In the context of a PRMT5 inhibitor program, we describe our efforts to develop a flexible and robust strategy to access tetrahydrofuro[3,4-b]furan nucleoside analogues. Ultimately, it was found that a Wolfe type carboetherification from an alkenol derived from d-glucofuranose diacetonide was capable of furnishing the B-ring and installing the desired heteroaryl group in a single step. Using this approach, key intermediate 1.3-A was delivered on a gram scale in a 62% yield and 9.1:1 dr in favor of the desired S-isomer. After deprotection of 1.3-A, a late-stage glycosylation was performed under Mitsunobu conditions to install the pyrrolopyrimidine base. This provided serviceable yields of nucleoside analogues in the range of 31–48% yield. Compound 1.1-C was profiled in biochemical and cellular assays and was demonstrated to be a potent and cellularly active PRMT5 inhibitor, with a PRMT5-MEP50 biochemical IC₅₀ of 0.8 nM, a MCF-7 target engagement EC₅₀ of 3 nM, and a Z138 cell proliferation EC₅₀ of 15 nM. This work sets the stage for the development of new inhibitors of PRMT5 and novel nucleoside chemical matter for alternate drug discovery programs.

中文翻译：

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四氢呋喃[3,4- b ]呋喃核苷类似物的灵活鲁棒合成方法的建立

在PRMT5抑制剂计划的背景下，我们描述了我们为开发一种灵活而强大的策略来获取四氢呋喃[3,4- b ]呋喃核苷类似物的努力。最终，发现得自衍生自d-葡萄糖呋喃糖二丙酮化物的烯醇的Wolfe型碳醚化能够提供B环并在单个步骤中安装所需的杂芳基。使用这种方法，关键的中间体1.3-A以克为单位以62％的收率和9.1：1 dr的量进行输送，有利于所需的S-异构体。脱保护1.3-A后，在Mitsunobu条件下进行后期糖基化以安装吡咯并嘧啶碱。这提供了核苷类似物的有用产率，产率为31-48％。在生化和细胞分析中对化合物1.1-C进行了分析，并证明是有效的且具有细胞活性的PRMT5抑制剂，PRMT5-MEP50生化IC ₅₀为0.8 nM，MCF-7目标参与EC ₅₀为3 nM， Z138细胞增殖EC ₅₀为15 nM。这项工作为开发替代药物发现计划的PRMT5新抑制剂和新型核苷化学物质奠定了基础。