Concise Synthesis of Dictyoquinazol A via a Dimerisation–Cyclocondensation Sequence

Abstract

A two-step total synthesis of the neuroprotective alkaloid, dictyoquinazol A, has been achieved. The brevity of this synthesis was enabled by exploiting the hidden symmetry of the target molecule. Several structural analogues were also prepared using a similar strategy. These results provide a platform for future structure–activity relationship studies in the quest for a novel treatment for stroke.

Key words

quinazolinone - natural products - neuroprotective activity - total synthesis - stroke

• References and Notes

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Various intermediates in related cyclocondensation processes have been proposed:
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• 13 A microwave reaction vessel was charged with compound 6 (355 mg, 1.96 mmol) then cooled to –20 °C. Trimethyl orthoformate (110 μL, 1.01 mmol) was added, and the mixture was irradiated at 170 W (155 ± 4 °C) for 4 h. The mixture was cooled and concentrated under a stream of nitrogen. The residue was diluted with CH₂Cl₂ (25 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc–CH₂Cl₂ (1:6) as eluent to give compound 5 as a white solid (303 mg, 91%); mp 155–156 °C. IR (neat): ν_max = 3081, 2626, 2105, 1938, 1847, 1719, 1668, 1610, 1482 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.92 (s, 1 H, ArH), 7.72 (d, J = 9.0 Hz, 1 H, ArH), 7.70 (d, J = 3.0 Hz, 1 H, ArH), 7.67 (d, J = 2.9 Hz, 1 H, ArH), 7.38 (dd, J = 8.9, 3.0 Hz, 1 H, ArH), 7.29 (d, J = 8.6 Hz, 1 H, ArH), 7.20 (dd, J = 8.7, 2.9 Hz, 1 H, ArH), 3.92 (s, 6 H, OMe), 3.70 (s, 3 H, OMe). ¹³C{¹H} NMR (75 MHz, CDCl₃): δ = 165.0, 161.4, 160.2, 159.0, 144.4, 142.6, 130.6, 130.2, 129.3, 129.2, 124.7, 123.2, 119.4, 116.8, 106.8, 55.6, 56.0, 52.7. ESI-HRMS (+ve): m/z calcd for C₁₈H₁₆N₂O₅Na⁺ [MNa⁺]: 363.0951; found: 363.0948.

For spectral data of similar compounds, see:
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• 15 A solution of compound 5 (57.7 mg, 0.170 mmol) and LiBH₄ (5.0 mg, 0.23 mmol) in anhydrous THF (1 mL) was heated at reflux for 2 h, then quenched by the addition of sat. aq NH₄Cl solution at 0 °C. The mixture was diluted with CH₂Cl₂ (20 mL) then washed with H₂O (2 × 20 mL) and brine (2 × 20 mL). The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (1:6 → 1:2 EtOAc–CH₂Cl₂) to give compound 4 as a white solid (12.7 mg, 24%); mp 199–202 °C. IR (neat): ν_max = 3163, 3058, 2909, 2837, 2685, 2111, 2081, 1684, 1611, 1493 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (s, 1 H, ArH), 7.71–7.69 (m, 2 H, ArH), 7.41 (dd, J = 8.9, 2.9 Hz, 1 H, ArH), 7.18 (d, J = 2.8 Hz, 1 H, ArH), 7.16 (d, J = 8.6 Hz, 1 H, ArH), 6.99 (dd, J = 8.6, 2.9 Hz, 1 H, ArH), 4.45 (d, J = 12.6 Hz, 1 H, CHH), 4.39 (d, J = 12.6 Hz, 1 H, CHH), 3.93 (s, 3 H, OMe), 3.88 (s, 3 H, OMe). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 162.0, 160.8, 159.3, 144.6, 142.8, 139.7, 129.3, 128.9, 128.6, 125.3, 122.9, 115.6, 115.0, 106.7, 61.7, 56.1, 55.8. ESI-HRMS (+ve): m/z calcd for C₁₇H₁₆N₂O₄Na⁺ [MNa⁺]: 335.1002; found: 335.0948.
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