A short de novo synthesis of nucleoside analogs

• Published in: Science (American Association for the Advancement of Science) Vol. 369; no. 6504; pp. 725 - 730
• Main Authors: Meanwell, Michael, Silverman, Steven M., Lehmann, Johannes, Adluri, Bharanishashank, Wang, Yang, Cohen, Ryan, Campeau, Louis-Charles, Britton, Robert
• Format: Journal Article
• Language: English
• Published: Washington The American Association for the Advancement of Science 07.08.2020
• Subjects: Aldehydes; Analogs; Carbohydrates; Catalysis; Chemical synthesis; Conformation; Deoxyribonucleic acid; DNA; DNA biosynthesis; Enantiomers; Fluorides; Fluorination; Nucleic acids; Nucleoside analogs; Nucleosides; Nucleotide analogs; Nucleotides; Proline; Purines; Pyrimidines; Replication; Ribose; Viruses
• DOI: 10.1126/science.abb3231
• ISSN: 0036-8075

Nucleotide analogs are valuable tools and therapeutics because of their ability to interfere with processes such as DNA synthesis, which are vital to rapidly dividing cells and replicating viruses. These molecules are challenging to synthesize chemically. Meanwell et al. developed a “ribose last” synthetic strategy in which a fluorinated acyclic nucleic acid is formed by an l - or d -proline–catalyzed aldol reaction (see the Perspective by Miller). This intermediate can then be cyclized to yield the nucleic acid analog in one pot with control of anomeric conformation based on cyclization conditions. Nucleotide analogs accessible by this strategy include those with modifications at C2′ and C4′, purines and pyrimidines, and locked and protected products. Science , this issue p. 725 ; see also p. 623 Proline catalysis enables rapid and flexible nucleoside analog synthesis. Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of d - or l -nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.