Department of Chemistry, University of York, Heslington, York, North Yorks, U.K., YO10 5DD.
Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, U.K., CB2 1EW.
Org Lett. 2020 Oct 16;22(20):8116-8121. doi: 10.1021/acs.orglett.0c03090. Epub 2020 Sep 29.
The development of an asymmetric "clip-cycle" synthesis of 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines, which are increasingly important scaffolds in drug discovery programs, is reported. Cbz-protected bis-homoallylic amines were activated by "clipping" them to thioacrylate via an alkene metathesis reaction. Enantioselective intramolecular aza-Michael cyclization onto the activated alkene, catalyzed by a chiral phosphoric acid, formed a pyrrolidine. The reaction accommodated a range of substitutions to form 2,2- and 3,3-disubstituted pyrrolidines and spiropyrrolidines with high enantioselectivities. The importance of the thioester activating group was demonstrated by comparison to ketone and oxoester-containing substrates. DFT studies supported the aza-Michael cyclization as the rate- and stereochemistry-determining step and correctly predicted the formation of the major enantiomer. The catalytic asymmetric syntheses of -methylpyrrolidine alkaloids ()-irnidine and ()-bgugaine, which possess DNA binding and antibacterial properties, were achieved using the "clip-cycle" methodology.
本文报道了一种非对映选择性“夹循环”合成 2,2-和 3,3-取代吡咯烷和螺吡咯烷的方法，这些化合物在药物发现计划中越来越重要。Cbz 保护的双同烯丙基伯胺通过烯烃复分解反应将其“夹”到硫代丙烯酸酯上被激活。手性磷酸催化的对激活的烯烃的对映选择性分子内氮杂迈克尔环化形成吡咯烷。该反应适应了一系列取代基，形成了具有高对映选择性的 2,2-和 3,3-取代的吡咯烷和螺吡咯烷。硫酯活化基团的重要性通过与酮和氧代酯基取代底物的比较得到了证明。DFT 研究支持氮杂迈克尔环化作为决定速率和立体化学的步骤，并正确预测了主要对映异构体的形成。使用“夹循环”方法实现了具有 DNA 结合和抗菌特性的 -甲基吡咯烷生物碱（）-irnidine 和（）-bgugaine 的催化不对称合成。
