Asymmetric alkylation of enolates is one of the most direct and important reactions to prepare α-chiral carbonyl compounds. Except for the classical methods that rely on the use of chiral auxiliaries, asymmetric catalysis emerged as a powerful tool, especially asymmetric phase-transfer catalysis. However, in the field of transition metal catalysis, only limited success with asymmetric alkylation of enolates was achieved. Hereby, we disclose a copper(I)-catalyzed asymmetric alkylation of α-imino-esters with various alkyl halides, including allyl bromides, propargyl bromide, benzyl bromides, α-bromo carbonyl compounds, and alkyl iodides. Both linear and cyclic α-imino-esters serve as competent pronucleophiles in the alkylation, which affords α-amino acid derivatives bearing either a trisubstituted or a tetrasubstituted stereogenic carbon center in high to excellent enantioselectivity. Control experiments indicate that the α-imino-ester is activated by a chiral copper(I)-phosphine complex through coordination, thus enabling facile deprotonation to provide a stabilized copper(I)-enolate in the presence of a mild base. Finally, the mildly basic nature allows the asymmetric alkylation of chiral dipeptides with excellent both chemo- and enantioselectivities.

烯醇化物的不对称烷基化是制备α-手性羰基化合物最直接、最重要的反应之一。除了依赖于使用手性助剂的经典方法外，不对称催化作为一种​​强大的工具应运而生，尤其是不对称相转移催化。然而，在过渡金属催化领域，烯醇化物的不对称烷基化只取得了有限的成功。在此，我们公开了铜 (I) 催化的 α-亚氨基酯与各种烷基卤化物的不对称烷基化反应，包括烯丙基溴、炔丙基溴、苄基溴、α-溴羰基化合物和烷基碘。线性和环状 α-亚氨基酯在烷基化反应中都可作为亲核试剂，它以高对映选择性提供带有三取代或四取代立体碳中心的 α-氨基酸衍生物。对照实验表明，α-亚氨基酯通过配位被手性铜 (I)-膦络合物激活，从而能够在弱碱存在下轻松去质子化以提供稳定的铜 (I)-烯醇化物。最后，弱碱性使得手性二肽的不对称烷基化具有出色的化学选择性和对映选择性。