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 94 Progress in the Chemistry of Organic Natural Products Authors: S.S. Ebada, N. Lajkiewicz, J.A. Porco Jr, M. Li-Weber, and P. Proksch M.A.R.C. Bulusu, K. Baumann, and A. Stuetz R.I. Misico, V.E. Nicotra, J.C. Oberti, G. Barboza, R.R. Gil, and G. Burton 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. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machines or similar means, and storage in data banks. # 2011 Springer-Verlag/Wien SpringerWienNewYork is a part of Springer Science þ Business Media springer.at Product Liability: The publisher can give no guarantee for the information contained in this book. This also refers to that on drug dosage and application thereof. In each individual case the respective user must check the accuracy of the information given by consulting other pharmaceutical literature. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Typesetting: SPI, Chennai Printed on acid-free and chlorine-free bleached paper SPIN: 80022757 With 45 (partly coloured) Figures and 4 coloured Plates ISSN 0071-7886 ISBN 978-3-7091-0747-8 e-ISBN 978-3-7091-0748-5 DOI 10.1007/978-3-7091-0748-5 SpringerWienNewYork Contents Contributors ............................................................... ix Chemistry and Biology of Rocaglamides (¼ Flavaglines) and Related Derivatives from Aglaia Species (Meliaceae) .............. 1 Sherif S. Ebada, Neil Lajkiewicz, John A. Porco Jr., Min Li-Weber, and Peter Proksch 1. Introduction .............................................................. 2 2. Structural Classification of Rocaglamides and Related Compounds ............................................................... 5 2.1. Rocaglamide Derivatives ........................................... 5 2.2. Aglain Derivatives ................................................. 12 2.3. Aglaforbesin Derivatives ........................................... 17 2.4. Forbagline Derivatives ............................................. 18 3. Biosynthesis of Rocaglamides and Related Metabolites ............... 20 4. Pharmacological Significance of Rocaglamides and Related Compounds .............................................................. 23 4.1. Insecticidal Activity ................................................ 23 4.2. Anti-inflammatory Activity ........................................ 26 4.3. Anticancer Activity ................................................ 28 5. Chemical Synthesis of Cyclopenta[b]benzofurans ..................... 34 5.1. First Approaches to the Synthesis of Rocaglamides .............. 34 5.2. The First Total Synthesis of Rocaglamide . ........................ 36 5.3. Syntheses of Rocaglamide and Related Natural Products ......... 37 5.4. New Approaches to Rocaglamide and Related Natural Products ................................................... 39 5.5. Syntheses of Silvestrol ............................................. 44 5.6. Development of Rocaglates and Analogues as Therapeutic Agents .............................................................. 47 6. Concluding Remarks .................................................... 51 References .. ................................................................ 51 v vi Contents Chemistry of the Immunomodulatory Macrolide Ascomycin and Related Analogues .................................................... 59 Murty A.R.C. Bulusu, Karl Baumann, and Anton Stuetz 1. Introduction ............................................................. 59 1.1. Ascomycin and Related Natural Products . ........................ 60 1.2. Ascomycin Derivatives, a Novel Class of Anti-inflammatory Compounds ......................................................... 62 1.3. Structural Features of Ascomycin ................................. 66 2. Synthesis Aspects ....................................................... 70 2.1. Synthesis of the Four Diastereomeric “Furano-Ascomycins” ..... 70 2.2. Synthesis of 13C Labelled Ascomycin ............................. 72 2.3. Reactivity of the Binding Domain ................................. 75 2.4. Modifications in the Effector and Cyclohexyl Domains .......... 94 3. Summary ............................................................... 116 References .. ............................................................... 118 Withanolides and Related Steroids ..................................... 127 Rosana I. Misico, Viviana E. Nicotra, Juan C. Oberti, Gloria Barboza, Roberto R. Gil, and Gerardo Burton 1. Introduction ............................................................ 128 2. Withanolides in the Plant Kingdom ................................... 129 2.1. Solanaceous Genera Containing Withanolides .................. 129 2.2. Non-Solanaceous Genera Containing Withanolides ............. 132 3. Classification of Withanolides ......................................... 132 3.1. Withanolides with a d-Lactone or d-Lactol Side Chain ......... 132 3.2. Withanolides with a g-Lactone Side Chain ...................... 134 4. Withanolides with an Unmodified Skeleton ........................... 135 4.1. The Withania Withanolides ...................................... 135 4.2. Other Withanolides with an Unmodified Skeleton .............. 143 5. Withanolides with Modified Skeletons ................................ 157 5.1. Withanolides with Additional Rings Involving C-21 ........... 157 5.2. Physalins and Withaphysalins ................................... 163 5.3. Withanolides Containing an Aromatic Ring and Related Steroids ............................................. 168 5.4. Withanolides with a g-Lactone Side Chain ...................... 172 5.5. 18-Norwithanolides .............................................. 181 5.6. Spiranoid Withanolides at C-22 ................................. 184 6. Chemical and Bio-transformations of Withanolides .................. 185 6.1. Chemical Transformations ....................................... 186 6.2. Photochemical Transformations ................................. 188 6.3. Biotransformations ............................................... 189 7. Biological Activities of the Withanolides ............................. 192 7.1. Insecticidal Activities ............................................ 193 Contents vii 7.2. Phytotoxic Activities ............................................. 196 7.3. Antiparasitic Activities ........................................... 197 7.4. Antimicrobial Activities ......................................... 199 7.5. Anti-inflammatory and Glucocorticoid Related Activities ...... 200 7.6. Cancer-Related Activities ........................................ 203 7.7. CNS-Related Activities .......................................... 208 8. Chemotaxonomic Considerations ...................................... 209 8.1. Tribe Physaleae .................................................. 210 8.2. Tribes Hyoscyameae, Lycieae, and Solaneae ................... 213 8.3. Tribe Datureae ................................................... 213 8.4. Genera with Uncertain Positions in the Solanaceae Taxonomic System ............................................... 213 References .. ............................................................... 216 Author Index ............................................................. 231 Subject Index ............................................................. 249 Listed in PubMed . Contributors Gloria Barboza Departamento de Farmacia and IMBIV (CONICET), Facultad de Ciencias Quı´micas, Universidad Nacional de Co´rdoba, Ciudad Universitaria, Co´rdoba 5000, Argentina, [email protected] Karl Baumann Novartis Institutes for BioMedical Research Vienna, Muthgasse 11/2, A-1190, Vienna, Austria Murty A.R.C. Bulusu Novartis Institutes for BioMedical Research Vienna, Muth- gasse 11/2, A-1190, Vienna, Austria Gerardo Burton Departamento de Quı´mica Orga´nica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabello´n 2, Buenos Aires C1428EGA, Argentina, [email protected] Sherif S. Ebada Institute of Pharmaceutical Biology and Biotechnology, Heinrich-Heine University of Duesseldorf, Universitaetsstrasse 1, D-40225, Duesseldorf, Germany; Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity 1, 11566 Cairo, Egypt, [email protected] Roberto R. Gil Department of Chemistry, Carnegie Mellon University, 4400 Fifth Ave Pittsburgh, PA 15213, USA, [email protected] Neil Lajkiewicz Department of Chemistry and Center for Chemical Methodology and Library Development (CMLD-BU), Boston University, Commonwealth Avenue 590, Boston,