An Efficient Synthesis of (1R,4S)-1-Methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine. A Formal Synthesis of (-)-Aphanorphine

Abstract

We report a highly efficient synthesis of (1R,4S)-1-methyl-8-methoxy-3-(4-toluenesulfonyl)-2,3,4,5-tetrahydro-1,4-methano-3-benzazepine in six steps from 5. The present work constitutes a new formal synthesis of marine alkaloid (-)-aphanorphine.

aphanorphine - benzazepine - Friedel-Crafts alkylation - marine alkaloid - synthesis

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10

Compound 2, a colorless solid: mp 137-138 °C; 99.8% ee; [α]_D ²⁰ -13.4 (c 0.969, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.41 (s, 3 H, CH₃), 1.46 (ddd, J = 11.1, 6.3, 1.5 Hz, 1 H, 0.5CH₂), 1.79 (d, J = 11.1 Hz, 1 H, 0.5CH₂), 2.43 (s, 3 H, benzylic CH₃), 2.93 (dd, J = 16.6, 2.8 Hz, 1 H, 0.5 CH₂), 3.02 (d, J = 8.7 Hz, 1 H, 0.5 CH₂), 3.12 (d, J = 16.8 Hz, 1 H, 0.5 CH₂), 3.40 (dd, J = 8.6, 1.4 Hz, 1 H, 0.5 CH₂), 3.79 (s, 3 H, OCH₃), 4.39-4.45 (m, 1 H. NCH), 6.72 (dd, J = 8.6, 2.8 Hz, 1 H, CH), 6.78 (d, J = 2.1 Hz, 1 H, CH), 6.98 (d, J = 8.1 Hz, 1 H, CH), 7.28 (d, J = 8.1 Hz, 2 H, 2 CH), 7.69 (d, J = 8.4 Hz, 2 H, 2 CH). ¹³C NMR (75 MHz, CDCl₃): δ = 20.7, 21.5, 38.2, 41.7, 42.3, 55.3, 57.8, 62.9, 110.0, 111.7, 125.2, 127.1, 129.6, 130.4, 135.6, 143.1, 144.9, 157.9. MS (EI): 357 (18) [M⁺], 202 (15), 173 (100). Anal. Calcd for C₂₀H₂₃NO₃S: C, 67.20; H, 6.49; N, 3.92. Found: C, 67.18; H, 6.55; N, 3.80.