State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
University of Chinese Academy of Sciences, Beijing, China.
Nat Commun. 2021 Aug 16;12(1):4958. doi: 10.1038/s41467-021-25198-y.
Polyketide oligomers containing the structure of tetracyclic isochroman comprise a large class of natural products with diverse activity. However, a general and stereoselective method towards the rapid construction of this structure remains challenging due to the inherent instability and complex stereochemistry of polyketide. By mimicking the biosynthetic pathway of this structurally diverse set of natural products, we herein develop an asymmetric hetero-Diels-Alder reaction of in-situ generated isochromene and ortho-quinonemethide. A broad range of tetracyclic isochroman frameworks are prepared in good yields and excellent stereoinduction (up to 95% ee) from readily available α-propargyl benzyl alcohols and 2-(hydroxylmethyl) phenols under mild conditions. This direct enantioselective cascade reaction is achieved by a Au(I)/chiral Sc(III) bimetallic catalytic system. Experimental studies indicate that the key hetero-Diels-Alder reaction involves a stepwise pathway, and the steric hindrance between in-situ generated isochromene and t-Bu group of Sc(III)/N,N'-dioxide complex is responsible for the enantioselectivity in the hetero-Diels-Alder reaction step.
聚酮寡聚物含有四环异苯并呋喃的结构，构成了一大类具有多种活性的天然产物。然而，由于聚酮内在的不稳定性和复杂的立体化学，对于这种结构的快速构建，仍然存在着具有挑战性的通用和立体选择性方法。通过模拟该结构多样的天然产物的生物合成途径，我们在此开发了一种不对称的偕二异戊二烯-狄尔斯-阿尔德反应，其中原位生成的异苯并呋喃和邻醌亚甲醚发生反应。在温和条件下，从易得的α-炔丙基苄醇和 2-（羟甲基）苯酚出发，以良好的收率和优异的立体诱导（高达 95%ee）制备了广泛的四环异苯并呋喃骨架。这种直接的对映选择性级联反应是通过 Au(I)/手性 Sc(III)双金属催化体系实现的。实验研究表明，关键的偕二异戊二烯-狄尔斯-阿尔德反应涉及分步途径，原位生成的异苯并呋喃和 Sc(III)/N,N'-二氧杂环戊烷配合物中叔丁基之间的空间位阻是偕二异戊二烯-狄尔斯-阿尔德反应步骤中对映选择性的原因。
