Hypervalent Bromine for Novel Synthesis

提出了一种高效、可持续的环状和手性*3-溴的合成及其综合利用的方法。在这种转化中使用电子作为试剂将取代化学计量比有毒试剂的使用和不需要的副产品形成，从而提高该过程的产量和效力。由于溴的反应性高于碘烷，因此生成的*3-溴将成为在较温和的反应条件下进行氟烷基化反应的通用试剂。合成的氟烷基-*3-溴将通过各种光谱技术进行表征。首次通过使用不对称的*3-溴代盐来揭示立体选择性的氟烷基化策略。手性溴盐的反应性也将通过访问发散的手性环境进行评估。环*3-溴的应用将通过伯位和仲位的后期氟烷基化反应来展示。苄基氟烷基化策略的成功结果将进一步扩展到在流动条件下商业上可获得的药物分子的苄基氟烷基化。最后，将结合微反应器技术的挑战性方面，在多肽的后期修饰以及广泛使用的降压药卡托普利的反应中，借助高效液相色谱和定量LC-MS，通过同位素氟烷基化和炔化反应，实现自动自我优化。将利用光谱证据对环状和手性*3-溴的生成以及它们在医药用途分子合成中的合成应用进行详细的机理研究。

A highly efficient and sustainable route to cyclic and chiral *3-bromane synthesis and their synthetic utilization has been proposed by the application of electric current. The use of electrons as reagent in such transformations would replace the use of stoichiometric toxic reagents and unwanted by-product formation and thereby increase the yield and the potency of the process. Owing to the enhanced reactivity of bromanes over iodanes would make the resulting *3-bromanes a versatile reagent for the fluoroalkylation reactions under milder reaction conditions. The synthesized fluoroalkyl-*3-bromane will be characterised by the various spectroscopic techniques. First time, the stereoselective fluoroalkylation strategies will be disclosed by using asymmetric *3-bromane salts. The reactivity of the chiral bromane salts will also be evaluated by accessing divergent chiral environment. The application of cyclic *3-bromanes will be demonstrated by the late stage fluoroalkylation at the primary and secondary benzylic sites. The successful outcome of the benzylic fluoroalkylation strategy will be further extended to the benzylic fluoroalkylation of commercially available drug molecules under flow conditions. Finally, the challenging aspect of microreactor technology would be incorporated for an automated self-optimization in late stage modification of peptides as well as reaction of captopril, a widely used antihypertensiondrug, via isotopic fluoroalkylation and alkynylation with the aid of HPLC and quantitative LC-MS. Detailed mechanistic studies for the generation of cyclic and chiral *3-bromane as well as their synthetic utilization in pharmaceutically useful molecule synthesis will be performed with spectroscopic evidences.