基于Rh(I)催化不对称共轭加成反应的新型磺酰氟化合物的合成、机理研究及应用探索

The sulfur (VI) motif, contributing significant physiochemical properties and a wide range of pharmaceutical application, represents one of the most common functional group in clinical drugs. There are 152 drugs that possess the features and fidelity of sulfonyl group, which is about 8% of the overall amount of FDA approved drugs. Thus the development of methods to introduce sulfur (VI) motif into bioactive molecules is of great importance to the strategy of drug design and discovery. On the other hand, the biological activities of a molecule vary significantly upon the chirality of the molecule. Accordingly, the development of protocol that allows the enantioseletive assembly of compounds containing sulfur (VI) motif will make great contribution to the organic chemistry and pharmaceutical industry. 2-Substitutedethenesulfonyl fluorides is a unique and important starting material for the asymmetric synthesis of sulfonyl group containing compounds as a selectively addressable bis-electrophile. This research will investigate Rh (I) catalyzed conjugate addition of aryl boronic acid to 2-substitutedethenesulfonyl fluorides, for the formation of high enantioselectively pure unique "clickable" molecules with sulfur (VI) fluorides motif through performing an asymmetric carbon-carbon building process. A series of chiral ligands with novel skeleton were designed and synthesized to examine the Rh (I) catalyzed asymmetric addition. The developed asymmetric synthesis methods will provide SuFEx-abilities to achieve "clickable" functionalization in service of design and discovery of novel covalent drugs as well as multiple disciplines of medicinal chemistry, biology, material science and industry.

含磺酰基药物在临床治疗药物中占有相当大的比重，美国FDA批准的含磺酰基的药物高达152个，约占所有已批准药物的8%。因此将磺酰基引入到小分子中是药物分子结构改造的重要策略之一。同时，分子的药物活性通常与对映体的结构有着密切的关系。因此，发展高效的不对称引入磺酰基的合成方法，在有机合成、药物研发等领域具有重要的科学意义和经济价值。2-取代乙烯基磺酰氟具有独特的双功能亲电作用，是不对称引入含磺酰基官能团的手性化合物的绝好的起始物料，本课题旨在应用自行设计的新型手性配体，研究Rh(I)催化的芳基硼酸对2-取代乙烯基磺酰氟的共轭加成反应，以实现高效、高对映选择性地将有机官能团引入到乙烯基磺酰氟化合物中，开发这类新型具有SuFEx“点击”功能化合物的不对称合成方法，为研究基于磺酰氟类共价键药物及多样化合成磺酰基药物分子的基础研究做贡献。

含磺酰基药物在临床治疗药物中占有相当大的比重，美国FDA批准的含磺酰基的药物高达150余个，约占所有已批准药物的8%。因此将磺酰基引入到小分子中是药物分子结构改造的重要策略之一。本课题设计了一种新型手性配体，实现了Rh(I)催化的芳基硼酸对2-取代乙烯基磺酰氟的共轭加成反应，高效、高对映选择性地将有机官能团引入到乙烯基磺酰氟化合物中，构建了一类具有SuFEx“点击”功能的新型磺酰氟类化合物。同时本课题开发的该类化合物，在抗菌、抗氧化、抗炎等活性的研究中取得进展，并在乙酰、丁酰胆碱酯酶抑制剂的研发中有所突破。本课题实现了多种生物活性的研究，且取得了一系列积极的研究成果，为研究基于磺酰氟类共价键药物及多样化合成磺酰基药物分子的基础研究做出了重要贡献。