Catalytic asymmetric synthesis of 3,4′-indole–pyrazole derivatives featuring axially chiral bis-pentatomic heteroaryls

Abstract

The atroposelective synthesis of bis-pentatomic heteroaryl systems is challenging due to the low rotation barrier and configurational instability of the 5,5-ring system. 3,4′-Indole–pyrazole is a bis-pentatomic heteroaryl scaffold existing in many bioactive molecules, and the axial chirality of these skeletons has not been reported before. This work described the catalytic asymmetric construction of axially chiral 3,4′-indole–pyrazole derivatives. A chiral axis and a quaternary stereocenter could be synergistically installed through a single stereodetermining C–C bond-forming step of the chiral phosphoric acid-catalyzed Mannich reaction. High diastereoselectivities and enantioselectivities could be obtained in most cases. The 5-pyrazolyl acetate moiety in the substrate proved crucial for improving the reactivity. The new axially chiral 3,4′-indole–pyrazole system exhibited good configurational stability.