Transition Metals in Organic Synthesis, Part 85. [1] A General Approach to 1,6-Dioxygenated Carbazole Alkaloids - First Total Synthesis of Clausine G, Clausine I, and Clausine Z

Abstract

Using the palladium-catalyzed construction of the carbazole framework, a highly efficient route to 1,6-dioxygenated carbazole alkaloids has been developed and applied to the total synthesis of clausenine, 6-methoxymurrayanine, clausenol, clausine G, clausine I, and clausine Z. The three latter natural products have been synthesized for the first time.

Key words

alkaloids - antibiotics - catalysis - cyclizations - palladium

References and Notes

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15

Characteristic Spectroscopic Data of the 1,6-Dioxygenated Carbazole Alkaloids 1-6.
Clausenine (1): colorless crystals; mp 149-150 °C (lit. [6] 151 °C). UV (MeOH): λ_max = 226, 241, 258 (sh), 287 (sh), 299, 340, 354 nm. IR (ATR): ν = 3385, 2955, 2918, 2852, 1619, 1581, 1505, 1486, 1459, 1451, 1437, 1394, 1304, 1268, 1207, 1145, 1129, 1035, 1025, 940, 838, 821, 800, 769 cm^-1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.45 (s, 3 H), 3.82 (s, 3 H), 3.95 (s, 3 H), 6.78 (s, 1 H), 6.97 (dd, J = 8.7, 2.4 Hz, 1 H), 7.33 (d, J = 8.7 Hz, 1 H), 7.46 (s, 1 H), 7.55 (d, J = 2.4 Hz, 1 H), 10.92 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, DMSO-d ₆): δ = 21.57 (CH₃), 55.23 (CH₃), 55.51 (CH₃), 102.64 (CH), 107.53 (CH), 111.97 (CH), 112.31 (CH), 114.56 (CH), 122.75 (C), 123.48 (C), 127.45 (C), 128.56 (C), 134.68 (C), 145.33 (C), 152.80 (C). MS (EI): m/z (%) = 241 (91) [M⁺], 226 (100), 211 (11), 198 (20), 183 (7), 167 (9), 155 (17), 154 (14). Anal. Calcd (%) for C₁₅H₁₅NO₂: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.88; H, 6.36; N, 5.50.
6-Methoxymurrayanine (2): colorless crystals; mp 230-231 °C (lit. [5] 231-233 °C). UV (MeOH): λ_max = 240, 253, 277, 296, 337, 350 nm. IR (ATR): ν = 3138, 3010, 2921, 2852, 1655, 1628, 1608, 1578, 1496, 1466, 1437, 1360, 1327, 1305, 1262, 1239, 1217, 1185, 1139, 1105, 1031, 1023, 944, 844, 805, 782, 749, 705, 668 cm^-1. ¹H NMR (500 MHz, acetone-d ₆): δ = 3.92 (s, 3 H), 4.08 (s, 3 H), 7.12 (dd, J = 8.8, 2.4 Hz, 1 H), 7.43 (d, J = 1.0 Hz, 1 H), 7.56 (d, J = 8.8 Hz, 1 H), 7.79 (d, J = 2.4 Hz, 1 H), 8.34 (d, J = 1.0 Hz, 1 H), 10.03 (s, 1 H), 10.83 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d ₆): δ = 56.06 (CH₃), 56.08 (CH₃), 103.64 (CH), 103.78 (CH), 113.50 (CH), 116.86 (CH), 120.81 (CH), 124.44 (C), 124.87 (C), 130.71 (C), 135.45 (C), 135.80 (C), 147.27 (C), 155.60 (C), 191.72 (CHO). MS (EI): m/z (%) = 255 (100) [M⁺], 240 (96), 225 (10), 224 (11), 212 (13), 184 (8), 169 (8).
Clausine Z (6): colorless crystals; mp 151 °C (dec.). UV (MeOH): λ_max = 226, 246, 279, 298, 342, 355 nm. IR (ATR): ν = 3219, 2922, 2853, 1657, 1579, 1457, 1327, 1196, 1136, 958, 851, 800, 711 cm^-1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 6.93 (dd, J = 8.6, 2.4 Hz, 1 H), 7.24 (d, J = 1.0 Hz, 1 H), 7.34 (d, J = 8.6 Hz, 1 H), 7.44 (d, J = 2.4 Hz, 1 H), 8.13 (d, J = 1.0 Hz, 1 H), 9.12 (br s, 1 H), 9.90 (s, 1 H), 10.29 (br s, 1 H), 11.41 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, DMSO-d ₆): δ = 104.93 (CH), 106.44 (CH), 112.42 (CH), 115.73 (CH), 118.88 (CH), 123.15 (C), 123.84 (C), 128.71 (C), 134.04 (C), 134.48 (C), 143.65 (C), 151.30 (C), 191.72 (CHO). MS (EI): m/z (%) = 227 (100) [M⁺], 226 (60), 198 (27), 197 (24), 170 (13), 169 (10). HRMS: m/z calcd for C₁₃H₉NO₃ [M⁺]: 227.0582; found: 227.0573.
Clausine G (5): light yellow crystals; mp 145-147 °C (lit. [7b] >280 °C). UV (MeOH): λ_max = 224, 241, 250, 268, 284, 325 (sh), 334, 349 nm. IR (ATR): ν = 3355, 2952, 2922, 2833, 1667, 1630, 1612, 1582, 1500, 1471, 1431, 1355, 1322, 1297, 1251, 1202, 1172, 1125, 1087, 1026, 1001, 916, 871, 828, 793, 765, 751, 723 cm^-1. ¹H NMR (500 MHz, acetone-d ₆): δ = 3.88 (s, 3 H), 3.92 (s, 3 H), 7.08 (dd, J = 8.8, 2.5 Hz, 1 H), 7.52 (d, J = 8.8 Hz, 1 H), 7.55 (d, J = 1.1 Hz, 1 H), 7.77 (d, J = 2.5 Hz, 1 H), 8.37 (d, J = 1.1 Hz, 1 H), 9.04 (br s, 1 H), 10.45 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d ₆): δ = 51.91 (CH₃), 56.07 (CH₃), 103.59 (CH), 111.10 (CH), 113.23 (CH), 115.71 (CH), 116.67 (CH), 121.96 (C), 124.94 (C), 124.98 (C), 134.35 (C), 136.09 (C), 143.46 (C), 155.26 (C), 168.01 (C=O). Anal. Calcd (%) for C₁₅H₁₃NO₄: C, 66.41; H, 4.83; N, 5.16. Found: C, 66.43; H, 4.95; N, 4.76.
Clausenol (3): light yellow crystals; mp 191-192 °C (lit. [6] 139 °C). UV (MeOH): λ_max = 227, 242, 292 (sh), 299, 343, 357 nm. IR (ATR): ν = 3367, 3228, 2921, 2851, 1652, 1621, 1590, 1578, 1520, 1481, 1457, 1434, 1388, 1318, 1298, 1269, 1210, 1178, 1142, 1095, 1024, 1005, 988, 943, 871, 833, 796, 748 cm^-1. ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.37 (s, 3 H), 3.81 (s, 3 H), 6.61 (s, 1 H), 6.95 (dd, J = 8.7, 2.5 Hz, 1 H), 7.31 (s, 1 H), 7.32 (d, J = 8.7 Hz, 1 H), 7.51 (d, J = 2.5 Hz, 1 H), 9.59 (s, 1 H), 10.64 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, DMSO-d ₆): δ = 21.38 (CH₃), 55.55 (CH₃), 102.67 (CH), 110.92 (CH), 111.38 (CH), 111.91 (CH), 114.39 (CH), 123.00 (C), 124.00 (C), 127.45 (C), 128.47 (C), 134.74 (C), 142.88 (C), 152.68 (C).
Clausine I (4): colorless crystals; mp 222-223 °C (lit. [7a] 222-224 °C). UV (MeOH): λ_max = 225 (sh), 242, 255, 278, 296, 340 (sh), 354 nm. IR (ATR): ν = 3385, 2955, 2919, 2852, 1619, 1581, 1486, 1460, 1437, 1393, 1304, 1268, 1207, 1184, 1145, 1130, 1111, 1035, 1025, 940, 838, 821, 800, 769, 733, 712 cm^-1. ¹H NMR (500 MHz, acetone-d ₆): δ = 3.92 (s, 3 H), 7.11 (dd, J = 8.8, 2.4 Hz, 1 H), 7.40 (d, J = 0.6 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.77 (d, J = 2.4 Hz, 1 H), 8.25 (d, J = 0.6 Hz, 1 H), 9.27 (s, 1 H), 9.98 (s, 1 H), 10.64 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d ₆): δ = 56.05 (CH₃), 103.66 (CH), 107.95 (CH), 113.46 (CH), 116.76 (CH), 119.60 (CH), 125.04 (C), 125.08 (C), 130.79 (C), 135.43 (C), 136.03 (C), 144.40 (C), 155.47 (C), 191.76 (CHO). MS (EI): m/z (%) = 241 (100) [M⁺], 240 (10), 226 (78), 198 (15). HRMS: m/z calcd for C₁₄H₁₁NO₃ [M⁺]: 241.0739; found: 241.0735.