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Highly efficient asymmetric synthesis process directed for optically pure medicines

针对光学纯药物的高效不对称合成工艺

基本信息

批准号：
13557196
负责人：
KUNIEDA Takehisa
金额：
$ 8.77万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

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 comformational 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.(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, which is an alternative method for optical resolution with "MAC-acid" (2-exo-methoxy-1-apocamphanecarboxylic acid).(2)Development of highly efficient chiral 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 :i)"2-Aminoalcohol" ligands :a)asymmetric borane reduction of ketones with oxazaborolidine-borane system.b)Practical synthesis of versatile chiral synthons, 4,5-dimethoxy-2-oxazolidinone and 4,5-demethoxy-2-imidazolidinone.c)asymmetric aldol reaction with Cu(II) catalyst.ii)"cis-1,2-Diamine" ligands :a)Ruthenium (II)-catalyzed asymmetric transfer hydrogenation of ketones.iii)"2-Aminothiol" ligands:a)Pd (II)-catalyzed asymmetric alkylation of allylacetates.b)Cu (II)-catalyzed asymmetric Diels-Alder reaction.

本研究的目的是建立一种方法，1)通过催化分解，简单制备具有构象刚性和位阻性的三环“顶”2-恶唑烷酮、2-咪唑烷酮和2-噻唑烷酮作为极强的手性助剂，2)与上述三环化合物及其衍生物衍生的双环2-氨基醇、1,2-二胺和2-氨基硫醇进行优异的不对称反应。(1)通过动力学拆分容易获得高效的手性助剂用恶唑烷类催化剂进行动力学拆分容易得到具有光学活性的“顶”型2-恶唑烷酮、2-咪唑烷酮和2-噻唑烷酮，这是用“mac酸”（2-外氧甲氧基-1-apocamphanecarboxylic acid）进行光学拆分的替代方法。(2)高效手性配体的开发由相应的三环化合物衍生的双环“顶”2-氨基醇、1,2-二胺和2-氨基硫醇已被证明是金属催化不对称反应的优秀手性配体：1)“2-氨基醇”配体；a)恶唑硼烷-硼烷体系对酮类的不对称硼烷还原。b)多用途手性化合物4,5-二甲氧基-2-恶唑烷酮和4,5-去甲氧基-2-咪唑烷酮的实际合成。c) Cu（II）催化剂催化的不对称醛醇反应。ii)“顺-1,2-二胺”配体：a)钌（ii）催化酮的不对称转移氢化反应。iii)“2-氨基硫醇”配体：a)Pd （II）催化的烯丙酸酯的不对称烷基化反应。b)Cu （II）催化不对称Diels-Alder反应。