Department of Chemistry, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
Department of Process Research and Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
Science. 2020 Aug 7;369(6504):725-730. doi: 10.1126/science.abb3231.
Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of d- or l-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2'- and C4'-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.
核苷类似物常用于癌症和病毒感染的治疗。它们的合成得益于几十年的研究，但往往耗时冗长，难以多样化，并且依赖于有限的手性碳水化合物起始材料库。我们提出了一种从简单的非手性材料快速构建核苷类似物的方法。仅使用脯氨酸催化，取代的杂芳基乙醛被氟化，然后在一锅反应中直接进行对映选择性羟醛反应。随后的分子内氟取代反应提供了功能化的核苷类似物。该方法的多功能性在 d-或 l-核苷类似物、锁核酸、亚氨基核苷以及 C2'-和 C4'-修饰的核苷类似物的多克合成中得到了突出体现。这种从头合成为多样性文库的制备创造了机会，并将支持药物发现和开发方面的努力。
