Selective Iridium-Catalyzed Reductive Amination Inside Living Cells

Given that amino groups are ubiquitous in bioactive molecules, abiotic routes to incorporate them into cellular species offer new opportunities to study and manipulate living systems. In the present work, we report the first biocompatible method to prepare 1°, 2°, or 3° amines selectively starting from an aldehyde and nitrogen precursor through iridium-catalyzed reductive amination. To prevent overalkylation, we developed a nontoxic self-immolative agent comprising 4-(1-aminoethyl)phenol that can condense with carbonyl groups and undergo 1,6-elimination upon reduction to the desired 1° amines. The use of an electron-poor half-sandwich Ir catalyst favored the formation of amine over alcohol products. To synthesize 2° or 3° amines, the aldehydes were combined with the appropriate 1° or 2° amine, respectively, under our standard reaction conditions. Our method is sufficiently mild to perform on proteins, as demonstrated by the conversion of aldehyde-containing allysine residues in bovine serum albumin to lysine. Importantly, we showed that Ir-catalyzed reductive amination could be applied inside living cells, such as by generating the alkaloid phenethylamine or calcium-reducing drug cinacalcet to elicit different biological responses. The amines formed via intracellular reductive amination were quantified by high performance liquid chromatography, revealing that turnover numbers of up to ∼20 were achieved. This work is expected to enable greater versatility and precision in transforming a wide range of aldehyde-containing entities within living environments, further expanding our biosynthetic chemistry toolbox.