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New Reactions of Cyclic Oxygen, Nitrogen and Sulfur Acetal Derivatives

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New Reactions of Cyclic Oxygen, Nitrogen and Sulfur Acetal Derivatives New Reactions of Cyclic Oxygen, Nitrogen and Sulfur Acetal Derivatives Samuel Edward Mann Supervisor Dr. Tom Sheppard A thesis submitted to University College London in partial fulfilment of the requirements for the degree of Doctor of Philosophy Declaration I, Samuel Edward Mann confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. ………………………… i Abstract Abstract This thesis describes the development of new reactions of cyclic oxygen, nitrogen and sulfur acetal derivatives and their applications in a diverse range of synthetic organic and organometallic chemistry. Detailed herein are advances in three main areas of acetal chemistry, namely: studies towards a new methodology for the synthesis of medium ring heterocycles; the use of thioacetals as directing groups for the palladium-mediated oxidation of olefins; and multi-component reactions for the synthesis of drug-like heterocyclic compounds. A brief overview of the chemistry of cyclic acetal derivatives is given in the first chapter, followed by a chapter on each of the three areas investigated. Relevant introductory literature is reviewed at the beginning of each chapter. Firstly, the ring expansion chemistry of unsaturated cyclic oxygen, nitrogen and sulfur acetal derivatives was explored for the development of a new methodology for the synthesis of medium ring heterocycles. This methodology has thus far proved unsuccessful in the synthesis of medium rings, although several interesting and unusual transformations were observed, such as the unexpected formation of an intriguing bicyclic enaminium salt. The use of thioacetals as directing groups for the palladium-mediated oxidation of terminal olefins was also explored, leading to the evolution of a new methodology for the catalytic, regioselective formation of either vinyl or allylic acetates. Dithianes were shown to stabilise intermediates in the allylic oxidation pathway, allowing their structure elucidation and characterisation by low-temperature NMR spectroscopy and in one case X-ray crystallography. This enabled a detailed mechanistic study leading to the observation of two finely balanced, divergent reaction mechanisms. Finally, building upon previously unpublished results, a number of three and four- component reactions were investigated, giving drug-like -aminoamides; this methodology was applied to the synthesis of some medium ring heterocycles. ii Contents Contents Declaration i Abstract ii Contents iii Abbreviations v Acknowledgements vii 1. Introduction to the Chemistry of Cyclic Acetals 1.1 Cyclic Acetals as Protecting Groups 1 1.2 Asymmetric Induction with Cyclic Acetals 7 1.3 Reactions of Cyclic Acetals with Nucleophiles 11 1.4 Reactions of Cyclic Acetals with Electrophiles 15 1.5 Conclusions 20 2. Development of Ring Expansions of Acetals for Medium Ring Synthesis 2.1 Introduction 22 2.2 Design of Methodology 31 2.3 Synthesis of Unsaturated O, N- and S-Acetals 33 2.4 Results and Discussion 34 2.5 Conclusions and Future Work 45 3. Thioacetals as Directing Groups in Palladium-Mediated Oxidations 3.1 Introduction 48 3.2 Catalytic Oxidation of Olefins 75 3.3 Mechanistic Study 87 3.4 Pd-C -Complexes 94 3.5 Oxidation of Unsaturated Linear Thioethers 107 3.6 Aryl C-H Activation 109 3.7 Conclusions and Future Work 112 4. Isocyanide-Based Multi-Component Reactions of N, O-Acetals 4.1 Introduction 115 4.2 Objectives and Synthetic Rationale 121 iii Contents 4.3 Results and Discussion 123 4.4 Conclusions and Future Work 127 5. Experimental Section 5.1 General Methods 129 5.2 Experimental Procedures 130 6. References 185 Appendix A: 1H and 13C NMR Spectra of Palladium Complexes Appendix B: X-Ray Crystal Data (.cif) Files for Compounds 127, 314 and 402 iv Abbreviations Ac Acetyl acac Acetylacetonyl Ar Aryl Boc tert-Butyl carbamate Bu Butyl Bn Benzyl bpy 2,2’-Bipyridyl p-BQ p-Benzoquinone Bz Benzoyl CAN Ceric ammonium nitrate cat. Catalytic coll 2,4,6-Trimethylpyridyl Cp Cyclopentadienyl CSA Camphorsulfonic acid dba Dibenzylidene acetone DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-Dichloroethane DCM Dichloromethane de Diastereomeric excess DEAD Diethyl azodicarboxylate dec. Decomposition DET Diethyltartrate DFT Density functional theory DIBAL Diisobutylaluminium hydride DIEA Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP N,N-Dimethylaminopyridine DMBQ Dimethylbenzoquinone DMF N,N-Dimethylformamide DMM Dimethoxymethane dmphen 2,9-Dimethyl-1,10-phenanthroline DMSO Dimethylsulfoxide DPPA Diphenylphosphoryl azide E Electrophile ee Enantiomeric excess EDMS Ethyldimethylsilyl EPHP 1-Ethylpiperidine hypophosphite Et Ethyl eq Equivalents Grubbs I Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium HMBC Heteronuclear multi bond coherence HMPA Hexamethylphosphoramide HRMS High resolution mass spectrometry iPr Isopropyl LDA Lithium diisopropylamide LHMDS Lithium hexamethyldisilazide KHMDS Potassium hexamethyldisilazide Me Methyl MNBA 2-Methyl-6-nitrobenzoic anhydride m.p. Melting point v Abbreviations Ms Mesyl MW Microwaves n Integer number NBS N-Bromosuccinimide NMM N-Methylmorpholine NMR Nuclear magnetic resonance NOE Nuclear Overhauser enhancement Nu Nucleophile o- Ortho p- Para Ph Phenyl PMA Phosphomolybdic acid PhBQ Phenylbenzoquinone ppm Parts per million RCM Ring-closing metathesis rt Room temperature (19-22 C) t or tert Tertiary TBAF Tetrabutylammonium fluoride TBS tert-Butyldimethylsilyl Tf Triflyl TFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilyl Tol Tolyl UCL University College London UV Ultraviolet vi Acknowledgements First of all, I would like to thank my supervisor Dr. Tom Sheppard for giving me the opportunity to work on this project. As well as the motivation and continued support he has given me throughout my time in the group, his knowledge and enthusiasm have been a source of inspiration from the start. To everyone I’ve worked with over the last two years, I would like to say thank you for making my time at UCL absolutely unforgettable. Special shouts go to Fav, Lauren, Matt and Vincent for keeping me compos mentis on a day-to-day basis and for always being there to celebrate the good times (of which there have been many over the last two years). Os, Fil, Chris, Rhian, Rachel and Martin also deserve a big thank you for making the lab such an enjoyable place to spend my days. I am particularly grateful to Dr. Abil Aliev for his work on the DFT calculations, but also for his ability and willingness to help with pretty much anything NMR-related. A big thank you goes to Dr. Lisa Haigh for her help with mass spec analyses and to Dr. Graham Tizzard for X-ray crystal structures. I would also like to thank my second supervisor Dr. Jamie Baker and Dr. Claire Carmalt for their support and professionalism in facilitating my supervisor change and subsequent transfer to the Sheppard group. Finally and by no means least I would like to thank my friends and in particular my family for all their love and support over the last couple of years, without which the completion of this thesis would not have been even remotely possible. vii For my parents 1. Introduction to the Chemistry of Cyclic Acetals 1. Introduction to the Chemistry of Cyclic Acetals Derived from the condensation of two molecules of an alcohol with either an aldehyde or a ketone, the acetal moiety is composed of a gem-diether at an sp3 hybridised carbon atom.1 The terms acetal and ketal describe gem-diethers derived from aldehydes and ketones respectively, although both are often grouped under the former term. In the context of this thesis, the term oxygen, nitrogen or sulfur acetal derivative will serve to describe any gem-O, N- or S-disubstituted sp3 carbon atom. Some examples of naturally occurring and biologically important O, N- and S-acetal and hemiacetal derivatives are shown below in figure 1.1.2-10 OH O HO H HO O O Cl O N O CO2H HO OH O O O OH O -D-Glucose Mycorrhizin A (R)-MDMA (-)-Sarracenin antibiotic psychoactive Pitcher plant insect attractant NH O 2 HO CO H N N O N 2 OH O N N N O S N MeO O OH O O (-)-BCH-1230 Aclidinomycin A Pteridic acid A anti-HIV agent antibiotic plant growth promoter Figure 1.1 1.1 Cyclic Acetals as Protecting Groups Due to their greater stability to a range of basic, nucleophilic and redox conditions, cyclic acetals are most commonly used as protecting groups for their parent diols and carbonyl compounds.11 Formed by acid-catalysed condensation with acetone, acetonides are among the most common protecting groups for 1,2- and 1,3-diols.12 They are both easily prepared and readily cleaved under mildly acidic conditions, making them excellent protecting groups in the multi-step syntheses of molecules with sensitive functional groups. The 1 1. Introduction to the Chemistry of Cyclic Acetals preparation of acetonides derived from triols usually results in the 1,2-acetonide being favoured over the 1,3-derivative (scheme 1.1).13,14 OH a O O O HO 80% (5:1) OH O HO OH a OH OH O quant. (9:1) OH O O O OH OH a) p-TsOH (cat.), acetone, rt Scheme 1.1 The selective protection of 1,2- and 1,3-diols is central to carbohydrate chemistry and a number of elegant methods have therefore been developed for this purpose.15 For example, as with the linear triols discussed above, D-glucose undergoes selective 1,2-acetonation with acidified acetone to give the thermodynamically favoured diisopropylidene diacetal 1 (scheme 1.2).16 OH O OH a O H O O O 1 55% HO OH OH HO O a) H2SO4 (cat.), acetone, reflux Scheme 1.2 Under kinetic control however, the same monosaccharide selectively undergoes acetonation at the primary alcohol to give 1,3-acetonide 2 (scheme 1.3).17 Formation of acetonides by this method is often favoured over the use of acidified acetone as it is generally higher yielding and employs much milder reaction conditions.18 OH H O OAc O OH a O 2 95% O OAc HO OH H OH OAc o a) 2-Methoxypropene (2 eq), p-TsOH (cat.), DMF, 0 C, then Ac2O Scheme 1.3 2 1.
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