CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, 200032, Shanghai, China.
Nat Commun. 2023 Apr 17;14(1):2187. doi: 10.1038/s41467-023-37967-y.
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反应是制备α-手性羰基化合物最直接和最重要的反应之一。除了依赖于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，特别是不对称相转移催化。然而，在手性过渡金属催化领域，仅在烯醇化物的不对称烷基化方面取得了有限的成功。在此，我们公开了一种铜（I）催化的各种卤代烃与α-亚胺酯的不对称烷基化反应，包括烯丙基溴、炔丙基溴、苄基溴、α-溴代羰基化合物和碘代烷烃。线性和环状的α-亚胺酯都可以作为烷基化反应中的有效亲核试剂，以高至优异的对映选择性得到带有三取代或四取代立体中心的α-氨基酸衍生物。控制实验表明，α-亚胺酯通过配位被手性铜（I）-膦配合物激活，从而在温和碱的存在下提供稳定的铜（I）-烯醇化物。最后，温和的碱性允许具有优异的化学选择性和对映选择性的手性二肽的不对称烷基化。
