Development of highly efficient asymmetric synthesis process directed for "racemic switch" of the racemic medicines

本研究的目的是建立如下方法：1)通过催化拆分，简单地合成具有构象刚性和空间拥堵的三环2-恶唑烷酮、2-咪唑烷酮和2-噻唑烷酮；2)与上述三环化合物及其衍生物衍生的二环2-氨基醇、1，2-二胺和2-氨基硫醇进行优良的不对称反应，以实现外消旋药物的外消旋开关。1.通过动力学拆分容易获得高效的手性助剂2.高效手性“有顶”配体的应用从相应的三环化合物衍生的双环“有顶”的2-氨基醇、1，2-二胺和2-氨基硫醇已被证明对于下列金属催化的不对称反应是很好的或很好的手性配体：(1)酮与恶唑硼烷-硼烷体系(“2-氨基醇”配体)的不对称硼烷还原。(2)多用途手性合成子的实用合成，4，5-二烷氧基-2-咪唑烷酮(“2-氨基醇”配体)。(3)Ru(II)催化的酮的不对称转移氢化(“顺-1，2-二胺”配体)。(4)Pd(II)催化的烯丙基乙酸酯的不对称烷基化(“2-氨硫醇”配体)。(5)铜(II)催化的不对称Diels-Alder反应(“2-氨硫醇”配体)。

The aim of this research is to establish the methodology for i) simple preparation of tricyclic "roofed" 2-oxazolidinones, 2-imidazolidinones and 2-thiazolidinones with conformational rigidity and steric congestion as extremely powerful chiral auxiliaries by catalytic resolution, and ii) excellent asymmetric reactions with bicyclic 2-amino alcohols, 1,2-diamines and 2-aminothiols derived from the above tricyclic compounds and their derivatives, directed for "racemic switch" of the racemic medicines.1.Easy access to highly efficient chiral auxiliaries by kinetic resolutionThe optically active "roofed" 2-oxazolidinones, 2-imidazolidinones and 2-thiazolidinones were readily obtained from kinetic resolution with oxazaborolidine catalysts.2.Application of highly efficient chiral "roofed" ligandsBicyclic "roofed" 2-amino alcohols, 1,2-diamines and 2-aminothiols derived from the corresponding tricyclic compounds have been proven to be good to excellent chiral ligands for following metal-catalyzed asymmetric reactions :(1)Asymmetric borane reduction of ketones with oxazaborolidine-borane system ("2-Aminoalcohol" ligands).(2)Practical synthesis of versatile chiral synthons, 4,5-dialkoxy-2-imidazolidinone ("2-Aminoalcohol" ligands).(3)Ruthenium (II)-catalyzed asymmetric transfer hydrogenation of ketones ("cis-1,2-Diamine" ligands).(4)Pd (II)-catalyzed asymmetric alkylation of allylacetates ("2-Aminothiol" ligands).(5)Cu (II)-catalyzed asymmetric Diels-Alder reaction ("2-Aminothiol" ligands).