A Solid-Phase Approach for the Synthesis of N 6-, N 7-, and C8-Substituted Adenine Derivatives

Abstract Adenine derivatives have been widely utilized as biologically active compounds owing to their diverse pharmacological properties. Although numerous synthetic approaches have been developed to access structurally diverse adenine analogues, their preparation is often hampered by limited chemoselectivity and the inherently low reactivity of the adenine scaffold. Herein, we report a solid-phase approach to the synthesis of adenine derivatives featuring sequential functionalization of the purine scaffold. A Dimroth rearrangement served as the key step for N6-functionalization, enabling the preparation of 47 adenine derivatives with three sites of diversification. Furthermore, the influence of substituents at each substitution site on the reaction outcome was investigated. This methodology provides an efficient platform for the preparation of structurally diverse purine-based libraries and may facilitate future medicinal chemistry and drug discovery efforts.