氢胺化构筑alpha-季碳胺的反应研究

a-Tertiary amines existed extensively in natural alkaloids, pharmaceutical products, and biologically potent molecules, which justify the intensive synthetic studies. Besides the nucleophilic addition of organometallic reagents to ketimines and the nitrene insertion into the tertiary C-H bonds, the hydroamination of substituted alkene is a potential strategy to construct amine derivatives. However, due to the lability of the product from hydroamination and harsh conditions of deprotection, the hydroamination for a-tertiary amine derivatives remains a challenge. Recently we disclosed an intermolecular hydroamination of di- and trisubstituted alkene with sulfamate ester, giving rise to the a-tertiary amine derivatives with up to almost quantitative yield. We planned to explore more applications and establish the asymmetric catalysis. This proposal includes:.1).Apply the buffering anions and ligands to the catalyst to quench the undesired side reaction and improve the selectivity. By screening inexpensive Lewis acids from early transition metal species, we attempt to realize a concerted transition state which makes the hydroamination much more controllable than that via stepwise pathway. Meanwhile, we apply some polyene substrates in the cascade version of the hydroamination. By introducing different combinations of sulfamate esters and alkenes, we planned several tendam or one pot reactions. Based on the photoredox removal of PMB group reported by our group recently, we also plan to design a sulfamate ester that could facilitate the deprotection of the a-tertiary amine derivatives from hydroamination employing visible light as driving force. .2).Based on the results achieved in part 1), we shall carry out asymmetric intermolecular and intramolecular hydroamination to construct chiral a-tertiary amine derivatives. Recently we have established a novel chiral phosphate showing excellent enantioselectivities in an asymmetric catalysis. We decide to apply this new chiral phosphate along with other well-established chiral phoshpate as the buffering anion precursor in the enantioselective hydroaminations. Meanwhile, some chiral ligands bearing different combinations of heteroatoms such as P, N, S, O will be synthesized and tested in our asymmetric hydroamination. On the other hand, we decide to explore the enantioselective phase transfer catalysis with the insoluble sulfamate ester to control the enantioselectivity of hydroamination. .3) We plan to apply the asymmetric hydroamination in the synthesis of pharmacuetical molecules containing chiral a-tertiary amines.

a-季碳胺官能团在天然产物，药物分子，非天然氨基酸等分子中普遍存在，其合成研究是近年来的热点。我们发现磺酰胺酯为氮源的氢胺化反应，克服了以往氢胺化中如反应可逆、产物不稳定、游离胺难以获得等瓶颈因素，反应条件温和，催化效率高，原子经济性高，纯化简单，非常适合制备a-季碳胺化合物。我们计划深入研究该反应，用阴离子，配体，前过渡金属Lewis酸等手段抑制副反应，提升反应活性，研究反应机理，控制反应的历程。设计含不同官能团的底物实现级联、串联形式的氢胺化反应。开发出可见光催化降解的磺酰胺酯试剂。设计合成多种新型手性阴离子和手性配体，并应用于不对称的氢胺化反应，实现分子内和分子间的不对称氢胺化反应，探索利用相转移催化的方式控制氢胺化的立体选择性，发现控制氢胺化反应立体选择性的规律，发展出新颖的手性a-季碳胺合成策略，并利用发展出的方法实现生物活性分子的不对称合成。

Alpha-季碳胺在药物设计上具有特殊的功能，且其难以通过还原胺化等方法制备，发展这类化合物的合成方法具有重要意义。本项目以烯烃为底物，以磺酰胺酯为氮源合成Alpha-季碳胺。在工作中，我们利用多种手段向分子中引入胺，构建C-N键。发展出了利用可见光条件下对烯烃的反苄位季碳胺合成，电化学条件下含季碳胺官能团的氮杂环丙烷合成，电化学条件下的C-H键无催化剂无氧化剂的胺化反应。在这些工作同时，我们对氮源的亲核性和电子转移能力进行了进一步的研究，发展出了氮核心的汉斯酯介导的可见光二氟官能团化反应，取代汉斯酯为自由基源的可见光双自由基偶联反应。发展出了以氨气为氢源的电化学氢化反应。特别是以氨气为氢源的电化学氢化反应有可能替代工业上的易爆燃金属催化剂催化的氢化反应。