A201A is a structurally unique nucleoside antibiotic, distinguished by its furanose unit that contains an exo-ene ether—a feature not observed in any other natural product. First isolated from *Streptomyces capreolus* NRRL 3817 by Eli Lilly and Company in 1976, A201A exhibits potent antibacterial activity against Gram-positive bacteria and many anaerobic Gram-negative species. Its mechanism of action is believed to involve the ribosome’s A site, as it contains a 3′-amido nucleoside fragment that mimics the end of tRNA, thereby inhibiting protein synthesis.
In 2012, the Jianhua Group at the South China Sea Institute of Oceanology, Chinese Academy of Sciences, accidentally discovered A201A in *Actinomycetes thermotolerans*, a strain obtained from the seabed of the South China Sea. This discovery led to extensive research into its biosynthetic pathway, revealing novel insights into its formation.
Recently, Yu Yu from the State Key Laboratory of Bioorganic Chemistry at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, successfully completed the first full chemical synthesis of A201A (J. Am. Chem. Soc., 2014, 136, 4157–4160). The synthesis employed a linear strategy, involving the assembly of five distinct blocks through glycosidation and amidation. Key steps included the highly stereoselective formation of the 1,2-cis-glucosidic bond using Mitsunobu glycosidation, the optimized stereoselective synthesis of the E-enol methyl ether, and the use of valency-promoted glycosidation for N-glycosylation of hydrazine. Additionally, the method enabled glycosylation of complex substrates containing acid-sensitive groups and basic nitrogen atoms.
This modular and linear synthetic approach not only provides a robust platform for the total synthesis of A201A but also opens new avenues for the development and study of its analogs. It enables more efficient exploration of structure-activity relationships, which is crucial for drug discovery and optimization. With this breakthrough, researchers can now explore variations of A201A to enhance its therapeutic potential or overcome resistance mechanisms.
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