State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, P. R. China.
University of Chinese Academy of Sciences, Beijing, 100049, P. R. China.
Chemistry. 2019 Dec 18;25(71):16425-16434. doi: 10.1002/chem.201904543. Epub 2019 Nov 22.
Chiral α,α-difluoromethyl carbinols are recurring structural motifs in many therapeutic agents. Despite the indubitable interest in the catalytic asymmetric synthesis of such compounds, this research field still remains largely underexplored. Herein, an efficient approach to a range of chiral homopropargylic α,α-difluoromethyl carbinols has been developed, through a Cu-catalyzed enantioselective propargylation of α,α-difluoroketones with (pinacolato)allenylboron. In the presence of a cuprous complex, generated in situ from CuCl and a spiroketal-based diphosphine (SKP) ligand, a variety of aryl-, heteroaryl-, alkyl-, alkynyl, alkenyl, or benzyloxycarbonyl-substituted α,α-difluoromethyl carbinols were obtained in 75-99 % yields with 84-98 % ee values. The catalytic system was further investigated using a combined dynamic NMR spectroscopic, X-ray crystallographic, and non-linear effect studies. The origin of the enantioselectivity was rationalized based on DFT calculations. Finally, several efficient transformations were showcased to highlight the utilities of the protocol in synthesis of complex compounds bearing an α,α-difluoromethyl carbinol moiety.
手性 α,α-二氟甲基手性醇是许多治疗剂中常见的结构基序。尽管对手册化合物的催化不对称合成具有不可否认的兴趣，但该研究领域仍然在很大程度上未得到充分探索。在此，通过 Cu 催化的 α,α-二氟酮与（频哪醇）烯丙基硼酸的对映选择性炔丙基化反应，开发了一系列手性同型丙炔基 α,α-二氟甲基手性醇的有效方法。在铜配合物的存在下，由 CuCl 和基于螺环缩酮的双膦（SKP）配体原位生成，各种芳基、杂芳基、烷基、炔基、烯基或苄氧羰基取代的 α,α-二氟甲基手性醇以 75-99%的产率和 84-98%的对映选择性获得。还使用结合动态 NMR 光谱学、X 射线晶体学和非线性效应研究进一步研究了催化体系。基于 DFT 计算，对立体选择性的起源进行了合理化。最后，展示了几种有效的转化，以突出该方案在手性 α,α-二氟甲基手性醇部分复杂化合物合成中的实用性。
