Design and Synthesis of Isonucleosides Constructed on a 2-Oxa-6-thiabicyclo[3.2.0]heptane Scaffold

• Published in: Journal of organic chemistry 2010-06, Vol.75 (12), p.4161-4171
• Main Authors: Yoshimura, Yuichi, Asami, Kazuhiro, Imamichi, Tomozumi, Okuda, Tomoko, Shiraki, Kimiyasu, Takahata, Hiroki
• Format: Article
• Language: English
• Subjects: Alkanes - chemical synthesis; Alkanes - chemistry; Analytical, structural and metabolic biochemistry; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Biological and medical sciences; Bridged Bicyclo Compounds - chemical synthesis; Bridged Bicyclo Compounds - chemistry; Chemistry; Drug Design; Exact sciences and technology; Free radicals chemistry; Fundamental and applied biological sciences. Psychology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Lamivudine - chemistry; Models, Molecular; Molecular Structure; Nucleic acids; Nucleic bases, nucleotides; Nucleosides - chemical synthesis; Nucleosides - chemistry; Organic chemistry; Preparations and properties; Quantum Theory; Reactivity and mechanisms
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo100556u

A novel method for the design and synthesis of an isonucleoside containing a 2-oxa-6-thiobicyclo[3.2.0]heptane skeleton is described. 2,2-Dimethyl-1,3-dioxan-5-one 13 was converted into a dioxabicyclohexane derivative in six steps. After cleavage of the epoxide group with a thiol (thiophenol or PMB mercaptan), the resulting product was subjected to the Mitsunobu reaction in the presence of a nucleobase. The reaction proceeded via the migration of the thiosulfide groups and gave the desired isonucleoside derivatives. In the case of a phenyl sulfide derivative, radical desulfurization followed by deprotection gave 4′-substituted 2′,3′-dideoxyisonucleosides. A PMB sulfide derivative, on the other hand, was converted into the corresponding dimesylate, which was then treated with mercury acetate and trifluoroacetic acid to remove the PMB group. The resulting thiol derivative was treated with DBU to give the desired isonucleoside constructed on a 2-oxa-6-thiobicyclo[3.2.0]heptane scaffold after deprotection. The optimized conformer of the isonucleoside was calculated using DFT at the B3LYP/6-31G** level and was compared with that of lamivudine using model compounds.