l-tert-Leucine-Derived AmidPhos–Silver(I) Chiral Complexes for the Asymmetric [3+2] Cycloaddition of Azomethine Ylides

Abstract

The l-tert-leucine-derived AmidPhos/silver(I) catalytic system has been developed for the asymmetric [3+2] cycloaddition of azomethine ylides with electronic-deficient alkenes with or without Et₃N. Under optimal conditions, highly functionalized endo-4-pyrrolidines were obtained with modest to high yields (up to 99% yield) and enantioselectivities (up to 98% ee).

Key words

l-tert-leucine - amidophosphane - silver(I) - [3+2] cycloaddition - azomethine ylide

• References and Notes

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• 12 Synthesis of the Representative Ligand 1g The 1g′ (334 mg, 1 mmol), which was synthesized according to the procedure of the Supporting Information, was dissolved in CH₂Cl₂ (10 mL) and TFA (1 mL) was added dropwise at 0 °C. Then the reaction mixture was stirred for 18 h at r.t. All volatile compounds were removed in vacuo, and the residue was dissolved in water and treated with the sat. Na₂CO₃ solution. The resulting mixture was extracted with CH₂Cl₂ (3×), and the combined organic layers were dried over Na₂SO₄. After filtration and then evaporation of the solvent, the crude free amine was obtained without purification for the next step. To the solution of the free amine in CH₂Cl₂ (8 mL) was added O-benztriazole-1-N,N,N′,N′-tetraethyluronium hexafluorophosphate (HBTU, 417 mg, 1.1 mmol), followed by the addition of diisopropylethylamine (367 μL, 2.2 mmol) and 2-(diphenylphosphino)benzoic acid (306 mg, 1 mmol), The reaction mixture was then stirred for 18 h at r.t. The mixture was combined with CH₂Cl₂ and water, and the organic layer was separated, washed with sat. NaHCO₃ (2×), and dried over Na₂SO₄. The solvent was removed in vacuo to afford the crude product as colorless oil, which was purified by flash chromatography (15% EtOAc in hexane) yielding the ligand 1g. White solid (407 mg, 78%); mp 77–79 °C; [α]_D ³⁰ –25.6 (c 0.88, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.63–7.62 (m, 1 H), 7.40–7.20 (m, 17 H), 7.02–6.95 (m, 1 H), 6.71–6.70 (m, 1 H), 6.62 (br s, 1 H), 5.12–5.08 (m, 1 H), 4.38–4.35 (m, 1 H), 1.44 (d, J = 6.8 Hz, 3 H), 0.84 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃; C–P coupling not removed): δ = 169.3, 168.9, 143.0, 136.7, 134.5, 133.9, 133.8, 133.7, 133.6, 130.5, 129.1, 128.8, 128.6, 128.6, 128.6, 128.5, 127.8, 127.8, 127.3, 126.3, 61.3, 49.1, 34.7, 26.6, 21.8. ³¹P NMR (162 MHz, CDCl₃) δ = –10.4. ESI-HRMS: m/z calcd for C₃₃H₃₅N₂O₂P [M + H]⁺: 523.2509; found: 523.2511.
• 13 General Procedure of 1,3-Dipole Cycloaddition Ligand of 1g (3.132 mg, 0.006 mmol) and Ag₂CO₃ (0.83 mg, 0.003 mmol) were dissolved in toluene (1.4 mL). The reaction mixture was stirred for 1 h at r.t., followed by the addition of the activated olefins (0.33 mmol), Et₃N (0.015 mmol), and imine substrate (0.3 mmol). Once starting material was consumed (monitored by TLC), the mixture purified by column chromatography to give the corresponding cycloaddition product, which was then directly analyzed by chiral HPLC. (2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(Pyridin-3-yl)pyrolidine-2,3,4-tricarboxylate (4i) White solid, yield 89 mg (85%); mp 102–105 °C; [α]_D ³⁰ +50.2 (c 0.90, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 8.60–8.52 (m, 2 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.29–7.26 (m, 1 H), 4.51 (d, J = 6.4 Hz, 1 H), 4.17–4.12 (m, 3 H), 3.81 (s, 3 H), 3.78–3.63 (m, 4 H), 3.37 (br s, 1 H), 1.25 (t, J = 7.2 Hz, 3 H), 0.84 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.7, 170.2, 170.0, 149.0, 148.9, 134.3, 133.1, 123.2, 62.8, 62.2, 61.2, 60.6, 52.4, 52.3, 50.9, 14.0, 13.6. The ee value was 92%, t _R (major) = 9.28 min, t _R (minor) = 10.83 min (Chiralcel AS-H, λ = 230 nm, i-PrOH–hexanes = 50:50, flow rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C₁₇H₂₂N₂O₆ [M + H]⁺ 351.1551; found: 351.1554. (2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(3,4-Dichlorophenyl)-pyrolidine-2,3,4-tricarboxylate (4l) White solid, yield 81 mg (65%); mp 127–128 °C; [α]_D ³⁰ +46.8 (c 1.00, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (s, 1 H), 7.38 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.4 Hz, 1 H), 4.39 (d, J = 6.8 Hz, 1 H), 4.14–4.08 (m, 3 H), 3.79 (s, 3 H), 3.78–3.67 (m, 3 H), 3.59–3.55 (m, 1 H), 3.27 (brs, 1 H), 1.22 (t, J = 6.8 Hz, 3 H), 0.89 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 170.7, 170.0, 137.8, 132.3, 131.6, 130.2, 129.1, 126.3, 64.0, 61.9, 61.2, 60.6, 52.3, 52.2, 51.1, 14.0, 13.6. The ee value was 87%, t _R (major) = 7.75 min, t _R (minor) = 13.00 min (Chiralcel AS-H, λ = 230 nm, i-PrOH–hexanes = 50:50, flow rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C₁₈H₂₁Cl₂N₁O₆ [M + H]⁺: 418.0819; found: 418.0824. (2S,3R,4S,5R)-3,4-Diethyl 2-Methyl 5-(2-Chlorophenyl)-pyrrolidine-2,3,4-tricarboxylate (4m) Colorless oil, yield 100 mg (87%); [α]_D ³⁰ +60.1 (c 1.02, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (dd, J = 7.6, 1.6 Hz, 1 H), 7.35 (dd, J = 7.6, 1.6 Hz, 1 H), 7.28–7.20 (m, 2 H), 4.72 (d, J = 6.8 Hz, 1 H), 4.14–4.08 (m, 3 H), 3.92 (dd, J = 8.4, 6.8 Hz, 1 H), 3.83 (s, 3 H), 3.77 (dd, J = 8.8, 8.8 Hz, 1 H), 3.70–3.60 (m, 2 H), 3.40 (br s, 1 H), 1.21 (t, J = 7.2 Hz, 3 H), 0.78 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 171.1, 170.3, 169.9, 134.5, 133.3, 129.1, 128.8, 127.4, 126.7, 62.0, 61.1, 61.0, 60.3, 52.3, 51.0, 50.2, 14.0, 13.5. The ee value was 90%, t _R (major) = 8.22 min, t _R (minor) = 16.46 min (Chiralcel AS-H, λ = 230 nm, i-PrOH–hexanes = 50:50, flow rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C₁₈H₂₂Cl₁NO₆ [M + H]⁺: 384.1208; found: 384.1212. (2R,3R,4S,5R)-3,4-Diethyl 2-Methyl 2,5-Diphenylpyrrolidine-2,3,4-tricarboxylate (4s) Colorless oil, yield 60 mg (47%); [α]_D ³⁰ +15.1 (c 0.90, CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 7.87 (d, J = 7.6 Hz, 2 H), 7.45–7.37 (m, 4 H), 7.35–7.25 (m, 4 H), 4.49 (d, J = 7.2 Hz, 1 H), 4.36–4.22 (m, 2 H), 4.05 (br s, 1 H), 3.91 (d, J = 8.0 Hz, 1 H), 3.70 (s, 3 H), 3.69–3.64 (m, 1 H), 3.55–3.44 (m, 2 H), 1.35 (t, J = 7.2 Hz, 3 H), 0.75 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.7, 171.5, 170.2, 139.4, 137.8, 128.7, 128.6, 128.2, 128.1, 128.1, 127.8, 127.8, 126.6, 126.4, 76.0, 63.9, 61.2, 60.3, 57.2, 53.6, 52.7, 14.0, 13.5. The ee value was 82%, t _R (minor) = 9.13 min, t _R (major) = 10.87 min (Chiralcel AD-H, λ = 210 nm, i-PrOH–hexanes = 15:85, flow rate = 0.8 mL/min). ESI-HRMS: m/z calcd for C₂₄H₂₇N₁O₆ [M + H]⁺: 426.1911; found: 426.1914.