A Short and Enantiospecific Synthesis of (-)-Nupharamine

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.

catalysis - reductive amination - terpenes - alkaloids - cross metathesis

References

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<A NAME="RG28205ST-10">10</A> 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

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<A NAME="RG28205ST-13">13</A> 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

<A NAME="RG28205ST-14">14</A> 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

<A NAME="RG28205ST-15">15</A> 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.

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