Studies towards the total synthesis of biological active gamma-butyrolactones

257 Pages·2007·7.11 MB·English

by  Andreas Schall

Studies Towards the Total Synthesis of
Biological Active γ-Butyrolactones

Dissertation

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

vorgelegt von

Andreas Schall
aus
Runding

Regensburg 2007
Die Arbeit wurde angeleitet von: Prof. Dr. O. Reiser

Promotionsgesuch eingereicht am: 25. Mai 2007

Promotionskolloquium am: 26. Juni 2007

Prüfungsausschuss: Vorsitz: Prof. Dr. H. Krienke
1. Gutachter: Prof. Dr. O. Reiser
2. Gutachter: Prof. Dr. B. König
3. Prüfer: Prof. Dr. S. Elz

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Der experimentelle Teil der vorliegenden Arbeit wurde unter der Leitung von Herrn Prof. Dr.
Oliver Reiser in der Zeit von Oktober 2003 bis Mai 2007 am Institut für Organische Chemie
der Universität Regensburg sowie in der Gruppe von Prof. Dr. Paul Hanson, University of
Kansas, angefertigt,

Herrn Prof. Dr. Oliver Reiser möchte ich herzlich für die Überlassung des äußerst
interessanten Themas, die anregenden Diskussionen und seine stete Unterstützung während
der Durchführung dieser Arbeit danken.

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for my family…

“If you want to build a ship,
don't drum up the men to gather wood,
divide the work and give orders.

Instead, teach them to yearn for the vast and endless sea.”

Antoine de Saint-Exupéry (1900 - 1944)

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Table of Content

Table of Content

1. APPROACHES TO THE TOTAL SYNTHESIS OF BIOLOGICAL ACTIVE
GUAIANOLIDES WITH A TRANS-ANNULATED LACTONE MOIETY 8
1.1 INTRODUCTION 8
1.2 BIOSYNTHESIS OF GUAIANOLIDES 10
1.3 RACEMIC APPROACHES TOWARDS GUAIANOLIDES 15
1.4 STEREOSELECTIVE TOTAL SYNTHESIS OF GUAIANOLIDES 21
1.5 HEMI-SYNTHESIS STARTING FROM SANTONIN 28
1.6 CONCLUSIONS 35
2. AIM OF THIS WORK 36
2.1 CYNAROPICRIN - THE HERB PRINCIPLE OF ARTICHOKE 36
2.2 IXERIN Y - A GUAIANOLIDE SESQUITERPENE LACTONE GLUCOSIDE 37
2.3 RETROSYNTHETIC ANALYSIS OF THE TARGET COMPOUNDS 38
3. SYNTHESIS OF CHIRAL ALLYLSILANES 40
3.1 SYNTHESIS OF THE ENANTIOMERIC PURE CYCLOPENTENONE 41
3.2 SYNTHESIS OF THE CHIRAL ALLYLSILANES 44
4. SYNTHESIS OF THE CYCLOPROPYLCARBALDEHYDE 47
5. FORMATION OF THE ANTI-SUBSTITUTED LACTONE ALDEHYDE 50
6. INVESTIGATIONS TOWARDS 5,6,5-RING SYSTEMS 53
6.1 INTRAMOLECULAR CARBONYL-ENE REACTION 53
6.2 SMI -PROMOTED RADICAL CYCLIZATION 55
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7. INVESTIGATIONS TOWARDS THE GUAIANOLIDE CORE SKELETON 56
7.1 RADICAL CYCLIZATION APPROACH 56
7.2 RING CLOSING METATHESIS APPROACH 59
7.3 SYNTHESIS OF A 3X3 SCAFFOLD LIBRARY 65

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Table of Content

8. TOWARDS CYNAROPICRIN AND IXERIN Y 73
8.1 INVERSION OF THE C4-STEREOCENTER 73
8.2 INVESTIGATIONS ON EPOXIDATIONS 75
8.3 TAMAO-FLEMING OXIDATION 76
8.4 OXIDATION AT THE C8-POSITION 81
8.5 ELIMINATION REACTIONS 82
9. STEREOSELECTIVE SYNTHESIS OF SMALL MOLECULE HAT INHIBITORS 88
10. SUMMARY 94
11. EXPERIMENTAL PART 97
11.1 GENERAL 97
11.2 ABBREVIATIONS 99
11.3 SYNTHESIS OF CHIRAL ALLYLSILANES 100
11.4 SYNTHESIS OF THE CYCLOPROPYLCARBALDEHYDE 115
11.5 FORMATION OF THE ANTI-SUBSTITUTED LACTONE ALDEHYDE 119
11.6 RADICAL CYCLIZATION 121
11.7 PRECURSORS FOR RING CLOSING METATHESIS 124
11.8 RING CLOSING METATHESIS 131
11.9 SYNTHESIS OF A 3X3 SCAFFOLD LIBRARY 137
11.10 TOWARDS CYNAROPICRIN AND IXERIN Y 150
11.11 STEREOSELECTIVE SYNTHESIS OF GCN5 INHIBITORS 165
12. APPENDIX 170
12.1 NMR - SPECTRA 170
12.2 X-RAY DATA 231
13. REFERENCES 244

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Introduction
1. Approaches to the total synthesis of biological active
guaianolides with a trans-annulated lactone moiety

1.1 Introduction
Guaianolides, consisting of a tricyclic 5,7,5-ring system represent a large subgroup of
naturally occurring sesquiterpene lactones exhibiting significant biological activity.[1,2] Plants
containing such compounds as the active principles have been used in traditional medicine
throughout history for treating conditions ranging from rheumatic pains, increase of bile
production to pulmonary disorders.

Figure 1. Skeletal relationships.

As the name itself indicates, the core structure of the guaianolides is derived from Guaiane, a
natural product with a cis-fused 5,7-bicyclic hydroazulene ring-system (Figure 1). With only a
few exceptions the hydroazulene core is also cis-fused in the 5,7,5-tricyclic carbon skeleton,
while the γ-butyrolactone ring is trans-annulated in approximately 85% of all known
guaianolides.[3]
This interesting class of natural products shows a broad range of biological activity (Figure 2)
stimulating the development of research towards their total synthesis. Although several
strategies especially towards monocyclic γ-butyrolactones are reported to date,[4-10] only a few
groups succeeded in the total synthesis of guaianolides.[10-14]

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Introduction

H H H
H O H H H H
O O O O O O O
H H H
Dehydrocostus
Cladantholide(3)
Arglabin(1) Lactone(2)
isolatedfrom isolatedfrom isolatedfrom
Artemisiaglabella costusroot(mokko) Cladanthusarabicus
farnesyltransferase antimycobacterialactivity antifeedantactivity
inhibitor (MIC=2-16µg/ml)
(IC =0.9-5.0µg/ml) R1O
50
H HOHO OAc
H
H H H H H R2
O O O O O
O H H
H
OR3
O
Estafiatin(4) Eremanthin(5) Thapsigargins(6)
isolatedfrom isolatedfrom isolatedfrom
Artemisiamexicana Eremanthuselaeagnus Thapsiagarganica
antihelminthicactivity schistosomicidalactivity potentCa-modulating
properties
Figure 2. Some guaianolides, representing the structural diversity of this class of compounds.

The structure-activity relationship (SAR) of α-methylene sesquiterpene lactones was
intensively studied.[15-20] It was shown that these compounds can react by conjugate addition
of various biological nucleophiles such as cystein or thiol-containing enzymes (E-SH)
(Scheme 1). Consequently, α-methylene sesquiterpene lactones are good alkylation agents
manifesting their biological activity but also their cytotoxicity.

Scheme 1. Michael addition on α-methylene sesquiterpene lactones.

There is further evidence, that compounds of this type inhibit cellular enzyme activity and do
not show DNA-alkylating properties.[18,21-26] Furthermore it is assumed that the residual
substitution pattern of the guaianolides determines the specificity and the resulting biological
activity.[11]

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Introduction
1.2 Biosynthesis of guaianolides
1.2.1 The mevalonate pathway
Since ancient times various oils with intensive and mostly delightful fragrances were
extracted from numerous plants. In the beginning direct distillation and later on steam
distillation were common techniques to afford the essential oils, which mainly consisted of
terpenes. Until now more than 30,000 terpenes from all sources have been identified, making
them a large and structurally highly diverse family of natural products. It was early
recognized that terpenes are formally derived from C -isoprene units (7), but that isoprene (8)
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itself, a metabolite produced naturally, is not involved in their formation (Figure 3).

Figure 3. Comparsion of C -units.
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The biochemically active isoprene units are isopentenyl-pyrophosphate (IPP, 9) and
γ,γ-dimethylallyl-pyrophosphate (DMAPP, 10). These important precursors are formed via
certain biochemical pathways that have been extensively studied over the last 50 years leading
to the generally accepted mevalonate (MVA) biosynthesis pathway of terpenes in
organisms.[27-30] More recently a second biosynthetic route was discovered in plants also
leading to IPP (9) and DMAPP (10) as the final products.[30-32] This so called mevalonate
independent pathway or methylerythritol-phosphate pathway (MEP) is only found in a few
plants and microorganisms. It was also recognized that the MVA-pathway is located in the
cytosol and the MEP-pathway takes place in the plastids (chloroplasts, leukoplasts, etc.).
Furthermore, in organisms equipped with both pathways, a limited exchange of intermediates
between MVA and MEP also appears. This may explain why the MEP pathway was
completely overlooked until labeling experiments revealed its existence.[33-36]
The biosynthesis in the cytosol starts with the assembly of three molecules of activated acetic
acid (acetyl-CoA) (11) by an initial Claisen-condensation and a subsequent aldol reaction to
give β-hydroxy-β-methyl-glutaryl-CoA (13) (Scheme 2).

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