J Org Chem 2021 Apr 11;86(7):4944-4956. Epub 2021 Mar 11.
Laboratory of Biological Chemistry, Division of Biotechnology Review and Research IV, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, United States.
The implementation of protecting groups for the 2'-hydroxyl function of ribonucleosides is still challenging, particularly when RNA sequences must be of the highest purity for therapeutic applications as nucleic acid-based drugs. A 2'-hydroxyl-protecting group should optimally (i) be easy to install; (ii) allow rapid and efficient incorporation of the 2'--protected ribonucleosides into RNA sequences to minimize, to the greatest extent possible, the formation of process-related impurities (, shorter than full-length sequences) during solid-phase synthesis; and (iii) be completely cleaved from RNA sequences without the production of alkylating side products and/or formation of mutagenic nucleobase adducts. The reaction of 2'--aminoribonucleosides with ethyl pyruvate results in the formation of stable 2'--imino-2-methyl propanoic acid ethyl esters and, subsequently, of the fully protected ribonucleoside phosphoramidite monomers, which are required for the solid-phase synthesis of two chimeric RNA sequences (20-mers) containing the four canonical ribonucleosides. Read More