LaCl3-Enabled Synthesis of 2′-C-Substituted Galidesivir Analogues

IF 4.7 1区化学 Q1 CHEMISTRY, ORGANIC

Organic Letters Pub Date : 2026-10-21 DOI:10.1021/acs.orglett.6c03942

James M. Wood,Rinu Shrestha,Ashley Nutsford,Blake Sullivan-Hill,Scott A. Cameron,Hong Wang,Gary B. Evans,Justin Julander,Natalie E. Netzler,Lawrence D. Harris

引用次数: 0

Abstract

The first synthesis of 2′-C-ethynylgalidesivir is reported. Access to this highly congested imino-C-nucleoside required development of a LaCl3·2LiCl-enabled addition of a 9-deazaadenine-derived Grignard reagent to 2′-C-substituted cyclic nitrones. The reaction proceeds with high β selectivity and enables the synthesis of galidesivir, 2′-C-methylgalidesivir, and 2′-C-ethynylgalidesivir. The respective syntheses required 6, 11, and 11 steps from known intermediates and proceeded in 54%, 22% and 17% overall yield. NMR titration and order-of-addition studies suggested that LaCl3·2LiCl perturbs both the nitrone substrate and Grignard speciation. Antiviral evaluation of the ethynyl analogue and its phosphoramidate prodrug revealed only weak activity at high concentration.

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2 ' - c -取代加利德西韦类似物的lacl3激活合成

报道了2′- c -乙基加利德西韦的首次合成。要获得这种高度拥挤的亚氨基c核苷，需要开发一种LaCl3·2licl使能的9-二氮杂腺苷衍生的格氏试剂添加到2 ' - c取代环硝基上。该反应以高β选择性进行，可以合成galidesivir， 2 ' - c -甲基galidesivir和2 ' - c -乙基galidesivir。从已知中间体中分别合成6、11和11步，总产率分别为54%、22%和17%。核磁共振滴定和加成顺序研究表明，LaCl3·2LiCl干扰了硝酮底物和格氏形态。对乙炔类似物及其磷酰胺前药的抗病毒评价显示，在高浓度时活性较弱。

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来源期刊

Organic Letters 化学-有机化学

CiteScore

9.30

自引率

11.50%

发文量

1607

审稿时长

1.5 months

期刊介绍： Organic Letters invites original reports of fundamental research in all branches of the theory and practice of organic, physical organic, organometallic,medicinal, and bioorganic chemistry. Organic Letters provides rapid disclosure of the key elements of significant studies that are of interest to a large portion of the organic community. In selecting manuscripts for publication, the Editors place emphasis on the originality, quality and wide interest of the work. Authors should provide enough background information to place the new disclosure in context and to justify the rapid publication format. Back-to-back Letters will be considered. Full details should be reserved for an Article, which should appear in due course.