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  • Diastereoselective multicomponent [3+2] and [4+2] cycloadditions

    Verónica Selva Martínez

    https://www.ua.es/ http://www.eltallerdigital.com/es/index.html

  • Departamento de Química Orgánica

    Instituto de Síntesis Orgánica (ISO)

    Facultad de Ciencias

    DIASTEREOSELECTIVE MULTICOMPONENT

    [3+2] AND [4+2] CYCLOADDITIONS

    Verónica Selva Martínez

    Tesis presentada para aspirar al grado de

    DOCTORA POR LA UNIVERSIDAD DE ALICANTE

    MENCIÓN DE DOCTORA INTERNACIONAL

    Doctorado en Síntesis Orgánica

    Dirigida por:

    Carmen Nájera Domingo José Miguel Sansano Gil

    Catedrática de Química Orgánica Catedrático de Química Orgánica

    Alicante, Abril de 2018

  • 2

  • 3

    Table of contents

    PREFACE 7

    SUMMARY 9

    GENERAL INTRODUCTION 11

    1,3-DIPOLAR CYCLOADDITIONS 13

    Azomethine ylides 15

    1,3-Dipolar cycloadditions of azomethine ylides 18

    CHAPTER 1: Multicomponent synthesis of indolizidines 27

    BIBLIOGRAPHIC BACKGROUND 27

    Multicomponent reactions 27

    Synthesis of indolizidines 27

    Synthesis of indolizidines using multicomponent 1,3-DC 31

    OBJECTIVES 35

    RESULTS AND DISCUSSION 37

    CONCLUSIONS 53

    EXPERIMENTAL SECTION 55

    General methods 55

    General procedure for the synthesis of indolizidines 72-73 56

    Characterization of indolizidines 72-73 56

    General procedure for the synthesis of indolizidine 74 61

    Characterization of indolizidine 74 61

    General procedure for the synthesis of indolizidine 75 62

    Characterization of indolizidine 75 62

  • 4

    General procedure for the synthesis of indolizidines 77 and 79

    63

    Characterization of indolizidines 77 and 79 63

    CHAPTER 2: Thermal 1,3-DC of unactivated azomethine ylides

    71

    BIBLIOGRAPHIC BACKGROUND 71

    Synthesis of substituted pyrrolidines 71

    OBJECTIVES 77

    RESULTS AND DISCUSSION 79

    CONCLUSIONS 97

    EXPERIMENTAL SECTION 99

    General methods 99

    General procedure for the synthesis of pyrrolidines 98, 101

    and 103 99

    Characterization of pyrrolidines 98, 101 and 103 99

    General procedure for the synthesis of 104 113

    Characterization of 104 113

    CHAPTER 3: Multicomponent periselective cycloadditions of

    nitroprolinates 115

    BIBLIOGRAPHIC BACKGROUND 115

    Diversity-oriented synthesis 115

    OBJECTIVES 119

    RESULTS AND DISCUSSION 121

    CONCLUSIONS 135

    EXPERIMENTAL SECTION 137

    General methods 137

    General procedure for the synthesis of pyrrolizidines 116 137

  • 5

    Characterization of pyrrolizidines 116 137

    General procedure for the synthesis of compounds 119 146

    Characterization of compounds 119 146

    General procedure for the synthesis of pyrrolizidines endo-

    120-123 153

    Characterization of pyrrolizidines endo-120-123 154

    LIST OF ABBREVIATIONS 157

    RESUMEN EN CASTELLANO 159

    INTRODUCCIÓN GENERAL 161

    1,3-Cicloadiciones dipolares 161

    Cicloadiciones 1,3-dipolares de iluros de azometino 164

    CAPÍTULO 1: SÍNTESIS MULTICOMPONENTE DE

    INDOLIZIDINAS 167

    Antecedentes bibliográficos: Reacciones multicomponente 167

    Antecedentes bibliográficos: Síntesis de indolizidinas 167

    Resultados y discusión 168

    CAPÍTULO 2: 1,3-DC LIBRE DE METALES DE ILUROS DE

    AZOMETINO DESACTIVADOS 175

    Antecedentes bibliográficos: Síntesis de pirrolidinas

    sustituidas 175

    Resultados y discusión 176

    CAPÍTULO 3: CICLOADICIONES MULTICOMPONENTE

    PERISELECTIVAS DE NITROPROLINATOS 187

    Antecedentes bibliográficos: Síntesis de orientación diversa

    187

    Resultados y discusión 188

    REFERENCES 199

  • 6

  • 7

    PREFACE

    In this thesis, the main projects in which I have been involved during my

    Ph.D. studies are described. The research concerns the study of 1,3-dipolar

    cycloaddition, where an azomethine ylide is generated as intermediate, in both

    their diastereoselective and non diastereoselective version. This work has been

    carried out under the supervision of Prof. Carmen Nájera Domingo and Prof. José

    Miguel Sansano Gil in the Organic Chemistry Department and the Organic

    Synthesis Institute at the University of Alicante (Spain). Another research line was

    developed during my three months stay in Tokyo at Gakushuin University under

    the supervision of Prof. Takahiko Akiyama where many good results were

    obtained, but the diffussion of these results is not authorized till publication.

    The thesis is divided into a general introduction and three chapters. In

    General introduction, the mechanism of the 1,3-dipolar cycloaddition involving

    azomethine ylides is explained. Chapter 1 is focused on the synthesis of

    substituted indolizidine derivatives through a multicomponent 1,3-dipolar

    cycloaddition. Chapter 2 covers the study of multicomponent thermal 1,3-dipolar

    cycloaddition reaction between unactivated azomethine ylides, generated in situ

    from amines, aromatic aldehydes, and electrophilic alkenes. Finally, in Chapter 3

    it is described the diverse oriented synthesis of diastereomerically enriched

    pyrrolizidines from enantiomerically enriched nitroprolinates through a

    multicomponent 1,3-dipolar cycloaddition and also the cyclohex-2-en-1-

    ylprolinate cores by means of an amine-aldehyde-dienophile reaction.

    Most of the results described herein have been published in the following

    international peer reviewed journals:

    “Multicomponent diastereoselective synthesis of indolizidines via 1,3-

    dipolar cycloadditions of azomethine ylides”.

    Castelló, L. M.; Selva, V.; Nájera, C.; Sansano, J. M. Synthesis 2017, 49, 299–309.

  • Preface

    8

    “Diastereoselective [3 + 2] vs [4 + 2] cycloadditions of nitroprolinates with

    α,β-unsaturated aldehydes and electrophilic alkenes: an example of total

    periselectivity”.

    Selva, V.; Larrañaga, O.; Castelló, L. M.; Nájera, C.; Sansano, J. M.; de Cózar, A. J. Org.

    Chem. 2017, 82, 6298–6312.

    “Sequential metal-free thermal 1,3-dipolar cycloaddition of unactivated

    azomethine ylides”.

    Selva, V.; Selva, E.; Nájera, C.; Sansano, J. M. Org. Lett. accepted. DOI:

    10.1021/acs.orglett.8b01292.

    These studies have been supported by Spanish Ministerio de Economía y

    Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-

    REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia

    Estatal de Investigación (AEI) and Fondo Europeo de Desarrolo Regional (FEDER,

    EU) (projects CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat

    Valenciana (PROMETEO2009/039 and PROMETEOII/2014/017) and by the

    University of Alicante.

    I also thank Prof. Fernando P. Cossío, Dr. Abel de Cózar and Dr. Olatz

    Larrañaga from the University of the Basque Country for their suggestions and

    ideas about the elucidation of the mechanisms of these reactions, as well as for the

    realization of computational calculations. I thank Dr. Tatiana Soler from Research

    Technical Services of the University of Alicante for her work performing X-ray

    diffraction analyses.

  • 9

    SUMMARY

    In this Doctoral Thesis the synthesis of substituted indolizidine,

    pyrrolizidine, pyrrolidine and prolinate derivatives, from stabilized azomethine

    ylides in situ generated, through different methodologies which involve a 1,3-

    dipolar cycloaddition, multicomponent or multicomponent sequencial, in both

    their diastereoselective and no diastereoselective way, is described.

    In Chapter 1, the multicomponent free-metal synthesis of indolizidine

    derivatives by intermediancy of iminium intermediate form by alkyl pipecolinates

    or pipecolic acid with aldehydes reacting afterwards with dipolarophiles in both

    thermal and decarboxylative way, are depicted.

    In Chapter 2, it is described the one-pot synthesis of different pyrrolidine

    derivatives through a sequencial 1,3-dipolar cycloaddition in a thermal free-metal

    version of CH activation from unactivated azomethine ylides, generated in situ, and

    dipolarophiles.

  • Summary

    10

    In Chapter 3, the multicomponent [3+2] 1,3-dipolar cycloaddition of

    enantiopure exo-4-nitroprolinates with aldehydes and dipolarophiles giving the

    corresponding pyrrolizidines is described. The same three components using

    isomerizable aldehydes experiment a [4+2] cycloaddition (Amine-Aldehyde-

    Dienophile reaction) giving the corresponding cyclohexenes.

    Finally, at the end of each chapter the corresponding conclusions are

    detailed. And after Chapter 3 references, abbreviations and biography are added

    in this order.

  • 11

    GENERAL INTRODUCTION

    Nitrogen-cont

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