Synthetic Studies on Daphmanidin C and Maytenone Based on Biosynthetic Considerations and Natural Product Hybrids as Tools for Quorum Sensing
The isolation and characterisation of natural products remains a challenge in chemistry owing to nature's magnificent diversity. Natural products or natural product derivatives have always been used in traditional medicine to treat a variety of diseases. To date, these compounds or their derivatives represent 40-60 % of total drugs found on the market. Hence, they provide key leads and structural inspiration in the search for next generation therapeutic drugs. This thesis is divided in two parts and comprises three research projects, which are presented in Chapter 2, 3 and 4. Each chapter presents the synthesis of three types of natural products that could be used as potential therapeutic agents. Each chapter includes an introduction, an overview of previous contributions in the field, a detailed account of our work and a conclusion. Experimental procedures and references are reported at the end of each chapter for convenience. After the presentation of the general conclusion in Chapter 5, spectroscopic data is available. The first part of this thesis documents the synthetic efforts towards daphmanidin C and maytenone, two natural products with interesting biological properties. Daphmanidin C is an Daphniphyllum alkaloid which displayed promising results for the treatment of neurodegenerative diseases during biological testings. Chapter 2 describes the synthesis of the three fragments into which this molecule was divided. The synthetic strategy was then studied on a model system and shown to be relevant. Chapter 3 presents an improved synthetic sequence towards ferruginol, postulated precursor of maytenone and iso-maytenone, two bis-homoditerpenes possessing a complex skeleton which has challenged chemists since the 1960s. Studies of the oxidative biomimetic dimerisation of ferruginol are discussed and an outlook on a potential new strategy to address the synthesis of these dimers is proposed. Part II presents a novel approach to the field of quorum sensing which involves the use of natural product hybrids. Natural product hybrids result from the fusion of two or more fragments of natural products while retaining the biological function of each entity. Chapter 4 describes the design and the synthesis of hybrids which may interact with quorum sensing pathways. These hybrids may be used for surface functionalisation, as molecular probes in chemical biology or as potential antibacterial agents. The General Conclusion (Chapter 5) synthesis the achievements of the two main parts of this thesis.
Keywords: Natural products ; Total synthesis ; Neurodegenerative diseases ; Quorum sensing ; Bacteria ; Substances naturelles ; Synthèse totale ; Maladie neurodégénératives ; Quorum sensing ; BactérieThèse École polytechnique fédérale de Lausanne EPFL, n° 4638 (2010)
Programme doctoral Chimie et Génie chimique
Faculté des sciences de base
Institut des sciences et ingénierie chimiques
Laboratoire de synthèse chimique
Record created on 2010-02-03, modified on 2016-08-08