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

Keisuke Hatakeyama; Ken Ohmori; Keisuke Suzuki

doi:10.1055/s-2005-868485

LETTER

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;

Abstract

Alle Artikel dieser Rubrik

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

Volltext

Referenzen

References

<A NAME="RU07305ST-1A">1a</A> Bohm BA. Introduction to Flavonoids Harwood Academic Publishers; Amsterdam: 1998.

<A NAME="RU07305ST-1B">1b</A> Hatano T. Yoshida T. Hemingway RW. Plant Polyphenols 2: Chemistry, Biology, Pharmacology, Ecology Kluwer Academic Plenum; New York: 1999.

<A NAME="RU07305ST-1C">1c</A> Ferreira D. Li X.-C. Nat. Prod. Rep. 2000, 17: 193

<A NAME="RU07305ST-2A">2a</A> The Handbook of Natural Flavonoids Vol. 2: Harborne JB. Baxter H. Wiley; Chichester: 1999. p.499

<A NAME="RU07305ST-2B">2b</A> Hwang T.-H. Kashiwada Y. Nonaka G. Nishioka I. Phytochemistry 1990, 29: 279

For isolation of related compounds, see:

<A NAME="RU07305ST-2C">2c</A> Karl C. Pedersen AP. Müller G. Z. Naturforsch., C: Biosci. 1981, 36: 607

<A NAME="RU07305ST-2D">2d</A> Tanaka N. Orii R. Ogasa K. Wada H. Murakami T. Saiki Y. Chen C.-M. Chem. Pharm. Bull. 1991, 39: 55

<A NAME="RU07305ST-2E">2e</A> Baek N.-I. Kennelly EJ. Kardono LBS. Tsauri S. Padmawinata K. Soejarto DD. Kinghorn AD. Phytochemistry 1994, 36: 513

<A NAME="RU07305ST-3">3</A> Porzel A. Lien TP. Schmidt J. Drosihn S. Wagner C. Merzweiler K. Sung TV. Adam G. Tetrahedron 2000, 56: 865

<A NAME="RU07305ST-4">4</A> Kanchanapoom T. Kasai R. Chumsri P. Kraisintu K. Yamasaki K. Tetrahedron Lett. 2002, 43: 2941

<A NAME="RU07305ST-5A">5a</A> Ohmori K. Ushimaru N. Suzuki K. Tetrahedron Lett. 2002, 43: 7753

<A NAME="RU07305ST-5B">5b</A> Ohmori K. Hatakeyama K. Suzuki K. Tetrahedron 2004, 60: 1365

<A NAME="RU07305ST-5C">5c</A> Ohmori K. Ushimaru N. Suzuki K. Proc. Natl. Acad. Sci., U.S.A. 2004, 101: 12002

<A NAME="RU07305ST-6">6</A> 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

Afzelechin is available from Apin Chemicals in milligram quantities.

<A NAME="RU07305ST-8">8</A> Clark-Lewis JW. Skingle DC. Aust. J. Chem. 1967, 20: 2169

<A NAME="RU07305ST-9A">9a</A> Kawamoto H. Nakatsubo F. Murakami K. J. Wood Chem. Technol. 1989, 9: 35

<A NAME="RU07305ST-9B">9b</A> Kawamoto H. Nakatsubo F. Murakami K. Synth. Commun. 1996, 26: 531

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.

<A NAME="RU07305ST-11A">11a</A> Larock RC. Yum EK. J. Am. Chem. Soc. 1991, 113: 6689

<A NAME="RU07305ST-11B">11b</A> Zhang H.-C. Brumfield KK. Maryanoff BE. Tetrahedron Lett. 1997, 38: 2439

<A NAME="RU07305ST-12">12</A> Shinada T. Miyachi M. Itagaki Y. Naoki H. Yoshihara K. Nakajima T. Tetrahedron Lett. 1996, 39: 7099

<A NAME="RU07305ST-13">13</A> Hirashima T. Manabe O. Chem. Lett. 1975, 259

<A NAME="RU07305ST-14">14</A> Markó IE. Bayston DJ. Tetrahedron 1994, 50: 7141

<A NAME="RU07305ST-15">15</A> Lal B. Pramanik BN. Manhas MS. Bose AK. Tetrahedron Lett. 1977, 1977

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.

<A NAME="RU07305ST-17">17</A> Garcia J. Urpí F. Vilarrasa J. Tetrahedron Lett. 1984, 25: 4841

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.

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.