Syntheses of the Proposed Structures of Poison-Frog Alkaloids 179 and 207E and Their Inhibitory Effects on Neuronal Nicotinic Acetylcholine Receptors

Naoki Toyooka; Dejun Zhou; Soushi Kobayashi; Hiroshi Tsuneki; Tsutomu Wada; Hideki Sakai; Hideo Nemoto; Toshiyasu Sasaoka; Yasuhiro Tezuka; Subehan; Shigetoshi Kadota; H. Martin Garraffo; Thomas F. Spande; John W. Daly

doi:10.1055/s-2007-1000831

LETTER

Syntheses of the Proposed Structures of Poison-Frog Alkaloids 179 and 207E and Their Inhibitory Effects on Neuronal Nicotinic Acetylcholine Receptors

Naoki Toyooka*^a, Dejun Zhou^a, Soushi Kobayashi^a, Hiroshi Tsuneki^a, Tsutomu Wada^a, Hideki Sakai^a, Hideo Nemoto^a, Toshiyasu Sasaoka^a, Yasuhiro Tezuka^b, Subehan^b, Shigetoshi Kadota^b, H. Martin Garraffo^c, Thomas F. Spande^c, John W. Daly^c
^a Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
e-Mail: toyooka@pha.u-toyama.ac.jp;
^b Institute of Natural Medicine, University of Toyama, Sugitani 2630, Toyama 930-0194, Japan
^c Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA

Abstract

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Abstract

Syntheses of the structures postulated for 179 and 207E, members of a proposed new class of poison-frog alkaloids, 6,7-dehydro-5,8-disubstituted indolizidines, are described. The FT-IR spectrum and GC retention time of the synthetic 207E were different from those of the natural product; consequently the original structure of 207E needs to be revised. It is likely that the position of the double bond is instead at the 7,8-position.

Key words

poison-frog alkaloids 179 and 207E - inhibitory effects on neuronal nicotinic acetylcholine receptors - dehydro-5,8-disubstituted indolizidines

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References and Notes

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The spectral and analytical data of synthetic 1 are as follows: IR (neat): 3025, 2957, 2871, 2781, 1456, 1377, 1326, 1287, 1179, 913, 798, 715 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.93 (3 H, t, J = 7.5 Hz), 0.94 (3 H, d, J = 6.8 Hz), 1.25-1.34 (1 H, m), 1.35-1.41 (1 H, m), 1.42-1.52 (2 H, m), 1.61-1.67 (1 H, m), 1.68-1.75 (1 H, m), 1.76-1.83 (1 H, m), 1.84 (1 H, td, J = 9.1, 6.9 Hz), 1.99-2.07 (2 H, m), 2.08-2.14 (1 H, m), 2.64 (1 H, dtd, J = 11.0, 3.6, 1.9 Hz), 3.35 (1 H, td, J = 8.4, 1.9 Hz), 5.50 (1 H, dt, J = 10.2, 1.9 Hz), 5.57 (1 H, dt, J = 10.2, 1.9 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 14.39 (q), 18.14 (q), 18.64 (t), 20.77 (t), 29.38 (t), 36.04 (t), 37.61 (d), 52.79 (t), 63.00 (d), 67.83 (d), 128.55 (d), 131.53 (d). HRMS: m/z calcd for C₁₂H₂₁N: 179.1674; found: 179.1686. [α]_D ²⁶ +129.3 (c 2.74, CHCl₃).

The spectral and analytical data of synthetic 2 are as follows: IR (neat): 3030, 2957, 2929, 2871, 2781, 1458, 1378, 1329, 1260, 1177, 1105, 929, 803, 713 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.89 (3 H, t, J = 6.8 Hz), 0.91 (3 H, t, J = 7.3 Hz), 1.12-1.21 (1 H, m), 1.23-1.34 (2 H, m), 1.35-1.40 (2 H, m), 1.43-1.53 (3 H, m), 1.59-1.68 (1 H, m), 1.69-1.74 (1 H, m), 1.76-1.82 (1 H, m), 1.93 (1 H, td, J = 9.4, 6.8 Hz), 1.99-2.06 (3 H, m), 2.63 (1 H, dtd, J = 11.0, 3.4, 1.7 Hz), 3.34 (1 H, td, J = 8.5, 2.1 Hz), 5.60 (1 H, dt, J = 9.8, 1.7 Hz), 5.63 (1 H, dt, J = 9.8, 1.7 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 14.43 (2 × q), 18.64 (t), 19.67 (t), 20.92 (t), 29.69 (t), 34.91 (t), 36.11 (t), 42.54 (d), 52.76 (t), 62.97 (d), 66.13 (d), 129.01 (d), 129.44 (d). HRMS: m/z calcd for C₁₄H₂₅N 207.1986; found: 207.1973. [α]_D ²⁶ +109.1 (c 0.32, CHCl₃). The GC-MS instrument is a Finnigan-Thermoquest Polaris Q with a Restek-RTX-5MS column (30 m × 0.25 mm i.d.) and the program was 100-280 °C at 10 °C/min with a final hold time of 10 min; t _R = 7.69 min.; natural product from Oophaga granulifera: t _R = 8.41 min. MS (EI): m/z (%) = 208 (12), 207 (4), 206 (8), 164 (100), 162 (13), 136 (13), 134 (13), 132 (8), 120 (52), 106 (8), 93 (22), 92 (11), 91 (10), 79 (13), 77 (16), 70 (16), 67 (24), 65 (14). MS (EI) of natural product from Dendrobates granuliferous: m/z (%) = 207 (2), 206 (4), 17 (10), 164 (100), 162 (78), 134 (18), 120 (28), 91 (12), 79 (14), 77 (20), 65 (11).

<A NAME="RU09407ST-15">15</A> Tsuneki H. You Y. Toyooka N. Kagawa S. Kobayashi S. Sasaoka T. Nemoto H. Kimura I. Dani JA. Mol. Pharmacol. 2004, 66: 1061