College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China.
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China.
J Am Chem Soc. 2022 Nov 2;144(43):20025-20034. doi: 10.1021/jacs.2c08811. Epub 2022 Oct 20.
An enantiomerically enriched 3-hydroxymethyl pentenal unit is one of the key structural cores in plenty of natural products and drug candidates with significant biological activities. However, very few synthetic methodologies for the facile construction of the related skeletons have been reported to date. Herein, an elegant iridium-catalyzed asymmetric cascade allylation/retro-Claisen reaction of readily available β-diketones with VEC was successfully developed, and a wide range of functionalized chiral 3-hydroxymethyl pentenal derivatives could be prepared in good yields with excellent enantioselectivities. Various 1,3-diketones and functionalized ketones containing different electron-withdrawing groups on the β-position were well tolerated as outstanding partners with high reactivity and excellent regio-/chemo-/enantioselectivity. The synthetic utility of product chiral 3-hydroxymethyl pentenal derivatives was well shown through gram-scale transformation, hydrogenation, cyclopropanation, hydroboration, and olefin metathesis. Moreover, this elegant protocol demonstrated synthetic applications in the concise synthesis of synthetically useful chiral building block ()-Taniguchi lactone and the formal synthesis of natural product cytisine. A rational reaction pathway was proposed based on the experimental results and control experiments.
手性富集的 3-羟甲基戊烯醛单元是许多具有显著生物活性的天然产物和药物候选物的关键结构核心之一。然而，迄今为止，报道的用于方便构建相关骨架的合成方法学非常少。在此，成功开发了一种优雅的铱催化不对称级联烯丙基化/反-Claisen 反应，可将易得的β-二酮与 VEC 反应，以高收率和优异的对映选择性得到广泛的功能化手性 3-羟甲基戊烯醛衍生物。各种 1,3-二酮和β位带有不同吸电子基团的功能化酮作为优秀的反应伙伴，具有高反应性和优异的区域/化学/对映选择性。通过克级转化、氢化、环丙烷化、硼氢化和烯烃复分解等反应，充分展示了产物手性 3-羟甲基戊烯醛衍生物的合成实用性。此外，该优雅的方案还在手性构建块（)-Taniguchi 内酯的简洁合成和天然产物 cytisine 的形式合成中展示了合成应用。基于实验结果和控制实验提出了一个合理的反应途径。
