The N-acyloxyiminium ion aza-prins route to octahydroindoles: Total synthesis and structural confirmation of the antithrombotic marine natural product oscillarin
The N-acyloxyiminium ion aza-prins route to octahydroindoles: Total synthesis and structural confirmation of the antithrombotic marine natural product oscillarin
复制标题
DOI：
10.1021/ja030669g
复制
发表时间：
2004-05-19
影响因子：
15
通讯作者：
Petersen, JFW
中科院分区：
文献类型：
--
作者：
Hanessian, S;Tremblay, M;Petersen, JFW
首次报道了海洋天然产物振荡素的对映体控制全合成。因此，所提出的结构和绝对构型的oscillarin被证实，和以前指定的结构的一个亚基被证明是不正确的。振荡素-凝血酶复合物的X射线结构以2.0埃分辨率解析，这验证了其对酶的有效抑制活性，IC 50 = 28 nM。发展了一种合成对映体纯的、在C-6处具有可用官能度的八氢吲哚-2-羧酸的方法。该方法包括在四氯化锡或四溴化锡的存在下使含有烯系链的N-酰氧基亚胺鎓离子卤代碳环化。这种N-酰氧基亚胺离子氮杂-Prins碳环化被证明是一般的八氢吲哚和全氢喹啉2-羧酸的建设。机械原理是基于对亚胺离子上的末端烯烃的反周面攻击，导致通过赤道攻击被卤化物捕获的初期仲碳阳离子。产物的X射线晶体结构证实了预期的立体化学。
The first enantiocontrolled total synthesis of the marine natural product oscillarin is described. The proposed structure and absolute configuration of oscillarin is thus confirmed, and a previously assigned structure of a subunit was shown to be incorrect. The X-ray structure of an oscillarin-thrombin complex was resolved at 2.0 Angstrom resolution, which validated its potent inhibitory activity against the enzyme with an IC50 = 28 nM. Methodology was developed for the synthesis of enantiopure octahydroindole-2-carboxylic acids with usable functionality at C-6. The method consists of the halocarbocyclization of N-acyloxyiminium ions containing an olefinic tether in the presence of tin tetrachloride or tin tetrabromide. This N-acyloxyiminium ion aza-Prins carbocyclization proved to be general for the construction of octahydroindole and perhydroquinoline 2-carboxylic acids. Mechanistic rationales are based on an antiperiplanar attack of the terminal alkene on the iminium ion, leading to an incipient secondary carbocation which is trapped by halide via an equatorial attack. X-ray crystal structures of products corroborate the expected stereochemistry.