Cox Lydia, Zhu Yuxiang, Smith Philip J, Christensen Kirsten E, Sidera Portela Mireia, Donohoe Timothy J
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford, OX1 3TA, UK.
Vertex Pharmaceuticals, 86-88 Jubilee Ave, Milton, Abingdon, OX14 4RW, UK.
Angew Chem Int Ed Engl. 2022 Aug 22;61(34):e202206800. doi: 10.1002/anie.202206800. Epub 2022 Jul 13.
A Ti(Oi-Pr) promoted 5- or 6-endo-trig cyclisation to make nitrogen heterocycles is presented. The utilisation of HFIP as a key solvent enables the stereoselective preparation of di- & tri-substituted pyrrolidines and piperidines while forming a new C-C bond at the same time. The process is triggered by a cationic intermediate generated from an allylic or benzylic alcohol and leads to the simultaneous generation of both a C-C and a C-N bond in a single step. Notably, either 2,3-trans- or 2,3-cis-substituted heterocycles can be obtained by using a nucleophilic amine bearing different substituents. Lastly, the stereoselective synthesis of enantiopure products was achieved by using readily available enantiopure acyclic starting materials.
本文介绍了一种由钛酸异丙酯促进的5-或6-内型-环化反应以制备含氮杂环化合物。使用六氟异丙醇作为关键溶剂能够立体选择性地制备二取代和三取代的吡咯烷和哌啶，同时形成一个新的碳-碳键。该过程由烯丙醇或苄醇生成的阳离子中间体引发，并在一步反应中同时生成碳-碳键和碳-氮键。值得注意的是，通过使用带有不同取代基的亲核胺，可以得到2,3-反式或2,3-顺式取代的杂环化合物。最后，通过使用容易获得的对映体纯的非环状起始原料，实现了对映体纯产物的立体选择性合成。
