手性磷酸催化非环状N,N′-缩酮的不对称合成  

Chiral Phosphoric Acid-catalyzed Asymmetric Synthesis of Acyclic N,N′-Ketals

作　　者：李敏[1,3] 李文哲 黄敏 张晓梅 LI Min;LI Wenzhe;HUANG Min;ZHANG Xiaomei(Chengdu Institute of Organic Chemistry,Chinese Academy of Sciences,Chengdu 610041,China;Department of Chemistry,Xihua University,Chengdu 610039,China;University of Chinese Academy of Sciences,Beijing 100049,China)

机构地区：[1]中国科学院成都有机化学研究所,四川成都610041 [2]西华大学化学系,四川成都610039 [3]中国科学院大学,北京100049

出　　处：《合成化学》2024年第7期634-642,共9页Chinese Journal of Synthetic Chemistry

基　　金：国家自然科学基金资助项目(21672208)。

摘　　要：手性N,N′-缩酮是药物分子和生物活性化合物最重要的核心结构之一,也是有机合成中重要的催化剂或配体。因此,不对称合成N,N′-缩酮具有重要意义。通过手性磷酸、溶剂、催化剂负载量和投料比的筛选,确定了最佳的反应条件:在手性磷酸的催化下,以1,4-二氧六环作为溶剂,5-氨基异噁唑与β,γ-炔基-α-酮亚胺酯在室温下发生区域选择性的氮杂-曼尼希反应,实现异噁唑的不对称N—H烷基化,以中等至良好的收率(46%~83% yield)和较好的对映选择性(82%~92%ee)合成非环状的N,N′-缩酮。所有产物结构由^(1)H NMR,^(13)C NMR和HR-MS(ESI)确证,绝对构型通过X-射线晶体结构分析确定。Chiral N,N′-ketal is one of the most important core structures of drug molecules and biologically active compounds,as well as important catalyst or ligand in organic synthesis,accordingly the asymmetric synthesis of N,N′-ketal is of great significance.Screening of chiral phosphoric acid,solvent,catalyst loading,and ratio,the optimal reaction condition was determined,that is,under the catalysis of chiral phosphoric acid,with 1,4-dioxane as solvent,the asymmetric N—H alkylations of isoxazoles were achieved by regioselective aza-Mannich reactions of 5-amino-isoxazoles with β,γ-alkynyl-α-ketimino esters to synthesize the acyclic N,N′-ketals in moderate to good yield(46%~83% yield)and good enantioselectivity(82%~92%ee).The structures of all the products were confirmed by ^(1)H NMR,^(13)C NMR and HR-MS(ESI)and the absolute configuration was determined by X-ray crystal structure analysis.

关 键 词：N N′-缩酮 手性磷酸催化 5-氨基异噁唑 β γ-炔基-α-酮亚胺酯 区域选择性 不对称合成 氮杂-曼尼希反应 

分 类 号：O622.6[理学—有机化学]