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Scalable and economical methods for the production of optically pure amino acids, both natural and unnatural, are essential for their use as synthetic building blocks. Currently, enzymatic dynamic kinetic resolution (DKR) underpins some of the most effective processes. Here we report the development of enantioselective extraction coupled with racemization (EECR) for the chirality conversion of underivatized amino acids. In this process, the catalytic racemization of amino acids in a basic aqueous solution is coupled with the selective extraction of one enantiomer into an organic layer. Back-extraction from the organic layer to an acidic aqueous solution then completes the deracemization of the amino acid. The automation of the EECR process in a recycling flow reactor is also demonstrated. Continuous EECR is made possible by the sterically hindered chiral ketone extractant 5, which prevents the coextraction of the copper racemization catalyst because of its nonplanar geometry. Furthermore, the extractant 5 unexpectedly forms imines with amino acids faster and with greater enantioselectivity than less bulky derivatives, even though 5 cannot participate in intramolecular resonance-assisted hydrogen bonding. These features may allow EECR to challenge the preponderance of enzymatic DKR in the production of enantiomerically enriched amino acids.

A class of carbonyl extractors, (R)‐3, (R)‐4, and (R)‐5, with nonaxial chirality containing asymmetric carbons has been synthesized and studied for their efficiencies in enantioselective liquid–liquid extraction for underivatized amino acids. The bulky t‐butyl ketone extractors, (R)‐4 and (R)‐5, showed the stereoselectivities ranging 5.4–9.4 of l/d ratio much better than those of the aldehyde extractor, (R)‐3, ranging 2.4–5.2. The imine formation rates and yields of the t‐butyl ketones were not significantly affected by their bulkiness and even in the absence of resonance‐assisted hydrogen bond. This work confirms that a bulky t‐butyl ketone can be a good choice in the development of an extractor not only with axial chirality but also with nonaxial chirality for the enantioselective extraction of unprotected amino acids. [ABSTRACT FROM AUTHOR]

The derivative of aminophenyl‐aldehyde with an asymmetric carbon and an uryl group, (S)‐2, was synthesized. The combination of (S)‐2 and aliquat‐336 in CDCl3 extracted underivatized amino acids in water layer by imine formation with enantioselectivities of 12/1 for Phe, 13/1 for Val, and 12/1 for Leu, which are comparable with those of previously reported binaphthol‐based extractor (S)‐1. The enantioselectivities of (S)‐2 is remarkable considering the low molecular weight compared to (S)‐1. Density functional theory computations and experimental data demonstrate that imine bond is strengthened by resonance‐assisted hydrogen bond with the nearby NH group. [ABSTRACT FROM AUTHOR]

The hydroxyphenyl chiral ketone, ( S)- 3, reacts with D-amino acids bearing hydrophobic side chains exclusively over the L-amino acids in a two-phase liquid-liquid extraction, and thus acts as a highly stereoselective extractant. Calculations for the energy-minimized structures for the imine diastereomers and the comparison of the selectivities with other phenyl ketones, ( S)- 4 and ( S)- 5, demonstrate that the hydrogen bond between the carboxylate group and the phenolic hydroxyl group contributes to the remarkable enantioselectivities. The multiple hydrogen bonds present in the imine of ( S)- 3 reinforce the rigidity, and results in the difference between the stabilities of the imine diastereomers. The imine could be hydrolyzed in methanolic HCl solution, and the extraction of the evaporated residues revived the organic layer of ( S)- 3, which could enter into a new extractive cycle and leaves the D-amino acid with enantiomeric excess ( ee) values of over 97 % in the aqueous layer. [ABSTRACT FROM AUTHOR]