First expedient syntheses of naturally occuring protoilludane type sesquiterpenes and analogues; Application of innovative and unprecedented routes for the formation of cyclobutenes, alkylidenecyclobutanes and unsaturated four-membered heterocycles

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Unsaturated four-membered ring systems are important synthons in synthetic organic chemistry. However, a lack of diverse and available methodologies limit the current scope for possible studies. Through innovative and unprecedented strategies, we wish to develop a new toolbox that would simplify access and sophistication of such architectures. We already demonstrated the great potential of one-pot sequences to undergo the diastereo- and enantioselective formation of alkylidenecyclobutanes by combining boron-homologation and boron-allylation reactions. In order to develop rapid and diversified syntheses of four-membered ring derivatives, we will take on the challenge of introducing heteroelements to the core of cyclic structures. As four-membered heterocycles have been recognized as important patterns in drug discovery, novel and straightforward methods towards their construction will represent highly valuable tools in organic and medicinal chemistry. Azete, oxete and thiete will be obtained via new synthetic methods and further derivatized into alkylidene four-membered heterocyclic molecules, employing either boron-allylations or gamma-selective cross-coupling reactions. In addition, their functionalization will be explored to open a landscape of entirely new substrates for further studies. The obtained vinyl-cyclobutenes, -azetes, -oxetes and -thietes will be taken to the next level of molecular architectures by developing stereo- and regioselective Diels-Alder reactions, to furnish complex fused ring systems. In parallel, efforts will be made to apply these unique one-pot sequences to the synthesis of naturally occurring sesquiterpenoids of the protoilludane class, which present interesting biological properties. Expedient and stereoselective routes have been designed to access such 4-6-5 fused cyclic systems, based on the methodologies that we have previously established, and these would allow for a wide diversification of the different scaffolds, starting from common intermediates. In collaboration with the pharmaceutical department, surrogates will be evaluated for their antibacterial and antifungal properties to ultimately lead to great improvements in medicinal chemistry on this specific class of compounds, the synthesis of which has scarcely been explored.