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Synlett 2006(14): 2207-2210  
DOI: 10.1055/s-2006-948203
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
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Publication History

Received 27 May 2006
Publication Date:
24 August 2006 (online)

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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

13

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).

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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.

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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.

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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.

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(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).

18

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.