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SynthesisofHydantoin,Benzodiazepine‐andPiperazinedione‐FusedTricyclicCompoundLibrary
DimasPaz,Ph.D.WipfGroupResearchTopicSeminar
15January2011
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Hydantoin,Benzodiazepine‐andPiperazinedioneBiologicallyAcAve
TetrahedronLe,.2006,47,6099
Eur.J.Org.Chem.2005,610
Org.Biomol.Chem.2004,2,2415
Angew.Chem.Int.Ed.2003,42,2379
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TheseheterocyclesarepresentinavarietyofbiologicallyacIvecompounds.
Skeletonsimilartothoseoftricyclicthrombininhibitors.
Hydantoin,Benzodiazepine‐andPiperazinedioneFusedTricyclicCompound
OverviewandBiologicalImportance
Org.Biomol.Chem.,2004,2,13393
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Hydantoin,Benzodiazepine‐andPiperazinedioneScaffolds
ThestructureofpiperazinedioneisparIallyrelatedtodiketopiperazine‐basedinhibitorsofhumanhormone‐sensiIvelipase.
J.Med.Chem.2003,46,11204
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Hydantoin,Benzodiazepine‐andPiperazinedioneScaffolds
BenzodiazepinedionecontainsaprivilegedbenzodiazepineMoietythathasawiderangeofpharmaceuIcaluIliIes.
Synthesis2003,1707Chem.Rev.2003,103,893 5
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FluorousDiversity‐OrientedSynthesisofHydantoin,Benzodiazepine‐andPiperazinedione
CompoundLibrary
Eur.J.Org.Chem.2006,2055J.Comb.Chem.2006,8,687J.Comb.Chem.2009,11,452
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D.P.Curran.;Zhangandet.al.
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FluorousSynthesisAdvantages
FluoroussynthesisishighlyefficientsoluIon‐phasesynthesistechnology.Itemploysperfluoroalkyl(RF)groupsas“phasetags”tofacilitatereacIonmixtureseparaIon.
CharacterisIcs:
1Thistechnologyhasbeenappliedtoparallelandmixturesynthesisofsmallmolecules,pepIdes,oligosaccharides,andothersbiomolecules.
2FluorousmoleculescanbeseparatedbythefluorousaswellasconvenIonalmethodssuchaschromatography,disIllaIonandrecrystallizaIon.
3CanbemonitoredbyconvenIonalanalyIcalmethodssuchasTLC,HPLC,IRandNMR.
4GoodcompaIbilitywithothersyntheIctechniquessuchasmicrowaveandmulIcomponentreacIons.
Chem.Rev.2009,109,749Chem.Rev.2004,104,2531
Arkivoc2004,101Aldrichm.Acta2006,39,3
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SynthesisoftheBicycleProlineIntermediates
PreparaIonoffluorousaminoesters.
Eur.J.Org.Chem.2006,2055J.Comb.Chem.2006,8,687J.Comb.Chem.2009,11,452 Chem.Rev.2005,105,2765 8
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Synthesisoffluorousprolinebyone‐potthreecomponent[3+2]cycloaddiIonreacIon.
Eur.J.Org.Chem.2006,20559
SynthesisoftheBicycleProlineIntermediates
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StereochemistryofBicycleProlineIntermediateSingle‐CrystalX‐rayDiffracAon
Org.Le,.2001,3,3491
Eur.J.Org.Chem.2006,2055
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FluorousSynthesisofHydantoin
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StereochemistryofHydantoin–Single‐CrystalX‐rayDiffracAon
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Eur.J.Org.Chem.2006,2055
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FluorousSynthesisofBenzodiazepinedione
Eur.J.Org.Chem.2006,205513
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FluorousSynthesisofPiperazinedione
14J.Comb.Chem.2009,11,452
D.P.Curran.;Zhangandet.al.
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15J.Comb.Chem.2009,11,452
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FluorousSynthesisof90‐CompoundLibraryofPiperazinedione
J.Comb.Chem.2009,11,452 16
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SynthesisofFluorousProlineIntermediates
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Methyl–MethylSeries
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SynthesisofFluorousProlineIntermediates
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Methyl–PhenylSeries
J.Comb.Chem.2009,11,452
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SynthesisofFluorousProlineIntermediates
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Methyl–EsterSeries
J.Comb.Chem.2009,11,452
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SynthesisofFluorousProlineIntermediates
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Phenyl–MethylSeries
J.Comb.Chem.2009,11,452
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SynthesisofFluorousProlineIntermediates
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Phenyl–PhenylSeries
J.Comb.Chem.2009,11,452
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SynthesisofFluorousProlineIntermediates
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Phenyl–EsterSeries
J.Comb.Chem.2009,11,452
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Piperazinedione‐BiologicalAcAviAes
• 63compoundshavebeensubmieedtotheNIHrepositoryandevaluatedinseveralhigh‐throughputscreeningprogams.
• 6compoundsshowedacIviIesagainstSchistosomaMansoni.
• 2compoundshowedinhibitorsofBacillussubNlisSfpphosphopantetheinyltransferase(PPTase).
• 1compoundshowedacIveagainstParkinson’sdisease(5’UTRprotein).
hep://pubchem.ncbi.nlm.nih.gov/
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Piperazinedione‐BiologicalAcAviAes
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CurrentStrategyandObjecAves
• Synthesizedofapiperazinedione–compoundlibrary• TostorethecollecIonofcompoundsUPCMLD• Futurebiologicalassay
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CurrentWork
PreparaIonofthebicycleprolinederivaIve–Furylseries
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PreparaIonofthebicycleprolinederivaIve–Cinnamylseries
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Acknowledgements
• Dr.Wipf• Wipfgroupmembers• UniversityofPiesburghandCNPq(ConselhoNacionaldeDesenvolvimentoCienjficoeTecnológico)forFellowship
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