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.

近期开发的、可在被认为是前生物（prebiotic）的条件下、用于合成活化嘧啶核苷酸的高产率串联路线，是朝着构建合理前生物RNA合成路径、进而实现RNA世界这一宏大目标迈出的令人鼓舞的一步。然而，该合成方法使得现有用于分步构建经典嘧啶与嘌呤核苷酸的方法出现了显著失衡。为解决这一问题，并进一步探索前生物可及的化学体系，我们开发了一种高产率、水相一锅法多组分反应，可将掩蔽糖基团锚定至具有前生物合理性的嘌呤前体之上。我们发现了一种pH依赖型三组分反应体系，该体系借助关键核苷酸合成子（synthon）2-氨基恶唑与5-氨基咪唑，由此首次提出了首例发散型嘧啶与嘌呤核苷酸合成路线。由于该路径采用区域选择性氨基咪唑锚定连接策略，仅允许在N9位发生嘌呤化反应，因此这一机制首次为前生物条件下区域选择性N9位嘌呤化提供了合理的解释。