Transition Metals in Organic
Synthesis, Part 95: First
Total Synthesis of the 1,7-Dioxygenated Carbazole Alkaloids Clausine
Q and Clausine R

Müge Fuchsenberger; Ronny Forke; Hans-Joachim Knölker

doi:10.1055/s-0030-1260972

LETTER

Transition Metals in Organic Synthesis, Part 95: [¹] First Total Synthesis of the 1,7-Dioxygenated Carbazole Alkaloids Clausine Q and Clausine R

Müge Fuchsenberger, Ronny Forke, Hans-Joachim Knölker*
Department Chemie, Technische Universität Dresden, Bergstraße 66, 01069 Dresden, Germany
Fax: +49(351)46337030; e-Mail: hans-joachim.knoelker@tu-dresden.de;

Abstract

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Abstract

The sequence of palladium(0)-catalyzed amination and palladium(II)-catalyzed oxidative formation of the biaryl bond provides a direct route to the 1,7-dioxygenated tricyclic carbazole alkaloids clausine Q and clausine R.

Key words

alkaloids - catalysis - cyclization - oxidation - palladium

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References

References and Notes

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Experimental Procedure for the Palladium(II)-Catalyzed Oxidative Cyclization of 7: The N,N-diarylamine 7 (301 mg, 0.7 mmol), K₂CO₃ (9.8 mg, 0.07 mmol), and pivalic acid (680 mg) were heated under air at 130 ˚C. Freshly recrystallized Pd(OAc)₂ (8.0 mg, 0.036 mmol) was added and the reaction mixture was heated under air at 130 ˚C with vigorous stirring. After cooling to r.t., the mixture was taken up in EtOAc and washed first with a sat. solution of K₂CO₃ and then with a sat. solution of NaCl. The aqueous layers were subsequently extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and the solvent was removed in vacuum. Purification of the crude product by flash chromatography (pentane-CH₂Cl₂-EtOAc, gradient elution from 55:5:1 to 25:5:1) on silica
gel provided methyl 7-triisopropylsilyloxy-1-methoxy-carbazole-3-carboxylate (8; yield: 255 mg, 85%) as colorless crystals (mp 164-165 ˚C). UV (MeOH): λ_max = 216, 239, 250, 278 (sh), 283, 305 (sh), 318, 330 nm. IR (ATR): 3351, 2941, 2864, 1685, 1609, 1590, 1504, 1457, 1430, 1396, 1346, 1258, 1218, 1163, 1107, 1035, 997, 968, 921, 881, 851, 839, 823, 800, 754, 707, 672, 623 cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 1.13 (d, J = 7.4 Hz, 18 H), 1.31 (sept, J = 7.4 Hz, 3 H), 3.97 (s, 3 H), 4.04 (s, 3 H), 6.86 (dd, J = 8.5, 2.1 Hz, 1 H), 6.96 (d, J = 2.1 Hz, 1 H), 7.53 (d, J = 1.2 Hz, 1 H), 7.89 (d, J = 8.5 Hz, 1 H), 8.31 (br s, 1 H), 8.36 (br s, 1 H). ^¹³C NMR and DEPT (125 MHz, CDCl₃): δ = 12.71 (3 × CH), 17.95 (6 × Me), 51.98 (Me), 55.72 (Me), 101.84 (CH), 105.93 (CH), 114.11 (CH), 115.47 (CH), 117.91 (C), 121.17 (CH), 121.89 (C), 123.85 (C), 132.85 (C), 140.79 (C), 144.84 (C), 155.58 (C), 168.04 (C=O). MS (EI): m/z (%) = 427 (100) [M⁺], 396 (8), 385 (21), 384 (71), 356 (23), 352 (42), 328 (17), 314 (15), 296 (9), 282 (19). Anal. Calcd for C₂₄H₃₃NO₄Si: C, 67.41; H, 7.78; N, 3.28. Found: C, 67.30; H, 7.94; N, 3.29.

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Manganese dioxide (precipitated, active) from Merck (art. 805958).

Characteristic Spectroscopic Data of the 1,7-Dioxy-genated Carbazole Alkaloids 3 and 4: Clausine Q (3): colorless crystals; mp 189-191 ˚C (lit.⁶ 85-87 ˚C). UV (MeOH): λ_max = 202, 242, 285, 295 (sh), 338 nm. IR (ATR): 3438, 3236, 2930, 2844, 1641, 1609, 1570, 1542, 1484, 1368, 1342, 1298, 1241, 1218, 1155, 1131, 1104, 1030, 954, 881, 829, 810, 780, 704, 666 cm^-¹. ^¹H NMR (500 MHz, acetone-d ₆): δ = 4.07 (s, 3 H), 6.85 (dd, J = 8.5, 2.1 Hz, 1 H), 7.08 (d, J = 2.1 Hz, 1 H), 7.39 (d, J = 1.0 Hz, 1 H), 8.01 (d, J = 8.5 Hz, 1 H), 8.21 (d, J = 1.0 Hz, 1 H), 8.57 (br s, 1 H), 10.02 (s, 1 H), 10.69 (br s, 1 H). ^¹³C NMR and DEPT (125 MHz, acetone-d ₆): δ = 56.01 (Me), 98.25 (CH), 103.37 (CH), 110.82 (CH), 117.35 (C), 119.25 (CH), 122.09 (CH), 125.04 (C), 131.03 (C), 134.74 (C), 142.92 (C), 146.89 (C), 158.09 (C), 191.87 (CHO). MS (EI): m/z (%) = 241 (100) [M⁺], 240 (20), 226 (28), 212 (10), 198 (12), 170 (44). Anal. Calcd for C₁₄H₁₁NO₃: C, 69.70; H, 4.60; N, 5.81. Found: C, 69.20; H, 4.35; N, 5.27.
Clausine R (4): colorless crystals; mp 293-295 ˚C (lit.⁶ 178-181 ˚C). UV (MeOH): λ_max = 214, 240, 251, 282, 305 (sh), 319, 333 nm. IR (ATR): 3439, 3355, 3303, 3011, 2956, 2923, 2852, 1658, 1644, 1631, 1618, 1594, 1490, 1456, 1435, 1390, 1360, 1334, 1311, 1268, 1233, 1169, 1087, 995, 963, 925, 882, 824, 798, 767, 751 cm^-¹. ^¹H NMR (500 MHz, acetone-d ₆): δ = 3.87 (s, 3 H), 6.81 (dd, J = 8.5, 2.1 Hz, 1 H), 7.04 (d, J = 2.1 Hz, 1 H), 7.50 (d, J = 1.1 Hz, 1 H), 7.97 (d, J = 8.5 Hz, 1 H), 8.24 (d, J = 1.1 Hz, 1 H), 8.47 (s, 1 H), 8.95 (s, 1 H), 10.38 (br s, 1 H). ^¹³C NMR and DEPT (125 MHz, acetone-d ₆): δ = 51.83 (Me), 98.01 (CH), 110.21 (CH), 110.49 (CH), 114.38 (CH), 117.51 (C), 121.95 (CH), 122.32 (C), 125.46 (C), 133.41 (C), 142.87 (C), 143.01 (C), 157.91 (C), 168.05 (C=O). MS (EI): m/z (%) = 257 (100) [M⁺], 226 (67), 198 (28), 170 (14). Anal. Calcd for C₁₄H₁₁NO₄: C, 65.37; H, 4.31; N, 5.44. Found: C, 65.24; H, 4.95; N, 5.03.

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