Tryptophan Bioconjugation through Auxiliary Boron-Accelerated, Additive-Free Friedel-Crafts Alkylation

Chemical tools have allowed the interrogation of molecular events in biological systems through the realization of additive-free labeling approaches such as strain-promoted chemistry. Although design and synthesis of strained compounds remain challenging tasks, efforts to identify an alternative chemical strategy to achieve such additive-free labeling are lacking. Serendipitously, we found that a trifluoroborate unit can act as an auxiliary group to enable the additive-free Friedel-Crafts alkylation reaction at room temperature in the potentially protein-compatible solvent hexafluoroisopropanol (HFIP) without any additional catalysts such as a Lewis acidic metal and a Brønsted acid. The structure-reactivity relationship of a set of thiophene electrophiles for the dehydrative alkylation of tryptophan revealed the inability of various functional groups to cause such an additive-free labeling process, while all of the synthesized trifluoroborate variants displayed substantially enhanced reactivity even in the absence of additives. As the boron moiety serving as an auxiliary group remains on the thiophene unit after the tryptophan bioconjugation, facile secondary functionalization of alkylated tryptophan through boron-based chemistry proved to be possible at a protein level. Because strain-promoted chemistry has shown great promise for diverse applications beyond small-molecule studies by eliminating the need for additives/catalysts, the boron auxiliary approach may be a promising chemical strategy in a wide variety of contexts.