La lecture à portée de main
Découvre YouScribe en t'inscrivant gratuitement
Je m'inscrisDécouvre YouScribe en t'inscrivant gratuitement
Je m'inscrisDescription
Informations
Publié par | Thesee |
Nombre de lectures | 37 |
Langue | English |
Poids de l'ouvrage | 3 Mo |
Extrait
THÈSE
Pour obtenir le grade de
DOCTEUR DE L’UNIVERSITÉ DE GRENOBLE
Spécialité : CHIMIE ORGANIQUE
Arrêté ministériel : 7 août 2006
Présentée par
ANUSHREE KAMATH
Thèse dirigée par Dr. PHILIPPE DELAIR
préparée au sein du DCM-SERCO
dans l'École Doctorale Chimie et Sciences du Vivant
Contribution à la synthèse
totale de l'alcaloïde (-)-205B
Thèse soutenue publiquement le 24 Mai, 2011
devant le jury composé de :
Prof. Mercedes AMAT
Professeur, Université de Barcelone, Rapporteur
Dr. Bernard DELPECH
Directeur de Recherche, Institut de Chimie des Substances
Naturelles CNRS, Gif-sur-Yvette, Rapporteur
Prof. Yannick VALLÉE
Professeur, Départment de Chimie Moléculaire, Université Joseph
Fourier, Grenoble, Examinateur
Dr. Philippe DELAIR
Maître de Conférence, Départment de Chimie Moléculaire,
Université Joseph Fourier, Grenoble, Directeur de thèse
Dr. Andrew E. GREENE
Directeur de Recherche, Départment de Chimie Moléculaire,
Université Joseph Fourier, Grenoble, Invité
tel-00609829, version 1 - 20 Jul 2011Table of Contents
Abbreviations 3
General Introduction 6
I. Introductions to Alkaloids 11
1.1 Introduction: General 12
1.2 Biosynthesis of alkaloids 14
1.3 Ecological role of alkaloids 15
II. Alkaloids from the Amphibian skin 18
2.1 Introduction 19
2.2 Coding System of dendrobatid alkaloids 22
2.3 Structural Classification 23
2.4 Biosynthesis and ecological role 24
2.5 Alkaloid (-)-205B: Isolation and Structure elucidation 27
III. Amphibian Alkaloids: Biological Perspectives 29
3.1 General principles 30
3.2 Nicotinic Acetyl Choline Receptors: Structure and Functions 32
3.3 Alkaloids from the frog skin: Pharmacological activities 35
IV. Reported Syntheses 38
4.1 First total synthesis of the antipode of Alkaloid (-)-205B 39
4.2 A convergent Multi-Component Linchpin coupling strategy for synthesis of (-)-205B 44
V. Results and Discussions 51
5.1 Thermal [2 + 2] cycloaddition: Synthetic Methodology 52
5.2 Retrosynthetic Strategy 63
5.3.1 Model studies for methylation and aza-Prins cyclisation 65
5.3.2 Formation of the pyrolidinone, I 67
tel-00609829, version 1 - 20 Jul 2011 5.3.3 Formation of indolizidinone, III 70
5.3.4 Introduction the equatorial methyl group on C8 75
5.3.5 Installation of the C6 axial methyl group 83
5.3.6 Formation of the azaacenaphthylene ring system 104
5.3.7 Towards Alkaloid (-)-205B 107
VI. Conclusions and Perspectives 109
VII. Experimental Section 113
tel-00609829, version 1 - 20 Jul 2011
Abbreviations
Ac Acetate
AIBN Azobisisobutyronitrile
aq. Aqueous
atm. Atmosphere
Bn Benzyl
Boc tert-butoxycarbonyl
cat. Catalyst
CSA Camphor sulphonic acid
DCM Dichloromethane
DIBAL-H Diisopropylbutylaluminium hydride
DMAP N,N-dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO N,N-dimethylsulfoxyde
EDA Ethylene diamine
eq. Equivalents
HMPA Hexamethylphosphoramide
HOMO Highest Occupied Molecular Orbital
IR Infrared
LAH Lithium Aluminium Hydride
LDA Lithium diisopropylamide
LUMO Lowest Unoccupied Molecular Orbital
m-CPBA meta- chloroperbenzoic acid
min Minute
MOM Methyloxymethyl
nAChR Nicotinic Acetyl Choline Receptors
NaHMDS Sodium bis(trimethylsilyl)amide
NMP N-Methyl pyrolidinone
NMR Nuclear Magnetic Resonance
tel-00609829, version 1 - 20 Jul 2011PMB para-methoxybenzyl
pTSA para-toluenesulphonic acid
Py Pyridine
RT Room Temperature
RCM Ring Closing Metathesis
SEMCl 2-(Chloromethoxyethyl)trimethylsilane
TBS tert-Butyldimethylsilyl
TBDPS tert-Butyldiphenylsilyl
TESOTf Triethylsilyltrifluoromethanesulphonate
TBSOTf tert-butyldimethylesilyl trifluoromethansulphonate
TFA Trifluoroacetic acid
THF Tetrahydrofuran
TMEDA Tetramethylethylenediamine
TMS Trimethylsilyl
Ts Tosyl
UV Ultraviolet
tel-00609829, version 1 - 20 Jul 2011General Introduction
tel-00609829, version 1 - 20 Jul 2011General Introduction
General Introduction
Throughout ages, Nature has been a vast and renewable source of useful compounds that have
served mankind. The innate human curiosity for a better understanding of the naturally occuring
components of the environment around him and his need to find sources of food, fabric and
medicines for survival has prompted him to constantly exploit this realm.
Historically, owing to their toxicity, one of the major applications of compounds extracted from
Nature had been as poisons for hunting and defence purposes. However, all over the world
traditional medicine has also been largely dominated by use of plants. For instance, the so called
1‘Ebers Papyrus’, an Egyption record dating back to 1500 B. C., is one of the oldest texts ever
known which mentions the use of over 700 medicinal compounds mainly obtained from vegetal
sources. In the Chinese traditional medicine, the ‘Bencao Gangmu’, a compendium of Materia
2Medica containing thousands of medicina