Regioselective Biocatalytic C4-Prenylation of Unprotected Tryptophan Derivatives.

Abstract

Regioselective carbon−carbon bond formation belongs to the challenging tasks in organic synthesis. In this context, C−C bond formation catalyzed by 4‐dimethylallyltryptophan synthases (4‐DMATSs) represents a possible tool to regioselectively synthesize C4‐prenylated indole derivatives without site‐specific preactivation and circumventing the need of protection groups as used in chemical synthetic approaches. In this study, a toolbox of 4‐DMATSs to produce a set of 4‐dimethylallyl tryptophan and indole derivatives was identified. Using three wild‐type enzymes as well as variants, various C5‐substituted tryptophan derivatives as well as N‐methyl tryptophan were successfully prenylated with conversions up to 90 %. Even truncated tryptophan derivatives like tryptamine and 3‐indole propanoic acid were regioselectively prenylated in position C4. The acceptance of C5‐substituted tryptophan derivatives was improved up to 5‐fold by generating variants (e. g. T108S). The feasibility of semi‐preparative prenylation of selected tryptophan derivatives was successfully demonstrated on 100 mg scale at 15 mM substrate concentration, allowing to reduce the previously published multistep chemical synthetic sequence to just a single step.