Synthesis of Chiral Tricyclic Pyrone Molecules via Palladium(0)-Catalyzed Displacement Reactions of Chiral Tricyclic Pyrone Acetate With Azide or Amine.
Synthesis of Chiral Tricyclic Pyrone Molecules via Palladium(0)-Catalyzed Displacement Reactions of Chiral Tricyclic Pyrone Acetate With Azide or Amine.
复制标题
通过钯(0)催化手性三环吡喃酮乙酸酯与叠氮化物或胺的置换反应合成手性三环吡喃酮分子。
DOI：
10.1002/slct.202301435
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发表时间：
2023
期刊：
影响因子：
2.1
通讯作者：
Hua,DuyH
中科院分区：
文献类型：
--
作者：
Morita,Shunya;Ren,Zhaoyang;Fan,Huafang;Hua,DuyH
三环吡喃酮（TP）分子已显示出通过SβC基因保护淀粉样β蛋白诱导的MC 65神经母细胞瘤细胞死亡，降低淀粉样β肽水平，并改善阿尔茨海默病小鼠和大鼠模型的运动功能和记忆。机制研究表明TP分子调节N-甲基-D-天冬氨酸受体。使用Pd（0）催化的用叠氮化钠或取代的苄胺置换TP烯丙基乙酸酯中间体来寻求手性TP类似物的简短合成。发现通过用（Ph 3 P）4 Pd和叠氮化钠处理乙酸2-{（5aS，7S）-3-甲基-1-氧代-1，5a，6，7，8，9-六氢吡喃并[4，3-B]色烯-7-基}烯丙酯（9），然后用Zn-NH 4 OCHO还原并与3-氟-4-羟基苯甲醛和NaCNBH 3偶联的三步反应序列得到TP偶联分子（5aS，7S），7S）-7-（1-（3-氟-4-羟基苄基氨基）丙-2-烯-2-基）-3-甲基-6，7，8，9-四氢吡喃并[4，3-B]色烯-1（5aH）-酮（2）。另一种较短的途径-两步反应序列-通过用催化量的（Ph 3 P）4Pd在THF中用4-（叔丁基二甲基甲硅烷氧基）-3-氟-苄胺置换9，然后除去甲硅烷基醚保护基得到2，尽管化学产率较低。所描述的合成应该提供用于合成TP分子库以发现抗阿尔茨海默病药物的一般程序。
Tricyclic pyrone (TP) molecules have shown protection of MC65 neuroblastoma cells death induced by amyloid‐β proteins through SβC gene, a decrease of amyloid‐β peptide levels, and improvement of motor functions and memory in Alzheimer's disease mouse and rat models. Mechanistic studies suggest TP molecules modulateN‐methyl‐D‐aspartate receptor. A short synthesis of chiral TP analogs was sought using a Pd(0)‐catalyzed displacement of TP allylic acetate intermediate with sodium azide or substituted benzylamines. A three‐step sequence of reactions by the treatment of 2‐{(5aS,7S)‐3‐methyl‐1‐oxo‐1,5a,6,7,8,9‐hexahydropyrano[4,3‐b]chromen‐7‐yl}allyl acetate (9) with (Ph3P)4Pd and sodium azide, followed by reduction with Zn‐NH4OCHO and coupling with 3‐fluoro‐4‐hydroxybenzaldehyde and NaCNBH3was found to give TP coupling molecule, (5aS,7S)‐7‐(1‐(3‐fluoro‐4‐hydroxybenzylamino)prop‐2‐en‐2‐yl)‐3‐methyl‐6,7,8,9‐tetrahydropyrano[4,3‐b]chromen‐1(5aH)‐one (2), in a good yield. An alternative shorter pathway – a two‐step sequence of reactions – by the displacement of9by 4‐(t‐butyldimethylsilyloxy)‐3‐fluoro‐benzylamine with a catalytic amount of (Ph3P)4Pd in THF followed by removal of the silyl ether protecting group gave2, albeit in a lower chemical yield. The described syntheses should provide general procedures for the synthesis of a library of TP molecules for the discovery of anti‐Alzheimer drugs.