A new approach to chiral α-amino acid synthesis - photo-driven nitrogen heterocyclic carbene catalyzed highly enantioselective radical α-amino esterification

(Press-News.org) Professor Jian Wang's research group at Tsinghua University reported a photocatalyzed/nitrogen heterocyclic carbene-catalyzed asymmetric radical α-alkoxycarbonylation reaction of amines. Using dibenzylaniline derivatives and readily available pyrocarbonates as starting materials, chiral α-amino acid esters can be synthesized in one step. Further deprotection reactions yield chiral α-amino acids containing primary, secondary, or tertiary amine groups. This research provides a novel method for obtaining structurally diverse chiral α-amino acid derivatives and has significant potential applications in drug development (especially peptide drugs) using chiral α-amino acids as basic structural units. The article was published as an open access communication in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background information:
Chiral α-amino acid derivatives containing tertiary, secondary, or primary amine structural units are widely found in bioactive molecules or drugs, such as the potent antiplatelet and antithrombotic drug clopidogrel, TRPM8 antagonists, and the commonly used antibiotic ampicillin (Figure 1). Asymmetric catalytic strategies for α-amino acids have been extensively explored, with the most mature studies involving the construction of C–N bonds through the amination of enolates, functionalization of glycine derivatives, or addition of α-imine esters . In contrast, the α-carbamylation strategy has not yet been fully developed. Although some studies have attempted to synthesize α-amino acid derivatives using carbon dioxide and other carbonyl sources, there are currently no successful reports on their enantioselective catalytic construction (Figure 2).

Highlights of this article:
To address the above challenges, Professor Wang's research group at Tsinghua University proposed an "asymmetric radical coupling reaction catalyzed by photo/nitrogen heterocyclic carbene," achieving for the first time the asymmetric α-carbamylation of organocatalyzed amines. This reaction can yield a variety of chiral α-amino acid derivatives with good to excellent yields and high enantioselectivity. Furthermore, the reaction exhibits good substrate versatility and functional group compatibility, tolerating common heterocycles such as indole, benzofuran, benzothiophene, and thiophene (Figure 3). Particularly noteworthy is that, after a simple deprotection transformation, this reaction can be used to rapidly prepare chiral α-amino acids encompassing key primary, secondary, and tertiary amine structural units (Figure 4).

Summary and Outlook:
In summary, this study achieved a highly efficient photo-induced, nitrogen-heterocyclic carbene-catalyzed enantioselective radical coupling reaction. For the first time, it successfully constructed a chiral α-amino acid ester using readily available pyrocarbonate as an acyl source. The reaction combines the advantages of mild conditions, broad substrate scope, and easy product derivatization, providing more possibilities for the efficient synthesis of chiral α-amino acids and the modification of drug molecules. It also strongly demonstrates the excellent chiral control capability of nitrogen-heterocyclic carbene catalysts in radical coupling reactions.

The findings were published as a Communication in CCS Chemistry, with Professor Jian Wang of the School of Pharmaceutical Sciences at Tsinghua University as the corresponding author and doctoral student Yuhan Liu as the first author. This work was supported by the National Natural Science Foundation of China.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.

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