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Synlett 2009(15): 2421-2424  
DOI: 10.1055/s-0029-1217810
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Transition Metals in Organic Synthesis, Part 91: [¹] Palladium-Catalyzed Approach to 2,6-Dioxygenated Carbazole Alkaloids - First Total Synthesis of the Phytoalexin Carbalexin C

Marika Schmidt, 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;
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Publication History

Received 5 June 2009
Publication Date:
07 August 2009 (online)

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Abstract

The palladium(0)-catalyzed C-N bond formation and palladium(II)-catalyzed oxidative cyclization provide an efficient route to a series of 2,6-dioxygenated carbazole alkaloids including the first total synthesis of the phytoalexin carbalexin C.

Key words

alkaloids - antibiotics - catalysis - cyclization - palladium

    References and Notes

  • 1 Part 90: Knott KE. Auschill S. Jäger A. Knölker H.-J. Chem. Commun.  2009,  1467 
    CrossrefGoogle Scholar
  • 2a Chakraborty DP. Roy S. In Progress in the Chemistry of Organic Natural Products   Vol. 57:  Herz W. Grisebach H. Kirby GW. Steglich W. Tamm C. Springer; Wien: 1991.  p.71 
    Google Scholar
  • 2b Chakraborty DP. In The Alkaloids   Vol. 44:  Cordell GA. Academic Press; New York: 1993.  p.257 
    Google Scholar
  • 3a Knölker H.-J. Reddy KR. Chem. Rev.  2002,  102:  4303 
    Google Scholar
  • 3b Knölker H.-J. Reddy KR. In The Alkaloids   Vol. 65:  Cordell GA. Academic Press; Amsterdam: 2008.  p.1 
    Google Scholar
  • 4a Knölker H.-J. Curr. Org. Synth.  2004,  1:  309 
    Google Scholar
  • 4b Fröhner W. Krahl MP. Reddy KR. ; Knölker H.-J. Heterocycles 2004, 63, 2393
  • 4c Knölker H.-J. Top. Curr. Chem.  2005,  244:  115 
    Google Scholar
  • 4d Knölker H.-J. Chem. Lett.  2009,  38:  8 
    Google Scholar
  • 5a Pindur U. Chimia  1990,  44:  406 
    Google Scholar
  • 5b Bergman J. Pelcman B. Pure Appl. Chem.  1990,  62:  1967 
    Google Scholar
  • 5c Kawasaki T. Sakamoto M. J. Indian Chem. Soc.  1994,  71:  443 
    Google Scholar
  • 5d Moody CJ. Synlett  1994,  681 
    Google Scholar
  • 5e Hibino S. Sugino E. In Advances in Nitrogen Heterocycles   Vol. 1:  Moody CJ. JAI Press; Greenwich / CT: 1995.  p.205 
    Google Scholar
  • 5f Kirsch GH. Curr. Org. Chem.  2001,  5:  507 
    Google Scholar
  • 5g Lemster T. Pindur U. Recent Res. Dev. Org. Bioorg. Chem.  2002,  5:  99 
    Google Scholar
  • 6 Kataeva O. Krahl MP. Knölker H.-J. Org. Biomol. Chem.  2005,  3:  3009 
    Google Scholar
  • 7 Krahl MP. Jäger A. Krause T. Knölker H.-J. Org. Biomol. Chem.  2006,  4:  3215 
    CrossrefPubMedGoogle Scholar
  • 8 Forke R. Krahl MP. Krause T. Schlechtingen G. Knölker H.-J. Synlett  2007,  268 
    Article in Thieme ConnectGoogle Scholar
  • 9 Börger C. Knölker H.-J. Synlett  2008,  1698 
    Article in Thieme ConnectGoogle Scholar
  • 10 Forke R. Krahl MP. Däbritz F. Jäger A. Knölker H.-J. Synlett  2008,  1870 
    Article in Thieme ConnectGoogle Scholar
  • 11a Chakraborty DP. Das BP. Sci. Cult.  1966,  32:  181 
    Google Scholar
  • 11b Chakraborty DP. Das BP. Basak SP. Plant Biochem. J. (India)  1974,  1:  73 
    Google Scholar
  • 12 Bhattacharyya P. Chowdhury BK. J. Nat. Prod.  1985,  48:  465 
    CrossrefGoogle Scholar
  • 13 Bhattacharyya P. Chakraborty PK. Chowdhury BK. Phytochemistry  1985,  24:  882 
    CrossrefGoogle Scholar
  • 14 Chakravarty AK. Sarkar T. Masuda K. Shiojima K. Phytochemistry  1999,  50:  1263 
    CrossrefGoogle Scholar
  • 15 Pacher T. Bacher M. Hofer O. Greger H. Phytochemistry  2001,  58:  129 
    CrossrefGoogle Scholar
  • 16 Prakash D. Raj K. Kapil RS. Popli SP. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.  1980,  19:  1075 
    Google Scholar
  • 17 Wu T.-S. Huang S.-C. Wu P.-L. Teng C.-M. Phytochemistry  1996,  43:  133 
    CrossrefGoogle Scholar
  • 18 Ma C. Case RJ. Wang Y. Zhang H.-J. Tan GT. Hung NV. Cuong NM. Franzblau SG. Soejarto DD. Fong HHS. Pauli GF. Planta Med.  2005,  71:  261 
    Article in Thieme ConnectGoogle Scholar
  • 19a Choi TA. Czerwonka R. Fröhner W. Krahl MP. Reddy KR. Franzblau SG. Knölker H.-J. ChemMedChem  2006,  1:  812 
    Google Scholar
  • 19b Choi TA. Czerwonka R. Knöll J. Krahl MP. Reddy KR. Franzblau SG. Knölker H.-J. Med. Chem. Res.  2006,  15:  28 
    Google Scholar
  • 19c Choi TA. Czerwonka R. Forke R. Jäger A. Knöll J. Krahl MP. Krause T. Reddy KR. Franzblau SG. Knölker H.-J. Med. Chem. Res.  2008,  17:  374 
    Google Scholar
  • 19d Knölker H.-J. Sitzungsber. der Sächsischen Akad. d. Wiss. zu Leipzig - Math.-naturwiss. Klasse  2008,  131(1):  1 
    Google Scholar
  • 20a Kureel SP. Kapil RS. Popli SP. Chem. Ind. (London)  1970,  1262 
    Google Scholar
  • 20b Islam A. Bhattacharyya P. Chakraborty DP. J. Chem. Soc., Chem. Commun.  1972,  537 
    Google Scholar
  • 20c Sharma RB. Kapil RS. Chem. Ind. (London)  1980,  158 
    Google Scholar
  • 20d Chowdhury BK. Hirani SK. Mustapha A. Bhattacharyya P. Chem. Ind (London)  1987,  128 
    Google Scholar
  • 20e Iwao M. Takehara H. Furukawa S. Watanabe M. Heterocycles  1993,  36:  1483 
    Google Scholar
  • 20f Bedford RB. Betham M. J. Org. Chem.  2006,  71:  9403 
    Google Scholar
  • 21a Hartwig JF. Angew. Chem. Int. Ed.  1998,  37:  2046 
    Google Scholar
  • 21b Muci AR. Buchwald SL. Top. Curr. Chem.  2002,  219:  131 
    Google Scholar
  • 22a Åkermark B. Eberson L. Jonsson E. Pettersson E. J. Org. Chem.  1975,  40:  1365 
    Google Scholar
  • 22b Miller RB. Moock T. Tetrahedron Lett.  1980,  21:  3319 
    Google Scholar
  • 22c Furukawa H. Ito C. Yogo M. Wu T.-S. Chem. Pharm. Bull.  1986,  34:  2672 
    Google Scholar
  • 22d Knölker H.-J. O’Sullivan N. Tetrahedron  1994,  50:  10893 
    Google Scholar
  • 22e Knölker H.-J. Fröhner W. Reddy KR. Synthesis  2002,  557 
    Google Scholar
  • 22f Knölker H.-J. Reddy KR. Heterocycles  2003,  60:  1049 
    Google Scholar
  • 22g Knölker H.-J. Knöll J. Chem. Commun.  2003,  1170 
    Google Scholar
  • 23 Sridharan V. Martín MA. Menéndez JC. Synlett  2006,  2375 
    Article in Thieme ConnectGoogle Scholar
  • 25 Kim J. Kim YK. Park N. Hahn JH. Ahn KH. J. Org. Chem.  2005,  70:  7087 
    CrossrefGoogle Scholar
24

Characteristic Spectroscopic Data of the 2,6-Dioxy-genated Carbazole Alkaloids 1-5 and 9
Glycozolidine (1): light yellow solid; mp 158-161 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 2.35 (s, 3 H), 3.88 (s, 3 H), 3.91 (s, 3 H), 6.78 (s, 1 H), 6.95 (dd, J = 8.7, 2.5 Hz, 1 H), 7.23 (d, J = 8.7 Hz, 1 H), 7.44 (d, J = 2.5 Hz, 1 H), 7.70 (br s, 1 H), 7.74 (s, 1 H). ¹³C NMR and DEPT (125 MHz, CDCl3): δ = 16.70 (CH3), 55.47 (CH3), 56.03 (CH3), 92.42 (CH), 102.51 (CH), 110.88 (CH), 112.95 (CH), 116.20 (C), 118.94 (C), 121.37 (CH), 123.98 (C), 134.13 (C), 140.00 (C), 153.84 (C), 157.42 (C). Anal. Calcd (%) for C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found: C, 74.81; H, 6.33; N, 5.71.
Glycozolidal (2): yellow solid; mp 188-193 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 3.90 (s, 3 H), 3.98 (s, 3 H), 6.83 (s, 1 H), 7.00 (dd, J = 8.7, 2.5 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 1 H), 7.49 (d, J = 2.5 Hz, 1 H), 8.12 (br s, 1 H), 8.52 (s, 1 H), 10.47 (s, 1 H). ¹³C NMR and DEPT (125 MHz, CDCl3): δ = 55.83 (CH3), 55.92 (CH3), 92.35 (CH), 103.14 (CH), 111.34 (CH), 114.64 (CH), 117.47 (C), 118.76 (C), 121.85 (CH), 124.34 (C), 134.42 (C), 145.51 (C), 154.84 (C), 161.51 (C), 189.44 (CHO). Anal. Calcd (%) for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.71; H, 5.29; N, 5.39.
2,6-Dihydroxy-3-methylcarbazole (9): colorless solid; mp >250 ˚C (decomp.). ¹H NMR (500 MHz, acetone-d 6): δ = 2.35 (s, 3 H), 6.84 (dd, J = 8.5, 2.4 Hz, 1 H), 6.93 (s, 1 H), 7.23 (d, J = 8.5 Hz, 1 H), 7.40 (d, J = 2.4 Hz, 1 H), 7.70 (s, 1 H), 7.80 (br s, 1 H), 8.21 (br s, 1 H), 9.65 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, acetone-d 6): δ = 16.65 (CH3), 96.84 (C), 96.89 (CH), 105.02 (CH), 111.40 (CH), 113.44 (CH), 116.90 (C), 122.08 (CH), 125.15 (C), 135.08 (C), 141.76 (C), 151.47 (C), 155.48 (C).
Glycozolidol (3): yellow solid; mp 245-250 ˚C. ¹H NMR (500 MHz, DMSO-d 6): δ = 2.22 (s, 3 H), 3.82 (s, 3 H), 6.72 (dd, J = 8.5, 2.4 Hz, 1 H), 6.84 (s, 1 H), 7.16 (d, J = 8.5 Hz, 1 H), 7.23 (d, J = 2.4 Hz, 1 H), 7.65 (s, 1 H), 8.75 (br s, 1 H), 10.60 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, DMSO-d 6): δ = 16.62 (CH3), 55.24 (CH3), 92.51 (CH), 104.11 (CH), 110.83 (CH), 112.93 (CH), 115.18 (C), 116.56 (C), 121.08 (CH), 123.28 (C), 133.52 (C), 140.26 (C), 150.30 (C), 156.60 (C). Anal. Calcd (%) for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.74; H, 5.89; N, 6.17.
Carbalexin C (4): light yellow solid; mp 187-191 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 2.39 (s, 3 H), 3.90 (s, 3 H), 6.81 (s, 1 H), 6.94 (dd, J = 8.7, 2.5 Hz, 1 H), 7.24 (d, J = 8.7 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.70 (br s, 1 H), 7.73 (s, 1 H), 7.89 (br s, 1 H). ¹³C NMR and DEPT (125 MHz, CDCl3): δ = 16.14 (CH3), 56.07 (CH3), 96.52 (CH), 102.71 (CH), 110.88 (CH), 113.20 (CH), 116.03 (C), 117.40 (C), 121.70 (CH), 123.97 (C), 134.36 (C), 140.15 (C), 153.16 (C), 153.89 (C). Anal. Calcd (%) for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 73.32; H, 5.97; N, 6.26.
Lansine (5): yellow solid; mp 202-204 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 3.91 (s, 3 H), 6.82 (s, 1 H), 7.02 (dd, J = 8.7, 2.4 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 1 H), 7.47 (d, J = 2.4 Hz, 1 H), 8.11 (br s, 1 H), 8.12 (s, 1 H), 9.91 (s, 1 H), 11.43 (s, 1 H). ¹³C NMR and DEPT (125 MHz, CDCl3): δ = 56.01 (CH3), 96.79 (CH), 103.36 (CH), 111.41 (CH), 114.48 (CH), 115.30 (C), 117.81 (C), 123.96 (C), 127.49 (CH), 134.68 (C), 146.11 (C), 154.96 (C), 161.10 (C), 195.12 (CHO). Anal. Calcd (%) for C14H11NO3: C, 69.70; H, 4.60; N, 5.81. Found: C, 69.75; H, 4.70; N, 5.69.

26

Synthesis of 3-(tert-butyldiphenylsilyloxy)-4-methyl-aniline (13): 1. commercial 2-methyl-5-nitrophenol (1.0 equiv), t-BuPh2SiCl (1.5 equiv), imidazole (2 equiv), DMF, r.t., 4 h; 2. 10% Pd/C, H2 (5 bar), CH2Cl2, r.t., 24 h (100% overall yield).

27

Experimental Procedure for the Palladium(II)-Catalyzed Oxidative Cyclization The diarylamine 14 (132 mg, 283 µmol), Pd(OAc)2 (6.3 mg, 28 µmol), Cu(OAc)2 (128 mg, 705 µmol), and AcOH (1.5 mL) were heated in a 10 mL microwave vessel for 2 h at 130 ˚C. Removal of the solvent in vacuum and flash chro-matography (PE-EtOAc, 15:1) of the crude product on Celite/silica gel provided O-tert-butyldiphenylsilylcarba-lexin C (15; 100 mg, 76%) as a yellow oil. ¹³C NMR and DEPT (125 MHz, CDCl3): δ = 17.70 (CH3), 19.61 (C), 26.50 (3 CH3), 56.02 (CH3), 100.55 (CH), 102.55 (CH), 110.71 (CH), 113.03 (CH), 117.07 (C), 120.70 (C), 121.30 (CH), 123.73 (C), 127.84 (4 CH), 129.86 (2 CH), 132.91 (2 C), 134.23 (C), 135.45 (4 CH), 139.39 (C), 152.96 (C), 153.69 (C).