Design and synthesis of isonucleosides constructed on a 2-oxa-6-thiabicyclo[3.2.0]heptane scaffold.
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.
Yoshimura
Yuichi
Y
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. yoshimura@tohoku-pharm.ac.jp
Asami
Kazuhiro
K
Imamichi
Tomozumi
T
Okuda
Tomoko
T
Shiraki
Kimiyasu
K
Takahata
Hiroki
H
D000473:Alkanes / Q000138:chemical synthesis* / Q000737:chemistry; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D019259:Lamivudine / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D011789:Quantum Theory
D000473:Alkanes; D019380:Anti-HIV Agents; D001643:Bridged Bicyclo Compounds; D009705:Nucleosides; D019259:Lamivudine