钯催化不对称烯丙基化/去对称化反应合成无保护基的2-喹啉酮骨架环状氨基酸  

Enantioselective synthesis of unprotected 2‐quinolinone‐based cyclic amino acids via sequential palladium‐catalyzed asymmetric allylation/desymmetrization

作　　者：李倩[1,2] 刘 李灿 Qian Li;Yan Liu;Can Li(Zhang Dayu School of Chemistry,Dalian University of Technology,Dalian 116024,Liaoning,China;State Key Laboratory of Catalysis,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,Dalian 116023,Liaoning,China)

机构地区：[1]大连理工大学张大煜(化学)学院,辽宁大连116024 [2]中国科学院大连化学物理研究所,催化基础国家重点实验室,辽宁大连116023

出　　处：《Chinese Journal of Catalysis》2023年第4期222-228,共7页催化学报(英文)

基　　金：国家自然科学基金(21871254,22271276).

摘　　要：作为一类重要的含氮杂环化合物,3-氨基-2-二氢喹啉酮结构存在于一些药物和生物活性分子中.目前还没有手性催化的方法直接合成无保护基的此类结构.在过渡金属的催化作用下,乙烯基苯并噁嗪酮脱除一分子二氧化碳,生成的两性离子中间体可以参与多种反应合成含氮杂环化合物.我们设想乙烯基苯并噁嗪酮和2-氨基丙二酸酯直接发生不对称烯丙基化反应/去对称化反应,则可直接实现无保护基2-喹啉酮骨架环状氨基酸的手性合成.然而2-氨基丙二酸酯作为亲核试剂时,如何实现碳选择性进攻而不是固有的氮选择性进攻将成为此反应中一个重要挑战.本文通过钯催化的不对称烯丙基化/去对称化反应合成具有2-喹啉酮骨架的环状氨基酸.采用手性膦配体与钯作为催化剂,成功实现了乙烯基苯并噁嗪酮与2-氨基丙二酸酯的不对称α-烯丙基取代反应.随后无需提纯,烯丙基取代产物直接在三氟乙酸的作用下,发生分子内的去对称化内酰胺化反应,最终生成具有无保护基的2-喹啉酮骨架环状氨基酸产物.该催化方法反应条件温和,催化体系简单高效(钯催化剂负载量可降低至1 mol%,非对映选择性可高达15/1,对映选择性高达96%ee),并且具有良好的官能团兼容性.经盐酸处理后,反应终产物可以成功转化为3-氨基-2-二氢喹啉酮衍生物.机理研究表明,烯醇化的氨基丙二酸酯与π-烯丙基钯(II)配合物之间的双氢键导向效应对区域选择性的控制起到重要作用,手性膦配体上的手性基团与烯丙基之间的空间位阻导致了高对映选择性.综上,本文开发了一种合成无保护基的2-喹啉酮骨架环状氨基酸的方法,其有望在药物合成中获得应用.Chiral unprotected 3‐amino‐2‐quinolinone and 2‐quinolinone‐based cyclic amino acids have been recognized as important scaffolds in the structures of various drugs and bioactive molecules.However,a direct asymmetric method for the synthesis of these structures remains elusive.In this study,we report a Pd(0)‐catalyzed enantioselective sequential decarboxylative allylation/desymmetrization protocol.Various vinyl benzoxazinanones can be used as substrates to react with unprotected amino esters,affording enantioenriched 2‐quinolinone‐based cyclic amino acids with high enantioselectivities(up to 96%ee)and good diastereoselectivities(up to 15:1 dr).Moreover,the products could be successfully transformed to chiral 3‐amino‐2‐quinolinone derivatives after treatment with aqueous HCl.Mechanistic studies revealed that the double‐hydrogen‐bond‐directing effect between the enolate(2‐aminomalonate)andπ‐allyl Pd(II)complex plays an important role in the control of regioselectivity,and the steric hindrance between tert‐butyl group on the ligand and allyl group on the substrate is responsible for the high enantioselectivity.

关 键 词：钯催化 不对称烯丙基取代反应 去对称化反应 乙烯基苯并恶嗪酮 游离氨基酸 

分 类 号：O626.323[理学—有机化学]