A Cyclobutanol Ring-Expansion Approach to Oxygenated Carbazoles: Total Synthesis of Glycoborine, Carbazomycin A and Carbazomycin B

Abstract

The transition-metal-free total syntheses of the oxygenated carbazole natural products glycoborine, carbazomycin A and carbazomycin B are reported. The key step involves an NBS-mediated cyclobutanol ring expansion to 4-tetralones for the preparation of the tricyclic carbazole core.

Key words

total synthesis - ring expansion - cyclization - antifungal agents - rearrangement

Publication History

Received: 27 November 2022

Accepted after revision: 28 December 2022

Article published online:
24 January 2023

• References

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• 47 5-Methoxy-3-methyl-9H-carbazole (Glycoborine) To a solution of 5-methoxy-3-methyl-9-tosyl-9H-carbazole (9) (20 mg, 0.055 mmol) in degassed ethanol (5 mL) was added finely ground potassium hydroxide (15 mg, 0.27 mmol) in one portion. The resulting solution was heated at reflux for 20 hours, before cooling to room temperature and removal of the volatiles under reduced pressure. The concentrate was dissolved in ethyl acetate (10 mL), and the organic layer was washed with deionized water (2 × 10 mL) and saturated aqueous sodium chloride solution (15 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (10 mg, 0.047 mmol, 85%) as a white solid (mp 135.1–136.8 °C [Lit.¹ 155–156 °C; PE–CHCl₃]). IR (neat): 3405, 3042, 3004, 2948, 2915, 2837, 1606, 1586, 1506, 1459, 1260, 1100 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (br s, 1 H), 7.91 (br s, 1 H), 7.33 (t, J = 8.0 Hz, 1 H), 7.28 (dd, J = 8.2, 0.7 Hz, 1 H), 7.22 (ddd, J = 8.2, 1.7, 0.7 Hz, 1 H), 7.01 (dd, J = 8.2, 0.7 Hz, 1 H), 6.67 (dd, J = 8.0, 0.7 Hz, 1 H), 4.09 (s, 3 H), 2.55 (d, J = 0.8 Hz, 3 H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 156.2, 141.2, 136.9, 128.9, 126.5, 126.2, 123.0, 122.8, 112.5, 109.6, 103.5, 100.2, 55.4, 21.5. HRMS (APCI): m/z [M + H]⁺ calcd for C₁₄H₁₄ON: 212.1070; found: 212.1067. The spectroscopic data (¹H NMR, ¹³C{¹H} NMR and IR) are consistent with the literature.¹
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• 54 Carbazomycin B Carbazomycin B was synthesized according to a procedure by Nishida and co-workers.²⁸ A solution of anthracene (65 mg, 0.36 mmol) in THF (1.5 mL) was purged with nitrogen for 10 minutes, before sodium metal (13 mg, 0.57 mmol) was added. The suspension was stirred at room temperature for 30 minutes, before being sonicated for a further 20 minutes. The dark blue solution was removed from the sonication bath, and a solution of 3-methoxy-9-((4-methoxyphenyl)sulfonyl)-1,2-dimethyl-9H-carbazol-4-ol (14) (30 mg, 0.073 mmol) in THF (1 mL) was added in one portion. The resulting green solution was stirred at room temperature for 1 hour, before it was diluted with dichloromethane (10 mL), and deionized water (10 mL) was added. The aqueous layer was separated and extracted with dichloromethane (3 × 10 mL). The combined organic extracts were washed with deionized water (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (10–30% EtOAc/pentane) to afford the title compound (10 mg, 0.041 mmol, 57%) as a white solid. IR (neat): 3425, 3053, 2988, 2923, 2854, 1638, 1612, 1500, 1453, 1411, 1321, 1300, 1144, 1083, 1003 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.25 (m, 1 H), 7.78 (br s, 1 H), 7.43–7.32 (m, 2 H), 7.22 (ddd, J = 8.1, 6.8, 1.4 Hz, 1 H), 6.06 (s, 1 H), 3.83 (s, 3 H), 2.40 (s, 3 H), 2.37 (s, 3 H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 142.0, 139.2, 138.4, 136.7, 127.0, 124.8, 123.3, 122.6, 119.5, 110.0, 109.3, 109.3, 61.5, 13.2, 12.8. HRMS (APCI): m/z [M + H]⁺ calcd for C₁₅H₁₆NO₂: 242.1176; found: 242.1182. The spectroscopic data (¹H NMR, ¹³C{¹H} NMR and IR) are consistent with the literature.²⁸ Carbazomycin A Carbazomycin A was synthesized according to a procedure by Moody and Shah.²⁶ To a solution of carbazomycin B (8.0 mg, 0.033 mmol) in acetone (2 mL) was added dried potassium carbonate (50 mg, 0.36 mmol) and iodomethane (0.3 mL, 4.8 mmol) sequentially. The resulting reaction mixture was then heated at reflux for 3 hours, before it was allowed to cool to room temperature, and diluted with dichloromethane (5 mL). The organic phase was separated and washed with deionized water (3 × 5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography (10% EtOAc/pentane) to afford the title compound (7.3 mg, 0.029 mmol, 87%) as a yellow oil. IR (neat): 3436, 3351, 2998, 2989, 2930, 1610, 1498, 1455, 1395, 1293, 1088, 1051 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.23 (m, 1 H), 7.83 (s, 1 H), 7.45–7.33 (m, 1 H), 7.22 (ddd, J = 8.0, 6.8, 1.5 Hz, 1 H), 4.11 (s, 1 H), 3.90 (s, 1 H), 2.41 (s, 1 H), 2.39 (s, 1 H). ¹³C{¹H} NMR (101 MHz, CDCl₃): δ = 146.0, 144.5, 139.4, 136.4, 128.8, 125.1, 122.9, 122.5, 119.5, 114.4, 113.5, 110.3, 61.1, 60.6, 13.7, 12.6. IR (neat): 3436, 3351, 2998, 2989, 2930, 1610, 1498, 1455, 1395, 1293, 1088, 1051 cm^–1. HRMS (APCI): m/z [M + H]⁺ calcd for C₁₆H₁₈NO₂: 256.1332; found: 256.1329. The spectroscopic data (¹H NMR, ¹³C{¹H} NMR and IR) are consistent with the literature.²⁸