A scalable approach for constructing bicyclic hydantoin structures to synthesize crucial intermediates for d-biotin

Abstract

A novel, efficient method has been developed for the synthesis of bicyclic thiazolidine hydantoin, a key intermediate in the chiral pool-based synthesis of D-biotin. N-Benzyl-1H-imidazole-1-carbaldehyde, which is cost-effective and readily accessible, was used to replace the traditionally employed, flammable, and expensive benzyl isocyanate. Upon undergoing a cyclization reaction with (R)-2-phenylthiazolidine-4-carboxylic acid, it successfully constructed the bicyclic structure of the target compound. By optimizing reaction solvents, feeding methods, dosage, reaction temperature, and time, the most suitable reaction conditions were identified. This process was achieved without the need for any catalysts, resulting in an 85% yield. Meanwhile, two by-products were monitored during the reaction, and their formation mechanisms were investigated. Further studies demonstrated that this method exhibits excellent functional group tolerance, enabling the incorporation of a broad range of substrates. This study presents a scalable and efficient approach for the synthesis of bicyclic thiazolidine hydantoin, offering significant advantages in terms of safety, cost-effectiveness, and industrial applicability. Additionally, it establishes a preliminary foundation for the industrialization of the D-biotin chiral pool-based synthetic route.