Fortschritte der Chemie organischer Naturstoffe Progress in the Chemistry of Organic Natural Products Founded by L. Zechmeister Editors: A.D. Kinghorn, Columbus, OH H. Falk, Linz J. Kobayashi, Sapporo Honorary Editor: W. Herz, Tallahassee, FL Editorial Board: V.M. Dirsch, Vienna S. Gibbons, London N.H. Oberlies, Greensboro, NC Y. Ye, Shanghai 93 Fortschritte der Chemie organischer Naturstoffe Progress in the Chemistry of Organic Natural Products Authors: S.A. Begum, M. Sahai, and A.B. Ray E. Go¨ssinger M. Luzhetska, J. Ha¨rle, and A. Bechthold SpringerWienNewYork Prof. A. Douglas Kinghorn, College of Pharmacy, Ohio State University, Columbus, OH, USA em. Univ.-Prof. Dr. H. Falk, Institut fu¨r Organische Chemie, Johannes-Kepler-Universita¨t, Linz, Austria Prof. Dr. J. Kobayashi, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan This work is subject to copyright. 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Library of Congress Catalog Card Number: 2010926970 Typesetting: SPI, Chennai Printed on acid-free and chlorine-free bleached paper SPIN: 12794805 With 40 (partly coloured) Figures ISSN 0071-7886 ISBN 978-3-7091-0139-1 e-ISBN 978-3-7091-0140-7 DOI 10.1007/978-3-7091-0140-7 SpringerWienNewYork Contents List of Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Non-conventional Lignans: Coumarinolignans, Flavonolignans, and Stilbenolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Sajeli A. Begum, Mahendra Sahai, and Anil B. Ray 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2. Coumarinolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.1. Occurrence of Coumarinolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.2. Classification of Coumarinolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.3. Structure Elucidation of Coumarinolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 2.4. Chemistry of Coumarinolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 2.5. Biological Activity of Coumarinolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.6. Biogenesis of Coumarinolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 3. Flavonolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 3.1. Occurrence of Flavonolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 3.2. Features of Flavonolignans and Their Classification . . . . . . . . . . . . . . . . . . 29 3.3. Structure Elucidation of Flavonolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 3.4. Chemistry of Flavonolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 3.5. Biological Activity of Flavonolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 3.6. Biogenesis of Flavonolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 4. Stilbenolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 4.1. Occurrence and Features of Stilbenolignans . . . . . . . . . . . . . . . . . . . . . . . . . . 50 4.2. Structure Elucidation and Synthesis of Stilbenolignans . . . . . . . . . . . . . . . 52 4.3. Biological Activity of Stilbenolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 4.4. Biogenesis of Stilbenolignans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Picrotoxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Edda Go¨ssinger 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 v vi Contents 2. Tabular Overview of the Picrotoxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 3. Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 3.1. Systematic and Geographic Occurrence of Picrotoxane-Containing Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 3.2. Parasitic Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 3.3. Picrotoxanes Found in Animals and Animal Products . . . . . . . . . . . . . . 110 3.4. The Riddle of the Scattered Taxonomic Occurrence of Picrotoxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4. Isolation of Picrotoxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 4.1. Examples of Recent Isolation Procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 5. Structure Determination of Picrotoxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 5.1. Main Picrotoxanes of the Menispermaceae . . . . . . . . . . . . . . . . . . . . . . . . . . 117 5.2. Main Picrotoxanes of the Coriariaceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 5.3. Picrotoxanes Isolated from Toxic Honey . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 5.4. Picrotoxanes of the Picrodendraceae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 5.5. Picrotoxanes from Dendrobium Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 6. Total Syntheses of Picrotoxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 6.1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134 6.2. Description of the Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 7. Biosynthesis of Picrotoxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 7.1. Investigations on the Biosynthesis of Dendrobines . . . . . . . . . . . . . . . . . 181 7.2. Investigations on the Biosynthesis of Sesquiterpene Picrotoxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 8. Physiological Activity of Picrotoxanes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 8.1. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 8.2. Picrotoxanes as Therapeutics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 8.3. Picrotoxanes as Epileptogenic Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . 192 8.4. Picrotoxanes as Tools in Neurobiological Research . . . . . . . . . . . . . . . . 192 Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 Combinatorial and Synthetic Biosynthesis in Actinomycetes . . . . . . . . . . . . . 211 Marta Luzhetska, Johannes Ha¨rle, and Andreas Bechthold 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211 2. Combinatorial Biosynthesis and Synthetic Biosynthesis . . . . . . . . . . . . . . . . . . 212 2.1. Achievements in Combinatorial Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . 213 2.2. Challenges for Combinatorial Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . 215 2.3. Synthetic Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 Author Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 239 Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259 Listed in PubMed Contributors Andreas Bechthold Institut fu¨r Pharmazeutische Wissenschaften, Lehrstuhl fu¨r Pharmazeutische Biologie und Biotechnologie der Albert-Ludwigs-Universita¨t Freiburg, Stefan-Meier-Strasse 19, 79104 Freiburg, Germany Born in 1978 in Cuddalore, India, Dr. (Mrs) Sajeli A. Begum studied for her M. Pharm. in Pharmaceutical Chemistry (2001) and performed a chemical investi- gation into the non-alkaloidal constituents of Solanaceous plants for her doctoral thesis. She received a Ph.D. in Medicinal Chemistry (2005) from Banaras Hindu University, Varanasi, India. She is a recipient of a Council of Scientific Industrial Research (CSIR) – Senior Research Fellowship, India, for her Ph.D. project and a Deutscher Akademischer Austausch Dienst (DAAD) Fellowship (2004) to pursue part of her doctoral research at Eberhard Karls Universita¨t, Tu¨bingen, in the group of Dr. Roderich Suessmuth. Since 2005, she has been working as an assistant professor in the Department of Pharmaceutics, Institute of Technology, Banaras Hindu University, and doing research on phytochemical constituents. Her prime research interests are centered on isolation, structure elucidation, chemical trans- formation, and pharmacological screening of bioactive natural products. In 2008, she visited the Indian Institute of Chemical Technology (IICT-CSIR), Hyderabad, India, through a INSA-Visiting Fellowship. ix Dr. Mahendra Sahai received his Master’s degree (Organic Chemistry) from the University of Gorakhpur in 1972. He joined the laboratory of Professor A.B. Ray in the Department of Medicinal Chemistry, IMS, Banaras Hindu University, Varanasi, India, for his Ph.D. work on the chemistry of withasteroids and other natural products. He obtained his Ph.D. in 1978. He continued his research work in the laboratory until 1981 as a Research Associate, at CSIR, New Delhi. He then joined the Weizmann Institute of Science, Israel, as a Postdoctoral Fellow of the Feinberg Graduate School and worked in the group of Professor Ehud Keinan for a period of three years in the area of organic synthesis until 1984. In 1984, Dr. Sahai joined the Department of Medicinal Chemistry of Banaras Hindu University as a lecturer and subsequently became professor in the year 2004. He is still working in the depart- ment in the same capacity. He was selected as Visiting Scientist at the TECHNION, Israel (1988–1990), and worked there on organic synthesis. He received a Centenary Memorial Fellowship of The Tokyo Institute of Technology, Japan, in the year 1992. He has worked mainly on the chemistry of natural products and has a total of 82 publications in reputed refereed journals. x