Efficient Synthesis of Highly Enantioenriched Δ¹-Pyrrolines

Abstract

A general and efficient asymmetric synthesis of Δ¹-pyrrolines by a one-pot nitro-reduction, cyclization, and dehydration of (R,E)-1,5-diphenyl-3-(nitromethyl)-5-pent-4-en-1-ones with iron and aqueous hydrochloric acid has been developed. The Δ¹-pyrrolines were obtained with excellent enantioselectivities (up to 99%) and high yields (up to 83%).

Key words

pyrrolines - reductive cyclization - Michael addition - stereoselectivity

• References and Notes

• 1 Current address: Medicinal Chemistry Section, Experimental Therapeutics Programme, CNIO (Spanish National Cancer Research Centre), Madrid, Spain.
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• 15 A mixture of iron powder (30 g) and 10% HCl (25 mL) was stirred vigorously for 1 min. The solution was then filtered off and the iron powder was washed successively with distilled water (5 × 25 mL) and absolute EtOH (5 × 25 mL).
• 16 Synthesis of 4a–h; General Procedure: To a solution of (R,E)-1,5-diaryl-3-(nitromethyl)-5-pent-4-en-1-ones 3a–h (0.31 mmol) in a mixture of THF–MeOH (2:1, 6 mL) was successively added at r.t., AcOH (4.98 mmol) and activated iron powder (14.0 mmol). The resulting mixture was heated at 65 °C for 15 h under a nitrogen atmosphere. After cooling to r.t., the reaction mixture was filtered through Celite and rinsed with EtOAc. The resultant solution was washed with sat. aq NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (hexane–EtOAc, 80:20). Finally the residues were crystallized from hexane–EtOAc to furnish the desired compounds 4a–h. Compound 4a: Yield: 72%; brown oil. ¹H NMR (300 MHz, CDCl₃): δ = 7.85 (dd, J = 7.0, 2.3 Hz, 2 H, H-2′,6′), 7.45–7.19 (m, 8 H, H-3′,5′, H-4′, H-2′′,6′′, H-3′′,5′′, H-4′′), 6.47 (d, J = 15.8 Hz, 1 H, H-β), 6.24 (dd, J = 15.8, 7.9 Hz, 1 H, H-α), 4.33 (dd, J = 15.6, 7.2 Hz, 2 H, H-5), 3.90 (dd, J = 15.6, 5.1 Hz, 1 H, H-5), 3.36–3.19 (m, 2 H, H-3, H-4), 2.97–2.81 (m, 1 H, H-3). ¹³C NMR (75 MHz, CDCl₃): δ = 172.7 (C-2), 137.1 (C-1′′), 134.2 (C-1′), 132.2 (C-α), 130.5 (C-4′), 129.9 (C-β), 128.5 (C-3′,5′,C-3′′,5′′), 127.5 (C-2′,6′), 127.2 (C-4′′), 126.0 (C-2′′,6′′), 67.2 (C-5), 41.8 (C-3), 41.3 (C-4). HRMS (ESI⁺): m/z [C₁₈H₁₇N + H]⁺ calcd for C₁₉H₁₇N: 248.1434; found: 248.1433. HPLC (i-PrOH–hexane, 10:90; flow rate 0.7 mL/min; λ = 254 nm): t _r = 10.90 [(R)-4a] min (ee = 99%). Compound 4e: Yield: 44%; salmon solid; mp 110.6–111.3 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.71 (d, J = 8.6 Hz, 2 H, H-2′,6′), 7.55 (d, J = 8.6 Hz, 2 H, H-3′,5′), 7.37–7.18 (m, 5 H, H-2′′,6′′, H-3′′,5′′, H-4′′), 6.46 (d, J = 15.8 Hz, 1 H, H-β), 6.23 (dd, J = 15.8, 8.2 Hz, 1 H, H-α), 4.38–4.24 (m, 1 H, H-5), 3.94–3.82 (m, 1 H, H-5), 3.38–3.16 (m, 2 H, H-3, H-4), 2.92–2.79 (m, 1 H, H-3). ¹³C NMR (75 MHz, CDCl₃): δ = 171.8 (C-2), 137.0 (C-1′′), 133.2 (C-4′), 132.0 (C-α), 131.7 (C-3′,5′), 130.2 (C-β), 129.1 (C-2′,6′), 128.6 (C-3′′,5′′), 127.4 (C-4′′), 126.1 (C-2′′,6′′), 125.1 (C-1′), 67.4 (C-5), 41.8 (C-3), 41.4 (C-4). HRMS (ESI⁺): m/z [C₁₈H₁₆BrN + H]⁺ calcd for C₁₈H₁₇BrN: 326.0539; found: 326.0537. HPLC (i-PrOH–hexane, 10:90; flow rate 0.7 mL/min; λ = 254 nm): t _r = 13.07 [(R)-4e] min (ee = 99%).
• 17 Crystal data for 4d: C₁₈H₁₆ClN; M = 281.77; orthorhombic; space group P212121; Z = 4; a = 5.6675(7) Å, b = 7.8846(12) Å, c = 32.643(3) Å, α = β = γ = 90.00°; V = 1458.7(3) Å³; colorless crystal with crystal size of 0.10 × 0.08 × 0.04 mm was used. Of a total of 2942 reflections collected, 2022 were independent (Rint = 0.0968). Final R1 = 0.0614 [I > 2σ(I)] and wR2 = 0.1591 (all data). Crystal data for 4e: C₁₈H₁₆FN; M = 265.32; orthorhombic; space group P212121; Z = 4; a = 5.6544(6) Å, b = 7.9709(8) Å, c = 31.048(3) Å, α = β = γ = 90.00°; V = 1399.4(2) Å³; colourless flake with crystal size of 0.50 × 0.20 × 0.04 mm. Of a total of 3068 reflections collected, 2834 were independent (Rint = 0.0380). Final R1 = 0.0336 [I > 2σ(I)] and wR2 = 0.0796 (all data). CCDC-1033064 and 1033065 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/datarequest/cif.