Experimental and computational investigation of the α-amylase catalyzed Friedel–Crafts reaction of isatin to access symmetrical and unsymmetrical 3,3′,3′′-trisindoles

Abstract

Trisindoles are of tremendous interest due to their wide range of biological activities. In this context, a number of methods have been reported in the past to synthesize 3,3′,3′′-trisindoles. However, most of the methods are only able to produce symmetrical 3,3′,3′′-trisindoles. Herein, we develop a sustainable and efficient approach to synthesize symmetrical as well as unsymmetrical 3,3′,3′′-trisindoles in a very selective manner using the α-amylase enzyme as a catalyst. Furthermore, various differently substituted isatin and indoles were used to prove the generality of the protocol and symmetrical or unsymmetrical 3,3′,3′′-trisindoles were obtained in 43–97% isolated yields. Next, a probable mechanism is proposed and investigated using molecular dynamics (MD) investigation to gain more insight into the role of residues available in the active site of the α-amylase enzyme. These studies revealed that Glu230, Lys209, and Asp206 in the active site of α-amylase play an important role in this catalysis. Moreover, the DFT studies suggested the formation of bisindole and alkylideneindolenine intermediates during the transformation. We synthesized four different biologically important 3,3′,3′′-trisindoles on a gram scale, which proved the robustness and scalability of this protocol.