Purine Based Combinatorial Chemistry: Solution Phase Simultaneous Addition of Functionalities. Iterative Deconvolution by Orthogonal Protection to a Single Compound with Potent Antibacterial Activity

Abstract

We have recently described a method to prepare combinatorial chemistry libraries by solution phase simultaneous addition of functionalities (SPSAF).1–2 SPSAF has been used to create libraries based on the purine heterocycle. The nucleophilic sites (secondary nitrogens) in the planer heteroaromatic purine scaffold were built in via linkers. Thus, to continue the use of electophilic functionalities, as in previous libraries, a bifunctional nucleophilic linker was required. Piperazines readily served this purpose. Nucleophilic displacement of the chloro groups on 2,6-dichloropurine with piperazines provides reactive, constrained secondary amines for combinatorialization (Figure 1, 1). An additional piperazine was placed in the 9-position by alkylation of 2,6-dipiperazinylpurine. In this manner, the functionality that differentiates each pool (sublibrary) could be placed last in the synthetic scheme (fix last concept).1