Date: 10 September 2026 | Category: Headline News, News
Authors: Marcelo Straesser Franco, Rodrigo Costa e Silva, Rafael Alan Carvalho Souza, Eric Yoshitaka Lee, João Marcos Batista Junior, and Julio Cezar Pastre
Julio Cezar Pastre and co-workers from Universidade Estadual de Campinas (UNICAMP) and Universidade Federal de São Paulo (UNIFESP) in Brazil, have successfully used the Vapourtec R-Series Flow Chemistry System in conjunction with the UV-150 photochemical reactor to prepare enantioenriched natural and unnatural α-amino acids.[1] This was achieved by enantioselective addition of alkyl and benzyl radicals, derived from a dihydropyridine species, into α-imino esters using a chiral rhodium catalyst under irradiation with light of wavelength 440 nm, giving yields of up to 75% and enantiomeric ratios up to 99:1, Figure 1.
Figure 1: General continuous flow photochemical setup for synthesis of α-amino acids
Chiral α-amino acids: privileged building blocks with broad application
Chiral α-amino acids and their derivatives are widely considered to be valuable building blocks, with applications across several fields including pharmaceutical development, catalysis and materials science. In particular, unnatural α-amino acids offer valuable insight into protein–protein interactions, protein dynamics, and allow modulation of protein activity. In some cases, they can be incorporated into pharmaceutically-relevant materials. [2]
Photocatalytic approaches for the synthesis of these versatile building blocks have been developed in batch, but batch photochemistry can present challenges including scalability and reproducibility. The broad utility of using a chiral-at-metal Rh(III) species under continuous flow photocatalytic condition was recently showcased by de Assis et al, in the synthesis of brivaracetam, an epilepsy drug. [3,4]
Chiral-at-metal Rh(III) catalysts in photochemical chiral α-amino acid synthesis
Initial work focussed on preparation of chiral α-amino acids through irradiation of an α-imino ester and a dihydropyridine in the presence of the chiral rhodium catalyst at 440 nm (blue) under flow conditions. After a 30-minute residence time, the product was obtained in 75% yield and 22:78 e.r.. Optimization quickly showed that the reaction performance was sensitive to the structural match between the chiral rhodium catalyst and the coordinated α-imino ester, with stereo and electronic properties affecting the spatial orientation of the catalyst–substrate complex, and therefore the enantioselectivity and yield. Importantly, performing the reaction under optimized conditions in batch mode resulted in substantially reduced stereocontrol and yields, particularly during extended irradiation.
A broad scope of substrates was tolerated, delivering both natural and unnatural α-amino acid derivatives in good yields. Dihydropyridine precursors that form stabilised radicals afforded good reactivity and selectivity, whereas those with electron-withdrawing substituents performed less well. Steric effects also had a bearing, with ortho-substitution reducing yield and enantioselectivity, likely due to steric congestion near the radical site. Poorly stabilised radicals or highly strained systems did not undergo reaction.
The flow chemistry advantage:
The use of continuous flow as a means for undertaking photochemical reactions continues to facilitate access to new molecular scaffolds in a more efficient manner. Where the traditional batch approach was fraught with difficulties, use of the UV-150 flow module improved photochemical reactions due to:
- Improved light penetration and more uniform irradiation
- Improved scalability
- Enhanced reaction reproducibility
- Better thermal control (heating and cooling)
- Improved chemoselectivity
- Improved stereoselectivity
References:
[1] Continuous-Flow Asymmetric Photocatalysis for the Synthesis of Natural and Unnatural α Amino Acid Derivatives (M. Straesser Franco, R. Costa e Silva, R. A. Carvalho Souza, E. Y. Lee, João M. Batista Junior, J. Cezar Pastre, ACS Org. Inorg. Au, 2026, 6, 282–287). https://doi.org/10.1021/acsorginorgau.6c00024
[2] Unnatural amino acids: production and biotechnological potential (T. Narancic, S. A. Almahboub, K. E. O’Connor, World J. Microbiol. Biotechnol., 2019, 35, 67). https://doi.org/10.1007/s11274-019-2642-9
[3] Synthesis of the Brivaracetam Employing Asymmetric Photocatalysis and Continuous Flow Conditions (M. S. Franco, R. C. Silva, G. H. S. Rosa, L. M. Flores, K. T. de Oliveira, F. F. de Assis, ACS Omega, 2023, 8, (25), 23008–23016). https://doi.org/10.1021/acsomega.3c02134
[4] Asymmetric Photocatalysis with Bis-cyclometalated Rhodium Complexes (X. Huang, E. Meggers, Acc. Chem. Res., 2019, 53, (3), 833–847). https://doi.org/10.1021/acs.accounts.9b00028