Transition Metals in Organic Synthesis, Part 82. [1] First Total Synthesis of Methyl 6-Methoxycarbazole-3-carboxylate, Glycomaurrol, the Anti-TB Active Micromeline, and the Furo[2,3-c]carbazole Alkaloid Eustifoline-D

Abstract

The palladium(0)-catalyzed amination followed by palladium(II)-catalyzed oxidative cyclization of the resulting diaryl­amine provides a short route to a series of 6-oxygenated carbazole alkaloids: glycozoline, 3-formyl-6-methoxycarbazole, methyl 6-methoxycarbazole-3-carboxylate, glycozolinine (glycozolinol), glycomaurrol, micromeline, and eustifoline-D.

Key words

alkaloids - antibiotics - catalysis - nickel - palladium

References and Notes

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27

Pure glycomaurrol (5) was obtained by preparative HPLC on a Vydac C8 50 mm column (gradient elution with 50 mL/min MeCN-H₂O, 30-60% MeCN in 30 min).
Glycomaurrol (5): colorless crystals; mp 141 °C. UV (MeOH): λ_max = 257, 269, 292 (sh), 301, 350, 362 (sh) nm. IR (ATR): ν = 3409, 3214, 2917, 1589, 1512, 1499, 1476, 1442, 1390, 1349, 1309, 1282, 1267, 1225, 1166, 1148, 1100, 1069, 1030, 954, 871, 850, 797, 739, 694, 648 cm^-1. ¹H NMR (500 MHz, acetone-d ₆): δ = 1.72 (d, J = 1.2 Hz, 3 H), 1.98 (s, 3 H), 2.51 (s, 3 H), 4.01 (d, J = 6.5 Hz, 2 H), 5.37 (t, J = 6.5 Hz, 1 H), 7.03 (d, J = 8.5 Hz, 1 H), 7.19 (d, J = 8.5 Hz, 1 H), 7.20 (m, 1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.70 (s, 1 H), 7.95 (s, 1 H), 9.94 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d ₆): δ = 18.34 (CH₃), 21.67 (CH₃), 25.83 (CH₃), 26.24 (CH₂), 109.21 (CH), 111.09 (CH), 115.52 (CH), 122.15 (C), 122.97 (C), 123.29 (CH), 124.05 (CH), 124.34 (C), 126.87 (CH), 127.59 (C), 131.86 (C), 136.06 (C), 140.13 (C), 148.19 (C). MS (100 °C): m/z (%) = 265 (100) [M⁺], 210 (71), 209 (87), 181 (14), 180 (19), 167 (9). HRMS: m/z calcd for C₁₈H₁₉NO [M⁺]: 265.1467; found: 265.1454.

28

Crystal data for the bromocarbazole 12: C₁₄H₁₀BrNO₂, M = 304.14, monoclinic, space group: P2₁/c, a = 19.570(4), b = 8.296(2), c = 7.360(2) Å, β = 94.77(3)°, V = 1190.8(5) ų, Z = 4, D _c = 1.696 g cm^-3, µ = 3.444 mm^-1, T = 198(2) K, λ = 0.71073 Å, θ range: 3.13-30.00°, 29544 reflections collected, 3454 independent (R _int = 0.0629), 168 parameters. The structure was solved by direct methods and refined by full-matrix least-squares on F ²; final R indices [I > 2σ(I)]: R ₁ = 0.0405, wR ₂ = 0.0761; maximal residual electron density: 0.598 e Å^-3. CCDC-628163 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

29

Pure micromeline (6) was obtained by preparative HPLC on a Vydac C8 50 mm column (gradient elution with 50 mL/min MeCN-H₂O, 30-60% MeCN in 30 min).
Micromeline (6): colorless crystals; mp 205-206 °C. UV (MeOH): λ_max = 231, 252, 276 (sh), 278, 281, 295 (sh), 300, 340 nm. IR (ATR): ν = 3156, 2963, 2911, 2854, 2740, 1663, 1649, 1629, 1603, 1566, 1522, 1464, 1446, 1371, 1310, 1291, 1271, 1228, 1202, 1181, 1164, 1120, 1063, 1028, 958, 899, 883, 851, 811, 792, 717, 663 cm^-1. ¹H NMR (500 MHz, acetone-d ₆): δ = 1.72 (d, J = 1.1 Hz, 3 H), 2.03 (s, 3 H), 4.07 (d, J = 6.4 Hz, 2 H), 5.36 (t, J = 6.4 Hz, 1 H), 7.15 (d, J = 8.5 Hz, 1 H), 7.33 (d, J = 8.5 Hz, 1 H), 7.63 (d, J = 8.5 Hz, 1 H), 7.95 (dd, J = 8.5, 1.4 Hz, 1 H), 8.03 (br s, 1 H), 8.69 (s, 1 H), 10.09 (s, 1 H), 10.70 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d ₆): δ = 18.43 (CH₃), 25.80 (CH₃), 26.19 (CH₂), 110.07 (CH), 111.79 (CH), 116.63 (CH), 122.76 (C), 123.26 (C and CH), 124.05 (C), 126.63 (CH), 127.40 (CH), 129.39 (C), 132.83 (C), 136.07 (C), 145.38 (C), 149.40 (C), 191.85 (CHO). MS (150 °C): m/z (%) = 279 (93) [M⁺], 224 (81), 223 (100), 208 (7), 195 (13), 194 (10), 183 (11), 167 (11). HRMS: m/z calcd for C₁₈H₁₇NO₂ [M⁺]: 279.1259; found: 279.1262. Anal. Calcd (%) for C₁₈H₁₇NO₂: C, 77.40; H, 6.13; N, 5.01. Found: C, 77.50; H, 6.22; N, 5.03.

31

Amberlyst 15 from Fluka (art. 06423).

32

A separation of the two isomers 7 and 15 was achieved by preparative HPLC on a Vydac C8 30 mm column (gradient elution with 40 mL/min MeCN-H₂O, 30-46% MeCN in 32 min).
Eustifoline-D (7): colorless crystals; mp 156 °C. UV (MeOH): λ_max = 253, 260 (sh), 268, 298, 310, 339, 354 nm. IR (ATR): ν = 3406, 2919, 2856, 1615, 1575, 1484, 1443, 1432, 1409, 1360, 1300, 1275, 1242, 1229, 1209, 1139, 1074, 1051, 946, 886, 875, 800, 789, 780, 750, 731, 690, 659 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 2.59 (s, 3 H), 7.26 (dd, J = 8.3, 1.2 Hz, 1 H), 7.31 (d, J = 8.8 Hz, 1 H), 7.33 (dd, J = 2.0, 0.4 Hz, 1 H), 7.36 (d, J = 8.3 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.98 (s, 1 H), 8.03 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, CDCl₃): δ = 21.51 (CH₃), 105.40 (CH), 107.38 (CH), 109.43 (CH), 110.43 (CH), 114.80 (C), 120.42 (C), 120.93 (CH), 123.23 (C), 126.54 (CH), 128.71 (C), 135.92 (C), 137.65 (C), 145.14 (CH), 150.27 (C). MS (20 °C): m/z (%) = 221 (100) [M⁺], 220 (53), 192 (7), 191 (8). HRMS: m/z calcd for C₁₅H₁₁NO [M⁺]: 221.0841; found: 221.0853. Anal. Calcd (%) for C₁₅H₁₁NO: C, 81.43; H, 5.01; N, 6.33. Found: C, 81.23; H, 5.07; N, 6.24.
Isoeustifoline-D (15): colorless crystals; mp 154 °C. UV (MeOH): λ_max = 247, 255, 264, 272 (sh), 304, 311 (sh), 316, 349, 365 nm. IR (ATR): ν = 3403, 2918, 2854, 1617, 1533, 1504, 1483, 1446, 1342, 1326, 1307, 1292, 1262, 1220, 1175, 1154, 1125, 1097, 1030, 978, 879, 840, 799, 790, 756, 731, 697, 619 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 2.54 (s, 3 H), 6.83 (d, J = 2.1 Hz, 1 H), 7.24 (d, J = 8.2 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 7.47 (s, 1 H), 7.68 (d, J = 2.1 Hz, 1 H), 7.81 (br s, 1 H), 7.89 (s, 1 H), 8.10 (s, 1 H). ¹³C NMR and DEPT (125 MHz, CDCl₃): δ = 21.39 (CH₃), 100.56 (CH), 101.66 (CH), 106.53 (CH), 110.05 (CH), 120.17 (CH), 121.93 (C), 123.65 (C), 126.73 (C), 127.23 (CH), 128.34 (C), 137.38 (C), 139.00 (C), 145.65 (CH), 150.38 (C). MS (20 °C): m/z (%) = 221 (100) [M⁺], 220 (53), 192 (7), 191 (6). HRMS: m/z calcd for C₁₅H₁₁NO [M⁺]: 221.0841; found: 221.0851. Anal. Calcd (%) for C₁₅H₁₁NO: C, 81.43; H, 5.01; N, 6.33. Found: C, 80.59; H, 5.06; N, 6.15.