Tunable and Cooperative Catalysis for Enantioselective Pictet-Spengler Reaction with Varied Nitrogen-Containing Heterocyclic Carboxaldehydes.
Tunable and Cooperative Catalysis for Enantioselective Pictet-Spengler Reaction with Varied Nitrogen-Containing Heterocyclic Carboxaldehydes.
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DOI：
10.1002/anie.202109694
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发表时间：
2021-11-08
期刊：
影响因子：
--
通讯作者：
Miller SJ
中科院分区：
文献类型：
--
作者：
Chan YC;Sak MH;Frank SA;Miller SJ
在此，我们报告了一个有机催化的不对称功能化杂环甲醛通过Pictet-Spengler反应。通过精心配对的新型方酰胺和布朗斯特酸催化剂，我们的方法容忍的杂环的宽度，使一系列的杂环共轭β-（四氢）咔啉的制备在良好的产率和对映选择性。仔细选择羧酸助催化剂对于耐受各种区域异构杂环是必要的。通过三步立体选择性制备强效选择性雌激素受体下调剂和美国FDA批准的药物他达拉非的含吡啶类似物证明了效用。含氮杂环化合物是药物中非常重要的基序。然而，不同的电子效应和可能的配位氮严重限制了这些有价值的支架在不对称催化中的应用。本文报道了我们最近在Pictet-Spengler反应中利用不同的N-杂环甲醛和区域异构体的发现。通过在手性肽方酰胺的存在下微调非手性羧酸助催化剂来实现相容性。通过立体选择性合成医学相关分子的含吡啶类似物证明了合成效用，包括美国FDA批准的药物-他达拉非。研究所和/或研究员Twitter用户名：@MillerGroupYale
Herein we report an organocatalytic enantioselective functionalization of heterocyclic carboxaldehyde via Pictet−Spengler reaction. Through careful pairing of novel squaramide and Brønsted acid catalysts, our method tolerates a breadth of heterocycles, enabling preparation of a series of heterocycle conjugated β-(tetrahydro)carboline in good yield and enantioselectivity. Careful selection of carboxylic acid co-catalyst is essential for toleration of a variety of regioisomeric heterocycles. Utility is demonstrated via the three-step stereoselective preparation of pyridine-containing analogues of potent selective estrogen receptor downregulator and US FDA approved drug Tadalafil. Nitrogen containing heterocycles are very important motif in pharmaceuticals. However, the diverse electronic effect and presumably coordinating-nitrogen severely limited inclusion of these valuable scaffolds in asymmetric catalysis. Herein, we reported our recent finding on utilizing diverse N-heterocyclic carboxaldehyde and regioisomers in Pictet-Spengler reaction. Compatibility was enabled by fine tuning the achiral carboxylic acid co-catalyst in the presence of chiral peptidic squaramide. Synthetic utility was demonstrated by stereoselective synthesis of pyridine-containing analogues of medicinally related molecules, including U.S. FDA approved drug- Tadalafil. Institute and/or researcher Twitter usernames: @MillerGroupYale
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影响因子：
16.6
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