Novel heterocyclic methodologies and total syntheses

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Synthesis of bioactive compounds of pharmaceutical interests represents a continuing challenge and is crucial for finding new treatments for diseases and other nosocomial infections. Most of the compounds demonstrating biological properties against these pathologies possess a heterocyclic or a polycyclic skeleton such as vindoline (an important subunit of the anticancer drug vinblastine) as well as others related alkaloids. Unfortunately, the natural amount of these products is generally low and would require damaging an ecosystem to provide treatments to patients. Consequently, it is extremely important to support fundamental research to discover new synthetic tools to produce the main core of these structures quickly as well as their potential analogs. In this context, the research program presented in this proposal will be divided into two different and complementary parts dedicated to the development of novel environmental methodologies enabling the rapid formation of heterocyclic motifs and their direct applications in total synthesis of bioactive natural products.*******We would like to extend our research program on hypervalent iodine chemistry to develop novel applications such as an asymmetric dearomatizing [2+3] cyclo-addition process enabling the formation of polycyclic indoline subunits from aromatic cores derived from petroleum. We will develop an oxidative dearomatizing Diels-Alder (and related cycloaddition processes) that would allow transforming simple aromatics into functionalized polycyclic systems containing a quaternary carbon center.*We also envisage applying this strategy to indoles to produce new interesting functionalized structures.*In addition, further strategies to our previous research program involving iodanes will be described to produce complex alkaloids such as vindoline, deethylibophylidine, etc.*******We will also develop a new expertise in our laboratory based on our promising results to develop a functional protecting group. Indeed, we aim to change the protecting group approach, which would not be only a functionality modulator but also a final moiety of the desired target that could be incorporated during the deprotecting step via a Truce-Smiles rearrangement that would release only sulfur dioxide as a byproduct by gas evolution. This strategy should rapidly lead to indole and indoline subunits and their direct applications in total synthesis of bioactive compounds such as tabersonine or aspidospermidine to illustrate the potential of this environmentally friendly approach.**