Enantioselective Synthesis of <i>cis</i> -Hydroisoquinolines via Cross-[4 + 2] Cycloadditions of 2-Pyrones and Dihydropyridines

High Resolution Image Download MS PowerPoint Slide Chiral cis -hydroisoquinoline scaffolds are important pharmacophores and are prevalent in bioactive natural products and drug molecules. However, the straightforward construction of cis -hydroisoquinolines via asymmetric catalysis remains elusive. Herein, we report a Lewis acid-catalyzed enantioselective cross-[4 + 2] cycloaddition of 2-pyrones with dihydropyridines. This method enables the step-economical and divergent synthesis of densely functionalized cis -hydroisoquinolines with excellent yields and enantioselectivities. Density functional theory (DFT) calculations indicate that the cross-[4 + 2] cycloaddition proceeds via a stepwise reaction pathway, and reveal the origin of the chemo-, regio-, and stereoselectivity. Moreover, acid-sensitive silyloxydihydropyridine derivatives are compatible in this reaction when a ytterbium/BINOL complex is used as the catalyst, further enhancing the functional diversity of cis -hydroisoquinoline products. The synthetic utility of this method is unambiguously demonstrated by the concise synthesis of two yohimbine alkaloids (−)-alloyohimbane and (−)-rauwolscine.