Towards the Total synthesis of Phacelocarpus- 2-pyrone A: Novel 2-pyrone chemistry Michael J. Burns Supervisors: Prof. Ian Fairlamb and Prof. Richard Taylor 2010 Authors Declaration I declare that all of the work detailed within this thesis is my own, and that any material not my own is clearly referenced or acknowledged in the main body of the text. All work was conducted between October 2006 and May 2010. Michael John Burns 1st June 2010 i Contents Authors Declaration i Acknowledgements iv Abstract v Abbreviations vi Chapter 1: Introduction 1.1 − Introduction to natural products 1 1.2 – Introduction to pyrones and natural products containing the 3 pyrone motif 1.3 – Introduction to 1,4-skipped dienes and natural products 8 containing the 1,4-skipped diene motif 1.4 – Introduction to palladium catalysis in natural product synthesis 11 1.5 – Introduction to phacelocarpus pyrones 13 1.6 – RSA of phacelocarpus-2-pyrone A 15 1.7 – Proposed forward synthesis of phacelocarpus-2-pyrone A 16 1.8 – Aims and objectives 19 Chapter 2: Synthetic studies towards phacelocarpus-2-pyrone A 2.1 – Suzuki-Miyaura cross-coupling reactions 20 2.1.1 – Suzuki-Miyaura cross-coupling reactions of benzyl bromides 2.1.2 – Suzuki-Miyaura cross-couplings of prenyl and terpenyl substrates 2.2 – Initial studies towards phacelocarpus-2-pyrone A 23 2.2.1 – Alkylation/ lithiation strategy to AB fragment 2.2.2 – Synthesis of fragment B 2.2.3 – Synthesis of AB fragment 2.2.4 – Synthesis of fragment C 2.2.5 – Buchwald-Hartwig etherifications 2.2.6 – Synthesis of functionalised vinyl ethers 2.3 – Revised retrosynthetic analysis and forward synthesis 42 2.3.1 – Revised retrosynthetic analysis 2.3.2 – Synthesis of EA and EAB fragments 2.4 – Further revised retrosynthetic analysis and forward synthesis 56 2.4.1 – Revised retrosynthetic analysis 2.4.2 – Synthesis of the HA fragment ii 2.4.3 – Cross-coupling reactions of the HA fragment 2.4.4 – Synthesis of the HAB and HAB ′ fragments 2.5 – Synthesis of macrocyclic 2-pyrones 71 2.6 – Conclusions and future work 79 Chapter 3: Catalytic Intramolecular C-H arylation of 2-pyrones 3.1 – Reaction discovery and optimisation 83 3.2 – Reaction Scope 88 3.3 – Stoichiometric studies 97 3.4 – Conclusions and future work 107 Chapter 4: Natural product synthesis experimental 3.1 – General experimental details 109 3.2 – General procedures 109 3.3 – Characterisation data 110 Chapter 5: Intramolecular C-H arylation of 2-pyrones experimental 5.1 – General experimental details 158 5.2 – General procedures 158 5.3 – Characterisation data 159 References 187 Appendices Appendix 1 – Reaction optimisation tables 195 Appendix 2 – X-ray diffraction data table 201 Appendix 3 – Published Papers 202 iii Acknowledgements This thesis would not have been possible without the help and support of many people. It is difficult to mention all the people who have made such a difference to me during this period of my life, although there are a number who must be mentioned. First and foremost, I would like to thank my supervisors Ian and Richard for all the help, advice and encouragement they have given me over the last 3 ½ years. In particular to Ian who has kept me focused and greeted every, “I’ve had an idea” with (in addition to a wry smile) critical analysis and open discussion, from which I have learnt a great deal. I would also like to thank my CASE supervisors Drs. Mark York and Zoran Rankovic, and all the people working at the Newhouse site of Organon/Schering- Plough/Merck (the name keeps changing!) who made my placement there both intellectually stimulating and enjoyable. I need to thank the EPSRC for their funding, without which this work would never have started. In addition, I am in debt to the technical staff who have helped me throughout – Heather, Ralph and Dave for their NMR expertise, Trevor and Ben for running all my mass spectra and Adrian and Rob for running the crystallography. I must also thank all the friends I have made during my time in York. In particular both the Fairlamb and Taylor groups past and present who have made my time so enjoyable. I would also like to give a special mention to those who helped most during the beginning (Anant and Ben) whilst I was finding my feet, those who have been with me the whole way through (Tony, Tom, Jon, Johnny, Russ and Al) and those who have provided me with a welcome distraction on a regular basis (Stu, Rob and Quentin). Finally, I must thank those whose love and support means the most to me – to my Mum, Dad and Deborah who have always had faith in me, and to Kathryn who has put up with me and always been there when needed – I dedicate this thesis to you. iv Abstract This thesis describes the progress made towards the synthesis of the natural product phacelocarpus-2-pyrone A and the development of novel synthetic methodology for the synthesis of functionalised 2-pyrones. Initial studies focused on the synthesis of the natural product and the applications of Pd-catalysed cross-coupling reactions using the interesting palladium catalyst, CatCat. O O Br PPh3 O O Pd Ph3P N O CatCat Phacelocarpus-2-pyrone A Key findings in the studies towards the natural product include: i) the synthesis of two 6-alkyl-4-hydroxy-2-pyrone intermediates suitable for providing a synthetic platform for future work; ii) the first synthesis of a 2-pyrone bound vinyl ether; iii) the synthesis of a 19 membered macrocycle containing 2-pyrone and 1,4-en-yne functionality. O 4 steps O HO 2 examples HO R O O O 5 steps O Br HO O O O O O Grubbs II (10 mol %) DCM, 40 oC, 16 h O O (80%) Co (CO) 2 6 Co2(CO)6 In addition, the first Pd-catalysed intramolecular C-H arylation of a 2-pyrone has been developed and applied to a number of substrates. Pd2(dba-4,4'-OMe)3 (1 mol%), O O PPh3 (4 mol%), Cs2CO3 (3 eq.), X THF, 80 °C, 18 h O R' O 14 examples R' O R O R Abbreviations v Ac Acetyl Acp Acyl carrier protein AIBN Azobisisobutyronitrile app. Apparent aq. Aqueous Ar Aryl n-BuLi n-butyl lithium t-BuLi t-butyl lithium ca. Circa cat. Catalytic CI Chemical Ionisation cm -1 Wavenumber CoA Co-enzyme A COSY Correlated Spectroscopy CM Cross metathesis CMD Concerted metallation-deprotonation cp 1,3-Cyclopentadiene d (NMR) Doublet 13 δC Chemical shift for C carbon NMR spectroscopy 1 δH Chemical shift for H proton NMR spectroscopy dba E,E-Dibenzylidene acetone DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DEAD Diethyl azodicarboxylate DIAD Diisopropyl azodicarboxylate DIBAL-H Diisobutyl aluminium hydride DIC N,N ′-Diisopropylcarbodiimide DIPEA Diisopropylethylamine DMAP 4-(Dimethylamino)pyridine DME 1,2-Dimethoxyethane DMF N,N -Dimethylformamide DMP Dess Martin periodinane DMSO Dimethyl sulfoxide dppp 1,3-Bis (diphenylphosphino)propane vi Et Ethyl Ether Diethyl ether eq. Equivalents ESI Electrospray ionisation (mass spectrometry) FGI Functional group interconversion g (Prefix) Gram h Hours HMDS Hexamethyldisilazane HMPA Hexamethylphosphoramide HMQC Heteronuclear multiple quantum coherence HRMS High resolution mass spectrometry Hz Hertz IR Infrared (spectroscopy) IPA Isopropyl alcohol J Coupling constant in Hertz KHMDS Potassium hexamethyldisilazide l Litre LDA Lithium diisopropylamide LIFDI Liquid Injection Field Desorption/Ionisation m (NMR) Multiplet m (Prefix) Milli M (Prefix) Mega Me Methyl mol mole Ms Mesylate MS Mass spectroscopy MTBD N-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene mw Microwave m/z Mass to charge ratio NADP Nicotinamide adenine dinucleotide phosphate n (Prefix) Nano NOE Nuclear Overhauser effect NOESY Nuclear Overhauser effect spectroscopy O.A. Oxidative Addition vii p (NMR) Pentet Pet ether Petroleum ether (boiling fraction 40-60 ºC) PFP Pentafuorophenyl Pin Pinacol Piv Pivalate pK a Acid dissociation constant ppm Parts per million PTSA para -Toluenesulfonic acid q (NMR) Quartet RCM Ring closing metathesis R.E. Reductive elimination RSA Retrosynthetic analysis s (NMR) Singlet t (NMR) Triplet TBAF Tetrabutylammonium fluoride TBDMS Tertiarybutyldimethylsilane TEA Triethylamine Tf Triflate TFA Trifluoroacetic acid TFAA Trifluoroacetic acid anhydride THF Tetrahydrofuran TIPS Triisopropylsilyl TLC Thin layer chromatography TMEDA N,N,N ′,N ′-Tetramethylethylenediamine TMS Trimethylsilane Ts Tosylate UV Ultra violet Vis Visible µ (Prefix) Micro viii Chapter 1: Introduction 1.1 Introduction to natural products Natural products have formed the basis of medicine for many hundreds of years. It is well documented in historical literature with examples dating back to the ancient Egyptians, who used tea brewed from willow bark to treat conditions such as fever. 1 The analgesic effect of this treatment is now known to have originated from the medicinal properties of salicylic acid ( 1), a natural product found within willow bark. Subsequently a more potent form of 1 was developed, namely acetylsalicylic acid (more commonly known as Aspirin) one of the biggest selling pharmaceutical products in today’s market. 1 Other molecules can be found throughout nature which posess medicinal properties, such as quinine ( 2) (a treatment for malaria). 1 Natural products are usually in very limited supply, and in some cases as little as a few milligrams of the desired product can be isolated from a kilogram of biological material. As a result, the harvesting of natural products from nature rarely represents a feasible supply of such compounds, however the overexpression of the relevant gene in bacteria, such as E. coli , and subsequent fermentation can provide large scale quantities. 2 Unfortunately, the fermentation approach is not feasible for the screening of large numbers of natural products and has consequently resulted in the development of natural product synthesis as one of the key areas of research in organic synthesis.