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

不饱和四元环体系是有机合成中的重要配体。然而，由于缺乏多样和可用的方法，限制了目前可能进行的研究的范围。通过创新和前所未有的战略，我们希望开发一个新的工具箱，简化这些架构的访问和复杂性。我们已经证明了一锅序列进行非对映体和对映体选择性形成的亚烷基环丁烷结合硼同系物化和硼烯丙基化反应的巨大潜力。为了发展快速、多样化的四元环衍生物的合成，我们将接受在环状结构的核心引入杂原子的挑战。由于四元杂环已被认为是药物发现中的重要模式，因此新颖且直接的构建方法将成为有机化学和药物化学中非常有价值的工具。氮杂环丁烷、氧杂环丁烷和硫杂环丁烷将通过新的合成方法得到，并通过硼烯丙基化或γ-选择性交叉偶联反应进一步衍生为亚烷基四元杂环分子。此外，他们的功能化将被探索，为进一步的研究开辟一个全新的基板景观。所获得的乙烯基-环丁烯，-氮杂环丁烷，-氧杂环丁烷和-硫杂环丁烷将被带到下一个层次的分子结构，通过发展立体和区域选择性狄尔斯-阿尔德反应，提供复杂的稠环系统。与此同时，将努力将这些独特的一锅序列的合成天然存在的倍半萜类的protoilluminescent类，这提出了有趣的生物学特性。基于我们先前建立的方法，已经设计了便利的和立体选择性的途径来获得这样的4-6-5稠合环系统，并且这些将允许从常见中间体开始的不同支架的广泛多样化。与制药部门合作，将评估替代品的抗菌和抗真菌特性，最终导致这类化合物的药物化学的巨大改进，其合成几乎没有被探索过。

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.