Structure elucidation and total synthesis of complex polyketides and development of direct methods for the synthesis of chiral amines [Elektronische Ressource] / vorgelegt von Dirk Menche

Dirk Menche

Informations

• Publié par: gottfried_wilhelm_leibniz_universitat_hannover
• Publié le: 01 janvier 2007
• Nombre de lectures: 85
• Langue: English
• Poids de l'ouvrage: 4 Mo

Extrait

Structure Elucidation and Total Synthesis of
Complex Polyketides
and
Development of Direct Methods for the Synthesis of Chiral
Amines






HABILITATIONSCHRIFT


Der Naturwissenschaftlichen Fakultät vorgelegt von



Dr. Dirk Menche



Hannover, März 2007






























All results discussed within this report have been part of publications or are prepared for
[52,55,57,88,94,98,103,109,110,123,128,137,139,146]publication.

TABLE OF CONTENTS
GENERAL SECTION..............................................................................1
1 Introduction............................................................................................................... 1
2 Structural Elucidation and Total Synthesis of the Archazolids............................ 6
2.1 Introduction.. 6
2.2 Isolation and Structural Elucidation............................................................................ 7
2.2.1 Stereochemical Determination of Archazolid A and B............................................... 7
2.2.2 Archazolid-7-O-β-D-glucopyranoside from the Myxobacterium Cystobacter
violaceus: Isolation, Structural Elucidation and Solution Conformation.................. 13
2.2.3 Archazolid D: The First Hydroxylated Archazolid................................................... 20
2.3 Total Synthesis of Archazolid A............................................................................... 23
2.3.1 Retrosynthetic Analysis............................................................................................23
2.3.2 Synthesis of the C3-C13 subunit 25
2.3.3 the C20-C1'' subunit ............................................................................. 27
2.3.4 Synthesis of the C14-C19 subunit 28
2.3.5 Fragment union and completion of the total synthesis.............................................. 29
2.4 Design, Synthesis and Biological Evaluation of Simplified Analogues of
Archazolid................................................................................................................. 32
3 Etnangien: Stabilisation, Configurational Assignment and Modular Synthesis
of the C34 to C42 Subunit ...................................................................................... 39
3.1 Introduction............................................................................................................... 39
3.2 A Potent Novel Analogue of Etnangien: Stabilization by Esterification.................. 40
3.3 Configurational Assignment of Etnangien................................................................ 44
3.4 Retrosynthetic Analysis and Modular Synthesis of the C34 to C42 subunit ............ 50
4 Development of Practical Methods for the Stereoselective Synthesis of Chiral
Amines...................................................................................................................... 54
4.1 Introduction............................................................................................................... 54
4.2 Biomimetic Reductive Amination of Carbonyls....................................................... 55
4.2.1 Reductive Amination of Ketones.............................................................................. 56 TABLE OF CONTENTS
4.2.2 Reductive Amination of Aldehydes.......................................................................... 59
4.2.3 Synthesis of Hindered Tertiary Amines.................................................................... 62
4.2.4 Modular One-Pot Synthesis and Biological Evaluation of Tertiary Amines............ 67
4.3 Directed Reductive Amination.................................................................................. 70
4.3.1 Introduction............................................................................................................... 70
4.3.2 ination of β-Hydroxy-Ketones: Convergent Assembly of the
Ritonavir/Lopinavir Core.......................................................................................... 71
5 Summary.................................................................................................................. 76
EXPERIMENTAL SECTION .................................................................82
1 General experimental.............................................................................................. 82
1.1 Experiments of chapter 2.2.1 .................................................................................... 82
1.1.1 Tables of NMR Data and experimental procedures.................................................. 82
1.1.2 Molecular Modeling..................................................................................................93
1.2 Experiments of chapter 2.2.2 .................................................................................. 103
1.3 Experiments of chapter 2.2.3 113
1.4 Experiments of chapter 2.3 ..................................................................................... 114
1.5 Experiments of chapter 2.4 153
1.6 Experiments of chapter 3.2 156
1.7 Experiments of chapter 3.3 157
1.8 Experiments of chapter 3.4 ..................................................................................... 161
1.9 Experiments of chapter 4.2.1 .................................................................................. 175
1.10 Experiments of chapter 4.2.2 180
1.11 Experiments of chapter 4.2.3 185
1.11.1 Synthesis of tertiary amines of the type NR(R') .................................................... 185 2
1.11.2 ines of the type NRR'R'' 187
1.12 Experiments of chapter 4.2.4 190
1.13 Experiments of chapter 4.3.2 .................................................................................. 190 TABLE OF CONTENTS
ACKNOWLEDGEMENTS ...................................................................209
REFERENCES....................................................................................224

ABREVIATIONS
Abreviations
Å Ångström (100 pm) LDA Lithiumdiisopropylamid
Aq aqueous LiBH Lithiumborohydrid 4
Ac Acetyl Me Methyl
Ar Arylmg Milligramm
Bn Benzyl min Minute
BOP (benzotriazol-1-yloxy)tris- mmol Millimol
(dimethylamino)phosphonium mol Mol
hexafluorophosphat MS Molecular sieves
Bu Butyl MTBE Methyl-tert-butylether
t-Bu tert-Butyl MTPA Mosher acid
BuLi n-Butyllithium NaHMDS Sodium-bis(trimethylsilyl)amid
c Concentration [g/100 mL] NMO N-Methylmorpholin-N-oxid
cat Catalytic NOE Nuclear Overhauser Effect
CDCl Deuterated Chloroform NOESY NucleaOverEnhancement 3
COSY Correlation Spectroscopy Spectroscopy
CSA Camphersulphonic acid NMR Nuclear Magnetic Resonance
CH Cl Dichlormethane n.d. Not determined 2 2
CHCN Acetonitrile PCC Pyridiniumchlorochromat 3
δ Chemische Verschiebung PE Petroleum ether
PG Protecting group ds diastereoselectivity
DCM Dichlormethan Ph Phenyl
ppm Parts per million DDQ 2,3-Dichloro-5,6-dicyano-1,4-
benzoquinone PMB para-Methoxy-benzyl
PMBCl para-Methoxy-benzylchlorid DIBAl-H Diisobutlyaluminiumhydride
DMAP 4-Dimethylaminopyridine PPTS Pyridinium-4-toluolsulphonate
pyr Pyridine DME Dimethoxyethan
DMF N,N-Dimethylformamide R Non aromatic substituent
R Retention factor DMP Dess-Martin-Periodinane f
DMSO Dimethylsulfoxid rac Racemic
Ref Reference ee Enantiomeric excess
Et Ethyl ROESY Rotating Frame Overhauser
Enhancement Spectroscopy EtO Diethyl ether 2
EtOAc Ethyl acetate RT Room temperature
SAR Structure-Activity-Relationship eq Equivalents
exc. Excess sat. saturated
TBAF Tetra-n-butyl-ammoniumfluorid GC Gas chromatography
g Gramm TBDPS tert-Butyl-diphenylsilyl
TBS tert-Butyl-dimethylsilyl ges. Gesättigt
h Hour TBSCl tert-Butyl-dimethylsilylclorid
TBSOTf tert-Butyl-HMDS Hexamethyldisilazid
HRMS High resolution mass spectroscopy dimethylsilyltrifluormethansulfonat
TEMPO 2,2,6,6-Tetramethylpiperidine-N-HWE Horner-Wadsworth-Emmons
Hz Hertz oxid
TES triethylsilyl Ipc Isopinocampheyl
IpcBOMe Methoxydiisopinocampheylborane tert Tertiary 2
THF Tetrahydrofuran i-Pr iso-Propyl
IR Infrared TLC Thin layer chromatography
TPAP tetrapropylammonium perruthenate J Coupling constant
KHMDS Potassium-bis(trimethylsilyl)amid
L Litre
GENERAL SECTION 1
GENERAL SECTION
1 Introduction
Terrestrial and marine organisms provide a rich source of biologically active compounds with
new and exciting pharmacological properties. In fact, more than 60% of new chemical entities
1introduced as drugs during the last two decades are, or were inspired by, natural products.
However, structurally complex and, consequently, preparatively less accessible natural
1substances have received little attention as pharmaceutical leads. Providing such compounds
has traditionally been addressed by total synthesis in a target-oriented fashion, which, despite
certain achievements, tends to be lengthy, time-consuming and of limited practicality.
Conversely, in an activity-oriented approach, more accessible analogues with improved