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

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 eta(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.

Automated summary

An enantioselective dirhodium(II)-catalyzed cycloisomerization of diynes achieved by desymmetrization strategy provides valuable furan-fused dihydropiperidine derivatives with enantiomerically enriched alkynyl-substituted aza-quaternary stereocenter. The mechanism involving a concerted [3+2] cycloaddition/[1,2]-H shift of Rh(II) carbenoid intermediate was elucidated by DFT calculations, and weak hydrogen bondings between carboxylate ligands and alkynal were identified, which may differentiate the dirhodium(II) complex in catalyzing this transformation.