Stereoselective Process involving radicals. Synthesis and Methodology.

我们研究计划的长期目标之一是从战略和理论的角度做出贡献，找到在非环分子上创建新的立体中心的方法。我们特别感兴趣的是涉及自由基中间体的方法的发展。这些研究已经导致了各种工具的开发，我们计划将其用于合成具有生物学意义的天然产品或其类似物，作为我们药物化学努力的一部分。*立体选择性自由基反应和生物相关分子的合成。我们研究了碳中心自由基上的非对映选择性氢转移和烯丙化反应，侧翼分别是酯和立体中心。通过实验和密度泛函理论计算对这些反应的范围和机理进行了深入的研究。我们计划通过探索非对映选择性氟化和其他自由基加成反应来进一步发展这些方法。将氢转移与Mukaiyama Aldol反应相结合，使我们发展了一种合成聚酮(津可保林、离子霉素等)的最普遍的方法。盐霉素是一种新出现的用于消除对现有药物耐药的癌症干细胞(CSC)的分子，它是聚酮家族的成员。我们计划确定负责其活性的分子部分(即药效团)，并合成简化的类似物。*核苷类似物的合成。在上一个授权期，我们已经证明了我们可以合成在过去非常困难地制备的空间受阻的核苷。利用我们课题组开发的自由基反应，我们最近成功地制备了具有全碳立体生成四元中心的无环分子，侧翼带有各种官能团。这些分子可以利用我们实验室以前研究的反应序列来制备无环和环状核苷类似物。使用这些方法和本文提出的其他方法，我们将制备两个新的核苷类似物家族，它们在C3‘或C2’具有一个四元中心，具有重要的药用潜力。*生物活性多糖模拟物的合成。我们最近假设并报道了一个具有构象偏向的小分子可以有利地取代生物活性多糖亚单位之一。在我们的第一个研究中，我们选择修改sialyl Lewis X(SLeX)作为原理证明。我们计划通过在这种情况下测试其他非环小分子来扩大我们的研究。**

One of the long-term objectives of our research program is to contribute from a strategic and theoretical standpoint with approaches leading to the creation of new stereogenic centers on acyclic molecules. Of particular interest to us is the development of approaches involving free radical intermediates. These studies have already led to the development of various tools, which we plan to use in the synthesis of natural products of biological interest or analogues thereof, as part of our medicinal chemistry efforts.***Stereoselective free radicals reactions and synthesis of biologically relevant molecules. We have studied diastereoselective hydrogen transfer and allylation reactions on carbon-centered radical flanked by an ester and a stereogenic center. The scope of these reactions and their mechanisms has been studied thoroughly experimentally and by DFT calculations. We plan to further develop these methodologies by exploring diastereoselective fluorination and other radical addition reactions. Combining the hydrogen transfer with the Mukaiyama aldol reaction led us to develop one of the most general approach to the synthesis of polyketides (Zincophorin, Ionomycin, etc.). One of the emerging molecule of interest to eradicate cancerous stem cells (CSC) resistant to existing drugs, is Salinomycin, a member of the polyketide family. We plan to identify the portions of the molecule responsible for its activity (i.e. pharmacophores) and synthesize simplified analogues.***Synthesis of nucleoside analogues. In the last granting period, we have demonstrated that we can synthesize sterically encumbered nucleosides that were prepared with great difficulty in the past. Using the free radical reactions developed by our group, we recently succeeded in preparing acyclic molecules having an all-carbon stereogenic quaternary center, flanked by various functionalities. These molecules can be used to prepare acyclic and cyclic nucleoside analogues by taking advantage of the reaction sequences previously studied in our laboratory. Using these approaches, and others proposed herein, we will prepare two novel families of nucleoside analogues bearing a quaternary center at C3' or C2' that present an important medicinal potential.***Synthesis of a mimic of a bioactive polysaccharide. We have recently hypothesized and reported that a small molecule with a conformational bias could replace advantageously one of the subunit of a bioactive polysaccharide. In our first study, we chose to modify sialyl Lewis X (sLex) as a proof of principle. We plan to expand our study by testing other acyclic small molecules in this context.**