Enantioselective Synthesis of Tetrahydroindolizines via Ruthenium–Chiral Phosphoric Acid Sequential Catalysis

Abstract

A chiral phosphoric acid and a ruthenium complex were found to catalyze an olefin cross-metathesis–asymmetric intramolecular Friedel–Crafts alkylation of N-tethered olefin pyrroles and conjugated enones to provide a variety of chiral tetrahydroindolizine derivatives in moderate to good yields and enantioselectivity (up to 93% ee).

Key words

chiral phosphoric acid - Friedel–Crafts reaction - pyrrole, sequential catalysis - tetrahydroindolizine - Zhan-1B

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• 10 See the Supporting Information for details.
• 11 Typical Procedure for the Sequential Catalysis A flame-dried Schlenk tube was cooled to r.t. To a solution of olefin pyrrole 2a (42.2 mg, 0.20 mmol, 1.0 equiv) in toluene (2 mL) was added enone 3a (31.7 mg, 1.2 equiv) and 3 Å MS (50 mg), then chiral phosphoric acid (S)-1f (7.0 mg, 0.01 mmol, 5 mol%) and Zhan-1B (7.3 mg, 0.01 mmol, 5 mol%) were added in one portion. The reaction was stirred at r.t. After the reaction was complete (monitored by TLC), it was quenched with sat. NaHCO₃ solution and extracted with EtOAc. The organic layers were washed with brine, dried over anhydrous Na₂SO₄, and filtered. After the solvent was removed in vacuo, the crude product was purified by neutral Al₂O₃ column chromatography (PE–EtOAc, 30:1 to 20:1) to afford product 4aa. Yellow oil, 42.8 mg, 70% yield, 88% ee [Daicel Chiralcel OD-H (0.46 cm × 25 cm), n-hexane–2-PrOH, 95:5, v = 0.5 mL min^–1, λ = 254 nm, t _R (minor) = 41.34 min, t _R (major) = 30.02 min]; [α]_D ²⁵ –42.6 (c 0.65, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 8.04 (d, J = 7.2 Hz, 2 H), 7.63–7.58 (m, 1 H), 7.53–7.48 (m, 2 H), 7.44–7.37 (m, 4 H), 7.32–7.26 (m, 1 H), 6.24 (d, J = 3.3 Hz, 1 H), 6.05 (d, J = 3.9 Hz, 1 H), 4.07–4.00 (m, 1 H), 3.95–3.86 (m, 1 H), 3.75–3.66 (m, 1 H), 3.56 (dd, J = 16.8, 4.5 Hz, 1 H), 3.27 (dd, J = 16.5, 8.7 Hz, 1 H), 2.23–2.15 (m, 1 H), 2.08–1.84 (m, 2 H), 1.56–1.44 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 199.2, 137.4, 134.0, 133.8, 133.4, 133.2, 128.9, 128.5, 128.4, 126.7, 108.4, 104.5, 45.3, 45.1, 31.1, 27.6, 23.1. IR (thin film): ν_max = 3059, 2925, 2864, 1680, 1597, 1505, 1472, 1445, 1414, 1356, 1306, 1278, 1204, 1180, 1074, 1023, 995, 916, 801, 748, 692, 622 cm^–1. ESI-HRMS: m/z calcd for C₂₂H₂₂NO [M + H]⁺: 316.1696; found: 316.1696.