Guanidine natural products comprise an intriguing class of structurally diverse marine alkaloids. Several polycyclic guanidine alkaloids have been isolated from the sponge Crambe crambe and were found to elicit varied and potent biological responses, including antiviral, immunosuppressive, and ion channel blocking activities. Current efforts directed toward the total synthesis of members of the batzelladine and crambescidin alkaloids will be presented, focusing on novel annulation strategies for the construction of functionalized pyrimidine rings.