The Synthesis Of2’,3’-didehydro-2’,3’-dideoxyadenosine And Cordycepin

With the increasing incidence of HIV and hepatitis B virus infection, the development of effective antiviral drugs has been extremely important. Since2’,3’-didehydro-2’,3’-dideoxyadenosine is an important intermediate for synthesis of antiviral drugs such as2’,3’-dideoxyadenosine and2’,3’-didehydro-2’,3’-dideoxyadenosine derivatives, the synthesis of2’,3’-didehydro-2’,3’-dideoxyadenosine is of great significance.Based on the results of a thorough literature search, we designed and optimized a synthetic route to construct2’,3’-didehydro-2,3’-dideoxyadenosine; studied the reaction conditions of adenosine hydroxyl protection; and explored the chemical synthesis of cordycepin.1. We used pyridine and tert-butyldimethysilylchloride to protect the hydroxyl of adenosine, and found that reaetant ratio has great impact on the product distribution.5’-O-(tert-Butyldimethylsilyl)adenosine was the main product when the reaetant ratio was n(adenosine):n(TBDMSCl)=1:1.2, and the yield was80.2%;2’,5’-bis-O-(tert-Butyldimeth-ylsilyl)adenosine and3’,5’-bis-O-(tert-Butyldimethylsilyl)adenosine were the main product when the reaetant ratio was n (adenosine):n(TBDMSCl)=1:3.0, and the yield were49.1%and19.6%, respectively. We also explored the optimal conditions for the TBS migration of3’,5’-bis-O-(tert-Butyldimethylsilyl)adenosine into2’,5’-bis-O-(tert-Butyldimethylsilyl)-adenosine, under optimum conditions the conversion ratio was62.51%and after migration the yield of2’,5’-bis-O-(tcrt-Butyldimethylsilyl)adenosine was up to61.4%.2.2’,3’-didehydro-2’,3’-dideoxyadenosine was prepared from adenosine through Corey-Winter olefination over four steps. The intermediates and target products were confirmed by1HNMR and13CNMR.We significantly increased the yield of step2and3after optimization of reaction conditions for every step. Under optimum conditions the yield of5’-O-(tert-Butyldimethylsilyl)adenosine was80.2%, the yield of5’-O-(tert-Butyldimethylsilyl)-2’,3’-O-thionocarbonyladenosine was94.0%, the yield of5’-O-(tert-Butyldimethylsilyl)-2’,3’-didehydro-2’,3’-dideoxyadenosine was82.6%, the yield of2’,3’-didehydro-2’,3’-dideoxyadenosine was82.0%. The total yield was51.1%,25%percent higher than what was reported. 3. We explored the the chemical synthesis of cordycepin with2’,3’-didehydro-2’,3’-dideoxyadenosine as the starting material.The key step was hydroboration-oxidation which failed. The reason may be hemiacetal of five-membered ring was unstable after hydroboration. In the furture we can try the synthesis of cordycepin with2’,5’ hydroxyl-protected product as the starting material, oxidizing3’ hydroxyl group into a carbonyl group and then reduce it into methylene, followed by removal of the protecting group.