华东师范大学周剑团队报道了对映选择性丙炔胺化及其与α-叔乙胺和氮杂环相关的串联序列。相关研究成果于2024年3月19日发表在国际顶尖学术期刊《自然—化学》。

手性α-叔胺和相关的氮杂环化合物是药物开发中的热门化合物。尽管在催化不对称构建氮杂季立体中心方面取得了进展，但多功能α-叔胺的对映选择性合成仍不发达。对映体富集的α-二取代的α-乙炔胺是构建手性α-叔胺和氮杂环的有吸引力的合成子，但其催化对映体选择性合成方法需要扩展。

该文中，研究人员描述了简单酮衍生的炔丙基碳酸酯的，对映选择性不对称Cu（I）催化的炔丙基胺化（ACPA），得到α-二烷基化和α-烷基-α-芳基α-叔乙炔胺。具有C4屏蔽基团和中继基团的空间限制吡啶双恶唑啉（PYBOX）配体在实现优异的对映选择性方面发挥着关键作用。

该文报道了季2,5-二氢吡咯、二氢喹啉、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合成价值。研究还实现了以O和C为中心的亲核试剂对映体选择性Cu催化的炔丙基取代，进一步证明了PYBOX配体的潜力。

附：英文原文

Title: Enantioselective propargylic amination and related tandem sequences to α-tertiary ethynylamines and azacycles

Author: Zhang, Zheng, Sun, Ying, Gong, Yi, Tang, Da-Liang, Luo, Hui, Zhao, Zhi-Peng, Zhou, Feng, Wang, Xin, Zhou, Jian

Issue&Volume: 2024-03-19

Abstract: 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.

DOI: 10.1038/s41557-024-01479-z

Source: https://www.nature.com/articles/s41557-024-01479-z