Amines are crucial functional groups in pharmaceuticals and natural products, driving the need for sustainable and efficient synthetic methods. Direct C–H amination is an attractive strategy, but controlling regio- and stereoselectivity remains challenging, especially in intermolecular reactions. While directed C–H activation using transition metal catalysis offers a solution, it often relies on expensive and toxic noble metals. This research aims to overcome these limitations by employing a directed nitrene-mediated C–H insertion using a metal-coordinating functional group, specifically carboxylic acids, to achieve asymmetric α-amination. The direct α-amination of carboxylic acids is particularly challenging due to the acidity of the carboxyl group and the high pKa of the α-hydrogen. Previous attempts have involved multi-step procedures, strong bases, or resulted in limited enantioselectivity. This work proposes a novel one-step approach utilizing abundant carboxylic acid feedstocks and sustainable, earth-abundant iron catalysis to synthesize valuable chiral α-amino acids with a range of substituents. The method’s success is also attributed to the use of the readily applicable Boc protecting group, avoiding additional protection/deprotection steps.

Existing methods for α-amino acid synthesis often involve multi-step processes, strong bases, or limited enantioselectivity. Yamada et al. (1972) reported a one-pot procedure using a strong base but only yielded racemic products. Smith and colleagues (2012) demonstrated an enantioselective organocatalytic method, limited to *N*-aryl-α-glycine derivatives. Shimizu and colleagues (2019) introduced a boron-catalyzed approach with modest enantioselectivity. This research aimed to overcome the limitations of these approaches through a direct, single-step, enantioselective α-amination of readily available carboxylic acids.

The authors used phenylacetic acid (PAA) as a model substrate and (*R*,*R*)-[FeCl₂(BIP)] (a chiral iron catalyst) to catalyze the reaction. Various *N*-Boc-protected carbamates with different leaving groups were explored as nitrene precursors. Optimization studies focused on identifying the optimal leaving group (mesylate), base (piperidine), and solvent (1,2-dichlorobenzene or dichloromethane). The reaction was conducted under a nitrogen atmosphere at −15°C for 20 hours. The reaction's progress was monitored using ¹H NMR spectroscopy, and enantiomeric excess (e.e.) was determined by high-performance liquid chromatography (HPLC) analysis using chiral stationary phases. A general procedure for the iron-catalyzed α-amination of carboxylic acids is provided: the carboxylic acid, BocNHOMs, and (*R*,*R*)-FeBIP catalyst are added to a Schlenk tube, evacuated and backfilled with N2, the solvent and piperidine are added, and the mixture is degassed by freeze-pump-thaw. The reaction mixture is then stirred at -15°C for the indicated time. After the completion of the reaction, the mixture is diluted with diethyl ether and washed with aqueous NaHSO4 (1 M). The organic layer is separated, dried, and purified by column chromatography to obtain the chiral α-amino acid product. The use of different conditions, including the use of (S,S)-FeBIP and variation in equivalents of reagents and reaction time was tested in order to test the scope of the methodology.

The optimized reaction conditions yielded *N*-Boc-protected (*S*)-phenylglycine in 78% NMR yield (77% isolated yield) with 93% e.e. A wide range of substrates were successfully aminated, including those with electron-donating and electron-withdrawing substituents on aromatic and aliphatic chains. The reaction tolerated various substituents on the aromatic ring of PAA, resulting in satisfactory yields and high enantioselectivities (85–94% e.e.). Heteroaromatic and benzannulated arylglycines were also synthesized successfully. Aliphatic carboxylic acids with non-activated C(sp³)-H bonds were also aminated, providing α-amino acids in moderate to good yields (30–55%) and high e.e. (87–91%). The method proved effective for the synthesis of α,α-disubstituted α-amino acids, which are challenging to synthesize via conventional methods. These were obtained in high yields (68–89%) and high enantioselectivities (79–91% e.e.). Notably, the reaction with racemic α-branched carboxylic acids was enantioconvergent. Late-stage C–H aminations were also performed on various pharmaceutical molecules and natural products, showcasing the method's versatility. Kinetic isotope effect (KIE) studies (kH/kD = 2.0) indicated that C–H bond cleavage is the rate-determining step. Experiments ruled out alternative mechanisms, and mechanistic studies support a radical mechanism where the radical rebound step, not the initial C–H abstraction, determines stereochemistry. Density functional theory (DFT) calculations support the proposed mechanism, suggesting a long-lived diradical intermediate allowing for stereoablative bond rotation before the stereodetermining radical rebound step.

The successful development of this single-step, enantioselective α-amination of carboxylic acids addresses the long-standing challenge of synthesizing chiral α-amino acids efficiently and sustainably. The use of abundant and readily available carboxylic acids as starting materials, combined with the employment of earth-abundant iron catalysis and the convenient Boc protecting group, significantly enhances the efficiency and sustainability of the method. The broad substrate scope demonstrates its versatility in synthesizing diverse α-amino acids with a wide range of substituents, including those found in pharmaceuticals and natural products. The mechanistic understanding gained from KIE studies, control experiments, and DFT calculations provides valuable insights into the reaction pathway and the origin of stereoselectivity. The method represents a significant advance in the field of asymmetric C–H functionalization, highlighting the potential of directed C–H nitrene insertion as a powerful tool for organic synthesis.

This research presents a highly efficient and sustainable method for synthesizing a broad range of chiral α-amino acids via a single-step, enantioselective α-amination of carboxylic acids. The method utilizes readily available starting materials, earth-abundant iron catalysis, and the popular Boc protecting group, thereby addressing critical aspects of sustainability and practicality in organic synthesis. Future research could explore expanding the substrate scope further to encompass even more diverse carboxylic acids and investigate the use of alternative protecting groups or catalysts to enhance the efficiency and applicability of the method. The understanding gained from the mechanistic studies also opens avenues for further development of intermolecular asymmetric C–H aminations through directed C(sp³)–H nitrene insertion.

While the method demonstrates a broad substrate scope, some aliphatic α,α-disubstituted carboxylic acids yielded lower yields and enantioselectivities. The reaction conditions might not be universally applicable to all types of carboxylic acids. Further optimization might be needed to expand the applicability to specific substrates or to enhance yields in challenging cases. The use of dichloromethane as a solvent for some substrates is notable and could warrant further investigation to explore the cause of improved yields compared to o-DCB.