A General Approach to Stereospecific Cross-Coupling Reactions of Nitrogen-Containing Stereocenters
A General Approach to Stereospecific Cross-Coupling Reactions of Nitrogen-Containing Stereocenters
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DOI：
10.1016/j.chempr.2020.02.002
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发表时间：
2020-03-12
期刊：
影响因子：
23.5
通讯作者：
Biscoe, Mark R.
中科院分区：
文献类型：
--
作者：
Ma, Xinghua;Zhao, Haoran;Biscoe, Mark R.
采用环己基旁观者配体在Stille交叉偶联反应的一种新的策略已被开发作为一个通用的解决方案，在含氮立体中心进行立体特异性交叉偶联反应的长期挑战。该方法使得能够直接获得通过替代制备方法难以（或不可能）获得的对映体富集的产物。单个仲烷基单元的选择性和可预测的转移可以在利用活化和未活化烷基单元之间的细微电子差异的反应条件下实现。通过这种方法，对映体富集的α-甲锡烷基化含氮立体中心进行钯催化的芳基化和酰化反应，在所有情况下，具有非常高的立体保真度研究。我们证明了这一过程中使用α-甲锡烷基化吡咯烷，氮杂环丁烷，和开链（苄基和非苄基）的立体特异性反应中的亲核试剂。这一过程将有助于快速和可靠地获得具有氮取代的立体中心的对映体富集化合物，这些立体中心构成了药物发现过程中出现的生物活性化合物中普遍存在的结构基序。
A novel strategy employing cyclohexyl spectator ligands in Stille cross-coupling reactions has been developed as a general solution to the long-standing challenge of conducting stereospecific cross-coupling reactions at nitrogen-containing stereocenters. This method enables direct access to enantioenriched products that are difficult (or impossible) to obtain via alternative preparative methods. Selective and predictable transfer of a single secondary alkyl unit can be achieved under reaction conditions that exploit subtle electronic differences between activated and unactivated alkyl units. Through this approach, enantioenriched alpha-stannylated nitrogen-containing stereocenters undergo Pd-catalyzed arylation and acylation reactions with exceptionally high stereofidelity in all instances investigated. We demonstrate this process by using alpha-stannylated pyrrolidine, azetidine, and open-chain (benzylic and non-benzylic) nucleophiles in stereospecific reactions. This process will facilitate rapid and reliable access to enantioenriched compounds possessing nitrogen-substituted stereocenters, which constitute ubiquitous structural motifs in biologically active compounds emerging from the drug-discovery process.