An improved method for synthesizing cyclic bis(3′-5′)diguanylic acid (c-di-GMP)

This paper describes a new method for synthesizing biologically important cyclic bis(3'-5')diguanylic acid (c-diGMP) in a higher yield than that previously reported to be available by our synthetic method. In the new synthesis, the following two means, in place of those used in the previously reported synthesis, are employed as main strategies to obtain an increase in product yield. One is the use of di-tert-butylsilanediyl protection for 3'- and 5'-hydroxy groups of guanosine; this method allows regioselective production of a 2'-O-(tert-butyldimethylsilyl)guanosine derivative that is a key intermediate for the synthesis. The other is the use of a dimethylformamidine group as a protector for the 2-NH2 function of the guanine base, which can be easily introduced and results in an excellent yield.