Enantioselective Synthesis of Spirolactones and Spirolactams Under Low Catalyst Loadings

High Resolution Image Download MS PowerPoint Slide The stereoselective construction of spirocyclic compounds as medicinally relevant scaffolds is of considerable current interest. One underexplored area in this field is the asymmetric synthesis of spirocyclopropanes via transition-metal catalysis, using α-diazo lactones and lactams as carbene precursors. In this study, we report a Rh 2 ( S - p -PhTPCP) 4 -catalyzed [2 + 1] cyclopropanation between 3-diazo δ-lactones and lactams and a wide range of alkene substrates, enabling the facile synthesis of 5-oxa and 5-azaspiro[2.5]octanones in yields up to 98%, reasonable levels of diastereoselectivity (up to 11:1 d.r.), and high levels of enantioselectivity (up to 98% ee ). The reaction can be run with 0.00005 mol % of catalyst, resulting in 1,740,000 TON, while maintaining stereocontrol. The ring size of the diazo compound, in conjunction with the reaction temperature, has a considerable influence on the reaction. While the reaction with the 5-membered system gave diminished stereoselectivity, the 7-membered counterpart gave enhanced stereocontrol (>30:1 d.r., 99% ee ), but the reaction needed to be carried out at low temperatures to avoid a side-reaction caused by a 1,2-hydride shift.