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

Abstract

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 alkynylsubstituted 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 alkynedirhodium(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.

Effects of Axial Solvent Coordination to Dirhodium Complexes on the Reactivity and Selectivity in C–H Insertion Reactions: A Computational Study

“…Most reported X-ray crystal structures of dirhodium complexes contain bound axial ligands, usually solvent but sometimes substrates, other ligands, or other complexes (i.e., in coordination polymers). − Even though dirhodium complexes have been known since the 1960s, it was not until 2002 that an X-ray crystal structure of a dirhodium complex without axial ligands was reported . The few reported X-ray structures of dirhodium carbenes crystallize as coordination polymers: OMe or NMe 2 groups present in the carbene appendants coordinate to the rhodium not bearing the carbene carbon of the next unit. , These complexes require CH 2 Cl 2 and toluene to be stable in crystalline form and their unit cells contain highly disordered solvent molecules …”

In Situ Kinetic Studies of Rh(II)-Catalyzed C–H Functionalization to Achieve High Catalyst Turnover Numbers

“…See the Supporting Information). One should emphasize that similar conclusions have been made by Darko and co-workers in their study of the dirhodium catalysts with tethered axial coordinating groups, thioethers in particular. − Therefore, we explain the observed rate acceleration upon reaction of the carbene and unactivated traps in our studies through axial coordination with the rhodium carbene.…”

Cycloisomerization of enynones by aluminum halides: construction of bicyclo[3.1.0]hexanes by introducing halides

“…Since these processes are generally induced by alkyne π-bond activation, transition metal catalysts have been well studied for the selective construction of these cyclic products. 1 Among them, cycloisomerization of 1,6-enynes with introduction of functional groups 2 or hydrogen migration 3 has been developed for the synthesis of bicyclo[3.1.0]hexanes (Scheme 1a), which are important core structures found in many biologically active compounds. 4 However, although the methods based on the activation of acyloxy (Scheme 1b) 2 i or hydroxy groups 2 g ,3 d of propargyl alcohol derivatives have been reported, the cycloisomerization of enynones through the activation of carbonyl groups into bicyclo[3.1.0]hexanes has not been achieved.…”