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Fundamental Studies on 2,4,6- Trichlorophenyl Sulfonate Esters

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Fundamental Studies on 2,4,6- Trichlorophenyl Sulfonate Esters University College London Fundamental Studies on 2,4,6- Trichlorophenyl Sulfonate Esters By Lynsey J. Geldeard Doctor of Philosophy Faculty of Mathematical and Physical Sciences Department of Chemistry Declaration The work described in this thesis is the work of the author and has not previously been submitted to this or any other university for any other degree. Lynsey Geldeard February 2009 Abstract This thesis describes the application of 2,4,6-trichlorophenylsulfonate esters in the synthesis of sulfonamides. The sulfonamide unit is an important structural motif due to its frequent occurrence in a range of pharmaceuticals, particularly antibiotics. Sulfonamides can be readily synthesised from pentafluorophenyl (PFP) sulfonate esters and as an expansion to this 2,4,6 trichlorophenyl (TCP) sulfonates have been developed. These have the added advantage of lower toxicity and reduced cost of trichlorophenol. TCP sulfonates can be synthesised directly from sulfonic acids via activation by triphenylphosphine ditriflate in moderate to excellent yields. These compounds can then be utilised in the synthesis of sulfonamides and suitable conditions for reactions with both simple aliphatic amines and more challenging anilines have been found. The differing reactivity’s of the TCP and PFP sulfonate esters have been exploited in selective sulfonamide formation. The greater stability of TCP sulfonate in comparison to PFP sulfonate also means that a broader range of transformations can be achieved in its presence. This has been shown particularly in the application of palladium chemistry to synthesise more elaborate TCP sulfonates. Also, the synthesis of novel amino acids have been targeted inorder to further demonstrate the stability of the group when performing more diverse reactions on remote sites in the molecule. Contents Acknowledgements 1 Abbreviations 2 Chapter One 4 Introduction 4 1.1 Sulfonamides as Potent Therapies for Disease 4 1.1.2 Sulfonamides as Anti-Bacterial Agents 5 1.1.3 Sulfonamides as Carbonic Anhydrase Inhibitors 6 1.1.4 Sulfonamides and Protease Inhibition 13 1.1.5 Other applications for sulfonamides 16 1.2 Sulfonamide Synthesis 17 1.2.1 PFP sulfonate esters 22 Chapter Two 30 Synthesis and Aminolysis of 2,4,6-Trichlorophenyl (TCP) Sulfonate Esters 30 2.1 Introduction 30 2.2 Synthesis of 2,4,6-Trichlorophenyl Sulfonate Esters 31 2.3 Aminolysis of Trichlorophenyl Sulfonate Esters 32 2.3.1 Microwave Conditions 32 2.3.2 Investigation of Bases 34 2.4 Selectivity 40 2.5 Conclusions 44 Chapter Three 46 Synthetic Manipulation of TCP Sulfonates 46 3.1 Introduction 46 3.2 Palladium Reactions 47 3.2.1 Suzuki-Miyaura Reactions 47 3.2.2 Heck Reactions 49 3.3 Dynamic Kinetic Resolution 52 3.3.1 Introduction 52 3.3.2 Towards the synthesis of TCP amino acids 59 3.3.3 Conclusions 67 Chapter Four 69 Towards the synthesis of β-methoxy amino acids 69 4.1 Introduction 69 4.1.1 Previous syntheses of β-methoxy amino acids 70 4.1.1 Halomethoxylation reaction 73 4.2 Towards the synthesis of β-methoxy amino acids 76 4.2.1 Asymmetric Halomethoxylation Reaction 77 4.3 Conclusions and Future Work 83 Experimental 85 General Experimental 85 Experimental for Chapter 2 86 Synthesis of 2,4,6 Trichlorophenyl Sulfonyl Esters 86 Aminolysis 93 Experimental for Chapter 3 125 Suzuki Reactions 126 Heck Reactions 133 DKR 136 Experimental for Chapter 4 142 References 147 Acknowledgements Firstly, I would like to thank my supervisor Prof. Steve Caddick for his encouragement, advice and support throughout my PhD and also my industrial supervisor Dr Duncan Judd for his invaluable advice, ideas and enthusiasm. I would like to thank GSK for the funding and the opportunity to work there for 3 months. Also thanks to Kirit Pancholi and Dr Clive Smith for all their help and advice during my time at Harlow. I would like to thank Dr Jon Wilden and Dr Richard Fitzmaurice for the help and assistance they have offered me throughout my PhD. I’m indebted to everyone in the Caddick group past and present and everyone in lab 230 in the KLB for their help and friendship. A special thanks goes to James Mok, Olivier Thominet, Jack Lee, Nick Callan, Mona Saadi, Pui Shan Pang, Alex Sinclair and Pavel Starkov for making my time at UCL an enjoyable experience. I would like to thank my family for their love and support. 1 Abbreviations ACC – Acetyl CoA carboxylase ATP – Adenosine triphosphate AZA – Acetazolamide BINOL – 1,1'-Bi-2-naphthol BTCEAD – Bis(2,2,2-trichloroethyl)azodicarboxylate Bu – Butyl BZA – Brinzolamide CA – Carbonic anhydrase CAI – Carbonic anhydrase inhibitor CARP – Carbonic anhydrase related proteins cGMP – Cyclic guanosine monophosphate CI – Chemical ionisation Cy – Cyclohexyl DBU – 1,8-Diazabicyclo[5.4.0]undec-7-ene DCM – Dichloromethane DCP – Dichlorophenamide de – Diastereomeric excess DKR – Dynamic kinetic resolution DMF – Dimethylformamide DNA – Deoxyribonucleic acid DZA – Dorzolamide ee – Enantiomeric excess EI – Electron ionisation ES – Electrospray Et – Ethyl EZA – Ethoxzolamide HIV – Human immunodeficiency virus HMPA – Hexamethylphosphoramide HPLC – High pressure liquid chromatography HRMS – High resolution mass spectrometry ICE – Interleukin -1β converting enzyme IL-1β – Interleukin -1β 2 IOP – Intraocular pressure IR – Infrared spectroscopy KHMDS – Potassium hexamethyldisilazide LCMS – Liquid chromatography mass spectrometry LiHMDS – Lithium hexamethyldisilazide LRMS – Low resolution mass spectrometry MP – Melting point MZA – Methazolamide NBS – N-Bromosuccinimide NHMDS – Sodium hexamethyldisilazide NMR – Nuclear magnetic resonance PABA – para -Aminobenzoic acid PC – Pyruvate carboxylase PFP – Pentafluorophenyl RNA – Ribonucleic acid SYNPHOS – [(5,6),(5',6')-bis(ethylenedioxy)biphenyl-2,2'-yl]bis(diphenylphosphine) TBAB – tetra -Butyl-ammonium bromide TBAC – tetra -Butyl-ammonium chloride TBAI – tetra -Butyl-ammonium iodide TBS – tert -Butyldimethylsilyl TCCA – Trichloroisocyanuric acid TCP – 2,4,6-Trichlorophenyl TCT – 2,4,6-Trichloro-[1,3,5]-triazine TFA – Trifluoroacetic acid THF – Tetrahydrofuran TLC – Thin layer chromatography TMGA – Tetramethylguanidinium azide Troc - 2,2,2-Trichlorethoxycarbonyl chloride Ts – Tosyl Z – Benzyloxycarbonyl 3 Chapter One Introduction 1.1 Sulfonamides as Potent Therapies for Disease Since the discovery of the first sulfonamide antibiotic prontosil and its active metabolite sulphanilamide ( 1) the importance and diversity of sulfonamide drugs has grown placing them at the forefront of drug design.1 Although initially exploited as antibiotics their activity has since been demonstrated to encompass diuretic, antitumour, antithyroid, hypoglycaemic and protease inhibitory activity. 1-5 N S O NH O S H O N NH2 HO O S O O S O NH2 X 2 8 S O Metalloprotease inhibitors Sulfathiazole HN H O N Cl O 3 N N NH O O 2 Indisulam O O S S S NH2 O NH 7 O S 2 Acetazolamide NH2 Cl 1 O Sulfanilamide O O OH HN O Ph 4 O Furosemide HN O O HO N S O O O S O N N NH H H 2 Cl 6 N Amprenavir H OCH3 5 Glibenclamide Figure 1 The main classes of therapeutic agents developed from sulfanilamide The development of many therapeutic agents has started with sulfanilamide ( 1) as the lead molecule resulting in the discovery of drugs with a varied spectrum of biological actions. This is epitomised by the antibacterial agent sulfathiazole ( 2), 1 the anticancer 4 sulfonamide indisulam ( 3), 6 the diuretic furosemide ( 4), 7 the hypoglycaemic agent glibenclamide ( 5), 8 the HIV protease inhibitor amprenavir ( 6), 9 the carbonic anhydrase inhibitor acetazolamide ( 7)2 or the metalloprotease inhibitors of type 8 (Figure 1). 10 1.1.2 Sulfonamides as Anti-Bacterial Agents Starting with the first recognised sulfonamide antibacterial, sulfanilamide, in 1935 sulfonamides were initially employed as antibiotics. Sulfonamides were shown to act as bacteriostatic agents, disrupting the synthesis of folic acid. 7 By mimicking para -aminobenzoic acid (PABA) they inhibit dihydropteroate synthetase, an enzyme vital in the eventual synthesis of folic acid (Scheme 1). Folic acid is essential for the synthesis of purine nucleotides for DNA and RNA and thus, sulfonamides act by preventing DNA replication and transcription and therefore cell growth. 11 Humans are unaffected as their cells do not synthesise folic acid but instead they obtain it from the diet, and it is brought through the cell membranes by a transport protein not possessed by bacteria. O O O OH HO N N N Dihydrofolic NH acid DNA PABA 2 H H2N N N Dihydrofolic acid H H Synthetase O N N OH Dihydropteroate synthetase H2N N N H H O O S O O O R N S N N R H H2N N N NH2 H H Scheme 1 Inhibition of the synthesis of folic acid The development of bacterial resistance to some sulfonamides has seen their use as antibacterials restricted in modern therapy. Even so, it is worth highlighting some of the sulfonamide antibiotics still in clinical use. Nowadays sulfonamide antibiotics are often used in combination with other drugs, for example, sulfamethoxazole ( 9, Figure 2) and trimethoprim are used together in the treatment of urinary tract infections, acting synergistically to block sequential steps in bacterial folic acid 5 metabolism.12 Sulfathiazole ( 2, Figure 2) is used in combination with sulfacetamide and sulfabenzamide in the treatment of vaginal bacterial infections. 13 Another antibacterial used today is silver sulfadiazine (10 , Figure 2), which has found applications as a treatment of toxoplasmic encephalitis in HIV-infected patients and as a topical treatment for severe burns, where its anti-microbial properties aid healing. 14-16 NH2 O O S O O O S S N N N N H S O Ag H N H N O H N 2 2 NN 9 2 10 Sulfamethoxazole Sulfathiazole Siver Sulfadiazine Figure 2 Sulfonamide antibiotics 1.1.3 Sulfonamides as Carbonic Anhydrase Inhibitors Carbonic anhydrases (CA) are ubiquitous metalloenzymes consisting of a single polypeptide chain co-ordinated around a zinc centre. In mammals 16 different CA isozymes or CA related proteins (CARP) have been identified and these have a broad tissue and subcellular distribution.
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