A Stereoselective Synthesis of 4′‐α‐Fluoro‐methyl Carbocyclic Nucleoside Analogs

• Published in: ChemistrySelect (Weinheim) Vol. 8; no. 26
• Main Authors: Singh, Uma S., Jones, Ransom A., Kothapalli, Yugandhar, Mulamoottil, Varughese A., Wei, Pingrong, Chu, Chung K.
• Format: Journal Article
• Language: English
• Published: 14-07-2023
• Subjects: 4′-α-Fluoro-methyl carbocyclic synthesis; Carbocyclic nucleosides; Emerging viruses; Fluorination; Selective protection
• ISSN: 2365-6549; 2365-6549
• DOI: 10.1002/slct.202302043

The 4′ position modifications in carbocyclic nucleosides have not been investigated much as potential antiviral agents. Due to the higher ring strain and torsion of the cyclopentyl carbocyclic ring, it is not easy to carry out the modification at the 4′ position. Therefore, there is a need for a procedure that may tackle the synthesis of 4′ position substituted carbocyclic pentyl ring. In this communication, a stereoselective synthesis of 4′‐α‐fluoro‐methyl carbocyclic nucleosides has been reported. A stereoselective synthesis of the 4‐α‐fluoro‐methyl carbocyclic sugar moiety (16) was carried out via carbocyclic ketone 1. The oxidation of the 5‐methyl hydroxy of 9 followed by the aldol condensation gave a diol 11, which via selective protection followed by selective fluorination, yielded a MOM‐protected 4‐α‐fluoro‐methyl carbocyclic ring (16). Compound 16 served as a key intermediate for the synthesis of purines (21&24) and pyrimidine (28&31) nucleosides. The described synthesis may be utilized to construct the various 4′ position modified carbocyclic nucleos(t)ides for an elaborated structure‐activity relationship (SAR) as an antiviral and anticancer agent.
The article reports the synthesis of 4′‐fluoro‐methyl‐carbocyclic nucleoside analogs. The described procedure may open new synthetic avenues for the derivatization at the 4′‐position of carbocyclic nucleosides. 4′‐modified nucleoside analogs have not been well explored for biological activities, and their evaluation as antiviral and anticancer agents is awaited. This report may benefit medicinal/organic chemists in exploring the complete structure‐activity relationship of this class of molecules. A stereoselective synthesis of 4′‐fluoro‐methyl carbocyclic nucleoside was commenced with ketone 1, which via selective protection, oxidation, and fluorination, provides a key intermediate 16. Compound 16 was utilized for the synthesis of 4′‐fluoro‐methyl derivatized targeted nucleosides.