Design and Synthesis of Amine Building Blocks and - DiVA Portal PDF
Preview Design and Synthesis of Amine Building Blocks and - DiVA Portal
Design and Synthesis of Amine Building Blocks and Protease Inhibitors Susana Ayesa Alvarez Stockholm University ©SusanaAyesaAlvarez,Stockholm2008 ISBN978-91-7155-690-5 PrintedinSwedenbyUniversitetsserviceUS-AB,Stockholm2008 DepartmentofOrganicChemistry StockholmUniversity Tomyfamily Abstract The first part of this thesis addresses the design and synthesis of amine building blocks accomplished by applying two different synthetic procedures,bothofwhichweredevelopedusingsolid-phasechemistry. Chapter 1 presents the first of these methods, entailing a practical solid- phase parallel synthesis route to N-monoalkylated aminopiperidines and aminopyrrolidines achieved by selective reductive alkylation of primary and/or secondary amines. Solid-phase NMR spectroscopy was used to monitorthereactionsforwhichanewpulsesequencewasdeveloped. The second method, reported in Chapter 2, involves a novel approach to the synthesis of secondary amines starting from reactive alkyl halides and azides. The convenient solid-phase protocol that was devised made use of the Staudinger reaction in order to accomplish highly efficient alkylations of N-alkylphosphimineswithreactivealkylhalides. The second part of the thesis describes the design and synthesis of three classes of protease inhibitors targeting the cysteine proteases cathepsins S andK,andtheserineproteasehepatitisCvirus(HCV)NS3protease. Chapter 4 covers the design, solid-phase synthesis,and structure-activity relationships of 4-amidofurane-3-one P1-containinginhibitors ofcathepsinS and the effects of P3 sulfonamide groups on the potency and selectivity towards related cathepsin proteases. This work resulted in the discovery of highlypotentandselectiveinhibitorsofcathepsinS. Two parallel solid-phase approaches to the synthesis of a series of aminoethylamideinhibitorsofcathepsinKarepresentedin Chapter5. Finally, Chapter 6 reports peptide-based HCV NS3 protease inhibitors containing a non-electrophilic allylic alcohol moiety as P1 group and also outlines efforts to incorporate this new template into low-molecular-weight drug-likemolecules. List of Papers Thisthesisisbasedonthefollowingpapers,whicharereferredtointhetext bytheirRomannumerals: I. AnExpeditiousLibrarySynthesisofN-Monoalkylated Aminopiperidinesand–pyrrolidines SusanaAyesa,DimitrisArgyopoulus,TatianaMaltseva,Christian Sund,andBertilSamuelsson Eur.J.Org.Chem.,2004,2723-2737. II. AOne-Pot,Solid-PhaseSynthesisofSecondaryAminesfrom ReactiveAlkylHalidesandanAlkylAzide SusanaAyesa,BertilSamuelssonandBjörnClasson Synlett, 2008,1,97-99. III. Solid-PhaseSynthesisandSARof4-Amidofurane-3-oneInhibitors ofCathepsinS:theEffectofSulfonamidesatP3onPotencyand Selectivity SusanaAyesa,CharlottaLindquist,TatianaAgback,KurtBenkestock, BjörnClasson,IanHenderson,EllenHewitt,KatarinaJansson,Anders Kallin,DaveSheppardandBertilSamuelsson Submitted IV. PreparationandCharacterizationofAminoethylamideInhibitorsof theCysteineProteinaseCathepsinK SusanaAyesa,Jinq-MayChen,BjörnClasson,JoseGallego,Urszula Grabowska,IanHenderson,NarinderHeyer,TonyJohnson,Jussi Kangasmetsä,MarkLiley,MagnusNilsson,KevinParkes,Laszlo Rakos,MatthewJ.Tozer,andMichelleWilson Submitted V. InvestigationofAllylicAlcoholsintheP1PositionofInhibitorsof HepatitisC VirusNS3Protease SusanaAyesa,TatianaMaltseva,LaszloRakos,ElizabethHamelink, BjörnClasson,andBertilSamuelsson Manuscript Ihavealsocontributedtothefollowingarticle,whichisnotincludedinthis thesis.Thispublicationreportsfurther developmentoftheresearch describedinpaperV. VI. NovelpotentmacrocyclicinhibitorsofthehepatitisCvirusNS3 protease:UseofcyclopentaneandcyclopenteneP2-motifs Baeck,M.;Johansson,P.-O.;Waangsell,F.;Thorstensson,F.; Kvarnstroem,I.;Ayesa,S.;Waehling,H.t;Pelcman,M.l;Jansson,K.; Lindstroem,S.;Wallberg,H.;Classon,B.;Rydergaard,C.;Vrang,L.; Hamelink,E.;Hallberg,A.;Rosenquist,A.;Samuelsson,B. Bioorganic&MedicinalChemistry,2007,15(22),7184-7202 PapersIandIIwerereprintedwiththekindpermissionfromthepublishers. Abbreviations Ac acetyl APC antigen-presentingcells BAP boranepyridinecomplex BMD bonemassdensity BOC,Boc t-butoxycarbonyl Cha β-cyclohexylalanine CPMG Carr-Purcell-Meiboom-GillT -dependentspin-echosequence 2 COSY correlationspectroscopy DCM dichloromethane DIC diisopropylcarbodiimide DIEA N,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMF dimethylformamide DQF Double-quantumfilter EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ELSD evaporativelightscatteringdetector Fmoc 9-fluorenylmethyloxycarbonyl FTIR fouriertransformationinfraredspectroscopy h hour(s) HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl- methylene]-n-methylmethanaminiumhexafluorophosphonate N-oxide HBTU N-[(1H-benzotriazole-1-yl)-(dimethylamino)methylene]-N- methylmethanaminiumhexafluorophosphateN-oxide HCV hepatitisCvirus HIV humanimmunodeficiencyvirus HLA humanleukocyteantigen HMBC heteronuclearmultiplebondcorrelation HOBt 1-hydroxybenzotriazole HRMAS high-resolutionmagic-anglespinning HSQC heteronuclearsingle-quantumcorrelation HTS highthroughputscreening HPLC highpressureliquidchromatography Ii invariantchain IL interleukin K inhibitoryconstant/dissociationconstantforinhibitorbinding i LCMS liquidchromatographymassspectroscopy MeOH methanol MHC majorhistocompatibilitycomplex NMM 4-methylmorpholine NMP N-methylpyrrolidinone NMR nuclearmagneticresonance NS non-structural NS3 non-structuralprotein3 NTPase nucleosidetriphosphatase Nva norvaline PyBOP benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate RT roomtemperature SAR structure-activityrelationship SLP spinlockpulse SPE solid-phaseextraction RAPiD rationalapproachtoproteaseinhibitordesign TES triethylsilane TMOF trimethylorthoformate TMS trimethylsilyl TNFa tumornecrosisfactoralpha TFA trifluoroaceticacid TOCSY totalcorrelationspectroscopy
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