Chiral α-tertiary amines and related azacycles are sought-after compounds for drug development. Despite progress in the catalytic asymmetric construction of aza-quaternary stereocentres, enantioselective synthesis of multifunctional α-tertiary amines remains underdeveloped. Enantioenriched α-disubstituted α-ethynylamines are attractive synthons for constructing chiral α-tertiary amines and azacycles, but methods for their catalytic enantioselective synthesis need to be expanded. Here we describe an enantioselective asymmetric Cu(I)-catalysed propargylic amination (ACPA) of simple ketone-derived propargylic carbonates to give both α-dialkylated and α-alkyl–α-aryl α-tertiary ethynylamines. Sterically confined pyridinebisoxazoline (PYBOX) ligands, with a C4 shielding group and relaying groups, play a key role in achieving excellent enantioselectivity. The syntheses of quaternary 2,5-dihydropyrroles, dihydroquinines, dihydrobenzoquinolines and dihydroquinolino[1,2-α]quinolines are reported, and the synthetic value is further demonstrated by the enantioselective catalytic total synthesis of a selective multi-target β-secretase inhibitor. Enantioselective Cu-catalysed propargylic substitutions with O- and C-centred nucleophiles are also realized, further demonstrating the potential of the PYBOX ligand.

手性 α-叔胺和相关的氮杂环化合物是药物开发中广受欢迎的化合物。尽管氮杂季立体中心的催化不对称构建取得了进展，但多功能α-叔胺的对映选择性合成仍然不发达。对映体富集的α-二取代α-乙炔胺是构建手性α-叔胺和氮杂环化合物的有吸引力的合成子，但其催化对映选择性合成的方法需要扩展。在这里，我们描述了简单的酮衍生的炔丙碳酸酯的对映选择性不对称 Cu(I) 催化的炔丙胺化 (ACPA)，得到 α-二烷基化和 α-烷基-α-芳基 α-叔乙炔胺。空间限制的吡啶二恶唑啉 (PYBOX) 配体具有 C4 屏蔽基团和中继基团，在实现优异的对映选择性方面发挥着关键作用。报道了季铵2,5-二氢吡咯、二氢奎宁、二氢苯并喹啉和二氢喹啉并[1,2-α]喹啉的合成，并通过对映选择性催化全合成选择性多靶点β-分泌酶抑制剂进一步证明了其合成价值。还实现了以O和C为中心的亲核试剂的对映选择性 Cu 催化的炔丙基取代，进一步证明了 PYBOX 配体的潜力。