Selective Iridium-Catalyzed Reductive Amination Inside Living Cells

Area of Science:

• Chemical Biology
• Organic Synthesis
• Biotechnology

Background:

• Amino groups are essential components of bioactive molecules.
• Abiotic synthesis routes for incorporating amines into cellular systems are limited.
• Developing biocompatible methods for amine synthesis is crucial for studying and manipulating biological systems.

Purpose of the Study:

• To establish the first biocompatible method for selective synthesis of 1°, 2°, or 3° amines from aldehydes and nitrogen precursors.
• To develop a self-immolative agent to prevent overalkylation during amine synthesis.
• To demonstrate the application of iridium-catalyzed reductive amination within living cells and on proteins.

Main Methods:

• Iridium-catalyzed reductive amination using aldehydes and nitrogen precursors.
• Development of a nontoxic self-immolative agent (4-(1-aminoethyl)phenol) to control amine formation.
• Utilizing an electron-poor half-sandwich Iridium catalyst for selective amine production.
• Application of the method to proteins (bovine serum albumin) and within living cells.

Main Results:

• Selective synthesis of 1°, 2°, and 3° amines achieved.
• Successful prevention of overalkylation using the self-immolative agent.
• Demonstrated biocompatibility through modification of proteins and intracellular synthesis of bioactive molecules like phenethylamine and cinacalcet.
• Achieved intracellular turnover numbers of up to approximately 20 via high-performance liquid chromatography quantification.

Conclusions:

• The developed iridium-catalyzed reductive amination is a versatile and mild method for synthesizing diverse amines.
• The technique is applicable in vitro on proteins and in vivo within living cells.
• This advancement expands the toolbox for chemical biology, enabling precise modification of biological systems and the synthesis of novel compounds.