An Improved Strategy for the Chemical Synthesis of 3′,5′‐cyclic Diguanylic Acid

The physiological functions of c‐di‐GMP and its involvement in many key processes led to its recognition as a major and ubiquitous bacterial second messenger. Aside from being a bacterial signaling molecule, c‐di‐GMP is also an immunostimulatory molecule capable of inducing innate and adaptive immune responses through maturation of immune mammalian cells. Given the broad biological functions of c‐di‐GMP and its potential applications as a nucleic‐acid‐based drug, the chemical synthesis of c‐di‐GMP has drawn considerable interest. An improved phosphoramidite approach to the synthesis of c‐di‐GMP is reported herein. The synthetic approach is based on the use of a 5′‐O‐formyl protecting group, which can be rapidly and chemoselectively cleaved from a key dinucleotide phosphoramidite intermediate to enable a cyclocondensation reaction leading to a fully protected c‐di‐GMP product in a yield ∼80%. The native c‐di‐GMP is isolated, after complete deprotection, in an overall yield of 36% based on the commercial ribonucleoside used as starting material. © 2019 by John Wiley & Sons, Inc.