Enantioselective Rh(Ⅱ)-Catalyzed Desymmetric Cycloisomerization of Diynes: Constructing Furan-Fused Dihydropiperidines with an Alkyne-Substituted Aza-Quaternary Stereocenter

摘要

Described herein is an enantioselective dirhodium(Ⅱ)-catalyzed cycloisomerization of diynes achieved by the strategy of desymmetrization, which not only represents a new cycloisomerization reaction of diynes but also constitutes the first Rh(Ⅱ)-catalyzed asymmetric intramolecular cycloisomerization of 1,6-diynes. This protocol provides a range of valuable furan-fused dihydropiperidine derivatives with an enantiomerically enriched alkynyl-substituted aza-quaternary stereocenter in high efficiency, complete atom economy, and excellent enantioselectivity (up to 98% ee). Besides, the highly functionalized products could be easily transformed into various synthetically useful building blocks and conjugated with a series of pharmaceutical molecules. The mechanism involving a concerted [3+2] cycloaddition/[1,2]-H shift of the Rh(Ⅱ) carbenoid intermediate was elucidated by DFT calculations and mechanistic studies. More importantly, the first single crystal of alkyne-dirhodium(Ⅱ) was obtained to show that a η~2-coordinating activation of alkynal by dirhodium(Ⅱ) was involved. Weak hydrogen bondings between the carboxylate ligands and alkynal were found, which probably made the well-defined paddlewheel-like dirhodium(Ⅱ) distinctive from other metal complexes in catalyzing this transformation. Furthermore, the origin of the enantioselectivity was elucidated by a Rh_2(R-PTAD)_4-alkyne complex and additional calculational studies.