Liu Teng, Ni Shaofei, Guo Wusheng
Frontier Institute of Science and Technology (FIST), Xi'an Jiaotong University Yanxiang Road 99 Xi'an 710045 China
Department of Chemistry, Shantou University Shantou 515063 China.
Chem Sci. 2022 Jun 5;13(23):6806-6812. doi: 10.1039/d2sc02318k. eCollection 2022 Jun 15.
We report the first amine nucleophilic approach for the modular construction of enantioenriched protected α-quaternary amino acids. The key to success is the use of an alcohol solvent, which makes a rationally designed COOMe-bonded Cu-allenylidene electrophilic intermediate stable enough to couple with amine nucleophiles before its decomposition. The reaction features wide functional group tolerance with high enantioselectivity, typically >90% ee, and is amenable to the modification of commercially available bioactive molecules. The resultant protected α-amino acids could be readily converted into a number of precious enantioenriched amines featuring α-hindered tertiary carbon centers, which are otherwise synthetically quite challenging, including those of α-amino aldehyde, peptides or α-vinyl amino ester with >92% ee in excellent yields. This protocol could be utilized for the synthesis of the protected bioactive α-ethylnorvaline in 3 steps, a significant advancement in comparison to an 11-step sequence reported previously.
我们报道了首例用于模块化构建对映体富集的受保护α-季铵氨基酸的胺亲核方法。成功的关键在于使用醇类溶剂，这使得经过合理设计的与COOMe键合的Cu-亚丙二烯亲电中间体足够稳定，能够在分解之前与胺亲核试剂发生偶联。该反应具有广泛的官能团耐受性和高对映选择性，通常对映体过量值（ee）>90%，并且适用于对市售生物活性分子的修饰。所得的受保护α-氨基酸能够很容易地转化为许多具有α-位受阻叔碳中心的珍贵的对映体富集胺，否则这些胺在合成上颇具挑战性，包括α-氨基醛、肽或α-乙烯基氨基酯的对映体过量值>92%且产率优异。该方案可用于三步合成受保护的生物活性α-乙基正缬氨酸，与之前报道的11步合成序列相比有了显著进展。
