Synlett 2005(18): 2826-2828  
DOI: 10.1055/s-2005-918942
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Short and Enantiospecific Synthesis of (-)-Nupharamine

Julian Gebauer, Siegfried Blechert*
Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 135, 10623 Berlin, Germany
Fax: +49(30)31423619; e-Mail: blechert@chem.tu-berlin.de;
Further Information

Publication History

Received 31 August 2005
Publication Date:
12 October 2005 (online)

Abstract

A short and convergent synthesis of the naturally ­occurring sesquiterpenoid piperidine alkaloid (-)-nupharamine is presented starting from (-)-isopinocampheol via cross metathesis and reductive amination as the key steps.

    References

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  • 10 Preparation and Spectral Data of 10. To a stirred solution of alcohol 9a,b (154 mg, 1.0 mmol), phthalimide (162 mg, 1.1 mmol) and MePPh2 (220 mg, 1.1 mmol) in dry THF (5 mL) under nitrogen was added DEAD (191 mg, 1.1 mmol) dropwise at 0 °C. The mixture was allowed to warm to r.t. over a period of 1 h before it was diluted with Et2O, filtered and concentrated. Flash chromatography (SiO2) of the resulting residue gave 140 mg (50%) of 10 as a colorless oil. [α]D 20 -18.8 (c 0.85, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 7.78 (m, 2 H), 7.67 (m, 2 H), 5.58 (m, 1 H), 4.97 (t, J = 7.0 Hz, 1 H), 4.91 (dd, J = 16.9, 1.0 Hz, 1 H), 4.76 (dd, J = 10.1, 1.0 Hz, 1 H), 3.99 (dt, J = 11.0, 4.1 Hz, 1 H), 3.00 (m, 1 H), 2.85 (m, 1 H), 2.45 (m, 1 H), 1.53 (s, 3 H), 1.52 (s, 3 H), 1.14 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 168.8, 141.2, 134.6, 133.7, 131.8, 123.0, 120.3, 115.1, 56.8, 41.1, 28.4, 25.7, 18.4, 17.8 ppm. IR (ATR): ν = 2973, 2928, 1772, 1710, 1390, 1361, 1088, 919, 874, 721 cm-1. HRMS (EI): m/z calcd for C18H21NO2 [M+]: 283.1572; found: 283.1577. Anal. Calcd for C18H21NO2: C, 76.30; H, 7.47; N, 4.94. Found: C, 75.92; H, 7.55; N, 4.64
  • For a short review on its unique activity, see:
  • 11a Connon SJ. Blechert S. Angew. Chem.  2003,  115:  1944 
  • 11b Hoveyda HA. Gillingham DG. Van Veldhuizen JJ. Kataoka O. Garber SB. Kingsbury JS. Harrity JPA. Org. Biol. Chem.  2004,  2:  8 
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  • 13 Preparation and Spectral Data of 13. To a stirred solution of 10 (140 mg, 0.5 mmol) in CHCl3 (1.2 mL) was added TFA (0.4 mL, 5.0 mmol) dropwise at 0 °C. After 16 h at r.t. the volatiles were removed in vacuo. To the residue was added a 8 M solution of MeNH2 in EtOH (3 mL, 24 mmol) and the mixture was stirred at 55 °C for 24 h. Evaporation of the volatiles gave the crude amino alcohol which was dissolved in CHCl3 (4 mL) and treated with sat. NaHCO3 solution (0.5 mL) followed by Boc2O (120 mg, 0.54 mmol) in 1 mL CHCl3. After 16 h at r.t. H2O (5 mL) was added and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL). The combined organic phases were dried, concentrated, diluted with Et2O and filtered. Flash chromatography (SiO2) of the concentrate gave 97 mg (81%) of 13 as a clear viscous oil. [α]D 20 -7.0 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 5.76 (m, 1 H), 5.08 (m, 2 H), 4.29 (br d, J = 8.4 Hz, 1 H), 3.57 (m, 1 H), 2.34 (m, 1 H), 1.60-1.30 (m, 5 H), 1.44 (s, 9 H), 1.21 (s, 6 H), 1.03 (d, J = 6.8 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 156.2, 139.5, 115.9, 79.1, 70.7, 54.8, 41.6, 39.9, 29.6, 29.4, 28.5, 27.9, 16.3 ppm. IR (ATR): ν = 3345, 2969, 2932, 1690, 1504, 1365, 1250, 1173, 913 cm-1. HRMS (EI): m/z calcd for C14H26NO3 [M+ - CH3]: 256.1913; found: 256.1929. Anal. Calcd for C15H29NO3: C, 66.38; H, 10.77; N, 5.16. Found: C, 66.67; H, 10.58; N, 5.45
  • 14 Preparation and Spectral Data of 14. A solution of amine 13 (27 mg, 0.10 mmol), enone 6 (15 mg, 0.12 mmol) and the Hoveyda-Blechert catalyst (6.3 mg, 0.01 mmol) in dry CH2Cl2 (2 mL) under nitrogen was stirred for 72 h at 40 °C. The solvent was evaporated and the residue was purified by flash chromatography (SiO2) to give 27 mg (74%) of 14 as a brownish solid. Mp 92-94 °C. [α]D 20 -24.4 (c 0.5, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.45 (s, 1 H), 6.95 (dd, J = 15.5, 8.0 Hz, 1 H), 6.83 (s, 1 H), 6.56 (d, J = 8.0 Hz, 1 H), 4.44 (br d, J = 9.4 Hz, 1 H) 3.69 (m, 1 H), 2.58 (m, 1 H), 1.60-1.30 (m, 5 H), 1.42 (s, 9 H), 1.20 (s, 6 H), 1.13 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 184.4, 156.1, 148.9, 147.6, 144.3, 128.0 127.7, 109.2, 79.4, 70.6, 54.8, 41.6, 39.8, 29.6, 29.4, 28.4, 27.7, 16.3 ppm. IR (ATR): ν = 3345, 2970, 2932, 1692, 1668, 1619, 1512, 1365, 1250, 1158, 1055, 873 cm-1. HRMS (EI): m/z calcd for C16H23NO5 [MH+ - C(CH3)3]: 309.1576; found: 309.1580. Anal. Calcd for C20H31NO5: C, 65.73; H, 8.55; N, 3.83. Found: C, 65.28; H, 8.07; N, 3.63
  • 15 Preparation and Spectral Data of (-)-Nupharamine (1).To a solution of aminoenone 14 (35 mg, 0.096 mmol) in acetone (2 mL) was added 10% Pd/C (6 mg, 0.005 mmol) at r.t. and the heterogeneous mixture was stirred under 1 atm of hydrogen for 15 min. Filtration and evaporation of the solvent gave a residue which was dissolved in CH2Cl2 (1 mL), treated with TFA (0.1 mL) and stirred for 1 h. The solution was then diluted with CH2Cl2 (20 mL), washed with sat. NaHCO3 solution (5 mL), dried and concentrated. To the crude imine were added EtOH (1 mL) and at 0 °C NaBH4 (4 mg, 0.1 mmol). After 1 h the solvent was evaporated and the residue was purified by flash chromatography (Al2O3) to give 18 mg (75%) of a yellow oil. [α]D 20 -38.7 (c 0.75, CHCl3), {lit.2 [α]D 22 -35.4 (CHCl3)}. 1H NMR (500 MHz, CDCl3): δ = 7.34 (m, 2 H), 6.41 (s, 1 H), 3.61 (dd, J = 11.5, 2.0 Hz, 1 H), 2.38 (m, 1 H), 1.85 (m, 2 H), 1.75 (m, 2 H), 1.57 (m, 2 H), 1.45 (m, 2 H), 1.23 (m, 1 H), 1.21 (s, 3 H), 1.19 (s, 3 H), 0.90 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 143.1, 138.5, 129.0, 109.3, 68.9, 63.0, 53.1, 39.7, 34.3, 34.0, 33.7, 30.3, 29.3, 28.5, 18.6 ppm. IR (ATR): ν = 3385, 2966, 2926, 2871, 2850, 1458, 1377, 1161, 1025, 912, 874, 794, 765 cm-1. HRMS (EI): m/z calcd for C15H25NO2 [M+]: 251.1885; found: 251.1890.
  • 16 Itatani Y. Yasuda S. Hanaoka M. Arata Y. Chem. Pharm. Bull.  1976,  24:  2521 
6

The ratio of 9a:9b was determined by GCMS.