Design of Bio-Inspired Materials and Total Synthesis of Securinega Alkaloids

230 Pages·2017·11.5 MB·English

Design of Bio-Inspired Materials and
Total Synthesis of Securinega Alkaloids

Inauguraldissertation

zur
Erlangung der Würde eines Doktors der Philosophie
vorgelegt der
Philosophisch-Naturwissenschaftlichen Fakultät
der Universität Basel

von
Robin Wehlauch
aus Wolfen, Deutschland

Basel 2017

Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel
edoc.unibas.ch
Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät
auf Antrag von:

Prof. Dr. Karl Gademann
Prof. Dr. Konrad Tiefenbacher

Basel, den 13.12.2016
Prof. Dr. Jörg Schibler
Dekan
Für meine Familie

Table of Content

Abstract v
Abbreviations, Acronyms and Symbols vii

1 Nitrocatechols for Light-Induced Small Molecule Release 1
1.1 Introduction 1
1.1.1 Catechols in Nature 1
1.1.2 Catecholic Surface Coatings 6
1.2 A Tractable Surface Release System 12
1.3 Results and Discussion 16
1.3.1 Improved Synthesis of the Photo-Labile Anchoring Unit 16
1.3.2 Functional Group Evaluation 19
1.3.2.1 Synthesis of Functional Group Analogs 19
1.3.2.2 Photo-Cleavage 22
1.4 Conclusion 25

2 Catecholic Binders for Dynamic Functional Systems 27
2.1 Dynamic Covalent Bonds in Functional Systems 27
2.2 Results and Discussion 33
2.2.1 Synthesis of Catechol Derivatives 33
2.2.2 Application of Electron-Poor Catechols in Triply Dynamic Functional Systems
41
2.2.3 New Generation Binders 45
2.3 Conclusion 48

3 Rapamycin-Based Probes for the Structural Investigation of TOR
Complexes 51
3.1 Introduction 51
3.2 Concept of the Project 55
3.3 Results and Discussion 57
3.3.1 Synthesis of Rapamycin-Biotin Hybrids 57
3.3.2 Synthetic Studies towards a Rapamycin-Gold Nanoparticle Conjugate 63
3.4 Conclusion 66
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4 Synthetic Studies on the Securinega Alkaloids 69
4.1 The Securinega Alkaloids – A Literature Review 69
4.1.1 General Overview 69
4.1.2 Biological Activities 76
4.1.3 Biosynthesis 84
4.1.4 Total Synthesis of Securinega Alkaloids 91
4.1.5 The Total Syntheses of Bubbialidine and Virosaine A 100
4.1.6 Secu’amamine E and its Enantiomer Virosine A 102
4.2 The First Enantioselective Total Synthesis of Secu’amamine E 104
4.2.1 Synthetic Outline 104
4.2.2 Synthesis of the C Ring Fragment 105
4.2.3 Construction of the D Ring Butenolide 107
4.2.4 Final Assembly of Secu’amamine E 110
4.3 Rearrangements of Neo(nor)securinane- to (Nor)securinane-type Alkaloids 114
4.4 Conclusion 118

5 Conclusion 121

6 Experimental 125
6.1 General Information 125
6.2 UV-Labile Nitrocatechol Derivatives 127
6.3 New Electron-Poor Catechol Derivatives 135
6.4 Rapamycin-Based Probes 145
6.5 Securinega Alkaloids 152

7 Appendix 163
NMR Spectra 163
Acknowledgements 213

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Abstract
This thesis is divided into four chapters presenting distinct research projects that address
challenges in the fields of functional systems chemistry, chemical biology, and the total
synthesis of natural products. Experimental details, analytical data and appendices are enclosed
at the end of this work.
Chapter 1 introduces the concept of electron-poor catechols as surface binding agents and
highlights some of the natural role models. The development of a synthetic surface modification
platform for the controlled release of small molecules is described. Nitrocatechol-based
anchoring units allowed for the immobilization of a molecular cargo on titanium dioxide
surfaces and cleavage on demand by UV irradiation.

Chapter 2 expands the application of small catechol binders. The design and synthesis of new
polar derivatives facilitated the use of boronate esters in dynamic functional systems and led to
the discovery of the third orthogonal dynamic covalent bond.
Chapter 3 reports on the preparation of biochemical probes for the investigation of the cellular
target of rapamycin. An efficient assembly of natural product hybrids from rapamycin was
achieved without the need for protection of the macrolide. The antiproliferative activity of the
parent compound was shown to be largely conserved in the novel substances.
Chapter 4 provides a detailed review of the literature on Securinega alkaloids. The first
enantioselective total synthesis of secu’amamine E was accomplished in twelve linear synthetic
steps and 8.5% overall yield. Three examples of an intriguing rearrangement process were
studied allowing for the direct interconversion of natural products with implications for a new
biogenetic hypothesis.

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