Modular Combination of Enzymatic Halogenation of Tryptophan with Suzuki-Miyaura Cross-Coupling Reactions
The combination of the biocatalytic halogenation of l-tryptophan with subsequent chemocatalytic Suzuki-Miyaura cross-coupling reactions leads to the modular synthesis of an array of C5, C6, or C7 aryl-substituted tryptophan derivatives.
In a three-step one-pot reaction, the bromo substituent is initially incorporated regioselectively by immobilized tryptophan 5-, 6-, or 7-halogenases, respectively, with concomitant cofactor regeneration.
The halogenation proceeds in aqueous media at room temperature in the presence of NaBr and O2.
After the separation of the biocatalyst by filtration, a Pd catalyst, base, and boronic acid are added to the aryl halide formed in?situ to effect direct Suzuki-Miyaura cross-coupling reactions followed by tert-butoxycarbonyl (Boc) protection.
After a single purification step, different Boc-protected aryl tryptophan derivatives are obtained that can, for example, be used for peptide or peptidomimetic synthesis.
M. Frese, C. Schnepel, H. Minges, H. Voß, R. Feiner, N. Sewald, ChemCatChem 2016, 8, 1799–1803.