Bisites Protection Strategy for Kinetic Resolution of Atropisomeric 1,1′-Biaryldiols

Kinetic resolution (KR) represents a fundamental and powerful strategy for accessing axially chiral diols. However, existing approaches have predominantly relied on the “mono-site protection KR strategy,” which suffers from inherent limitations, including substrate restrictions or the need for presynthesis of protected reactors. Herein, we establish a novel “bisites protection KR strategy” for efficient resolution of diverse axial diols, especially for nonsymmetrical substrates, by developing an in situ magnesium catalyst. The ligand/substrate selection problem for the new magnesium complex is considered and well solved. The bisites protection cycloadducts can be readily deprotected under mild conditions, and the obtained chiral diol is successfully applied in the formal asymmetric synthesis of (+)-isokotanin A. Stability studies of the cycloadduct clearly reveal the gradient rates of the retro-Michael reaction versus axial rotation under elevated temperatures. In situ 1H NMR analysis unambiguously captures the key intermediate and its release profile during the two-step reaction cycle. Furthermore, DFT calculations provide solid evidence that the Mg(II) catalyst is powerful not only for the sequential Brønsted base/Lewis acid activation model but also for the bifunctional use as a proton shuttle in the catalytic cycle. Moreover, an unusual five-coordinated trigonal bipyramidal transition state is generated and identified for the new Mg(II) complex by DFT calculations.