Helical Amide Derivatives: Synthesis by Insertion of Aliphatic ­Primary Amines into Benzo-Fused 2,2′-Diphenoquinones and Dia­stereomeric Resolution

Abstract

We have developed a method for synthesizing novel helical amide derivatives. Nucleophilic primary amines were inserted into benzo-fused 2,2′-biphenoquinones to form helical amides containing seven-membered rings. When optically pure primary amines were used in this reaction, a mixture of two amide diastereoisomers was obtained and separated into diastereomerically pure products by high-performance liquid chromatography. In contrast, the reaction of enantiomerically pure benzo-fused 2,2′-biphenoquinones with achiral aliphatic primary amines afforded enantiomerically pure helical amides with stereospecificity and retention of configuration.

Key words

helical amides - caprolactam - insertion reaction - seven-membered rings - diastereomeric resolution - asymmetric synthesis

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• 12 2a(a,d–f); General ProcedureA round-bottomed flask was charged with quinone 1a (48.7 mg, 0.10 mmol), anhyd CHCl₃ (1.5 mL), and the appropriate primary amine (3.2 equiv), and the mixture was stirred at rt. The color of the solution changed from red to brown, and the reaction was complete in 24 h. The mixture was concentrated and passed through a normal-phase column chromatography [silica gel, hexane–EtOAc (4:6)] to give the helical amide [2a(a,d–f)] as a brown solid major product (yield: 18–64%) and a white solid HEBPOL (3a–d) as a byproduct (yield: 6–81%).(P)-2a and (M)-2aBrown solid; yield: 64%; mp 245–250 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.75 (t, J = 7.5 Hz, 3 H), 1.22–1.39 (m, 1 H), 1.63–1.79 (m, 1 H), 3.20–3.32 (m, 1 H), 4.42–4.53 (m, 1 H), 6.48 (d, J = 9.5 Hz, 1 H), 6.58 (d, J = 8.5 Hz, 3 H), 6.72 (dd, J = 8.0 Hz, 2 H), 6.79 (d, J = 8.0 Hz, 1 H), 7.07–7.15 (m, 3 H), 7.31 (d, J = 9.5 Hz, 1 H), 7.33–7.37 (m, 2 H), 7.39–7.43 (m, 2 H), 7.45–7.50 (dd, J = 9.0 Hz, 2 H), 7.63 (d, J = 6.5 Hz, 1 H), 8.17 (d, J = 8.5 Hz, 1 H), 8.62 (d, J = 8.5 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 194.92, 166.09, 145.58, 143.17, 140.68, 139.97, 133.62, 132.82, 132.63, 132.39, 131.78, 131.47, 131.30, 130.84, 129.71, 129.31, 128.82, 128.15, 128.02, 127.99, 127.97, 127.83, 127.27, 127.19, 127.17, 126.89, 126.69, 126.57, 126.47, 126.35, 125.55, 125.46, 125.28, 125.25, 124.73, 124.32, 55.33, 33.47, 11.14. HRMS (EI): m/z [M]⁺ calcd for C₃₉H₂₇NO₂: 541.2042; found: 541.2093. Chiral HPLC {Chiral PAK IG [CHCl₃–hexane (2:3), 5 μL, 0.8 mL/min; λ = 310 nm]}: t _R = 12.32 min [(P)-2aa], 8.16 min [(M)-2aa].