Synthetic Studies on Plakinidines

Dedicated to Prof. Peter Vollhardt for his enormous contributions to SYNLETT as Editor-in-Chief

Abstract

A synthetic route to the pentacyclic core of the plakinidines was developed. Our synthesis features the construction of the fused heterocycles (the A and the E rings) by the formation of carbon–nitrogen bonds using carbonyl functions prior to the late-stage aromatization of the B ring.

Key words

acridine - alkaloids - aromatization - Dieckmann condensation - Friedländer quinoline synthesis

• References and Notes

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• 4 For a recent review, see: Okano K, Tokuyama H, Fukuyama T. Chem. Commun. 2014; 50: 13650

For reviews of metal-catalyzed aromatic amination, see:
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• 10 Lactone 8 was obtained as a 1:1 mixture of diastereomers, and the Staudinger reaction of 8 converged into a single diastereomer. It was also observed that one of the diastereomers could be smoothly converted into the imine, while the Staudinger reaction of the other diastereomer proceeded sluggishly but gave the same imine in a low yield. Presumably, cyclization of the trans isomer was a slow reaction, and isomerization of the trans isomer into the cis isomer via an enamine might occur during the reaction to release the ring strain. Practically, the Staudinger reaction was carried out without separation of the diastereomers.
• 11 Experimental Procedure To a stirred solution of 9 (5.60 g, 12.7 mmol) in THF (170 mL) was added t-BuOK (1.57g, 14.0 mmol) at 0 °C. After stirring for 5 min at 0 °C, the mixture was warmed up to r.t. and stirred for 90 min. The reaction was quenched with aq NH₄Cl. The solution was partitioned between EtOAc and H₂O. The aqueous phase was extracted three times with EtOAc. The combined organic phase was washed with brine, dried over MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (neutral, 50–100% EtOAc–hexane) to afford 10 (3.95g, 10.8 mmol) as a white solid. Ketolactone 10 was obtained as a 1:1 mixture of two rotamers; mp 223 °C. IR: 1760, 1691, 1575, 1448 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.15 (d, J = 8.3 Hz, 1 H), 8.05 (m, 1 H), 7.77 (m, 1 H), 7.61 (m, 1 H), 5.64 (d, J = 9.0 Hz, 0.5 H), 5.01 (d, J = 9.0 Hz, 0.5 H), 4.84 (m, 1 H), 4.13 (s, 0.5 H), 4.10 (s, 0.5 H), 4.05 (m, 0.5 H), 3.92 (m, 0.5 H), 3.87 (br s, 1.5 H), 3.66 (br s, 1.5 H), 3.60 (m, 1 H), 3.50 (m, 1 H), 2.89 (s, 3 H), 2.18–1.95 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 191.3, 191.0, 171.6 (2 C), 157.4 (2 C), 154.4 (2 C), 148.6 (2 C), 147.7 (2 C), 131.5, 131.3, 130.4 (2 C), 127.3 (2 C), 127.2 (2 C), 127.1 (2 C), 125.3 (2 C), 76.4 (2 C), 56.8, 56.6, 53.2, 52.9, 50.6, 50.2, 36.0, 35.7, 35.0, 34.8, 26.5, 26.4, 14.5 (2 C). HRMS: m/z calcd for C₂₀H₁₉N₂O₅: 367.1294; found: 367.1299.
• 12 Boekelheide V, Linn WJ. J. Am. Chem. Soc. 1954; 76: 1286
• 13 Experimental Procedure To a stirred solution of 14 (10.6 mg, 30 μmol) in THF (0.50 mL) was added NBS (14.8 mg, 90 μmol) at 0 °C. After stirring for 60 min at 0 °C, H₂O (0.10 mL) was added. After stirring for 4 h at r.t., the reaction was quenched with aq NaHCO₃/Na₂S₂O₃. The solution was partitioned between EtOAc and H₂O. The aqueous phase was extracted three times with EtOAc. The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (neutral, 50% EtOAc–hexane) to afford 15 (6.3 mg, 17 μmol) as a white solid; mp 263 °C (decomp.). IR: 3217, 1765, 1714, 1689, 1653, 1619 cm^–1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 12.1 (s, 1 H), 8.72 (d, J = 8.8 Hz, 1 H), 8.34 (d, J= 9.0 Hz, 1 H), 8.04 (m, 1 H), 7.93 (dd, J = 8.8, 6.6 Hz, 1 H), 5.70 (dd, J = 11.2, 5.1 Hz, 1 H), 3.85 (m, 2 H), 3.76 (s, 3 H), 2.85 (m, 1 H), 1.67 (m, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.0, 166.8, 155.5, 151.2, 142.2, 140.1, 136.5, 132.0, 130.6, 130.2, 130.1, 123.6, 123.2, 122.6, 121.5, 102.7, 75.2, 52.8, 42.7, 30.5. HRMS: m/z calcd for C₂₀H₁₄N₃O₅: 376.0933; 376.0930.
• 14 Experimental Procedure To a stirred solution of 16 (78.0 mg, 185 μmol) in THF (10 mL) was added 1 M aq KOH (1.9 mL, 1.9 mmol) at r.t., and the reaction mixture was heated at 90 °C for 1 h. The resulting solution was then diluted with EtOAc and acidified with HCl. After separation of the phases, the aqueous phase was extracted three times with EtOAc. The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue containing 17 was used in the next step without further purification. To a stirred solution of the crude mixture of 17 in t-BuOH (5.0 mL) were added DPPA (153 mg, 0.555 μmol) and Et₃N (94 mg, 0.93 μmol) at r.t. After stirring for 30 min at r.t., the reaction mixture was heated for 2 h at 80 °C. The reaction was quenched with aq NaHCO₃. The solution was partitioned between EtOAc and H₂O. The aqueous phase was extracted three times with EtOAc. The combined organic phase was washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (neutral, 0–5% MeOH–CHCl₃) to afford 18 (38.0 mg, 79 μmol) as a pale orange solid; mp 115 °C. IR: 3365, 2985, 2933, 1689, 1515, 1457, 1436 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.98 (br s, 1 H), 8.90 (ddd, J = 8.3, 1.0, 0.6 Hz, 1 H), 8.35 (ddd, J = 8.8 Hz, 0.6, 0.6 Hz, 1 H), 8.13 (br s, 1 H), 7.83 (m, 1 H), 7.77 (m, 1 H), 4.62 (m, 1 H), 4.33 (m, 1 H), 3.65 (s, 3 H), 3.51 (s, 3 H), 2.45 (m, 1 H), 2.12 (m, 1 H), 1.58 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.0, 156.6, 153.2, 149.8, 139.9, 134.3, 131.0, 129.8, 129.4, 127.2, 123.9, 123.6, 122.2, 117.2, 82.1, 72.0, 54.1, 53.4, 42.3, 28.3, 27.7. HRMS: m/z calcd for C₂₅H₂₇N₄O₆: 479.1931; 479.1926.
• 15 The attempted reaction of 18, by heating in DMSO at 120 °C in the presence of CSA, induced cleavage of the Boc group and oxidation of the benzylic position by DMSO to give 19 (Figure 2). ¹H NMR (400 MHz, CDCl₃): δ = 10.4 (br s, 1 H), 8.83 (m, 1 H), 8.29 (m, 1 H), 7.75 (m, 2 H), 6.94 (br s, 2 H), 3.72 (s, 3 H), 3.00 (m, 2 H), 2.30 (m, 2 H, overlapped with impurities). MS: m/z = 363 [M + H⁺].