Synlett 2021; 32(09): 913-916
DOI: 10.1055/s-0037-1610769
letter

Concise Total Synthesis of (+)-Aphanorphine

Cheng Wang
,
Yukun Guan
This work was financially supported by the Natural Science Foundation of Shandong Province (ZR2018PB006).


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.

Supporting Information



Publication History

Received: 28 February 2021

Accepted after revision: 19 March 2021

Publication Date:
08 April 2021 (online)

© 2021. Thieme. All rights reserved

Georg Thieme Verlag KG
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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.