Development of Selective Catalytic Reactions by Simulation of the Function of Hepatic Flavoenzyme

我们用简单的有机分子或简单的过渡金属络合物催化剂模拟肝脏黄素酶的功能。在这个项目中，我们研究了两种类型的反应。1)简单的平面手性黄嘌呤催化的仿生不对称氧化反应。2)通过硝酮在胺的氮原子上引入α取代基，并将这些方法应用于含氮生物活性化合物的合成。平面手性黄素催化剂是通过在异四氧烷的一个平面上覆盖碳链而制备的。手性黄素催化的硫化物与过氧化氢的氧化反应，在高达70%ee的条件下得到了相应的光学活性亚硫醚。使用相同的催化体系，可以实现α-取代羟胺对映体选择性氧化和酮的不对称Baeyer-Villiger氧化的动力学拆分。在钛、硼、锌络合物等路易斯酸催化剂的作用下，乙烯酮硅基缩醛与硝酮的亲核加成反应可得到高效的β-氨基酸衍生物。在Lewis酸催化下，硝酮与光学活性的烯酮硅基缩醛发生非对映选择性反应，生成光学活性的N-羟基-β-氨基酸酯，产率高达99%。手性Lewis酸催化乙烯酮硅基缩醛与硝酮的对映选择性加成反应生成N-羟基-β-氨基酸酯，反应产率高达85%Ee。利用新的方法通过硝酮在胺的氮原子上立体选择性地引入α取代基，合成了含氮生物活性化合物，如β-内酰胺类抗生素和吲哚里西定、吡咯里西定和甜菜碱等。

We have been studied simulation of the function of hepatic flavoenzyme with simple organic molecules or simple transition metal complex catalysts. In this project, we studied two types of reactions. 1) Biomimetic asymmetric oxidation reaction catalyzed by simple planar-chiral flavinophanes. 2) Introduction of substituents at alpha to the nitrogen atom of amines via nitrones and application of these methodologies to the synthesis of nitrogen-containing biologically active compounds.1. Planar-chiral flavin catalysts are prepared by capping one of the planes of isoalloxane with a carbon chain. The chiral flavin-catalyzed oxidation of sulfides with hydrogen peroxide gives the corresponding optically active sulfoxides in up to 70% ee. Using the same catalytic system, kinetic resolution of alpha-substituted hydroxylamines by enantiospecific oxidation and asymmetric Baeyer-Villiger oxidation of ketones can be performed.2. Nucleophilic addition of ketene silyl acetals to nitrones can be performed using Lewis acid catalysts such as titanium, boron, and zinc complexes, affording beta-amino acid derivatives with high efficiency. Lewis acid-catalyzed diastereoselective reaction of nitrones with the optically active ketene silyl acetals gives optically active N-hydroxy-beta-amino acid esters in up to 99% de. Chiral Lewis acids catalyze the enantioselective addition of ketene silyl acetals to nitrones to give N-hydroxy-beta-amino acid esters in up to 85% ee.3. Using new methodologies for stereoselective introduction of substituents at alpha to the nitrogen atom of amines via nitrones, nitrogen-containing biologically active compounds such as beta-lactam antibiotics and indolizidine, pyrrolizidine, and necine alkaloids, are synthesized.