New synthetic approaches to 8,5'-neolignans [Elektronische Ressource] / von Ljubisa Jovanovic

Grau Sala

Informations

• Publié par: universitat_potsdam
• Publié le: 01 janvier 2005
• Nombre de lectures: 54

Extrait

Institut für Chemie
Arbeitsgruppe Prof. Peter




NEW SYNTHETIC APPROACHES TO 8,5’-NEOLIGNANS










Dissertation
zur Erlangung des akademischen Grades
"doctor rerum naturalium"
(Dr. rer. nat.)
in der Wissenschaftsdisziplin Organische Chemie











eingereicht an der
Mathematisch-Naturwissenschaftlichen Fakultät
der Universität Potsdam




von
Ljubisa Jovanovic





Potsdam, Juni 2005


TABLE OF CONTENTS

TABLE OF CONTENTS
AKNOWLEDGEMENTS
LIST OF ABREVIATIONS

CHAPTER 1: INTRODUCTION……………………………………………….….. 1

1.1 PHENOLICS……………………………………………………………………………….…....2
1.2 LIGNANS AND NEOLIGNANS…………………………………………………………….…3
1.3 DIHYDROBENZOFURANS AS A PART OF A COMPLEX MOLECULE……………….…5
1.4 SYNTHESIS OF NEOLIGNANS……………………………………………………………....7
1.4.1 BIOSYNTHESIS OF PHENYLPROPANOIDS………………………………………….….7
1.4.2 BIOSYNTHESIS OF NEOLIGNANS………………………………….8
1.4.3 CHEMICAL SYNTHESES OF NEOLIGNANS…………………………………………...10
1.4.3.1 The synthesis of dihydrobenzofuran compounds via directed
α-metalation………………………………………………………………...19
1.4.3.1.1 Some possible side reactions in the preparation of phosphamidates…......25
CHAPTER 2: AIM OF THE WORK…………………………………………..…………30

CHAPTER 3: RESULTS……………………………………………………………... 31

3.1 NEW SYNTHETIC APPROACHES TO DIHYDROBENZOFURAN COMPOUNDS….…...31
3.1.1 DIRECTED α-METALATION APPROACH…………………………………………..….31
3.1.1.1 Choice of potential DMG-s…………………………………………….....31
3.1.1.2 Preparation of bis (N,N-dialkylamino) chlorophosphines……………...…34
3.1.1.3 Synthesis of molecules with phosphorus DMG-s………………………....35
3.1.1.4 Reaction of 2-ethylphenol with bis(N,N-dialkylamino) chlorophosphines
to tetraalkyl phosphoamidous acid (2-ethyl)-phenyl esters…….…….…...36
3.1.1.5 Reaction of 2-ethylphenol to tetraalkyl phosphoroamidic acid (2-ethyl)-
phenyl ester…………………………..…………………………………....38
3.1.2 TRANSITION METAL CATALYSED CYCLOADDITION APPROACH…………...….40
3.1.2.1 Overview…………………………………………...……………………..40
3.1.2.1.1 Cross coupling reaction catalysed by palladium……………..…..…..40
3.1.2.1.2 The Heck reaction………………………………………………..…..41
3.1.2.1.3 The Heck oxyarylation reaction……………………………..………43
3.1.2.1.4 The Heck reaction of vicinal 1,2-disubstituted alkenes…………...…45
3.1.2.2 Synthetic approach to dihydrobenzofurans via palladium catalysed
cycloaddition reaction of halogen phenols…………………………….....47
3.1.2.2.1 Anethole as the starting material in the Heck oxyarylation reaction…48
3.1.2.2.2 Cinnamic alcohol as the starting material in
the Heck oxyarylation reaction………………………………...……..54
3.1.2.3 The influence of the geometry of the alkene substrate
on the stereochemistry of the dihydrobenzofuran product…………...…..59
3.1.2.4 Dihydrobezofurans via cycloaddition of pseudohalogen phenols………...59


3.1.2.5 Palladium catalysed cycloaddition reaction
in the presence of chiral ligands…………………………………...……..67
3.1.2.6 Transformation of aldehyde side chain of dihydrobenzofuran
compounds -approach to neolignan derivatives…………………………...75

CHAPTER 4: CONCLUSIONS………………………………………….………..…77
OUTLOOK………………………………………………………………………………………..…79

CHAPTER 5: EXPERIMENTAL PART……………………………………..…...…80

5.1 GENERAL INFORMATIONS…………………..……………………………………………..80
5.2 PREPARATION PROCEDURES…………………...…………………...…………………….81

REFERENCES
































Acknowledgements
I would like to thank Professor Martin G. Peter for giving me the opportunity to
work in his research group. My supervisor, Dr Sefkow was always there when I had a
problem, question or idea. His experience, kindness and professional knowledge were
always available to me.
Many thanks to my colleagues Alexander Janz, Andre Gessner, Attila Böhme, Viorel
Rusu, Arisara Isaree, Sven Bahrke, Derek Lightner, Solomon Derese, Zenko Zanev, Chuen-
How Ng, Frau Patzelt, Daniel Goltz, Fanny Lebouk, Frau Rotmann and all the others for a
pleasant working atmosphere and their kindness.
Special thanks to Frau Matern and Dirk Peikow for the fruitful discussions,
professional assistance and their contribution to my German language skills. It would have
been much harder without you.
Many thanks to Analytical chemistry department of the University of Potsdam
especially to Frau Dr. Starke and Frau Fürstenberg for recording and discussing the MS and
GC-MS spectra, Dr Koch, Dr Haydenreich and the NMR team as well as Frau Nachtigal and
Frau Priebus for recording the IR spectra.
Special thanks to Silvia Nita, MPI Golm, for motivation, advice, reading the PhD
draft and a lot of quality time.
Last but not least, I would like to thank my family and all my friends for all their help
and the support they have given me during my PhD period.






















Abbreviations
Abbreviations:


9-BBN................................................9-Borobicylco[3.3.1]nonane
acac.....................................................acetylacetonate
ATPA……………………………….Acids of Trivalent Phosphorus
Bn…………………………………...Benzyl
BINAP……………………………...(R)-(+)-2,2'-Bis(diphenylphosphino)-1’1’-binaphthyl
bmim................................................. 1-Butyl-3-methylimidazolium methylsulfate
Bu…………………………………...Butyl
COD……………………………..….cyclooctadecane
Cumyl…………………………….…α,α-dimethylbenzyl
dba……………………………….…dibenzylideneacetone
DMA………………………………..N,N-dimethylacetamide
DMF…………………………….…..Dimethylformamide
DMG…………………………….….Directing Metalation Group
DMSO………………………….…...Dimethylsulfoxide
DNA…………………………….…..Deoxyribonucleic Acid
DoM…………………………….…..Directed ortho Metalation Group
dppe.………………………………..1,2-Bis(diphenylphosphino)ethane
Et……………………………………Ethyl
EtOH………………………………..Ethanol
GC……………………………….....Gas Chromatography
HMPT………………………………Hexamethyl Phosphoroustriamine
HPLC.................................................High Performance Liquid Chromatography
iPr.......................................................2-Propyl
LDA………………………………...Lithiumdiisopropylamide
m-CPBA.............................................3-chloroperoxybenzoic acid
Me…………………………………..Methyl
NMP………………………………..N-methylpyrollidone
NMR………………………………..Nuclear Magnetic Resonance
OSEM……………………………....O-trimethylsilylethoxymethyl
PEG………………………………... Poly(ethylene)glycol
Ph…………………………………...phenyl
PTTL………………………………..N-phthaloyl–tert-Leucinate
QUINAP……………………………1-(2-Diphenylphosphino-1-naphyl)isoquinoline
sBuLi…………………………….…secondary butyllithium
TBAB………………………………tetrabutylammonium bromide
TBS………………………………....tert-Butyldimethylsilyl
tert……………………………….…tertiary
TLC………………………………...Thin Layer Chromatography
TMS………………………….……..trimethylsilyl
TMEDA………………….…………tetramethyl ethylenediamine
Ts………………………….………..para-toluenesulphonyl
Tf………………………….………..Triflate
THF……………………….………..Tetrahydrofuran
RT………………………….……….Room Temperature




Chapter 1 Introduction
CHAPTER 1 INTRODUCTION

Human health is one of the most important issues that has been addressed in the past
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trying to prevent, diagnose, treat and understand the reasons, mechanisms and pathways of
disorders in the normal function of the human body. Extracts from plants, since they have
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extracts, elucidation of their structure and understanding their mode of action.
An example of how natural compounds can become powerful anti-cancer drug is the
case of podophyllotoxin (1) (Figure 1). This natural compou