专一选择性反应策略合成2′-O-甲基腺嘌呤核苷

Synthesis of 2′-O-Methyladenine by A Specific Selective Reaction Strategy

2′-O-烷基核糖核苷由于其在赋予寡核苷酸高度的目标特异性、代谢稳定性以及优良的药代动力学和药效动力学特征上所展现的重要作用,成为了反义药物研究领域的热点,尤其是2′-O-甲基腺嘌呤核苷,作为第二代反义寡核苷酸的关键原料药,其的高效合成研究具有重要意义。现有合成方法存在的成本高和选择性不足等问题,本文基于专一选择性反应思路设计了一条新的合成路线,即以腺嘌呤核苷为起始物,经过缩醛化实现2′-和3′-位羟基选择性地保护、环状缩醛保护基可控区域选择性还原开环、2′-位羟基选择性甲基化及氢化脱苄反应,成功实现了2′-O-甲基腺嘌呤核苷的高效合成,单程总产率为36.7%。此策略不仅每一步反应表现出高选择性以及温和的反应条件,而且使用的试剂更加廉价易得,合成步骤也相对简短,为核苷类化合物核糖骨架上羟基的区域选择性功能化提供了新的思路。

2′- O -Alkylribonucleotides attract significant attention in the antisense drugs due to their pivotal role in endowing oligonucleotides with high target affinity, enhanced metabolic stability, and superior pharmacokinetic and pharmacodynamic attributes. Especially, the efficient synthesis of 2′- O -methyladenosine, a key precursor for the synthesis of second-generation antisense oligonucleotides, is of great importance. The current synthetic approaches have some deficiencies, including high cost and low selectivity. In this paper, a new synthetic route was developed based on exclusively selective reactions. Starting with adenosine, this route incorporated acetal protection of the 2′-and 3′-hydroxyl groups, reductive ring-opening of cyclic acetal moiety, the selective methylation of 2′-hydroxyl and hydrogenative debenzylation, and afforded 2′- O -methyladenosine with a one-run overall yield of 36.7% . This strategy exhibits some advantages such as exclusive selectivity, milder reaction conditions, cheap and readily available reagents and short synthetic route. It paves the way for new avenues in the regioselective functionalization of hydroxyl groups on the ribose scaffold of nucleoside compounds.