8, 32.4, 34.4, 47.4, 51.7, 55.7, 62.5, 115.0, 116.0, 139.9, 153.0, 208.1. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₅H₂₄O₃N: 266.1777; found: 266.1749. Enantiomeric excess was determined by HPLC analysis using a chiral column (DAICEL Chiralcel OD, hexane-i-PrOH = 3:1, 0.5 mL/min).

5-[(4-Methoxyphenyl)amino]octane-1,7-diol ( 6). Compound 2 was dissolved in THF (25 mL) and cooled to 0 °C, LiAlH₄ (264 mg, 6.96 mmol) was added. The reaction mixture was stirred for 3.5 h under an Ar atmosphere and was then quenched with H₂O. The resulting mixture was extracted with CH₂Cl₂ and the organic layer was dried over MgSO₄ and evaporated off. The product was purified using column chromatography (EtOAc-hexane, 7:3) to give compound 6 (445 mg, 72% from p-anisidine). The NMR spectra of the main diastereomer are given; ¹H NMR (CDCl₃): δ = 1.19 (d, J = 6.1 Hz, 3 H), 1.29-1.76 (m, 8 H), 2.85 (br s, 3 H), 3.44 (m, 1 H), 3.55-3.61 (m, 2 H), 3.75 (s, 3 H), 4.06 (m, 1 H), 6.77 (d, J = 4.9 Hz, 2 H), 6.79 (d, J = 5.1 Hz, 2 H); ¹³C NMR (CDCl₃): δ = 21.9, 23.9, 32.6, 35.1, 42.7, 55.7, 56.6, 62.5, 68.6, 114.9, 117.4, 140.4, 153.4. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₅H₂₆O₃N: 268.1969; found 268.1892.

1-[1-(4-Methoxyphenyl)piperidin-2-yl]propan-2-ol ( 7). To solution of compound 6 (400 mg, 1.50 mmol) in CH₂Cl₂ (25 mL) was added PPh₃ (472 mg, 1.80 mmol) and DEAD (950 µL, 2.10 mmol). The mixture was stirred for 2 h at r.t. under an Ar atmosphere. Then EtOAc was added and the mixture was extracted with 1 N HCl aqueous solution. The combined aqueous layers were neutralized with NaHCO₃ and extracted with CH₂Cl₂. The organic layer was dried over MgSO₄ and evaporated off. The product was purified by column chromatography (EtOAc-hexane, 1:4) to give compound 7 (328 mg, 88%). The NMR spectra of the main diastereomer are given; ¹H NMR (CDCl₃): δ = 1.17 (d, J = 6.1 Hz, 3 H), 1.45-1.90 (m, 8 H), 3.20-3.26 (m, 2 H), 3.52 (m, 1 H), 3.77 (s, 3 H), 3.95 (m, 1 H), 6.82-6.85 (m, 4 H); ¹³C NMR (CDCl₃): δ = 20.3, 24.0, 24.1, 28.1, 37.6, 51.9, 55.5, 56.4, 65.6, 114.4, 122.4, 145.3, 154.8. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₅H₂₄O₂N: 250.1852; found: 250.1792.

Although the mixture of diastereomers 7 could not be separated, the configuration of the major isomer was shown to be (2R,2ŽR), since (2R,2ŽR)-epimer 8 was obtained in 54% yield from the reaction of 7.

(2 R ,2Ž R )-Benzyl 2-(2-Hydroxypropyl)piperidine-1-carboxylate ( 8). To a cold solution (0 °C) of compound 7 (60 mg, 0.24 mmol) in MeCN (8.4 mL), CAN (658 mg, 1.2 mmol) in H₂O (8.4 mL) was added dropwise and the mixture was stirred for 5 h. The solution was then made basic using 5 N NaOH aqueous solution, CbzCl (690 µL, 4.80 mmol) was added. The reaction mixture was stirred for 10 min and neutralized with 1 N HCl aqueous solution. The mixture was filtered through a celite pad and the filtrate was extracted with CH₂Cl₂. The organic layer was dried over MgSO₄ and evaporated off. The product was purified by column chromatography (EtOAc-hexane, 1:9) to give compound 8 (36 mg, 54%). ¹H NMR (CDCl₃): δ = 1.18 (d, J = 6.1 Hz, 3 H), 1.20-1.76 (m, 7 H), 1.99 (td, J = 13.2, 2.2 Hz, 1 H), 2.76 (td, J = 12.9, 2.4 Hz, 1 H), 3.26 (br s, 1 H), 3.53 (br s, 1 H), 4.05 (br d, J = 12.2 Hz, 1 H), 4.50 (br s, 1 H), 5.13 (d, J = 13.4 Hz, 1 H), 5.15 (12.4 Hz, 1 H), 7.29-7.39 (m, 5 H); ¹³C NMR (CDCl₃): δ = 19.1, 22.5, 25.5, 29.3, 39.3, 39.4, 47.5, 63.3, 67.5, 127.9, 128.1, 128.4, 136.5, 157.0. HRMS-FAB: m/z [M + H]⁺ calcd for C₁₆H₂₄O₃N: 278.1703; found: 278.1777. [a]_D ²⁰ +26.1 (c 0.59, CHCl₃).

When benzoates of both isomers of 7 were oxidized with CAN and then protected with Cbz, both epimers of the benzoate derivatives of 8 were obtained. The result suggested that the free hydroxyl group participates in the mechanism of separation of 7.

Total Synthesis of ent-Sedridine Using Proline-Catalyzed Asymmetric ­Addition as a Key Step

Total Synthesis of ent-Sedridine Using Proline-Catalyzed Asymmetric Addition as a Key Step