Enantioselective Type II Cycloaddition of Alkynes via C–C Activation of Cyclobutanones: Rapid and Asymmetric Construction of [3.3.1] Bridged Bicycles

Synthesis
of bridged scaffolds via Type II cyclization constitutes
substantial challenges due to the intrinsic ring strain accumulated
in reaction transition states. Catalytic enantioselective Type II-cyclization
methods are even rarer. Here, we describe a detailed study of developing
a Rh­(I)-catalyzed enantioselective intramolecular Type II cyclization
of alkynes via C–C activation of cyclobutanones. This method
offers a rapid approach to access a wide range of functionalized [3.3.1]-bridged bicycles along with an exocyclic
olefin and an all-carbon quaternary stereocenter. Excellent enantioselectivity
has been achieved using a combination of cationic rhodium­(I) and DTBM-segphos.
Attributed to the redox neutral and strong acid/base-free reaction
conditions, high chemoselectivity has also been observed. For the
oxygen-tethered substrates, the reaction can proceed at room temperature.
In addition, partial kinetic resolution has been achieved for substrates
with existing stereocenters, forging interesting chiral tricyclic
scaffolds. The methylalkyne-derived substrates gave unexpected dimeric
structures in good yield with excellent enantioselectivity and complete
diastereoselectivity. Furthermore, the bridged bicyclic products can
be diversely functionalized through simple transformations. Finally,
mechanistic studies reveal a surprising reaction pathway that involves
forming a metal-stabilized anti-Bredt olefin intermediate.