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Biomimetic Total Synthesis of Natural Products Biomimetic Total Synthesis of Natural Products Thesis submitted for the degree of Doctor of Philosophy Hiu Chun Lam Bsc (Hons.) Chemistry Department of Chemistry University of Adelaide Aug, 2017 To my family II Declaration I certify that this work contains no material which has been accepted for the award of any other degree or diploma in my name, in any university or other tertiary institution and, to the best of my knowledge and belief, contains no material previously published or written by another person, except where due reference has been made in the text. In addition, I certify that no part of this work will, in the future, be used in a submission in my name, for any other degree or diploma in any university or other tertiary institution without the prior approval of the University of Adelaide and where applicable, any partner institution responsible for the joint-award of this degree. I give consent to this copy of my thesis, when deposited in the University Library, being made available for loan and photocopying, subject to the provisions of the Copyright Act 1968. I also give permission for the digital version of my thesis to be made available on the web, via the University’s digital research repository, the Library Search and also through web search engines, unless permission has been granted by the University to restrict access for a period of time. I acknowledge the support I have received for my research through the provision of an Australian Government Research Training Program Scholarship Hiu Chun Lam Date III Acknowledgements First, I would like to thank my supervisor Dr. Jonathan George for his guidance during my PhD. I remember when I first joined the George group during my 2nd year of undergraduate studies, Jonathan personally trained me in the laboratory. His passion and enthusiasm in organic chemistry has influenced me greatly during my research studies, and his constant presence in the laboratory has motivated me to work hard. In addition, Jonathan is extraordinarily generous to send me to conferences in Europe and Australia, where I could present my work and learn chemistry. For all the reasons above, my PhD experience has been superb and it is my pleasure to work with Jonathan. Next, I would like to thank the George group, for being supportive throughout my PhD. The regular Wednesday group lunch and Friday drinking sessions have always been enjoyable. To Kevin, thank you for being my mentor. To Justin, thanks for your help with the hyperjapone project. To Henry, thank you for helping me with the verrubenzospirolactone project. I would also like to thank Aaron where we worked on the rhodonoid project together. To all the new additions of the George group (Aaron, Lauren, Stefania and Laura), I wish you all the best in your PhD. To the prodigy JP, I also wish you good luck in your future postgraduate studies. I would like to specifically thank Kevin and Justin, for their company on my roller coaster research journey. Their encouragement has always been helpful. I will cherish the good times we had inside and outside of the laboratory. I would like to thank Professor Andrew Abell to allow me to use his group’s HPLC and polarimeter. To Professor Chris Sumby, thank you for running all the single crystal X-ray crystallography. To the Sumby/Doonan group (particular Michael, Alex, Natasha and Rob), thanks for examining the crystals after we have recrystallized them in the laboratory. I would like to thank eResearch SA to grant my access to the supercomputer Tizard and the database for theoretical calculations. To Professor Greg Metha and Dr. David Huang and their groups, thank you for teaching me to perform the theoretical calculations. To Phil, thank you for running the NMR machines and mass spectrometers. To Dr. Justin Chalker from Flinders University, thank you for giving us chemicals for my research project. I would like to thank the University of Adelaide, it is my privilege to study for a PhD here. At the end, I would like to thank my family for their support, specifically my parents Kent and Daisy, my sister Elva for their unconditional love. IV Abstract This thesis describes several syntheses of natural products. The overall synthetic approach is to mimic how these secondary metabolites could be derived in Nature, where we aim to gain insights into the biosynthesis of these natural products from the syntheses. The first synthesis of hyperjapones A-I was achieved by an oxidative hetero-Diels-Alder reaction. The transformation of hyperjapone A to hyperajaponols A and C was achieved via an epoxidation and an acid-catalysed rearrangement cascade reaction, forming 4 stereocenters and 2 rings in 1 step. The first synthesis of verrubenzospirolactone was achieved from a Diels-Alder reaction of the polyene in water. Capillobenzopyranol, the proposed biosynthetic precursor of verrubenzospirolactone was also synthesized and converted into verrubenzospirolactone by mirroring our proposed biosynthetic pathway. The first synthesis of rhodonoids C and D, and murrayakonine D was achieved. The key biomimetic step was the acid catalysed rearrangement of an epoxide, forming 3 stereocenters and 2 rings in 1 step. The biomimetic total synthesis of yezo’otogirin C was achieved via an oxidative radical cyclization cascade reaction, forming 2 rings, 2 stereocenters, 1 C=C bond, 1 C-C bond and 1 C-O bond in 1 step. V List of abbreviations ºC degree Celsius Å Angstrom 1H Hydrogen-1 13C Carbon-13 18-crown-6 1,4,7,10,13,16-Hexaoxacyclooctadecane Ac acetyl AIBN azobisisobutyronitrile aq. aqueous atm atmospheric Bn benzyl br broad Bu butyl c concentration for specific optical rotation measurements CAN ceric ammonium nitrate cm-1 wavenumber conc. correlation spectroscopy CSA 1-(S)-(+)-10-camphorsulfonic acid DBU 1,8-diazobicycloundec-7-ene DDQ 2,3-dichloro-5,6-dicyano-para-benzoquinone DIBAL-H diisobutylaluminium hydride DMF dimethylformamide DMSO dimethyl sulfoxide dr diastereomeric ratio ESI electrospray ionization epi epimer equiv. equivalents Et ethyl g grams h hours HMBC heteronuclear multiple bond correlation spectroscopy HPLC high performance liquid chromatography HRMS high resolution mass spectrometry HSQC heteronuclear single quantum correlation spectroscopy VI Hz Hertz hν light i-Pr isopropyl IR infrared J coupling constant KHMDS potassium hexamethyldisilazide KO-tBu potassium tert-butoxide LDA lithium diisopropylamine m-CPBA meta-chloroperoxybenzoic acid Me methyl MHz megahertz min minutes Mp melting point Ms mesyl NBS N-bromosuccinimide n-BuLi n-butyllithium NMO N-methylmorpholine NMR nuclear magnetic resonance NOESY Nuclear Overhauser Effect Spectroscopy Nu nucleophile o-DCB 1,2-dichlorobenzene o-quinone methide ortho-quinone methide p-TsOH para-toluenesulfonic acid PCC pyridinium chlorochromate Pd2(dba)3 tris(dibenzylideneacetone)dipalladium (0) PDC pyridinium dichromate Pd/C palladium on activated carbon PhI(OAc)2 (Diacetoxyiodo)benzene PhMe toluene P(o-tol)3 Tri(o-tolyl)phosphine ppm part per million Rf retention factor VII Rh2[(R)-RTAD]4 tetrakis[(R)-(–)-(1-adamantyl)-(N- phthalimido)acetate]dirhodium (II) rt room temperature SN1 unimolecular nucleophilic substitution SN2 bimolecular nucleophilic substitution TBAF tetrabutylammonium fluoride TBAB tetrabutylammonium bromide TBAI tetrabutylammonium iodide TBDPS tert-butyldiphenylsilyl TBS tert-butyldimethylsilyl TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy TFA trifluoroacetic acid Tf trifluoromethanesulfonate THF tetrahydrofuran TLC thin layer chromatography TMS trimethylsilyl TPAP tetrapropylammonium perruthenate w/w mass percentage VIII Table of Contents Declaration ............................................................................................................................. III Acknowledgements ................................................................................................................ IV Abstract ................................................................................................................................... V List of abbreviations .............................................................................................................. VI Chapter 1 - General Introduction 1.1. Natural products synthesis ........................................................................................... 1 1.2. Biomimetic total synthesis of natural products .......................................................... 4 1.3. References ...................................................................................................................... 7 Chapter 2 - Biomimetic Total Synthesis of Hyperjapones A-I, and Hyperjaponols A and C 2.1. Introduction ................................................................................................................... 8 2.1.1. Diels-Alder reaction ..................................................................................................... 8 2.1.2. Chemistry of humulene (2.11) ..................................................................................... 9 2.1.3. Chemistry of caryophyllene (2.30) ............................................................................. 11 2.1.4. Isolation of hyperjapones and hyperjaponols ............................................................. 14 2.1.5. Proposed biosynthesis of hyperjapone A (2.49) and hyperjaponols A-C (2.54–2.56)15 2.2. Results and discussion ................................................................................................. 17 2.2.1. Synthesis of norflavesone (2.58) ...............................................................................
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