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

• Published in: Organic & biomolecular chemistry 2024-02, Vol.22 (9), p.1839-1849
• Main Authors: Kamboj, Priya, Mohapatra, Abinash, Mandal, Debasish, Tyagi, Vikas
• Format: Article
• Language: English
• Subjects: alpha-Amylases; Amylases; Catalysis; Catalysts; Enzymes; Friedel-Crafts reaction; Indoles; Indoles - chemistry; Intermediates; Isatin; Molecular dynamics; Molecular Structure; Synthesis; α-Amylase
• ISSN: 1477-0520; 1477-0539; 1477-0539
• DOI: 10.1039/d3ob01928d

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. A highly selective and sustainable approach using α-amylase enzyme to synthesize biologically important symmetrical as well as unsymmetrical 3,3′,3′′-trisindoles has been reported.