Háskóli ÍslandsUniversity of IcelandPérez, OswaldoSchipper, NicolaasBollmark, Martin2021-12-022021-12-022021-10-19Pérez, O., Schipper, N., & Bollmark, M. (2021). Preparative Synthesis of an RP-Guanosine-3′,5′-Cyclic Phosphorothioate Analogue, a Drug Candidate for the Treatment of Retinal Degenerations. Organic Process Research & Development, 25(11), 2453-2460. doi:10.1021/acs.oprd.1c002301083-61601520-586X (eISSN)https://hdl.handle.net/20.500.11815/2725Post-printCyclic guanosine monophosphorothioate analogue 1a is currently showing potential as a drug for the treatment of inherited retinal neurodegenerations. To support ongoing preclinical and clinical work, we have developed a diastereoselective synthesis via cyclization and sulfurization of the nucleoside 5′-H-phosphonate monoester, which affords the desired RP-3′,5′-cyclic phosphorothioate in 9:1 ratio to the undesired SP-diastereomer. This route was made viable as a result of the silyl protection sequence used, which achieved >80% selectivity for 2′,5′-hydroxyls over 3′,5′-hydroxyls. Finally, the chromatography-free process allowed for a scale-up, as intermediates and the final product were isolated by crystallization to give 125 g of 1a (13.8% total yield) with over 99.9% HPLC purity.2453-2460eninfo:eu-repo/semantics/openAccessOrganic ChemistryPhysical and Theoretical Chemistrypreclinical developmentprocess developmentretinal neurodegenerationsnucleotide H-phosphonatecyclic guanosine monophosphorothioatecyclic guanosine monophosphateLífræn efnafræðiinfo:eu-repo/semantics/articleOrganic Process Research and Developmenthttps://doi.org/10.1021/acs.oprd.1c00230