View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Helsingin yliopiston digitaalinen arkisto Synthesis of lignano-9,9'-lactones and rearrangement studies Barbara Raffaelli University of Helsinki Faculty of Science Department of Chemistry Laboratory of Organic Chemistry Finland Academic dissertation To be presented, with the permission of the Faculty of Science of the University of Helsinki, for public criticism in Auditorium A110 of the Department of Chemistry, A.I. Virtasen aukio 1, on November 3rd, 2012, at 12 o’clock noon. Helsinki 2012 Supervisor Professor Kristiina Wähälä Laboratory of Organic Chemistry Department of Chemistry University of Helsinki Finland Reviewers Professor Emeritus Erkki Kolehmainen Department of Chemistry University of Jyväskylä Finland Professor George W. Francis Department of Chemistry University of Bergen Norway Opponent Professor Scott A. Snyder Department of Chemistry Columbia University NY, USA ISBN 978-952-10-8280-1 (paperback) ISBN 978-952-10-8281-8 (PDF) Helsinki 2012 Unigrafia Oy 2 Abstract Lignans are found as naturally occurring compounds in plants, and also as metabolites in mammals. Due to their biological activity, lignans have attracted the interest of scientists from different areas like food chemistry, synthetic chemistry, and clinical chemistry. The research is very active, as evident by the number of publications related to this subject that are published annually. The present work focuses on the chemistry of certain classes of lignan, namely lignano-9,9'- lactones and their rearranged products. The literature review is based on the synthesis of lignano-9,9'-lactones and 7'-OH-lignano-9,9'-lactones. Both racemic and asymmetric protocols appeared as from year 2000 have been extensively reviewed. In addition, the literature concerning the rearrangement reaction of 7'-OH-lignano-9,9'-lactones has been discussed. The experimental section presents the development of a stereoselective synthesis to obtain 7'-hydroxylignanolactones. Subsequently, the known rearrangement reactions affecting hydroxylignanolactones are discussed. The stereochemistry of certain lignanolactones is a core part of this work and the findings of this study allowed the revision of certain controversial data found in the literature. For the first time, the X-ray structures of 7'-OH- lignano-9,9'-lactones were obtained. In addition, the synthesis of possible lignan metabolites is also presented. A summary of the available 1H NMR data for selected (7'S)- and (7'R)-OH- lignano-9,9'-lactones and for various lignano-9,7'-lactone stereoisomers has been made available in the Appendix section. 3 Acknowledgements This study was carried out in the Laboratory of Organic Chemistry, Department of Chemistry, University of Helsinki. I am greatly indebted to my supervisor, Professor Kristiina Wähälä, for introducing me to the challenging field of lignans and for believing in this project more than I often did. Her support, criticism, and encouragement have never waned during these years. I wish to express my deepest gratitude to Professor Emeritus Tapio Hase for the stimulating discussions and precious advice. As we were sharing an office for many years, he was always near-at-hand for guidance through the countless problems encountered in this project. Thanks to Professor Christine Cardin and Dr. Yu Gan for the flawless work done on my crystals. I am grateful to the reviewers of my thesis, Professor Emeritus Erkki Kolehmainen and Professor George W. Francis, and to the language editor, Dr. Jennifer Rowland, for their careful and most useful comments. I wish to thank Professor Scott A. Snyder for agreeing to act as my opponent at the public defence of this dissertation. Several friends and colleagues deserve recognition for contributing to this thesis. I want to thank Monika for the invaluable help in the laboratory but particularly at arm's length. Her collaboration has also been crucial while writing the articles and the thesis. Thanks to Paula for her criticism and suggestions, for lending me the desilylation protocol, and also for visiting me in Belgium; to Gudrun, for her priceless assistance in the laboratory and the long chats; to my co-authors Eija, Clément, and Antti; to Sampo, for helping me with the X-ray figures. Thanks also to Sari (office- and life-experiences-mate), Emilia, Tuija, Somdatta, Ullastiina, Kirsti, and all the other present and past members or sympathizers of the ‘Phyto-Syn’ group, who definitely made my life more interesting, both in and out of the laboratory. A very special thank to Taina for being such a good friend and trusting me beyond the misunderstandings. Many thanks to the staff of the Laboratory of Organic Chemistry, in particular to Dr. Jorma Matikainen, Seppo Kaltia, and Dr. Sami Heikkinen for their help with the MS and NMR spectroscopy; to Dr. Jorma Koskimies and Dr. Leena Kaisalo for their assistance in various chemistry-related matters; and Matti Keinänen for building the best ever TLC-chamber lids. 4 Many thanks to my dearest friends of the ‘Rompighiaccio’ group for being there, and to my friends and colleagues in Belgium. I feel lucky to have met you all in these years. Financial support from the Graduate School of Bioorganic Chemistry, the Research Foundation of the University of Helsinki, the Orion-Farmos Research Foundation, the Chancellor of the University of Helsinki, the Finnish Chemical Society, the Kemian Päivät Foundation, the Magnus Ehnroth Foundation, and the Emil Aaltonen Foundation is gratefully acknowledged. Vorrei ringraziare i miei genitori Silvana e Giovanni, per avermi dato sempre il loro supporto e la sicurezza di sapere che: “quando hai bisogno chiama!” Grazie a tutti gli altri componenti della mia famiglia in Italia e in particolare alla mia cara sorella Alice. Tutti voi sapete il bene che vi voglio e quanto siete importanti per me. Kiitos myös mieheni perheelle, erityisesti Marjalle, joka on avuliaasti hoitanut lapsiamme. The person I need to thank the most is my husband Mikko. Without him this thesis would have never been realized, and I mean it literally. His endless patience, support, and encouragement have substantially contributed to the work. He is always reminding me to look on the bright side and, at the same time, to keep my feet on the ground. There are not enough words to express my love and gratitude, also for taking care of our kids. Finally, the most special thanks to my daughters Linda and Lisa. I am proud of you for being so patient and accepting to give up some of the time I could have spent playing with you. You are the blessing of my life. Vantaa, October 2012 Barbara Raffaelli 5 6 “All truths are easy to understand once they are discovered; the point is to discover them.” Galileo Galilei A Linda e Lisa, le mie pucciole 7 List of original publications I. Barbara Raffaelli, Kristiina Wähälä and Tapio Hase. Asymmetric synthesis, stereochemistry and rearrangement reactions of naturally occurring 7'-hydroxylignano-9,9'-lactones. Org. Bio. Chem. 2006, 4, 331–341. II. Barbara Raffaelli, Monika Pohjoispää, Tapio Hase, Christine J. Cardin, Yu Gan and Kristiina Wähälä. Stereochemistry and rearrangement reactions of hydroxylignanolactones. Org. Bio. Chem. 2008, 6, 2619–2627. III. Barbara Raffaelli, Yu Gan, Christine Cardin, Monika Pohjoispää and Kristiina Wähälä. Crystal structures of two hydroxylignanolactone regioisomers. Manuscript (to be submitted) 2012. IV. Barbara Raffaelli, Eija Leppälä, Clément Chappuis and Kristiina Wähälä. New potential mammalian lignan metabolites of environmental phytoestrogens. Env. Chem. Lett. 2006, 4, 1–9. V. Barbara Raffaelli, Antti Hoikkala, Eija Leppälä and Kristiina Wähälä. Enterolignans. J. Chromatogr. B 2002, 777, 29–43. The published articles are reproduced in the printed version of this thesis with the kind permission of the publishers. 8 Abbreviations Ac .................... acetyl hr ..................... hour(s) acac ................. acetylacetonate IUPAC .............. International Union of Pure ACCN .............. azobis(cyclohexanecarbonitri- and Applied Chemistry le) LC .................... liquid chromatography AIBN ................ 2,2'-azobisisobutyronitrile LDA .................. lithium diisopropylamide Ar ..................... aryl LHMDS ............ lithium hexamethyldisilazide ATC ................. atom transfer carbonylation LN .................... lithium naphthalenide BBN ................. borabicyclo[3.3.1]nonane Me .................... methyl BINOL .............. 1,1-binaphthol MOM ................ methoxymethyl Bn .................... benzyl MS ................... mass spectrometry Bu, n-Bu ........... normal butyl NADH ............... reduced nicotinamide adenine t-Bu .................. tert butyl dinucleotide BV .................... Baeyer-Villiger NADPH ............ reduced nicotinamide adenine BVMO .............. Baeyer-Villiger monooxygena- dinucleotide phosphate se NMM ................ N-methylmorpholine CHMO .............. cyclohexanone NMO ................ N-methylmorpholine-N-oxide monooxygenase NMR ................ nuclear magnetic resonance CHP ................. cumene hydroperoxyde NOESY ............ nuclear overhauser effect CPMO .............. cyclopentanone spectroscopy monooxygenase PCC ................. pyridinium chlorochromate COSY .............. correlation spectroscopy PDC ................. pyridinium dichromate DABCO ............ 1,4-diazabicyclo[2.2.2]octane PFA .................. paraformaldehyde dba .................. dibenzylideneacetone