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Selective Iridium-Catalyzed Reductive Amination Inside Living Cells

11 August 2025

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Importance of Amino Group:

The amino group is a key feature of numerous biomolecules and pharmaceuticals, owing to its Lewis basicity, nucleophilicity, hydrogen bonding capability, and/or tetrahedral geometry. Amine compounds play important roles in biology, such as neurotransmitters, hormones, and drugs. However, uncontrolled deamination processes within cells may lead to human health problems, such as Parkinson's disease and neurodegenerative diseases.

Limitations of Traditional Reductive Amination Methods:

·Reductive amination (RA): A chemical process that converts aldehydes or ketones into amines, involving the condensation of aldehydes or ketones with nitrogen donors to form imines, followed by reduction to obtain the target amine.
·Challenges of traditional methods: Traditional RA methods have multiple problems, such as over-alkylation, competition for aldehyde reduction to alcohols, toxicity of nitrogen donors, and instability of metal catalysts in biological media. These methods usually require heterogeneous catalysts that are impermeable to cells or potentially toxic hydride sources, and are therefore not applicable to living cells.

Exploration of New Methods (Figure 1):

·Metal-catalyzed transfer hydrogenation: The researchers explored transfer hydrogenation methods using metal catalysts such as iridium and ruthenium, which are widely used in organic synthesis but have limited application in living cells.
·Biocompatibility challenges: To achieve RA in living cells, new chemical methods need to be developed that can be carried out under physiological conditions and are non-toxic to cells.
·Development of new biocompatible methods: The goal of this article is to develop a biocompatible method that can selectively convert aldehydes to 1°, 2°, and 3° amines in living cells.
·Solving problems of traditional methods: By using self-immolative nitrogen donors and electron-deficient iridium catalysts, the researchers aim to solve the problems existing in traditional RA methods, such as over-alkylation and competing reactions for the reduction of aldehydes to alcohols.

Figure 1. Reductive amination of aldehydes to amines

Comparison of the structure and reaction products of iridium catalysts (Figure 2):

·Catalyst structure: The structure of the experimental iridium catalyst is presented in this paper, including the effect of different substituents (such as H, NMe2, OMe, OH, Cl, CF3, CN, NO2) on the catalytic activity.
·Product distribution: The product distribution of the reaction of aldehyde 1a with HCOONH4 under standard reaction conditions (DMSO/PBS, 37 °C, 20 h) over different iridium catalysts was compared by gas chromatography (GC). The results showed that electron-deficient catalysts (such as Ir6, Ir7, Ir8) mainly produced 2° and 3° amines, while electron-rich catalysts (such as Ir2, Ir3, Ir4) produced more alcohols and 2°/3° amine mixed products.

Figure 2. Structures of Ir complexes used in this study (A) and comparison of products obtained from the reaction of 1a with Ir and HCOONH4 (B).

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Screening of self-immolative nitrogen donors and product selectivity (Figure 3):

·Nitrogen donor screening: The researchers tested the product distribution of the reaction of different self-cleavable nitrogen donors (such as boronic acid, boric acid ester, 4-hydroxybenzylamine, 4-hydroxy-3-methoxybenzylamine, 4-(1-aminoethyl)phenol) with 1a, HCOONa and Ir6. The results showed that when 4-(1-aminoethyl)phenol (10) was used as a nitrogen donor, 1° amine 3a could be generated with a yield of up to 93%.
·Product selectivity: Under the optimized conditions, when 10 was used as a nitrogen donor, the reaction only produced 1° amine 3a, and no overalkylation products of 2° and 3° amines were observed. The electron-deficient catalyst Ir6 showed the highest selectivity for 1° amine.

Figure 3. Evaluation of nitrogen-precursors as possible self-immolative donors (A) and comparison of products obtained from the reaction of 1a with Ir, HCOONa, and 10 (B).

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Reductive amination of different aldehydes (Figure 4):

· Scope of aldehydes: The reductive amination of diverse aldehydes—including aliphatic, α,β-unsaturated, and aromatic aldehydes—was examined under identical conditions using Ir6, HCOONa, and 10. Aliphatic aldehydes (1a–1c) were converted to the corresponding primary amines (3a–3c) with excellent yields. The α,β-unsaturated aldehyde (1d) was aminated to a primary amine but the C=C bond was also reduced to afford 3a in 88% yield. Straight-chain aliphatic aldehydes (1e–1h) were successfully transformed to the desired primary amines (1e–1h), respectively, in moderate to high yields (56-85%). While the electron-rich derivative 4-dimethylaminobenzaldehyde was significantly less reactive, giving the corresponding amine 3j in only 23% yield. The natural product vanillin (1k) remained completely unreactive under these conditions.
· Effect of reaction conditions: Reactions performed in cell culture medium (DMEM) also mainly produced 1° amine 3a, but the yields were reduced in the presence of high concentrations of biological additives (e.g., lysine or glutathione).

Figure 4. Reductive amination of various aldehydes to the corresponding primary amines using Ir6, HCOONa, and 10.

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Synthesis of 2° and 3° amines:
The research team then screened a variety of starting materials containing aldehydes and amines to synthesize a variety of 2° and 3° amines in high yields. ·Synthesis of 2° amines: A variety of 2° amines were synthesized by reacting aldehyde 1a with different 1° amines in the presence of Ir6 and HCOONa. The results showed that the reaction had a high selectivity for 2° amines when Ir6 was used.
·Synthesis of 3° amines: A variety of 3° amines were synthesized by reacting aldehyde 1a with different 2° amines in the presence of Ir6 and HCOONa. The results showed that the reaction was able to produce 3° amines in moderate to high yields.

Later, the researchers applied this reductive amination reaction to proteins and living cells.
Reductive amination reaction on proteins (Figure 5):
·Oxidation and reductive amination of BSA: Allysine residues were introduced into bovine serum albumin (BSA) by oxidation treatment, and then reductive amination reaction was carried out using Ir6, HCOONa and 10. The results showed that the aldehyde group on BSA could be converted into 1° amine, and the presence of Ir6 was essential for the reaction.

Figure 5. Oxidation of the lysine side chains in bovine serum albumin (BSA) to allysine (BSAAld), followed by reductive amination using Ir6 in the presence of 10 and HCOONa to produce BSARA.

Reductive amination reaction in living cells (Figure 6):
In NIH-3T3 cells, phenylacetaldehyde (1c) was converted to phenethylamine (3c) by Ir-catalyzed reductive amination. The results showed that the reaction was able to increase cell viability, indicating that the generation of phenethylamine is beneficial to the cells. The products of 3c and 2c generated in the cells were confirmed by HPLC analysis, and the turnover numbers (TONs) of Ir1 and Ir6 were calculated, which were approximately 5 for Ir1 and approximately 14 for Ir6, indicating that Ir6 has higher selectivity.

Figure 6. Reductive amination in living cells: eliciting beneficial effects.

Synthesis of cinacalcet in living cells (Figure 7):
In SH-SY5Y cells, aldehyde 1p and (R)-41 were converted to cinacalcet by Ir-catalyzed reductive amination. The results showed that the reaction could reduce cell viability, indicating that the production of cinacalcet had an inhibitory effect on cells. The products of cinacalcet generated in cells were confirmed by HPLC analysis, and the turnover numbers (TONs) of Ir1 and Ir6 were calculated, which were approximately 20 for Ir1 and approximately 12 for Ir6, indicating that Ir1 was more active in the reaction.

Figure 7. Reductive amination in living cells: eliciting Inhibition effects.

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References

[1]Jana, Rahul D., Nguyen, Hieu D., Do, Loi H. Selective iridium-catalyzed reductive amination inside living cells. J. Am. Chem. Soc. 2025, 147(26), 23318-23330.

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