This article is part of a series on Indolizidines and quinolizidines: natural products and beyond, edited by Prof Joseph P Michael, University of Witwatersrand.

Full Research Paper

Flexible synthetic routes to poison-frog alkaloids of the 5,8-disubstituted indolizidine-class I: synthesis of common lactam chiral building blocks and application to the synthesis of (-)-203A, (-)-205A, and (-)-219F

Naoki Toyooka¹, Dejun Zhou¹, Hideo Nemoto¹, H Martin Garraffo², Thomas F Spande² and John W Daly²

¹Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani 2630, Toyama, 930-0194, Japan

²Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892, USA

Beilstein Journal of Organic Chemistry 2007, 3:29doi:10.1186/1860-5397-3-29

Published:	28 September 2007

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Abstract

Background

The 5,8-disubstituted indolizidines are the largest class of poison-frog alkaloids found in anuran skin, and are of considerable interest because of their inhibitory effects on the neuronal nicotinic acetylcholine receptors. Many synthetic strategies for the construction of this nucleus have been reported: however, a flexible route has not been reported to date.

Results

Synthesis of lactam chiral building blocks for the flexible synthesis of the title alkaloids has been achieved using a Michael-type conjugate addition reaction to a chiral cyclic enamine ester as the key step in constructing the trisubstituted piperidine ring system. To demonstrate the usefulness of these chiral building blocks, syntheses of (-)-203A, (-)-205A from 1, and (-)-219F from 2 have been achieved.

Conclusion

The total synthesis of (-)-203A, (-)-205A, and (-)-219F was achieved, and the absolute stereochemistry of natural 203A was determined to be 5S, 8R, 9S. In addition, the relative stereochemistry of natural 219F was determined.

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