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Total Synthesis and Semi-Synthesis of Secondary Metabolites Isolated from the Fermentation of Amycolatopsis DEM30355

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Total Synthesis and Semi-Synthesis of Secondary Metabolites Isolated from the Fermentation of Amycolatopsis DEM30355 Total Synthesis and Semi-Synthesis of Secondary Metabolites Isolated from the Fermentation of Amycolatopsis DEM30355 by Stephanie Morton A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy July 2016 Acknowledgements Acknowledgements First and foremost, I thank my supervisor, Dr Michael Hall, for his direction, support and patience throughout the past four years. Thanks to all the members of Team MJH, past and present, who have made the research lab and office such a wonderful place to work. A special thanks to Dr Joseph Cowell for his help (in everything but grammar) and entertainment. In addition, I thank Dr Nick Allenby and Dr Bernhard Kepplinger, without whom this research would not have been realised, as well as other members of Demuris Ltd. Thanks also to Professor William McFarlane, Dr Paul Waddell and Dr Joe Gray for their assistance and advice in NMR spectroscopy, X-ray crystallography and mass spectrometry respectively. I especially thank Dr Corinne Wills for all of her help and support throughout my PhD. Finally, thanks to my family and friends for their unending encouragement. A special thanks to Chris (and his endless supply of tea and biscuits), for putting up with me and for giving me the motivation to complete this work. I Abstract Abstract Part 1 The novel antibacterial DEM30355/A 1 was isolated from the fermentation broth of Amycolatopsis DEM30355. We aimed to synthesise DEM30355/A 1 to determine the absolute stereochemistry and access DEM30355/A analogues. Using a Baylis-Hillman reaction between tricarbonyl 2 and ketone 3, we constructed the oxygenated quaternary centre at C4a of DEM30355/A 1 in adducts 4 and 5 (Figure 1). Figure 1: Left – structure of DEM30355/A 1. Right - Baylis-Hillman reactions to synthesise adducts 4 and 5 In an alternate route, a Diels-Alder reaction between diene 6 and dienophile 7 was used to generate cycloadducts 8 – 11, containing the A, B, C ring core of DEM30355/A 1 (Figure 2). Figure 2: Synthesis of cycloadducts 8 – 11 via a Diels-Alder reaction from isobenzofuran 6 Alongside this Diels-Alder route, we aimed to synthesise dienophile 12 from shikimic acid 13, to generate DEM30355/A 1 as a single enantiomer (Figure 3). Figure 3: Planned route to DEM30355/A 1 as a single enantiomer from shikimic acid 13 Following the synthesis of alkene 14, a key sterically directed dihydroxylation reaction gave diol 15, which was oxidised to ketone 16. Base-catalysed conversion of ketone 16 to dienophile 12 was attempted, however the product of this reaction is compound 17 (Figure 4). II Abstract Figure 4: Two-step synthesis of ketone 16 from alkene 14 and the subsequent reaction with base generating aromatic compound 17 Part 2 Antibacterial DEM30355/B2 18 was identified in the fermentation broth of A. DEM30355 (Figure 5). We targeted new drug leads via semi-synthetic modification of DEM30355/B2 18. Figure 5: Structure of DEM30355/B2 18 Following isolation of DEM30355/B2 18 via a key acid-base extraction, we successfully generated semi-synthetic DEM30355/B2 derivatives 19 and 20 (Figure 6). These compounds are undergoing investigation to assess their inhibition activity against drug-resistant bacterial dependent RNA polymerase. Figure 6: Structures of DEM30355/B2 derivatives 19 and 20 III Abbreviations List of Abbreviations Ea Activation energy Ar Aromatic AIBN Azobisisobutyronitrile B Base Bz Benzoyl Bn Benzyl dppf 1,1'-Bis(diphenylphosphino)ferrocene Boc Tert-butyloxycarbonyl br Broad calcd Calculated CAN Ceric ammonium nitrate CDMT 2-Chloro-4,6-dimethoxy-1,3,5-triazine COSY Correlated spectroscopy CSA Camphorsulfonic acid d Days 6deb 6-Deoxyerythronolide B DEBS 6-Deoxyerythronolide B synthase DMP Dess-Martin periodinane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DABCO 1,4-Diazabicyclo[2.2.2]octane DDQ 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone DCM Dichloromethane D-A Diels-Alder DMDO Dimethyldioxirane DMAC Dimethylaluminium chloride DMAP 4-(Dimethylamino)pyridine DMSO Dimethyl sulfoxide eq. Equivalents FDA Food and Drug Administration g Grams GI50 Half maximal cell proliferation concentration IC50 Half maximal inhibitory concentration HMBC Heteronuclear Multiple Bond Connectivity HSQC Heteronuclear Single Quantum Coherence HOMO Highest occupied molecular orbital HOBT Hydroxybenzotriazole IV Abbreviations HRMS High resolution mass spectrometry h hours IR Infrared lit. Literature LUMO Lowest unoccupied molecular orbital Mp Melting point mCPBA Meta chloroperoxybenzoic acid MeOH Methanol MRSA Methicillin-resistant Staphylococcus aureus Me Methyl mg Milligram mL Millilitre MIC Minimum inhibitory concentration min Minutes M Molar nBuLi n-Butyl lithium NBS N-bromosuccinimide NMO N-Methylmorpholine N-oxide NMR Nuclear magnetic resonance pTSA Para-toluene sulfonic acid PBS Phosphate-buffered saline Ph Phenyl PTAD 4-Phenyl-1,2,4-triazoline-3,5-dione PCC Pyridinium chlorochromate Rf Retention factor RNAP Ribonucleic acid polymerase Rifr Rifampicin resistant rt Room temperature NaHMDS Sodium bis(trimethylsilyl)amide TBDMS Tert-butyldimethylsilyl TBSOTf Tert-butyldimethylsilyl trifluoromethanesulfonate THF Tetrahydrofuran TMEDA Tetramethylethylenediamine TLC Thin layer chromatography TFA Trifluoroacetic acid TSE 2-(Trimethylsilyl) ethyl TASF Tris(dimethylamino)sulfonium difluorotrimethylsilicate TB Tuberculosis V Table of Contents CHAPTER 1. INTRODUCTION........................................................................................... 1 Natural Products as Drug Sources .......................................................................... 1 Clinically Used Unmodified Natural Products ......................................................... 4 Natural Products as Anticancer Drugs ..................................................................... 4 Natural Products as Antibacterial Drugs .................................................................. 5 Clinically Used Modified Natural Products .............................................................. 6 Modified Natural Products as Anticancer Drugs ....................................................... 6 Modified Natural Products as Antibacterial Drugs .................................................... 6 Increasing Isolated Yield of Natural Products ......................................................... 8 Penicillin: Darwinian Selective Breeding (‘Bio’-Synthesis) ........................................ 8 Taxol: Plant Cell Cultures (‘Bio’-Synthesis) .............................................................. 9 6-Deoxyerythronolide B: Heterologous Host Expression .......................................... 9 Discodermolide: Total Synthesis of Natural Products (‘Chem’-Synthesis) .............. 10 Generation of New Natural Product Inspired Drug Leads .................................... 12 Total Synthesis of Natural Products as a Route to Natural Product Analogues ...... 13 Precursor-Directed Biosynthesis of Natural Product Analogues (‘Chem-Bio’- Synthesis) ............................................................................................................................ 14 Mutasynthesis (‘Chem-Bio’ Synthesis) ................................................................... 16 Recombinant DNA Technology .............................................................................. 17 The Hidden Potential of Wild-Type Microorganisms ............................................ 18 Genome Mining ..................................................................................................... 18 Extremophiles and “Unculturables” ........................................................................ 19 Project Focus: Actinomycete Bacteria .................................................................. 19 Project Aims .......................................................................................................... 19 CHAPTER 2. ISOLATION AND SEMI-SYNTHESIS OF DEM30355/B2 ........................... 21 Introduction ............................................................................................................. 21 Global Impact of Tuberculosis................................................................................ 21 Treatment of Tuberculosis ..................................................................................... 21 Development of Rifampicin 65 ............................................................................... 22 Project Background ................................................................................................ 24 VI Table of Contents Introduction to DEM30355/B2 ................................................................................ 24 Mode of Action of Rifampicin 65 ............................................................................ 25 Comparison of DEM30355/B2 73 and Rifampicin 65 ............................................. 26 Project Aims .......................................................................................................... 26 Results and Discussion .......................................................................................... 28 Structural Assignment of DEM30355/B2 73 ........................................................... 28 Isolation of DEM30355/B2 73 from the Crude Isolate of Amycolatopsis DEM30355 .. ............................................................................................................................. 36 Structure Activity Relationship Studies of the Rifamycins....................................... 38 Planned
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