Download PDF
Synlett 2005(8): 1311-1315  
DOI: 10.1055/s-2005-868485
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of (±)-Lotthanongine, a Novel Natural Product with a Flavan-Indole Hybrid Structure

Keisuke Hatakeyama, Ken Ohmori, Keisuke Suzuki*
Department of Chemistry, Tokyo Institute of Technology, and SORST-JST Agency, 2-12-1, O-okayama, Meguro-ku, Tokyo 152-8551, Japan
Fax: +81(3)57342788; e-Mail: ksuzuki@chem.titech.ac.jp;
Further Information

Publication History

Received 15 March 2005
Publication Date:
21 April 2005 (online)

    Permissions and Reprints All articles of this category

Abstract

First total synthesis of lotthanongine (3), a natural product with a flavan-indole composite structure, has been achieved via the Lewis acid-catalyzed C-C bond formation between the catechin and the indole units.

Key words

catechin - indole - polyphenol - heterocycle - hybrid

    References

  • 1a Bohm BA. Introduction to Flavonoids   Harwood Academic Publishers; Amsterdam: 1998. 
    CrossrefGoogle Scholar
  • 1b Hatano T. Yoshida T. Hemingway RW. Plant Polyphenols 2: Chemistry, Biology, Pharmacology, Ecology   Kluwer Academic Plenum; New York: 1999. 
    CrossrefGoogle Scholar
  • 1c Ferreira D. Li X.-C. Nat. Prod. Rep.  2000,  17:  193 
    CrossrefGoogle Scholar
  • 2a The Handbook of Natural Flavonoids   Vol. 2:  Harborne JB. Baxter H. Wiley; Chichester: 1999.  p.499 
    CrossrefGoogle Scholar
  • 2b Hwang T.-H. Kashiwada Y. Nonaka G. Nishioka I. Phytochemistry  1990,  29:  279 
    CrossrefGoogle Scholar
  • For isolation of related compounds, see:
  • 2c Karl C. Pedersen AP. Müller G. Z. Naturforsch., C: Biosci.  1981,  36:  607 
    CrossrefGoogle Scholar
  • 2d Tanaka N. Orii R. Ogasa K. Wada H. Murakami T. Saiki Y. Chen C.-M. Chem. Pharm. Bull.  1991,  39:  55 
    CrossrefGoogle Scholar
  • 2e Baek N.-I. Kennelly EJ. Kardono LBS. Tsauri S. Padmawinata K. Soejarto DD. Kinghorn AD. Phytochemistry  1994,  36:  513 
    CrossrefGoogle Scholar
  • 3 Porzel A. Lien TP. Schmidt J. Drosihn S. Wagner C. Merzweiler K. Sung TV. Adam G. Tetrahedron  2000,  56:  865 
    CrossrefGoogle Scholar
  • 4 Kanchanapoom T. Kasai R. Chumsri P. Kraisintu K. Yamasaki K. Tetrahedron Lett.  2002,  43:  2941 
    CrossrefGoogle Scholar
  • 5a Ohmori K. Ushimaru N. Suzuki K. Tetrahedron Lett.  2002,  43:  7753 
    CrossrefGoogle Scholar
  • 5b Ohmori K. Hatakeyama K. Suzuki K. Tetrahedron  2004,  60:  1365 
    CrossrefGoogle Scholar
  • 5c Ohmori K. Ushimaru N. Suzuki K. Proc. Natl. Acad. Sci., U.S.A.  2004,  101:  12002 
    CrossrefGoogle Scholar
  • 6 The β-stereochemistry of the major isomer was assigned by the NOE correlations of N-H proton of the indole with H(2) and H(4) of the flavan nucleus. On the other hand, the α-stereochemistry of the minor isomer was assigned by the NOE correlations between H(2) and H(4) of the flavan skeleton. The NOE correlations of the H(4) of the indole and the methylene protons of the indole side chain assured the connectivity as indicated, excluding the exchange of the C(2) and C(3) substituents (Figure 3). Compare: Jackson AH. Smith P. J. Chem. Soc., Chem. Commun.  1967,  264 
    Google Scholar
  • 8 Clark-Lewis JW. Skingle DC. Aust. J. Chem.  1967,  20:  2169 
    Google Scholar
  • 9a Kawamoto H. Nakatsubo F. Murakami K. J. Wood Chem. Technol.  1989,  9:  35 
    Google Scholar
  • 9b Kawamoto H. Nakatsubo F. Murakami K. Synth. Commun.  1996,  26:  531 
    Google Scholar
  • 11a Larock RC. Yum EK. J. Am. Chem. Soc.  1991,  113:  6689 
    CrossrefGoogle Scholar
  • 11b Zhang H.-C. Brumfield KK. Maryanoff BE. Tetrahedron Lett.  1997,  38:  2439 
    CrossrefGoogle Scholar
  • 12 Shinada T. Miyachi M. Itagaki Y. Naoki H. Yoshihara K. Nakajima T. Tetrahedron Lett.  1996,  39:  7099 
    Google Scholar
  • 13 Hirashima T. Manabe O. Chem. Lett.  1975,  259 
    Google Scholar
  • 14 Markó IE. Bayston DJ. Tetrahedron  1994,  50:  7141 
    CrossrefGoogle Scholar
  • 15 Lal B. Pramanik BN. Manhas MS. Bose AK. Tetrahedron Lett.  1977,  1977 
    CrossrefGoogle Scholar
  • 17 Garcia J. Urpí F. Vilarrasa J. Tetrahedron Lett.  1984,  25:  4841 
    CrossrefGoogle Scholar
7

Afzelechin is available from Apin Chemicals in milligram quantities.

10

Compound 13: colorless amorphous solids. 1H NMR (400 MHz, CDCl3): δ = -0.52 (s, 3 H), -0.20 (s, 3 H), -0.18 (s, 3 H), -0.10 (s, 3 H), 0.69 (s, 9 H), 0.85 (s, 9 H), 3.80 (dd, 1 H, J = 10.0, 2.4 Hz), 4.98 (s, 2 H), 5.01 (d, 1 H, J = 2.4 Hz), 5.02 (s, 2 H), 5.09 (s, 2 H), 5.33 (d, 1 H, J = 10.0 Hz), 6.19 (d, 1 H, J = 2.2 Hz), 6.21 (d, 1 H, J = 2.2 Hz), 6.95 (d, 2 H, J = 8.8 Hz), 7.28-7.44 (m, 17 H). 13C NMR (100 MHz, CDCl3): δ = -5.7, -5.3, -4.59, -4.58, 17.9, 18.4, 25.8, 26.0, 63.2, 70.0, 70.1, 70.2, 73.7, 76.1, 92.8, 94.1, 106.8, 114.6, 127.3, 127.6, 127.77, 127.82, 128.01, 128.04, 128.47, 128.52, 128.6, 129.2, 132.1, 136.6, 136.7, 137.1, 155.9, 157.2, 158.6, 160.5. IR (KBr): 3066, 3033, 2927, 2856, 1616, 1593, 1514, 1377, 1250, 1151, 1076, 883, 837, 775, 673 cm-1. Anal. Calcd for C48H60O6Si2: C, 73.05; H, 7.66. Found: C, 72.87; H, 7.86.

16

Compound 21: colorless powders, mp 234-236 °C. 1H NMR (400 MHz, DMSO): δ = 2.81 (br t, 2 H, J = 7.3 Hz), 3.43 (br td, 2 H, J = 7.3, 5.6 Hz), 5.09 (s, 2 H), 5.13 (s, 2 H), 6.47 (d, 1 H, J = 16.1 Hz), 6.72 (dd, 1 H, J = 8.5, 2.2 Hz), 6.90 (br d, 1 H, J = 2.2 Hz), 7.00 (br s, 1 H), 7.03 (d, 2 H, J = 8.6 Hz), 7.27-7.52 (m, 14 H), 8.10 (br t, 1 H, J = 5.6 Hz), 10.6 (br s, 1 H). 13C NMR (100 MHz, DMSO): δ = 25.4, 39.6, 69.3, 69.5, 96.0, 109.1, 111.8, 115.2, 118.9, 120.0, 121.4, 121.9, 127.5, 127.6, 127.7, 127.9, 128.4, 128.5, 129.0, 136.8, 137.7, 138.1, 154.4, 159.3, 165.1. IR (KBr): 3224, 1645, 1601, 1539, 1510, 1452, 1174, 694 cm-1. Anal. Calcd for C33H30N2O3: C, 78.86; H, 6.02; N, 5.57. Found: C, 78.94; H, 5.91; N, 5.43.

18

Compound 3: 1H NMR (500 MHz, CD3OD): δ = 2.98-3.10 (m, 2 H), 3.47-3.55 (m, 1 H), 3.69-3.77 (m, 1 H), 4.15 (dd, 1 H, J = 9.6, 5.7 Hz), 4.67 (d, 1 H, J = 5.7 Hz), 4.95 (d, 1 H, J = 9.6 Hz), 5.95 (d, 1 H, J = 2.4 Hz), 6.00 (d, 1 H, J = 2.4 Hz), 6.27 (d, 1 H, J = 15.7 Hz), 6.55 (dd, 1 H, J = 8.5, 2.2 Hz), 6.74 (d, 1 H, J = 2.2 Hz), 6.77 (d, 2 H, J = 8.7 Hz), 6.78 (d, 2 H, J = 8.7 Hz), 7.24 (d, 2 H, J = 8.7 Hz), 7.27 (d, 2 H, J = 8.7 Hz), 7.33 (d, 1 H, J = 8.5 Hz), 7.35 (d, 1 H, J = 15.7 Hz), 9.30 (br s, 1 H). 13C NMR (125 MHz, CD3OD): d = 25.3, 36.2, 41.3, 71.8, 79.6, 95.8, 96.8, 97.8, 102.9, 109.6, 111.7, 116.1, 116.7, 118.7, 119.4, 123.9, 127.9, 130.2, 130.6, 131.7, 133.9, 138.6, 141.5, 153.6, 157.5, 158.1, 158.5, 159.1, 160.4, 169.3. IR (KBr): 3300, 1647, 1514, 1458, 1227, 1146, 829 cm-1. Anal. Calcd for C34H30N2O8: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.41; H, 5.38; N, 4.42.

19

Compound 24: 1H NMR (400 MHz, CD3OD): δ = 2.90-3.05 (m, 1 H), 3.05-3.20 (m, 1 H), 3.46-3.58 (m, 1 H), 3.64-3.78 (m, 1 H), 4.08 (dd, 1 H, J = 9.8, 8.8 Hz), 4.33 (d, 1 H, J = 8.8 Hz), 4.62 (d, 1 H, J = 9.8 Hz), 5.95 (d, 1 H, J = 2.4 Hz), 5.98 (d, 1 H, J = 2.4 Hz), 6.38 (d, 1 H, J = 15.9 Hz), 6.52 (dd, 1 H, J = 8.6, 2.4 Hz), 6.66 (d, 1 H, J = 2.4 Hz), 6.75 (d, 2 H, J = 8.6 Hz), 6.81 (d, 2 H, J = 8.8 Hz), 7.25 (d, 2 H, J = 8.6 Hz), 7.27 (d, 1 H, J = 8.6 Hz), 7.33 (d, 2 H, J = 8.8 Hz), 7.37 (d, 1 H, J = 15.9 Hz), 8.02 (br s, 1 H), 9.52 (br s, 1 H). 13C NMR (100 MHz, CD3OD): δ = 25.3, 41.3, 41.8, 75.1, 83.4, 96.6, 97.7, 97.9, 104.1, 109.3, 110.6, 116.1, 116.7, 118.8, 119.0, 123.6, 127.9, 130.3, 130.6, 131.0, 136.9, 138.6, 141.5, 153.5, 158.4, 158.6, 158.8, 159.0, 160.4, 169.3. IR (KBr): 3326, 1647, 1604, 1516, 1458, 1234, 1173, 1145, 1068, 831 cm-1. Anal. Calcd for C34H30N2O8: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.43; H, 5.38; N, 4.46.