An Alternative Synthesis of the Antineoplastic Nucleoside 4‘-ThioFAC and Its Application to the Synthesis of 4‘-ThioFAG and 4‘-Thiocytarazid

Previously, we synthesized 4‘-thioFAC, a novel antineoplastic cytosine nucleoside, by developing an original method. However, several problems remained. To overcome these problems, we have developed an alternative method for the synthesis of 4‘-thionucleosides. In the original synthesis, carbons from C1 to C5 of d -glucose were used. The new method also starts from d -glucose but uses carbons closer to the tail (C2−C6). A dibenzoyl derivative obtained by this approach was brominated at the anomeric position to give a 1-bromide derivative. Fusion of the 1-bromide and persilylated acetylcytosine, followed by deprotection, predominantly gave a β-anomer of 4‘-thioFAC. The reaction of 2,6-diaminopurine with the 1-bromide in the presence of TMS triflate gave a glycosylated product in good yield. After deprotection, the resulting 1:1 anomeric mixture of free nucleosides was treated with adenosine deaminase to give a β-anomer of 4‘-thioFAG, a guanine congener of 4‘-thioFAC, selectively. Using a similar approach, we synthesized 4‘-thiocytarazid, which was not possible using the original method.