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Table of contents
I ACKNOWLEDGMENTS
III RESUME
V ABSTRACT
ABBREVIATIONS
FRENCH SUMMARY
1 GENERAL INTRODUCTION
I. BIBLIOGRAPHIC PART
I.1 THE MICHAEL ADDITION
I.1.1 HISTORY OF THE MICHAEL ADDITION
I.1.2 MECHANISM OF THE MICHAEL ADDITION
I.1.3 ENANTIOSELECTIVE MICHAEL ADDITION
I.2 ORGANOCATALYTIC ENANTIOSELECTIVE MICHAEL ADDITION OF 1,3 DICARBONYL SUBSTRATES
I.2.1 ORGANOCATALYSIS: DIFINITION AND HISTORICAL BACKGROUND
I.2.1.1 SIGNIFICANCE OF ORGANOCATALYSIS
I.2.1.2 DEFINITION OF ORGANOCATALYSIS
I.2.1.3 HISTORY OF ORG ANOCATALYSIS
I.2.1.4 DIFFERENT TYPES OF ORGANOCATALYSIS
I.2.2 THE MICHAEL ADDITION OF 1,3 DICARBONYLS : A VERY CONVENIENT P LATFORM FOR ENANTIOSELECTIVE ORGANOCATALYSIS
I.2.2.1 COVALENT ACTIVATION
I.2.2.2 NON COVALENT ACTIVATION
I.2.2.3 BIFUNCTIONAL ORGANOCATALYSTS
I.2.2.4 TRIFUNCTIONAL ORGANOCATALYSTS
I.2.2.5 PHASE TRANSFER CATALYSIS
I.3 DOMINO AND MULTICOMPONENT REACTIONS BASED ON THE MICHAEL ADDITION OF 1,3 DICARBONYL SUBSTRATES
I.3.1 ENANTIOSELECTIVE DOMINO REACTIONS BASED ON THE MICHAEL ADDITION OF 1,3 DICARBONYL SUBSTRATES
I.3.1.1 IMINIUM ENAMINE ACTIVATION MODE
I.3.1.2 IMINIUM ACTIVATION COMBINED WITH OTHER TRANSFORMATIONS
I.3.1.3 NON COVALENT ACTIVATION MODES
I.3.2 NON ENANTIOSELECTIVE MULTICOMPONENT REACTIONS BASED ON THE MICHAEL ADDITION OF 1,3 DICARBONYL SUBSTRATES
I.3.3 ORGANOCATALYTIC ENANTIOSELECTIVE MULTICOMPONENT REACTIONS BASED ON THE MICHAEL ADDITION OF 1,3 DICARBONYL SUBSTRATES
I.4 SUMMARYSUMMARY
II. ORGANOCATALYSTORGANOCATALYST–CONTROLLED CHEMOSELECONTROLLED CHEMOSELECTIVE CTIVE THREETHREE–COMPOCOMPONENT REACTIONSNENT REACTIONS
II.1 SELECTIONSELECTION OFOF SUBSTRATESSUBSTRATES ANDAND SYNTHESISSYNTHESIS OFOF RACEMICRACEMIC PRODUCTPRODUCT
II.2 ORGANOCATALYSTORGANOCATALYST–CONTROLLEDCONTROLLED CHEMODIVERGENTCHEMODIVERGENT THREETHREE–COMPONENTCOMPONENT REACTION:REACTION: PRELIMINARYPRELIMINARY RESULTSRESULTS
II.2.1 CATALYST SCREENINGCATALYST SCREENING
II.2.1.1 IMINIUM/ENAMINEIMINIUM/ENAMINE–TYPE ACTIVATIONTYPE ACTIVATION
II.2.1.2 NONNON–COVALENT ORGANOCATALYSTSCOVALENT ORGANOCATALYSTS
II.2.2 STUDY OF THE RELATIVE CONFIGURATIONSTUDY OF THE RELATIVE CONFIGURATION
II.2.2.1 BRIDGED BICYCLEBRIDGED BICYCLE
II.2.2.2 FUSED BICYCLEFUSED BICYCLE
II.3 CONCLUSIONSCONCLUSIONS
III. ORGANOCATALYTIC ENANORGANOCATALYTIC ENANTIOSELECTIVE MULTICOTIOSELECTIVE MULTICOMPONENT MPONENT SYNTHESIS OF PYRROLOSYNTHESIS OF PYRROLOPIPERAZINESPIPERAZINES
III.1 CATALYSTCATALYST SCREENINGSCREENING
III.1.1 IMINIUM/ENAMINEIMINIUM/ENAMINE–TYPE ACTIVATIONTYPE ACTIVATION
III.1.2 BIFUNCTIONAL ORGANOCATALYSTBIFUNCTIONAL ORGANOCATALYST
III.2 OPTIMIZATIONOPTIMIZATION OFOF THETHE REACREACTIONTION CONDITIONSCONDITIONS
III.2.1 OPTIMIZATION OF THE TEMPERATUREOPTIMIZATION OF THE TEMPERATURE
III.2.2 OPTIMIZATION OF THE SOLVENTOPTIMIZATION OF THE SOLVENT
III.2.3 ADDITIVES AND COMPARISION WITH THE SEQUENTIAL REACTIONADDITIVES AND COMPARISION WITH THE SEQUENTIAL REACTION
III.3 SCOPESCOPE OFOF THETHE REACTIONREACTION
III.3.1 SCOPE OF βSCOPE OF β–KETOESTERSKETOESTERS
III.3.1.1 VARIATION OF THE ESTER SUBSTITUENTVARIATION OF THE ESTER SUBSTITUENT
III.3.1.2 VARIATION OF THE KETONE SUBSTITVARIATION OF THE KETONE SUBSTITUENTUENT
III.3.1.3 USE OF CYCLIC USE OF CYCLIC ββ–KETOESTERSKETOESTERS
III.3.2 SCOPE OF α,βSCOPE OF α,β–UNSATURATED ALDEHYDESUNSATURATED ALDEHYDES
III.3.2.1 ββ–AROMATIC ENALSAROMATIC ENALS
III.3.2.2 ββ–HETEROAROMATIC ENALSHETEROAROMATIC ENALS
III.3.2.3 ββ–ALKYL ENALSALKYL ENALS
III.3.2.1 (E)(E)–ETHYL 4ETHYL 4–OXOBUTOXOBUT–22–ENOATEENOATE
III.3.3 SCOPE OF SCOPE OF NN–(2(2–AMINOETHYL)PYRROLESAMINOETHYL)PYRROLES
III.3.3.1 PREPARATION OF THE STARTING MATERIALSPREPARATION OF THE STARTING MATERIALS
III.3.3.2 REACTIONS WITH THE SUBSTITUTED NREACTIONS WITH THE SUBSTITUTED N–(2(2–AMINOETHYL)PYRROLESAMINOETHYL)PYRROLES
III.3.3.3 ATTEMPTS TO USE NATTEMPTS TO USE N–(2(2–AMINOETHYL)INDOLE DERIVATIVESAMINOETHYL)INDOLE DERIVATIVES
III.4 SCOPESCOPE OFOF VARIOUSVARIOUS NUCLEOPHILESNUCLEOPHILES
III.4.1 ACYCLACYCLIC 1,3IC 1,3–DIKETONESDIKETONES
III.4.2 CYCLIC 1,3CYCLIC 1,3–DIKETONESDIKETONES
III.4.3 ββ–KETOAMIDESKETOAMIDES
III.4.4 ββ–KETOTHIOESTERSKETOTHIOESTERS
III.4.5 ββ–KETOSULFONESKETOSULFONES
III.4.6 ββ–KETOPHOSPHONATESKETOPHOSPHONATES
III.4.7 11–ACETYLINDOLINACETYLINDOLIN–33–ONESONES
III.5 STUDYSTUDY OFOF THETHE ABSOLUTEABSOLUTE ANDAND RELATIVERELATIVE CONFIGURATIOCONFIGURATIONSNS
III.6 CROSSOVERCROSSOVER STUDIESSTUDIES
III.7 POSTPOST–FUNCTIONALIZATIONFUNCTIONALIZATION
III.7.1 DIELSDIELS–ALDER REACTIONSALDER REACTIONS
III.7.2 REDUCTION OF THE DOUBLE BONDREDUCTION OF THE DOUBLE BOND
III.7.3 EPIMERIZATION OF THE STEREOGENIC CENTER BEPIMERIZATION OF THE STEREOGENIC CENTER BEARING THE ESTER EARING THE ESTER SUBSTITUENTSUBSTITUENT
III.7.4 REDUCTION OF THE ESTER PARTREDUCTION OF THE ESTER PART
III.8 CONCLUSIONSCONCLUSIONS
IV. SYNTHESIS OF ENANTIOSYNTHESIS OF ENANTIOENRICHED POLYFUNCTIOENRICHED POLYFUNCTIONALIZED NALIZED HETEROCYCLES BY 3HETEROCYCLES BY 3–CR OR 4CR OR 4–CRCR
IV.1 ORIGINSORIGINS OFOF THETHE REACTIONREACTION DESIGNDESIGN
IV.2 CHOICECHOICE OFOF THETHE BESTBEST FUNCTIONALIZEDFUNCTIONALIZED AMINEAMINE
IV.3 33–CRCR WITHWITH ΒΒ–KETOAMIDESKETOAMIDES
IV.3.1 pKa OF DIFFEpKa OF DIFFERENT 1,3RENT 1,3–DICARBONYL COMPOUNDSDICARBONYL COMPOUNDS
IV.3.2 OPTIMIZATION OF THE REACTION CONDITIONSOPTIMIZATION OF THE REACTION CONDITIONS
IV.3.2.1 OPTIMIZATION OF THE SOLVENT AND THOPTIMIZATION OF THE SOLVENT AND THE RATIO BETWEEN THE STARTING E RATIO BETWEEN THE STARTING MATERIALSMATERIALS
IV.3.3 EVALUATION OF ORGANOCATALYSTS, ADDITIVES, TEMPERATURES AND EVALUATION OF ORGANOCATALYSTS, ADDITIVES, TEMPERATURES AND REACTION TIMEREACTION TIME
IV.4V.4 SEQUENTIALSEQUENTIAL TRIMOLECULARTRIMOLECULAR TRANSFORMATIONTRANSFORMATION
IV.5 THETHE SCOPESCOPE
IV.6 POSTPOST–FUNCTIONALIZATIONFUNCTIONALIZATION
IV.7 FOURFOUR–COMPONENTCOMPONENT REACTIONREACTION
IV.8 CONCLUSIONSCONCLUSIONS
V. ORGANOCATALYTIC ENANORGANOCATALYTIC ENANTIOTIO– AND DIASTEREAND DIASTEREOSELECTIVE OSELECTIVE CONJUGATE ADDITION OCONJUGATE ADDITION OF ΒF Β–KETOAMIDES TO NITROOKETOAMIDES TO NITROOLEFINSLEFINS
V.1 PREPARATIONPREPARATION OFOF ΒΒ–KETOAMIDESKETOAMIDES
V.2 THETHE MICHAELMICHAEL ADDITIONADDITION OOFF ΒΒ–KETOAMIDESKETOAMIDES TOTO ΑΑ,,ΒΒ–UNSATURATEDUNSATURATED ALDEHYDESALDEHYDES
V.3 THETHE MICHAELMICHAEL ADDITIONADDITION OFOF ΒΒ–KETOAMIDESKETOAMIDES TOTO NITROOLEFINSNITROOLEFINS
V.3.1 WORKING HYPOTWORKING HYPOTHESISHESIS
V.3.2 ORGANOCATALYTIC ADDITION OF ACYCLIC βORGANOCATALYTIC ADDITION OF ACYCLIC β–KETOAMIDES TO KETOAMIDES TO NITROOLEFINSNITROOLEFINS
V.3.2.1 OPTIMIZATION OF THE REACTION CONDITOPTIMIZATION OF THE REACTION CONDITIONS WITH WEINREB βIONS WITH WEINREB β–KETOAMIDEKETOAMIDE
V.3.2.2 SCOPE OF NITROOLEFINSSCOPE OF NITROOLEFINS
V.3.2.3 SCOPE AND LIMITATIONS OF WEINREB βSCOPE AND LIMITATIONS OF WEINREB β–KETOAMIDESKETOAMIDES
V.3.2.4 SCOPE OF ACYCLIC TERTIARY βSCOPE OF ACYCLIC TERTIARY β–KETOAMIDESKETOAMIDES
V.3.2.5 ATTEMPTES TO EXTEND THE REACTION TO ACYCLIC SECONDARY βATTEMPTES TO EXTEND THE REACTION TO ACYCLIC SECONDARY β–KETOAMIDESKETOAMIDES
V.3.2.6 RELATIVE AND ABSOLUTE CONFIGURATIONS OF THE MICHAEL ADDUCTSRELATIVE AND ABSOLUTE CONFIGURATIONS OF THE MICHAEL ADDUCTS
V.3.3 RATIONALIZATION OF THE REACTIVITY AND THE SELECTIVRATIONALIZATION OF THE REACTIVITY AND THE SELECTIVITYITY
V.3.3.1 KINETIC STUDIESKINETIC STUDIES
V.3.3.2 ORIGIN OF DIASTEREOSELECTIVITYORIGIN OF DIASTEREOSELECTIVITY
V.3.3.3 PROPOSED TRANSITION STATE TO ACCOUNT FOR THE STEREOSELECTIVITIESPROPOSED TRANSITION STATE TO ACCOUNT FOR THE STEREOSELECTIVITIES
V.3.4 ATTEMPTS TO OBTAIN THE OTHER DIASTEREOMERATTEMPTS TO OBTAIN THE OTHER DIASTEREOMER
V.3.5 SYNTHETIC USEFULNESS OF THE TRANSFORMATIONSYNTHETIC USEFULNESS OF THE TRANSFORMATION
V.3.5.1 SCALESCALE–UP OF THE REACTIONUP OF THE REACTION
V.3.5.2 POSTPOST–FUNCTIONAFUNCTIONALIZATION OF THE ADDUCTSLIZATION OF THE ADDUCTS
V.3.6 CONCLUSIONSCONCLUSIONS
I.GENERAL CONCLUSION AND PERSPECTIVESND PERSPECTIVES
I. EXPERIMENTAL TECHNOLEXPERIMENTAL TECHNOLOGIESOGIES
I.1 GENERALGENERAL PROCEDURESPROCEDURES
I.2 STARTINGSTARTING MATERIALSMATERIALS
I.3 INSTRUMENTATIONINSTRUMENTATION
II. EXPERIMENTAL PART OFEXPERIMENTAL PART OF ORGANOCATALYSTORGANOCATALYST–CONTROLLED CONTROLLED CHEMOSELECTIVE THREECHEMOSELECTIVE THREE–COMPONENT REACTIONSCOMPONENT REACTIONS
II.1 CATALYTICCATALYTIC REACTIONREACTION
III. EXPERIMENTAL PART OFEXPERIMENTAL PART OF ORGANOCATALYTIC ENANORGANOCATALYTIC ENANTIOSELECTIVE TIOSELECTIVE MULTICOMPONENT SYNTHMULTICOMPONENT SYNTHESIS OF PYRROLOPIPERESIS OF PYRROLOPIPERAZINESAZINES
III.1 PREPARATIONPREPARATION OFOF STARTINGSTARTING MATERIALSMATERIALS
III.1.1 PREPARATION OF SUBSTITUTED PYRROLESPREPARATION OF SUBSTITUTED PYRROLES
III.1.2 PREPARATION OF NPREPARATION OF N–(2(2- AMINOETHYL)PYRROLESAMINOETHYL)PYRROLES
III.1.3 PREPARATION OF α,βPREPARATION OF α,β–UNSATURATED ALDEHYDESUNSATURATED ALDEHYDES
III.2 METHODOLOGYMETHODOLOGY FORFOR THETHE OPTIMIZATIONOPTIMIZATION OFOF REACTIONREACTION CONDITIONSCONDITIONS 171755
III.3 GENERALGENERAL PROPROCEDURE,CEDURE, SYNTHESISSYNTHESIS ANDAND CHARACTERIZATIONCHARACTERIZATION OFOF PRODUCTSPRODUCTS EXPERIMENTAL PART OF EXPERIMENTAL PART OF SYNTHESIS OF ENANTIOSYNTHESIS OF ENANTIOENRICHED ENRICHED POLYFUNCTIONALIZED HPOLYFUNCTIONALIZED HETEROCYCLES BY 3ETEROCYCLES BY 3–CR OR 4CR OR 4–CRCR
IV. EXPERIMENTAL PART OFEXPERIMENTAL PART OF ORGANOCATALYTIC ENANORGANOCATALYTIC ENANTIOTIO– AND AND DIASTEREOSELECTIVE CDIASTEREOSELECTIVE CONJUGATE ADDITION OFONJUGATE ADDITION OF ΒΒ- KETOAMIDES TO KETOAMIDES TO NITROOLEFINSNITROOLEFINS
IV.1 PPREPARATION OF ΒREPARATION OF Β–KKETOAMIDESETOAMIDES
IV.2 GGENERAL ENERAL PPROCEDUREROCEDURE,, SSYNTHESIS AND YNTHESIS AND CCHARACTERIZATION OF HARACTERIZATION OF PPRODUCTSRODUCTS
IV.3 PPREPARATIVEREPARATIVE–SSCALE CALE RREACTIONS AND EACTIONS AND PPOSTOST–FFUNCTIONALIZATIONSUNCTIONALIZATIONS::
IV.3.1 PreparativePreparative–scale reactions:scale reactions:
IV.3.1.1 PreparativePreparative–scale reaction (1.00scale reaction (1.00–mmol):mmol):
IV.3.1.2 Neat preparativeNeat preparative–scale reaction (2.00scale reaction (2.00–mmol):mmol):
IV.3.2 Diastereoselective ketone reductionDiastereoselective ketone reduction
IV.3.3 Other pOther postost–functionalizationsfunctionalizations RE
REFERENCESFERENCES
