Synthetic Studies Toward Daphnezomines A and B

Abstract

Synthetic studies toward daphnezomines A and B, members of Daphniphyllum alkaloid group with a rare azaadamantane core structure, are reported. The tricyclic carbon skeleton with two contiguous quaternary carbon centers was synthesized in nine steps from (R)-piperitone. An intramolecular Tsuji–Trost reaction was used as a key reaction for the assembly of the skeleton.

Key words

Daphniphyllum alkaloids - daphnezomines - total synthesis - natural products - Tsuji–Trost reaction

Publication History

Received: 26 February 2023

Accepted after revision: 21 March 2023

Article published online:
04 May 2023

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• 25 Aldehyde 14 K₂CO₃ (6.3 mg, 0.0458 mmol, 1.5 equiv) and Pd(PPh₃)₄ (3.5 mg, 0.00305 mmol, 0.1 equiv) were sequentially added to a solution of enol 13 (11.0 mg, 0.0305 mmol, 1.0 equiv) in DMSO (0.3 mL) at 23 °C. The resultant mixture was heated to 60 °C and stirred at 60 °C for 3 h, then cooled to 23 °C. The reaction was quenched with sat. aq NaHCO₃ (1 mL), and the mixture was extracted with EtOAc (3 × 3 mL). The combined organic phases were washed with brine (1 mL), dried (MgSO₄), filtered, and concentrated. The residue was purified by flash column chromatography [silica gel, EtOAc–PE (1:100 → 1:60)] to give a white solid; yield: 6.2 mg (68%); R_f = 0.75 (silica gel, EtOAc–PE, 1:20); [α]_D ¹¹.⁵ +8.5 (c = 0.5, CHCl₃). IR (film): 2930, 2872, 1723, 1692, 1385, 1197, 1128, 1091 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 9.98 (d, J = 1.3 Hz, 1 H), 5.57 (dd, J = 5.0, 2.4 Hz, 1 H), 4.81 (d, J = 2.2 Hz, 1 H), 4.66 (d, J = 1.9 Hz, 1 H), 3.34 (d, J = 15.5 Hz, 1 H), 3.13 (s, 1 H), 2.93 (d, J = 15.9 Hz, 1 H), 2.69 (td, J = 13.8, 4.5 Hz, 1 H), 2.49–2.39 (m, 1 H), 2.30–2.19 (m, 1 H), 2.11–2.02 (m, 1 H), 2.01–1.85 (m, 2 H), 1.82–1.70 (m, 1 H), 1.70–1.63 (m, 1 H), 1.50–1.41 (m, 1 H), 1.41–1.32 (m, 1 H), 1.32–1.24 (m, 2 H), 1.12 (s, 3 H), 0.97 (d, J = 6.8 Hz, 3 H), 0.92 (d, J = 6.8 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 212.24, 203.79, 149.74, 133.92, 121.95, 108.52, 68.19, 51.11, 46.88, 40.59, 39.93, 33.60, 26.07, 25.04, 24.69, 24.30, 22.33, 21.33, 21.16, 18.51. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₂₉O₂: 301.2162; found: 301.2159.
• 26 CCDC 2243631 contains the supplementary crystallographic data for compound 14. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures