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Asymmetric methodologies for the construction of 5,7,5- and 6,6,6-tricyclic sesquiterpene lactones towards the synthesis of Arglabin [Elektronische Ressource] / vorgelegt von Won Boo Jeong

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219 pages
Asymmetric methodologies for the construction of 5,7,5- and 6,6,6-tricyclic sesquiterpene lactones towards the synthesis of Arglabin Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) an der Fakultät für Chemie und Pharmazie der Universität Regensburg Vorgelegt von Won Boo Jeong aus Busan (Republic of Korea) Regensburg 2006 Diese Arbeit wurde angeleitet von : Prof. Dr. O. Reiser Promotionsgesuch eingereicht am : 7. Juni 2006 Promotionskolloquium am : 14. Juli 2006 Prüfungsausschuß : Vorsitz: Prof. Dr. S. Elz 1. Gutachter: Prof. Dr. O. Reiser 2. Gutachter: Prof. Dr. B. König 3. Prüfer: Prof. Dr. A. Pfitzner Die vorliegende Arbeit wurde in der Zeit von Oktober 2001 bis Mai 2006 am Institut für Organische Chemie der Universität Regensburg unter der Leitung von Prof. Dr. O. Reiser angefertigt. Meinem Lehrer, Prof. Dr. O. Reiser, möchte ich herzlich für die Überlassung des interessanten Themas, die beständige Unterstützung und Geduld in jeglicher Hinsicht während der Durchführung dieser Arbeit danken. To my father, mother, and family.
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Asymmetric methodologies for the construction of
5,7,5- and 6,6,6-tricyclic sesquiterpene lactones
towards the synthesis of Arglabin


Dissertation

zur Erlangung des Doktorgrades
der Naturwissenschaften (Dr. rer. nat.)
an der Fakultät für Chemie und Pharmazie
der Universität Regensburg




Vorgelegt von


Won Boo Jeong

aus

Busan (Republic of Korea)



Regensburg 2006
























Diese Arbeit wurde angeleitet von : Prof. Dr. O. Reiser

Promotionsgesuch eingereicht am : 7. Juni 2006

Promotionskolloquium am : 14. Juli 2006

Prüfungsausschuß : Vorsitz: Prof. Dr. S. Elz
1. Gutachter: Prof. Dr. O. Reiser
2. Gutachter: Prof. Dr. B. König
3. Prüfer: Prof. Dr. A. Pfitzner
Die vorliegende Arbeit wurde in der Zeit von Oktober 2001 bis Mai 2006 am Institut für
Organische Chemie der Universität Regensburg unter der Leitung von Prof. Dr. O. Reiser
angefertigt.






























Meinem Lehrer, Prof. Dr. O. Reiser, möchte ich herzlich für die Überlassung des
interessanten Themas, die beständige Unterstützung und Geduld in jeglicher Hinsicht
während der Durchführung dieser Arbeit danken.

























































To my father, mother, and family.

























































Index

A. Introduction···································································································· 1

1. Anticancer drug discovery·······························································································1
2. The methodological advances of drug development process ··········································1
3. FTIs (Farnesyl Transferase Inhibitors) as novel anticancer therapeutic agents···············3
4. The synthetic approaches towards guaianolides and pseudoguaianolides ······················7
5. 2,3-anti substituted γ-butyrolactone carbaldehyde as key building block for the
Guaianolide synthesis ····································································································17
6. Aim of this work ············································································································19


B. Main Part······································································································20

1. Asymmetric synthesis of guaianolides (GLs) towards Arglabin······························· 20
1.1 Stereoselective synthesis of γ-butyrolactones (GBLs) ··········································20
1.2 Synthesis of cyclic allylsilanes ··············································································24
1.2.1 Synthesis of optically active mono protected cis-2-cyclopenten-1,4-diol
derivatives······································································································24
1.2.2 Synthesis of cyclic silyl enol ether ·······························································28
1.2.3 Synthesis of cyclic allylsilanes ·····································································30
1.3 Asymmetric cyclopropanation and ozonolysis ······················································31
1.3.1 Asymmetric cyclopropanation······································································31
1.3.2 Cyclopropanation of furan-2-carboxylic ester··············································32
1.3.3 Ozonolysis of the cyclopropyl furan-2-carboxylic esters·····························34
1.4 Formation of γ-butyrolactone carbaldehyde··························································35
1.4.1 Determination of stereochemistry on nucleophilic addition to carbonyl
compound: Cram’s rule and Felkin-Anh rule···················································35
1.4.2 Synthesis of GBLs incorporating racemic nucleophiles·······························37
1.4.3 Synthesis of GBLs using optically active nucleophiles································38
1.4.4 Explanation of diastereoselectivity during the synthesis of GBLs using
enantiomerically pure allylsilanes ·································································39
1.4.5 Explanation of diastereoselectivity of GBLs using enantiomerically
enriched allylsilanes ······················································································42
1.5 Towards the total synthesis of Arglabin·································································45
1.5.1 Model study for the synthesis of Arglabin····················································45
1.5.2 Towards the total synthesis of Arglabin························································49 1.5.3 RCM under microwave irradiation ······························································ 52
1.5.4 Barton-McCombie desoxygenation······························································ 54
1.5.5 Epoxidation and debenzylation···································································· 56
1.5.6 Formation of double bond at C3-C4 via dehydration ·································· 60
1.5.7 α-functionalization of GBLs········································································ 61

2. Rearrangement of 5,7,5-tricyclic GBL to 6,6,6-tricyclic δ-valerolactone ··············· 64
2.1 Rearrangement of 5,7,5-tricyclic GBL to 6,6,6-tricyclic δ-valerolactone ············ 64
2.2 Wagner-Meerwein rearrangement ········································································· 70
2.3 Synthetic applications of 6,6,6-tricyclic δ-valerolactone analogues as building
blocks for natural products syntheses ··································································· 72

3. Conformational analysis of saturated GBL ester chromophore via CD ················· 75
3.1 Circular Dichroism································································································ 75
3.2 CD measurements of the C6-C7 trans-fused SLs containing GBL ester
Chromophore ········································································································ 78


C. Summary·······································································································86


D. Experimental Part ·······················································································92

1. General Remarks··········································································································· 92
2. Data Analysis ················································································································ 94


E. Appendix ·····································································································139

1. NMR spectra ··············································································································· 140
2. X-ray data···················································································································· 182


F. References····································································································197




Abbreviations

abs. absolute eq. equivalents
Ac Acetyl Et Ethyl
AcOH Acetic acid EtOH Ethanol
AIBN Azoisobutyronitrile EWG Electron Withdrawing Group
anhyd. anhydrous GBL γ-butyrolactone
Ar Argon GL(s) Guaianolide(s)
Bn Benzyl h hour(s)
BnBr Benzylbromide HMPA Hexamethylphosphoramide
BOX Bisoxazoline HRMS High Resolution Mass
Bu Butyl spectroscopy
BuLi Butyllithium IR Infrared Spectroscopy
cat. catalytic amounts L.A. Lewis Acids
CD Circular Dichroism LDA Lithiumdiisopropyl amide
CE Cotton Effect M.S. Molecular Sieve
DBU 1,8-Diazabicyclo[5.4.0]- M.W. Microwave irradidation
undec-7-ene MAOS Microwave Assisted Organic
DCE 1,2-dichloroethane Synthesis
DDQ 2,3-dichloro-5,6- mCPBA meta-chloroperbenzyoic
dicyanobenzoquinone acids
DEAD Diethylazodicarboxylate Me Methyl
DEPT Distortionless Enhancement MeI Methyliodide
by Polarization Transfer MeOH Methanol
diast. Diastereomer(s) Mes Mesityl
DIPA Diisopropylamine min minute(s)
DMAP Dimethylaminopyridine Ms Methansulfonyl
DMDO Dimethyldioxiranes MS Mass Spectroscopy
DMPU 1,3-dimethyl-3,4,5,6- NaHMDS Sodium-
tetrahydro-2-(1H)- hexamethyldisilazane
pyrimidinone NMR Nuclear Magnetic Resonance
DMS Dimethylsulfide NOE Nuclear Overhauser Effect
dr Diastereomeric ratio Nu Nucleophile
EA Ethyl Acetate org. organic
EDG Electron Donating Group PCC Pyridinium Chlorochromate
EDG Electron Donating Group PE Petroleum Ether
ee Enantiomeric excess PG Protecting Group
ent enantiomer PGL(s) Pseudoguaianolide(s)
epi epimer Ph Phenyl PMB para-methoxybenzyl TBDMS tert-butyldimethylsilyl
PMBCl para-methoxybenzylchloride TBDPS tert-butyldiphenylsilyl
PPh Triphenylphosphine TBME tert-butylmethylether 3
tPPL Porcine Pancreatine Lipase Bu tert-butyl
Prod. Product(s) tert tertiary
PTSA para-toluenesulfonicacid TES Triethylsilyl
quant. quantitative Tf O Trifluoromethanesulfonic 2
RCM Ring Closing Metathesis Anhydride
rt. room temperature THP Tetrahydropyran
S.M. Starting Material(s) TMEDA N,N,N',N'-
sat. saturated Tetramethylethylenediamine
sec secondary TMS Trimethylsisly
SLs Sesquiterpene Lactones TMSCl Trimethylsilylchloride
TBAF Tetrabutylammoniumfluoride