First Total Synthesis of Murrastifoline B and an Improved Route to Murrastifoline F

Abstract

We report the first total synthesis of murrastifoline B and an improved route to murrastifoline F using a twofold palladium-catalyzed Buchwald–Hartwig amination as key step. The mono­meric carbazole and the biaryl precursor are also prepared via ­palladium-catalyzed coupling reactions.

Key words

alkaloids - catalysis - cyclization - natural products - palladium

• References and Notes

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• 24 Experimental Procedure for the Twofold Buchwald–Hartwig Coupling to Murrastifoline B (2) A solution of the aminocarbazole 6 (19.1 mg, 0.061 mmol), the bistriflate 5 (30.2 mg, 0.061 mmol), Pd₂(dba)₃ (11.2 mg, 0.012 mmol), XantPhos (14.1 mg, 0.024 mmol), and K₃PO₄ (61.9 mg, 0.292 mmol) in o-xylene (3 mL) was heated at 130 °C for 64 h. The reaction mixture was diluted with EtOAc and a sat. aq. solution of NH₄Cl was added. The aqueous layer was separated and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over MgSO₄. Removal of the solvent and purification of the residue by flash chromatography on silica gel (isohexane–EtOAc, 6:1) afforded murrastifoline B (2); yield 16.4 mg (66%); colorless crystals; mp 58.5–59 °C (lit.⁷ oil). UV (MeOH): λ = 229 (sh), 242, 291, 335 nm. IR (ATR): ν = 3407, 3055, 2923, 2852, 1692, 1624, 1582, 1542, 1502, 1453, 1419, 1395, 1323, 1277, 1222, 1134, 1104, 1037, 1014, 991, 952, 909, 827, 765, 746, 698, 659, 638, 619 cm^–1. ¹H NMR (600 MHz, acetone-d ₆): δ = 2.55 (s, 3 H), 3.63 (s, 3 H), 4.06 (s, 3 H), 6.89 (s, 1 H), 7.07 (d, J = 1.6 Hz, 1 H), 7.21–7.25 (m, 3 H), 7.35–7.37 (m, 1 H), 7.46 (ddd, J = 8.3, 7.1, 1.2 Hz, 1 H), 7.66 (dd, J = 1.3, 0.8 Hz, 1 H), 7.68 (dt, J = 8.2, 0.8 Hz, 1 H), 7.84 (m, 1 H), 8.15–8.17 (m, 2 H), 10.61 (br s, 1 H). ¹³C NMR and DEPT (150 MHz, acetone-d ₆): δ = 21.68 (CH₃), 56.10 (CH₃), 56.24 (CH₃), 108.13 (CH), 110.82 (CH), 111.20 (CH), 112.30 (CH), 113.11 (CH), 113.36 (CH), 119.88 (CH), 120.16 (CH), 120.69 (CH), 121.29 (CH), 123.8 (C), 124.4 (C), 126.45 (CH), 126.56 (CH), 129.97 (C), 130.06 (C), 132.77 (C), 141.2 (C), 144.0 (C), 146.39 (C), 147.82 (C); 3 C signals are missing. ESI-MS (10 V): m/z = 407 [M + H]⁺.
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• 27 Murrastifoline F (3) Colorless crystals; 288–289 °C (lit.⁹ 289 °C). UV (MeOH): λ = 227, 242 (sh), 260 (sh), 287 (sh), 351 nm. IR (ATR): ν = 3055, 2923, 2852, 1653, 1592, 1500, 1460, 1444, 1395, 1318, 1281, 1227, 1192, 1170, 1104, 1072, 1041, 938, 822, 745, 695, 637, 606 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.30 (s, 3 H), 2.40 (s, 3 H), 3.80 (s, 3 H), 3.91 (s, 3 H), 6.50–6.56 (m, 3 H), 6.69–6.82 (m, 4 H), 6.83 (s, 1 H), 6.94 (s, 1 H), 7.33 (t, J = 7.6 Hz, 1 H), 7.53 (d, J = 7.6 Hz, 1 H), 7.73 (d, J = 7.0 Hz, 1 H). ESI-MS (25 V): m/z = 438 [M + NH₄]⁺.