Chemoselective Multicomponent One-Pot Assembly of Purine Precursors in Water

The recent development of a sequential, high-yielding route to activated pyrimidine nucleotides, under conditions thought to be prebiotic, is an encouraging step toward the greater goal of a plausible prebiotic pathway to RNA and the potential for an RNA world. However, this synthesis has led to a disparity in the methodology available for stepwise construction of the canonical pyrimidine and purine nucleotides. To address this problem, and further explore prebiotically accessible chemical systems, we have developed a high-yielding, aqueous, one-pot, multicomponent reaction that tethers masked-sugar moieties to prebiotically plausible purine precursors. A pH-dependent three-component reaction system has been discovered that utilizes key nucleotide synthons 2-aminooxazole and 5-aminoimidazoles, which allows the first divergent purine/pyrimidine synthesis to be proposed. Due to regiospecific aminoimidazole tethering, the pathway allows N9 purination only, thus suggesting the first prebiotically plausible mechanism for regiospecific N9 purination.

近期，在被认为是前生命期（prebiotic）的条件下，研究者开发出了一条可制备活化嘧啶核苷酸（pyrimidine nucleotides）的高产率分步合成路线，这向着构建可信的前生命期RNA合成路径、实现RNA世界（RNA world）的宏伟目标迈出了令人鼓舞的一步。然而，该合成方法使得经典嘧啶核苷酸与嘌呤核苷酸（purine nucleotides）的分步构建方法出现了失衡。为解决这一问题并进一步探索前生命期条件下可实现的化学体系，我们开发了一种高产率、水相、一锅法多组分反应，可将掩蔽糖基团（masked-sugar moieties）连接至前生命期可行的嘌呤前体（purine precursors）上。我们发现了一种依赖pH的三组分反应体系，该体系利用关键的核苷酸合成子（synthon）2-氨基恶唑（2-aminooxazole）与5-氨基咪唑（5-aminoimidazoles），从而首次提出了可实现嘌呤/嘧啶核苷酸的发散型合成路径。由于氨基咪唑的区域选择性连接，该路径仅允许在N9位发生嘌呤化（purination），由此首次提出了具备前生命期可行性的区域选择性N9位嘌呤化机制。