Enzymatic Synthesis of 3-Hydroxy Bisindoles and Further C-3 Sulfenylation via Combining a Carbocatalytic Approach in the Same Pot

Herein, we report the selective synthesis of 3-hydroxy bisindoles via an engineered myoglobin-catalyzed Friedel-Crafts reaction of isatin and indole. Initially, the reaction was carried out using wild-type myoglobin as a catalyst, but the conversion was low. Therefore, a library of Mb-variants was generated utilizing a site-directed mutagenesis technique and obtained the double-mutated Mb(H64V, V68A) variant as a highly reactive and selective biocatalyst for this transformation. Additionally, the robustness and generality of this protocol have been demonstrated by setting up scale-up reactions of variously substituted isatins and indoles which produce the desired 3-hydroxy bisindoles in 66-93 % isolated yield. Next, the enzymatic approach was combined with an carbocatalytic protocol by using graphene oxide as a catalyst to generate C-3 sulfenylated bisindole derivatives in a one-pot manner. A selective synthesis of 3-hydroxy bisindoles via an engineered myoglobin-catalyzed Friedel-Crafts reaction of isatin and indole has been developed. Moreover, the enzymatic approach was combined with a carbocatalytic protocol by using graphene oxide as a catalyst to generate C-3 sulfenylated bisindole derivatives in a one-pot manner. image