Unnatural chiral α-tertiary amino acids containing two different carbon-based substituents at the α-carbon centre are widespread in biologically active molecules. This sterically rigid scaffold is becoming a growing research interest in drug discovery. However, a robust protocol for chiral α-tertiary amino acid synthesis remains scarce due to the challenge of stereoselectively constructing sterically encumbered tetrasubstituted stereogenic carbon centres. Herein we report a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides, including alkyl iodides, alkyl bromides and alkyl chlorides, enabling the formation of chiral α-tertiary amino esters with a high level of enantioselectivity and excellent functional group tolerance. Primary, secondary and tertiary organoelectrophiles are all tolerated in this asymmetric reductive addition protocol, which provides a complementary method for the well-exploited enantioselective nucleophilic addition with moisture- and air-sensitive organometallic reagents. Moreover, the three-component transformation of α-ketoester, amine and alkyl halide represents a formal asymmetric deoxygenative alkylamination of the carbonyl group.

在α-碳中心含有两个不同碳基取代基的非天然手性α-叔氨基酸广泛存在于生物活性分子中。这种空间刚性支架正在成为药物发现领域日益增长的研究兴趣。然而，由于立体选择性构建空间阻碍的四取代立体碳中心的挑战，手性α-叔氨基酸合成的稳健方案仍然稀缺。在此，我们报道了钴催化的酮亚胺与各种未活化的烷基卤化物（包括烷基碘、烷基溴和烷基氯）的对映选择性氮杂巴比尔反应，能够形成具有高水平对映选择性和优异官能团的手性α-叔氨基酯宽容。在该不对称还原加成方案中，一级、二级和三级有机亲电试剂均被耐受，这为利用对湿气和空气敏感的有机金属试剂进行充分利用的对映选择性亲核加成提供了补充方法。此外，α-酮酯、胺和烷基卤的三组分转化代表了羰基的形式不对称脱氧烷基胺化。