Enantioselective Organocatalytic Reaction Cascades of Substituted Pyrroles
and their Application in Complex Alkaloid Natural Product Synthesis
Date du début: 1 sept. 2011,
Date de fin: 31 août 2013
"Tracking the footsteps of nature, organocatalytic systems allow the formation of highly enantioenriched products starting from simple achiral substrates. Within this context, enantioselective organocatalytic cascade reactions have emerged as a powerful tool for the design of complex molecular architectures in single-step conversions. During this Fellowship we intend, in a very early stage, to address new, straightforward and synthetically powerful enantioselective cascade reactions towards the complex perhydroindole ring structure; a saturated and functionalized 6,5-fused bicycle system which is present in several targets with significant biological activities.Specifically, our methodology will be supported by the development of new asymmetric, organo-catalysed Michael, Michael cyclization cascades of activated pyrrole substrates with α,β-unsaturated ketones. In this sense our proposal takes advantage of the chemical reactivity of activated pyrrole substrates, based on their high acidity, and therefore tendency to enolisation giving the tautomeric nucleophilic form. This species can react with electron deficient alkenes by means of an organo-catalysed Michael addition. At this point, favoring the optimal catalytic conditions, we have envisioned that the intermediate Michael adduct can undergo an intramolecular Michael addition cascade to afford the desired bicycle target.Highlighting the scope of our approach towards the perhydroindole ring core, we are aiming to accomplish the first total synthesis of Daphhniyunnine D, a complex and important alkaloid recently isolated from a shrub endemic of the Peoples Republic of China, and with a prominent cytotoxic activity against several tumor cell lines. The Fellowship will touch therefore contemporary areas of modern chemical research, such as asymmetric methodology, catalysis and target oriented synthesis approaches towards bioactive compounds."
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