Concise Total Synthesis of (+)-Aphanorphine

Abstract

A concise total synthesis of (+)-aphanorphine is described. The key features of the strategy include a Pd-catalyzed intermolecular trimethylenemethane [3+2]-cycloaddition to form ring C and a Co-catalyzed radical cyclization through a hydrogen-atom transfer to close ring B. The synthesis was completed in six steps.

Key words

aphanorphine - total synthesis - alkaloids - tert-butanesulfinimine - cycloaddition - hydrogen-atom transfer

Publikationsverlauf

Eingereicht: 28. Februar 2021

Angenommen nach Revision: 19. März 2021

Artikel online veröffentlicht:
08. April 2021

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• 15 Methyl (1S,4S)-8-methoxy-1-methyl-1,2,4,5-tetrahydro-3H-1,4-methanobenzo[d]azepine-3-carboxylate (18) A 4 mL vial was charged with sulfinimine 17 (13 mg, 0.05 mmol, 1.0 equiv), catalyst C7 (1.5 mg, 0.0025 mmol, 0.05 equiv), and oxidant O1 (29 mg, 0.1 mmol, 2.0 equiv). PhCF₃ (0.5 mL), previously dried in vacuo for 0.5 h, was then added and the solution was bubbled with N₂ for 10 min. PMHS (22 µL, 0.1 mmol, 2.0 equiv) was added, and the resulting mixture was stirred at 25 °C for 20 h then diluted with EtOAc (2 mL). The solution was washed with H₂O (0.5 mL) and brine (3 × 0.5 mL), then dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by preparative TLC (PE–EtOAc, 5:1) to give a yellow solid: yield; 10.8 mg (83%); mp 89–92 °C; [α]_D ²⁵ +167.3 (c 0.55, CHCl₃). IR (KBr): 3795, 2957, 1701, 1612, 1495, 1453, 1389, 863, 805, 769, 741, 698 cm^–1. Rotamer ¹H NMR (500 MHz, CDCl₃): δ = 7.03 (d, J = 8.4 Hz, 0.5 H), 6.99 (d, J = 8.3 Hz, 0.5 H), 6.85–6.80 (m, 1 H), 6.72 (td, J = 8.3, 2.5 Hz, 1 H), 4.50–4.43 (m, 0.6 H), 4.39–4.32 (m, 0.4 H), 3.82–3.74 (m, 3 H), 3.72–3.66 (m, 1.3 H), 3.63–3.58 (m, 1.7 H), 3.42 (d, J = 10.1 Hz, 0.5 H), 3.36 (d, J = 9.9 Hz, 0.5 H), 3.28 (d, J = 10.0 Hz, 0.5 H), 3.22 (d, J = 9.9 Hz, 0.5 H), 3.18 (d, J = 16.6 Hz, 0.5 H), 3.04 (d, J = 16.6 Hz, 0.5 H), 2.90 (d, J = 16.6 Hz, 1 H), 2.02–1.86 (m, 2 H), 1.57–1.45 (m, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 157.9, 157.8, 155.1, 154.9, 145.8, 145.7, 130.5, 130.3, 125.7, 125.4, 111.6, 111.4, 109.89, 109.86, 61.6, 61.2, 55.29, 55.27, 54.8, 54.6, 52.2, 52.0, 42.2, 41.7, 41.6, 40.8, 36.4, 35.7, 20.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₀NO₃: 262.1443; found: 262.1437.