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Synlett 2008(1): 61-64  
DOI: 10.1055/s-2007-1000831
LETTER
© Georg Thieme Verlag Stuttgart · New York

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 Zhoua, Soushi Kobayashia, Hiroshi Tsunekia, Tsutomu Wadaa, Hideki Sakaia, Hideo Nemotoa, Toshiyasu Sasaokaa, Yasuhiro Tezukab, Subehanb, Shigetoshi Kadotab, H. Martin Garraffoc, Thomas F. Spandec, John W. Dalyc
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
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Publication History

Received 1 October 2007
Publication Date:
11 December 2007 (online)

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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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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).

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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).