IMINIUM-TYPE ACTIVATION OR ENAMINE-TYPE ACTIVATION
Primary or secondary amines can be employed as catalysts in Michael additions by forming covalent bond with aldehydes or ketones. There are two main modes of activation: iminium-type activation and enamine-type activation.[44, 45].
Some examples of catalysts following this type of activation are presented in Figure I- 4. It is possible to tell from these examples that proline and its derivatives are the most common structural units in this family of catalysts. In addition to their mainly covalent activation mode, these catalysts IV, V, VI, VII can also bear additional functionalities that enable secondary interactions with the substrates. For example, catalysts VIII, IX, X possess a hydrogen-bonding donor unit, whereas catalyst exhibits a tertiary amino group that can activate the pronucleophile by deprotonation. These chiral primary and secondary amine catalysts have already been shown to catalyze the enantioselective Michael addition of enolizable carbonyl compounds to electron-poor alkenes via the formation of an iminium or an enamine. In the iminium-type activation mode, firstly, the catalyst reacts with the electrophile counterpart to form an intermediate iminium ion (Scheme I- 6).  Secondly, the nucleophile adds to the intermediate iminium ion and thus delivers an enamine intermediate. At last, the Michael adduct and the amine catalyst are released via an hydrolysis step. Meanwhile, a subsequent catalytic cycle restart. A key parameter of this mode of activation to achieve excellent enantioinduction is the control of the geometry of the iminium ion intermediate. Moreover it was found that a Brønsted acid as co-catalyst can often assist the formation and the hydrolysis of the iminium intermediate in these reactions.
In 1994, Kawara and Taguchi first reported the enantioselective Michael addition of malonates to cyclic and acyclic enones catalyzed by chiral (2-pyrrolidinylmethyl)ammonium hydroxide (XI) and hexafluoroisopropanol (HFIP) as the Brønsted acid co-catalyst to obtain the Michael adducts in moderate yields and enantioselectivities (Scheme I- 7a). The enones with the enantiopure amine catalyst forms an activated iminium ion with lowered LUMO energy, which reacts with the malonate anions.
Soon after, Yamaguchi and co-workers also reported the same reactivity via iminium-type activation, but catalyzed by L-proline rubidium salt XII (Scheme I- 7b). Several years after, Jørgensen and co-workers reported the Michael addition of malonates to acyclic enones with excellent yields and enantiomeric excess with the use of a novel imidazolidine catalyst XIII (Scheme I- 7c). Moreover, the outstanding performance of this methodology has been applied in the one step synthesis of the anticoagulant warfarin catalyzed by the chiral imidazolidine derivatives XIV. In 2006, Ley and co-worker also extended the use of their new proline tetrazole catalyst, called 5-pyrrolidin-2-yl tetrazole XV, in the same reaction with good yields and good to high enantioselectivities. A large variety of primary and secondary amine catalysts have since then been developed to catalyze the Michael addition of various nucleophiles to enones. For example, in 2009, Feng and co-workers utilized the C2-symmetric diamide catalysts (XVI) for iminium-type activation in the enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones with high yields (up to 99%) and enantioselectivities (up to 89% ee) under mild conditions.
In 2011, Cheng and co-workers first reported that the same reactivity can be observed with in situ formed primary amine-imine organocatalyst XVII, with excellent results. The primary amine-imine catalyst has been synthesized in situ under acidic conditions through hydrolysis of a chiral diimine precursor (Scheme I- 8).
HYDROGEN BONDING ACTIVATION
As early as 1985, Hine and co-workers have disclosed the opening of an epoxide by a nucleophile via hydrogen bonding with different phenols (Scheme I- 14). They investigated the reaction speed constants and realized that phenols able of multiple hydrogen bonding can dramatically increase the efficiency of the reaction. Multiple hydrogen bonding has since been recognized as a very efficient way to activate substrates.
Scheme I- 14 The reaction of phenyl glycidyl ether with diethylamine catalyzed by various phenols. Because the commercially available α,α-L-diaryl prolinol (XXII) includes a secondary amine and a hydroxyl group, which can recognize several functional groups through hydrogen-bonding interaction, this molecule has been employed as catalyst in several examples of Michael additions. In 2006, Lattanzi applied this catalyst (XXII) in the enantioselective Michael addition of malonate esters to nitroalkenes, obtaining good yields of product but with only moderate enantioselectivities (Scheme I- 15). The authors also proposed a mechanism where the secondary amine activates the malonate and the hydroxyl group activates the nitroalkene by hydrogen-bonding interactions, meaning that the catalyst was involved in simultaneous hydrogen-bonding activation of both the nucleophile and the electrophile.
In 2009, the same authors then extended their methodology to cyclic β-ketoesters, using hexafluorobenzene instead of p-xylene as solvent, allowing a dramatic improvement of the results in terms of enantioselectivity. At the same time, the origin of stereoselectivity and the role of hexafluorobenzene have been clarified by DFT calculations.
Reactions Catalyzed by Chiral Cinchona Alkaloid Derivatives
In 1981, Wynberg and Hiemstra reported that natural quinuclidine-type cinchona alkaloids can act as efficient bifunctional organocatalysts for the Michael addition. Unfortunately, the final product was obtained with moderate enantiomeric excesses. Since that time, because cinchona alkaloids possess a tunable functional group at the C9 position (OH, NH2 or NHTs), and the C6’ position, which can add further stabilizing interactions or may activate and coordinate suitable substrates, they have been largely used as starting materials to prepare diversified organocatalysts.[62-66] Several approaches have been directed toward extending their synthetic utility.
In 2004, Deng and co-workers first reported that bifunctional organic catalysts based on cinchona alkaloids can be applied in the conjugate addition of malonates and β-ketoesters to nitroalkenes. In spite of the long reaction time (up to 108 h), whatever aromatic or aliphatic nitroalkenes were put into reaction, the adducts were obtained with excellent enantiomeric excesses and yields (Scheme I- 16). It was demonstrated that the readily available 6’-demethylated quinine XXV and quinidine XXVI alkaloids are considerably more active and selective catalysts than their natural 6’-methylated analogues. Moreover, a model for the activation of the nucleophile and the electrophile by cinchona alkaloids was provided. The same authors then reported that this bifunctional chiral organic catalyst acts as an efficiency catalyst for the Michael addition of α-substituted β-dicarbonyl donors to α,β-unsaturated aldehydes.
DOMINO AND MULTICOMPONENT REACTIONS BASED ON THE MICHAEL ADDITION OF 1,3-DICARBONYL SUBSTRATES
Many research programs in modern organic chemistry focus on the development of green chemistry. Green chemistry is based on several important principles. For example, synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. Chemical products should be designed to produce their desired function while minimizing their toxicity. Moreover, in order to save steps in a synthetic plans, multiple bond-forming transformations (MBFTs) have been developed.
Domino and multicomponent reactions can allow the creation of several covalent bonds in the same reaction conditions, helping to meet the principles of green chemistry.
Because 1,3-dicarbonyl substrates display several nucleophilic and electrophilic potential reaction sites, they represent very interesting substrates for domino and multicomponent reactions.[41, 42] In this section, we will focus on the key seminal reports and the latest improvements of domino and multicomponent reactions based on the Michael addition of 1,3-dicarbonyl substrates. Since there is a very abundant literature on domino reactions and our research interests were focused on the control of enantioselectivity, we will restrict our presentation of domino reactions to enantioselective organocatalytic transformations. On the contrary, multicomponent reactions are rarer and a general overview of these transformations, either enantioselective or not, will be provided in this section.
ENANTIOSELECTIVE DOMINO REACTIONS BASED-ON THE MICHAEL ADDITION OF 1,3-DICARBONYL SUBSTRATES
In 1999, Tietze provided a generally accepted definition of domino reactions: “a domino reaction is a process involving two or more bond-forming transformations (usually carbon-carbon bonds) which take place under the same reaction conditions without adding additional reagents and catalysts, and in which the subsequent reactions result as a consequence of the functionality formed in the previous step”(Figure I- 14)..
Domino reactions are by nature step economic processes as several bonds are formed in one sequence. In particular, domino reactions mediated by organocatalysts are in a way biomimetic, as the same reactivity principle are involved in the biosynthesis of complex natural products. Thus, chemists have recently devoted efforts to the development of enantioselective domino reactions based on the Michael addition of 1,3-dicarbonyl substrates. Because organocatalysis involves several activation modes, the reactions will be presented by their type of activation.
IMINIUM-ENAMINE ACTIVATION MODE
The iminium-enamine activation is probably one of the most important activation mode in organocatalysis. In 2000, Bui and Barbas reported for the first time an organocatalytic domino reaction based on an iminium-enamine sequence with methyl vinyl ketones. This domino reaction includes two different processes: a Michael addition and an aldol condensation. Wieland-Miescher ketone was obtained from the reaction of 2-methylcyclohexane-1,3-dione 8 with methyl vinyl ketone by using L-proline (IV) (35 mol%), affording the final product in 49% yield with 76% ee (Scheme I- 37)..
ORGANOCATALYTIC ENANTIOSELECTIVE MULTICOMPONENT REACTIONS BASED ON THE MICHAEL ADDITION OF 1,3-DICARBONYL SUBSTRATES
An organocatalytic enantioselective multicomponent reaction can be defined as a reaction between three or more reagents introduced at the same time by using a substoichiometric amount of a chiral organocatalyst. During this reaction, the formation of two or more bonds occurs as well as control over at least one newly formed stereogenic center.[41, 170, 174, 190] As organocatalysts generally exhibit a high functional group tolerance, they are especially suited for multicomponent reactions. Indeed, one of the biggest challenges to develop these transformations is to prevent the non-productive interaction of the chiral catalyst with the additional reaction partners that are not involved in the enantioselective step.
The first example of organocatalytic enantioselective Michael-type multicomponent reaction was reported by the group of Barbas in 2001 (Scheme I- 71). The alkylidene malonates was synthesized in situ between benzaldehyde and diethylmalonate by a Knoevenagel reaction catalyzed by (S)-1-(2-pyrrolidinylmethyl)-pyrrolidine (LV), and then followed by the enantioselective Michael addition of the alkylidene malonates and acetone. Although the results of the sequence were not completely satisfactory in terms of yields and enantioselectivities, it opened the field of Michael addition-initiated multicomponent reactions.
STUDY OF THE RELATIVE CONFIGURATION
As early as 1995, our group has reported the structural assignment of similar derivatives, which could be achieved by the observation of the characteristic coupling constant patterns in the 1H NMR spectra. Indeed, as a consequence of the Karplus equation, the 3JHH coupling constants will depend on the dihedral angle between the two C-H bonds. More specifically, protons that are in a trans diaxial relationship will present the highest coupling constants (around 12 to 14 Hz).
In this context, the relative configuration of the bicyclic products obtained with acrolein in the racemic series had already been determined by studying the 1H NMR spectrum of compound 46’, after attribution of all the signals thanks to COSY, HMQC and HMBC analyses. The relative configuration of the two bridgehead carbon atoms is interdependent, which means we only need to determine the relative configuration of one of these carbon atoms with the last stereogenic center. The proton on the carbon atom α to the nitrogen atom has its signal at 3.03 ppm. It exhibits three 3JHH coupling constants of 11.4, 5.0 and 3.0 Hz, respectively. This observation means that this proton is in axial position and couples with only one other axial proton. For this reason, the proton on the bridgehead carbon atom is in equatorial position.
Table of contents :
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
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
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.5 STUDYSTUDY OFOF THETHE ABSOLUTEABSOLUTE ANDAND RELATIVERELATIVE CONFIGURATIOCONFIGURATIONSNS
III.6 CROSSOVERCROSSOVER STUDIESSTUDIES
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
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.7 FOURFOUR–COMPONENTCOMPONENT REACTIONREACTION
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
I.GENERAL CONCLUSION AND PERSPECTIVESND PERSPECTIVES
I. EXPERIMENTAL TECHNOLEXPERIMENTAL TECHNOLOGIESOGIES
I.1 GENERALGENERAL PROCEDURESPROCEDURES
I.2 STARTINGSTARTING MATERIALSMATERIALS
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