Practical and Scalable Total Syntheses of (+)-Dysidavarones A–C

Abstract

A practical and scalable enantioselective total syntheses of the marine anticancer sesquiterpene quinone meroterpenoids (+)-dysidavarones A–C has been accomplished. The central bridged bicyclo[3.3.1]nonane structure of dysidavarones was efficiently established by a one-pot intermolecular diastereoselective alkylation and intramolecular α-arylation of a Wieland–Miescher ketone derivative with a substituted benzylic bromide, without protection of the more-reactive C(4) carbonyl group. (+)-Dysidavarones A and ‘E’ were prepared on a 150-mg scale, demonstrating the efficiency and reliability of our synthetic route and providing sufficient amounts of the dysidavarones for further bioactivity evaluation.

Key words

total synthesis - natural products - dysidavarones - sesquiterpene quinones - meroterpenoids

Publikationsverlauf

Eingereicht: 28. Februar 2023

Angenommen nach Revision: 30. März 2023

Accepted Manuscript online:
30. März 2023

Artikel online veröffentlicht:
09. Mai 2023

• References and Notes

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• 18 Diketone 7 A 1.0 M solution of t-BuOK in THF (0.642 mL, 0.642 mmol, 1.0 equiv) was added to a stirred solution of Wieland–Miescher ketone derivative 8 (148 mg, 0.770 mmol, 1.2 equiv) in DMF (6 mL) at 0 °C, and the resulting mixture was heated to 23 °C and stirred at this temperature for 1 h. A solution of benzylic bromide 10 (217 mg, 0.642 mmol, 1.0 equiv) in DMF (2 mL) was added over 30 min at 23 °C under argon, and the resulting solution was stirred at 23 °C for 1 h. A 1.0 M solution of t-BuOK in THF (1.93 mL, 1.93 mmol, 3.0 equiv) was added to the resulting solution at 0 °C in three portions over 30 min each, on average, and the resulting solution was stirred at 100 °C for 2 h. The reaction was quenched with sat. aq NH₄Cl (10 mL) and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography [silica gel, PE–EtOAc (30:1→10:1)] to give a white foam; yield: 142 mg (60%, 0.385 mmol); R_f = 0.55 (silica gel, PE–EtOAc, 3:1); [α]_D ²³ +36.0 (c = 1.0, CHCl₃). FTIR (KBr): 3709, 3688, 3672, 3627, 2360, 2338, 1717, 1520, 1454, 1338, 1212, 1109 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 6.72 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 8.4 Hz, 1 H), 5.96 (t, J = 4.2 Hz, 1 H), 4.16 (dq, J = 9.3, 7.0 Hz, 1 H), 4.06–3.93 (m, 3 H), 3.84 (dd, J = 8.6, 1.8 Hz, 1 H), 3.31 (d, J = 16.0 Hz, 1 H), 2.97 (d, J = 16.0 Hz, 1 H), 2.47 (dt, J = 12.9, 6.3 Hz, 1 H), 2.41–2.29 (m, 4 H), 2.22 (dt, J = 13.2, 6.5 Hz, 1 H), 1.45–1.33 (m, 9 H), 1.23 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 217.3, 213.2, 150.5, 148.4, 145.4, 136.0, 126.5, 122.5, 121.5, 112.6, 68.5, 64.2, 50.3, 48.8, 46.1, 44.0, 42.9, 35.4, 26.4, 24.7, 24.5, 16.1, 15.0. HRMS (ESI-TOF): m/z [M + Na]⁺ calcd for C₂₃H₂₈NaO₄: 391.1880; found: 391.1878.