Synthesis of 3-Guaninyl- and 3-Adeninyl-5-hydroxymethyl-2-pyrrolidinone Nucleosides

Abstract

L- and D-glutamic acids, as well as trans-4-hydroxy-L-proline, are converted to the corresponding 3-guaninyl-5-hydroxymethyl-2-pyrrolidinone (4) or 3-adeninyl-5-hydroxymethyl-2-pyrrolidinone (5) nucleoside analog. The protecting group used to block the lactam nitrogen in key intermediates has a significant effect on the diastereoselectivity of the coupling reaction with adenine or guanine.

Synthesis of 9,9′-[1,2-Ethanediylbis(oxymethylene)]bis-2-amino-1,9-dihydro-6H-purin-6-one, an Impurity of Acyclovir

“…Thus, the acetyl group should be transferred to 9 , yielding the oxonium intermediate 11 , which is attacked by the basic nitrogen of 12 , displacing acetic anhydride and yielding 13 as the main product. The last step to deacylate 13 , has been extensively described for acyclovir [11], being ammonia in methanol the most common method [11,27,28], or alternatively, hot aqueous methylamine [29,30]. In our case, the best yields were obtained by adapting the methylamine procedures by treatment of 13 with 2-aminoethanol, which produced the final product 3 with the best purity and yield.…”

Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug

“…Several strategies have utilized this disconnection as part of both medicinal chemistry efforts and natural product syntheses. The Nielsen synthesis of peptide nucleic acids (PNAs) utilizes the chiral hydroxyl group of a related lactam in a Mitsunobu coupling with adenine to give clean inversion of configuration at the carbinol center . Ganesh has also performed similar transformations to other pyrrolidyl-PNA analogues using an N-alkylation displacement strategy of the −OMs pyrrolidinone .…”

Amino Acid and Peptide‐Based Antiviral Agents

“…The synthesis of this non‐proteinogenic amino acid could be accomplished starting from commercially available l ‐glutamic acid which is converted into corresponding l ‐pyroglutamic acid (Scheme 12B). Subsequent esterification and reduction of formed ester lead to alcohol derivative 64 which after condensation with benzaldehyde results in bicyclic structure 65 [62] . Phenylselenation of 65 , subsequent oxidation of selenide intermediate with hydrogen peroxide and elimination provide the α,β‐unsaturated lactam 67 .…”