Lay summary
The total synthesis of natural products and analogues proved over the years to be a very reliable method for the discovery of new drugs. Due the structural complexity of many natural products, efficient synthetic methods are required to synthesize them in order to make them (as well as analogues) available to scientists involved in drug discovery. Our research program aims at finding methods and strategies that can be applied for efficient synthesis of different classes of products possessing an interesting biological profile. Development of processes involving radical chemistry, organometallic chemistry and enantioselective catalysis will be investigated. Our research focus on increasing the efficiency of target molecule synthesis by minimizing the number of synthetic steps, by opening new synthetic pathways, and by developing environmentally friendly reagents. The project is subdivided in three sub-chapters according to synthetic methods:1) Boron reagents for radical chemistry. Radical reactions have been intensively investigated during the last two decades. The new synthetic methods that aroused from this work are characterized by their mildness and their complement to ionic processes. The potential of these reactions is immense as demonstrated by their recent use in the synthesis of complex natural products. Our effort will be concentrated on the development of non-toxic and environmentally friendly reagents to perform efficient radical reactions. Organoboranes will be used to generate radicals that are functionalized close to the radical center. The extremely rich chemistry of organoboron species will play a crucial role in developing these new reagents. The combination of organoborane chemistry with the chemistry of well-established antioxidants will also be investigated in order to develop a simple an efficient procedure to reduce radicals and to run unique radical rearrangements.2) Azide chemistry. The formation of carbon-nitrogen bonds under very mild reaction conditions represents a very useful tool for the total synthesis of alkaloids. Reagents and procedures to prepare alkyl azides via radical pathways are explored. They will allow the development of highly efficient and practical syntheses of polycyclic alkaloids isolated from marine organisms (cylindricines) and plants (aspidosperma alkaloids). A unique rearrangement of alkyl azides, the intramolecular Schmidt reaction, has been for the first time run under non-acidic conditions. Further development of this process is expected to offer exceptional opportunities for the preparation of complex alkaloid skeletons in an excitingly concise manner.3) Organocopper chemistry. Due to their exceptional reactivity, organocopper reagents play a unique role in organic synthesis. Two reactions will be investigated. The first process is an original annulation procedure that affords fused bicyclic systems in one step via a cascade reaction. The second process concerns the generation of congested quaternary amino substituted carbon centers. In a one-pot process, up to three carbon-carbon bond will be created. Applications for the synthesis of polycyclic Cephalotaxus and Erythrina alkaloids are foreseen.