SYNERGISTIC · A direct photocatalytic access to chiral β2-amino acids from alkenes using CO2 as the carbon source

A direct photocatalytic access to chiral β2-amino acids from alkenes using CO2 as the carbon source

Currently, a strong focus has been given to the development of catalytic enantioselective transformations due to the high demand of chiral molecules in the pharmaceutical and agrochemical industries. Furthermore, chiral compounds are very important in the biochemistry of living systems since the receptor of a living system is made of enantiomerically pure protein, therefore, preferentially allows only one enantiomer to bind with the active chiral site. Within this context, chiral β2-amino acids (β2-AAs), analogs of α-amino acids where the amino group is attached to the β-carbon instead of the α-carbon, are one of the prime targets as high-demanding chemicals. Particularly, peptides containing β-AA residues tend to have increased resistance to enzymatic degradation. Peptides containing two β-arylalanines, for instance, have been reported to be resistant to carboxypeptidase and chymotrypsin and it is clear that the incorporation of β-AAs improves the half-life of potential peptide-based drugs. Additionally, they have been proven as drugs for human beings, for example, cryptophycin 1, produced from (R)-3-amino-2-methylpropanoic acid is frequently used as an antifungal drug for immunodeficient patients, while the (S)-antipode is either inactive or weakly active in vivo. Therefore, the availability of β2-AAs as chiral building blocks leads to the development of a multitude of pharmaceutically active compounds and potential drugs. However, the development of stereoselective and economically feasible synthetic routes toward β2-AA is a challenging task, being more complicated than the preparation of their well-investigated 3-substituted counterparts (β3-AA). The proposed research envisions a sustainable strategy for the functionalization of alkenes to access chiral β²-AAs, employing carbon dioxide (CO2) as a renewable and abundant C1 synthon. The proposed core of the strategy lies in a one-pot, two-step transformation. In the first step, alkene substrate 1 undergoes a photocatalytic amino-bromination to generate intermediate 2. This is followed by a photoredox-mediated CO2 insertion step in the presence of a chiral nickel catalyst, enabling a face-selective transformation to afford the enantioenriched β²-AA product. The conceptual mechanism of the overall transformation is outlined in Figure 1a, with the stepwise reaction details and catalytic cycle illustrated in Figure 1b.

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