Organometallic Bridge Diversification of Bicyclo[1.1.1]pentanes
Organometallic Bridge Diversification of Bicyclo[1.1.1]pentanes
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DOI：
10.1002/chem.202304070
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发表时间：
2024-01-10
影响因子：
4.3
通讯作者：
Measom，Nicholas D.
中科院分区：
文献类型：
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作者：
Anderson，Joseph M.;Poole，Darren L.;Measom，Nicholas D.
近年来，双环[1.1.1]戊烷(BCP)衍生物在药物开发中引起了极大的兴趣，如炔烃、叔丁基和芳烃生物异构体，它们的掺入经常与化合物的溶解性和代谢稳定性有关。虽然桥头(1，3)位置的功能化战略已得到广泛开发，但允许在桥头(2，4，5)位置进行不同替换的平台仍然有限。最近的报道已经介绍了用于芳基化和加入少量其他取代基的1-电子策略，但在范围、产率或实际复杂性方面受到限制。在这里，我们展示了各种1，2，3-三官能化的BCP的合成，通过锂-卤素交换易于获得的BCP溴。当与医药相关的产品衍生，我们开发的2电子“后期”方法提供了前所未有的BCP结构多样性的快速和直接的途径(>；20 迄今未知的模体报告)。此外，我们还描述了一种通过新型立体选择性桥头去对称化反应合成手性双环[1.1.1]戊烷的方法。
Bicyclo[1.1.1]pentane (BCP) derivatives have attracted significant recent interest in drug discovery as alkyne,tert‐butyl and arene bioisosteres, where their incorporation is frequently associated with increased compound solubility and metabolic stability. While strategies for functionalisation of the bridgehead (1,3) positions are extensively developed, platforms allowing divergent substitution at the bridge (2,4,5) positions remain limited. Recent reports have introduced 1‐electron strategies for arylation and incorporation of a small range of other substituents, but are limited in terms of scope, yields or practical complexity. Herein, we show the synthesis of diverse 1,2,3‐trifunctionalised BCPs through lithium‐halogen exchange of a readily accessible BCP bromide. When coupled with medicinally relevant product derivatisations, our developed 2‐electron “late stage” approach provides rapid and straightforward access to unprecedented BCP structural diversity (>20 hitherto‐unknown motifs reported). Additionally, we describe a method for the synthesis of enantioenriched “chiral‐at‐BCP” bicyclo[1.1.1]pentanes through a novel stereoselective bridgehead desymmetrisation.