A facile synthesis of cyclic bis(3′→5′)diguanylic acid

Abstract

This paper describes a new method for synthesizing biologically important cyclic bis(3′→5′)diguanylic acid (cGpGp) in a higher yield than that of the existing synthetic method. In the new synthesis, the following two means, in place of those used in the existing synthesis are employed as main strategies to cause the increase in product yield. One of these distinctive strategies in the new synthesis is that the phosphoramidite method is used for the preparation of a key synthetic intermediate of a linear guanylyl(3′→5′)guanylic acid derivative. This method allowed higher-yield formation of the intermediate than that by the triester method used in the existing synthesis. The second distinctive strategy used in the new synthesis is that allyloxycarbonyl and allyl groups are used for the protection of two guanine bases and two internucleotide bonds, respectively. These four allylic protectors can be removed all at once by the organopalladium-catalyzed reaction under neutral conditions. Thus, deprotection of the protected cGpGp precursor was achieved in the present synthesis in a shorter step and under milder conditions than the deprotection achieved in the existing synthesis, which uses diphenylacetyl and o-chlorophenyl groups as protectors for two guanine bases and two internucleotide bonds, respectively, whose full removal requires two different procedures including rather harsh basic treatment. As a result, technical loss and decomposition of the target product in the new synthesis is remarkably reduced.