The formation of bacterial biofilms is a common mechanism for antibiotic resistance. It has been shown that bis-(3'-5')-cyclic dimeric guanosine monophosphate, c-di-GMP, plays a key role in bacterial biofilm formation; therefore, the proteins that regulate the metabolism or adaptive response of c-di-GMP are favorable targets for novel antimicrobials. We herein describe a solid-support methodology developed in the Sintim Laboratory and efforts toward its application to the synthesis of novel c-di-GMP analogs. Our selected targets are a series of analogs bearing various substitutions at the 2'-position of the ribose backbone. Syntheses of 2'-deoxy and 2'-methoxy analogs were achieved as well as that of key intermediates toward the 2'-fluoro and conformationally flexible analogs.