Enantioselective Synthesis of 1-Substituted 1,2,3,4-Tetrahydroisoquinolines through 1,3-Dipolar Cycloaddition by a Chiral Phosphoric Acid

Abstract

A new approach is described for the asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydroisoquinolines that is based on the enantioselective 1,3-dipolar cycloaddition reaction of a nitrone and a vinyl ether in the presence of a chiral phosphoric acid that gives the chiral tetrahydroisoquinolines in high yields and with high enantioselectivities. ¹H and ³¹P NMR analyses of the mixture of nitrone and chiral phosphoric acid suggest the formation of a 1:1 complex.

Key words

phosphoric acids - asymmetric synthesis - 1,3-dipolar cycloaddition - nitrones - vinyl ethers - tetrahydroisoquinolines

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• 10 (2S,10bS)-2-tert-Butoxy-1,5,6,10b-tetrahydro-2H-isoxazolo[3,2-a]isoquinoline (4aa); Typical ProcedureUnder a N₂ atmosphere, a mixture of nitrone 2a (0.15 mmol), MS 4Å (68 wt%, activated), and chiral phosphoric acid 1d (0.015 mmol, 10 mol%) in mesitylene (0.2 mL) was stirred at r.t. for 5 min. The mixture was then cooled to –10 °C and vinyl ether 3a (0.38 mmol, 2.5 equiv) was added. The mixture was stirred at –10 °C for 3 d. When the reaction was complete (TLC), it was quenched with sat. aq NaHCO₃. The resulting mixture was extracted with EtOAc (×3) and the combined organic layer was washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by preparative TLC [hexane–EtOAc–Et₃N (100:25:3)] to give a colorless oil; yield: 35 mg [94%, exo/endo = 97:3; 84% ee (exo)]; [α]_D ²⁴ +88.8 (c 1.1, CHCl₃).HPLC: Daicel Chiralpak IB column (4.6 × 250 mm), hexane–i-PrOH (100:1), 0.75 mL/min, λ = 244 nm; t _major = 12.00 min, t _minor = 9.9 min. ¹H NMR (400 MHz, CDCl₃): δ = 7.08–7.20 (m, 4 H), 5.57 (dd, J = 1.2, 5.6 Hz, 1 H), 4.76 (dd, J = 8.0, 8.4 Hz, 1 H), 3.28 (ddd, J = 4.8, 5.6, 10.4 Hz, 1 H), 3.14 (ddd, J = 5.2, 7.6, 12.8 Hz, 1 H), 2.81–2.99 (m, 2 H), 2.53 (ddd, J = 1.6, 6.8, 12.8 Hz, 1 H), 2.43 (ddd, J = 5.6, 8.8, 12.8 Hz, 1 H), 1.28 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 135.9, 133.8, 128.2, 127.5, 126.4 (2 peaks), 96.9, 74.6, 60.4, 49.5, 44.1, 29.0, 27.1.
• 11 Details of solvent screening are summarized in the Supporting Information.
• 12 Chiral phosphoric acids with electron-deficient substituents were also tested; see Supporting Information for details.
• 13 For the variations of the concentration and the addition of molecular sieves, see Supporting Information for details.
• 14 See Supporting Information for details.