Total Synthesis of the Angucylinone Antibiotic (+)-Rubiginone B₂ [1]

Abstract

A new chiral synthesis of (+)-rubiginone B₂ is reported. The intramolecular cobalt-mediated [2+2+2]-cycloaddition of a triyne precursor, synthesized from (+)-citronellal, afforded a chiral anthracene, which led after a two-step oxidation to the angucycli­none antibiotic.

angucyclinone antibiotics - benz[a]anthraquinones - natural products - catalysis - cobalt - cycloaddition

References

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Purchased from Fluka.

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Experimental Procedure: A solution of CpCo(CO)₂ (25.00 mg, 0.142 mmol, 10 mol%) in 2 mL toluene was added via canula to a solution of triyne 9 (0.58 g, 1.42 mmol) in 120 mL toluene and the mixture was heated to reflux and irradiated with a tungsten-lamp (osram vitalux 300 W) for 4 h. The organic phase was then concentrated in vacuo. Chromatography on silica gel (Et₂O-petroleum ether, 1:200) provided anthracene 10 (0.29 g, 1.051 mmol, 74% yield) as a white solid.
Mp 136-138 °C. [α]_D ²² +86.43 (c 0.14, CHCl₃). R_f = 0.31 (Et₂O-petroleum ether, 1:100). IR (CCl₄): 2935-2810 [C-H (OCH₃)] cm^-1. ¹H NMR (600 MHz, CDCl₃): δ = 1.16 (d, ³ J = 6.6 Hz, 3 H, 3-CH₃), 1.58 (m, 1 H, H-2), 2.00 (m, 1 H, H-3), 2.14 (m, 1 H, H-2), 2.60 (dd, ² J = 16.5 Hz, ³ J =10.5 Hz, 1 H, H-4), 2.95 (dd, ² J = 16.5 Hz, ³ J = 3.9 Hz, 1 H, H-4), 3.14 (m, 1 H, H-1), 3.40 (d, ² J = 16.5 Hz, 1 H, H-1), 4.09 (s, 3 H, OCH₃), 6.73 (d, J _o = 8.0 Hz, 1 H, H-9), 7.18 (d, J _o = 8.6 Hz, 1 H, H-5), 7.37 (t, J _o = 8.0 Hz, 1 H, H-10), 7.62 (d, J _o = 8.0 Hz, 1 H, H-11), 7.82 (d, J _o = 8.6 Hz, 1 H, H-6), 8.44 (s, 1 H, H-12), 8.78 (s, 1 H, H-7). ¹³C NMR (100 MHz, CDCl₃): δ = 21.79 (3-CH₃), 25.83 (C-1), 28.88 (C-3), 31.35 (C-2), 39.14 (C-4), 55.45 (OCH₃), 101.34 (C-9), 120.75 (C-12), 120.83 (C-11), 121.35 (C-7), 125.06 (C-10), 126.58 (C-6), 128.05 (C-5), 124.09, 130.34, 131.42, 132.64, 133.57, 155.38 (C_quart-arom.). EI-MS (70 eV): m/z = 276 (100%, M⁺), 261 (15%, M⁺ - CH₃), 246 (7%, 261 - CH₃), 233 (77%, 261 - C₂H₄). HRMS: calcd 276.1514 for C₂₀H₂₀O, found 276.1508.

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Experimental Procedure: Anthraquinone 11 (60.00 mg, 0.195 mmol) was dissolved in 5 mL CHCl₃ and irradiated with a tungsten-lamp (osram vitalux 300 W) over 18 h. The organic layer was then removed in vacuo. Chromatography on silica gel (petroleum ether-Et₂O, 1:2) provided (+)-rubiginone B₂ 12 (42.00 mg, 0.131 mmol, 67% yield) as a yellow solid.
Mp > 262 °C (dec.). [α]_D ²⁵ +71.64 (c 0.275, CHCl₃, recrystallized from petroleum ether-CHCl₃, 2:1). R_f = 0.14 (Et₂O-petroleum ether, 1:4). IR (CCl₄): 1673, 1677, 1708 (C=O) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.20 (d, ³ J = 6.4 Hz, 3 H, 3-CH₃), 2.45 (m, 1 H, H-3), 2.55 (dd, ² J = 15.6 Hz, ³ J = 11.0 Hz, 1 H, H-2), 2.67 (dd, ² J = 16.4 Hz, ³ J = 11.0 Hz, 1 H, H-2), 2.98 (m, 2 H, H-1 and H-4), 4.04 (s, 3 H, OCH₃), 7.24 (d, J _o = 8.2 Hz, 1 H, H-9), 7.45 (d, J _o = 8.0 Hz, 1 H, H-5), 7.65 (t, J _o = 8.2 Hz, J _o = 7.8 Hz, 1 H, H-10), 7.71 (d, J _o = 7.8 Hz, 1 H, H-11), 8.20 (d, J _o = 8.0 Hz, 1 H, H-6). ¹³C NMR (150 MHz, CDCl₃): δ = 21.43 (3-CH₃), 30.82 (C-3), 38.33 (C-4), 47.55 (C-2), 56.50 (OCH₃), 117.15 (C-9), 119.68 (C-11), 129.60 (C-6), 132.99 (C-5), 135.34 (C-10), 120.56, 134.98, 135.07, 137.67, 149.13, 159.81 (C_quart-arom.), 181.59, 184.51, 198.89 (C=O). EI-MS (70 eV): m/z = 320 (100%, M⁺), 305 (15%, M⁺ - CH₃), 292 (35%, M⁺- CO), 291 (15%, M⁺ - HCO), 261 (27%, 292 - OCH₃), 233 (24%, 261 - CO).