Asymmetric catalysis is currently one of the best choices for efficient preparation of molecules with high optical purity. However, the success of asymmetric catalysis highly depends on precise identification of steric hindrance and/or electronic properties of two substituents of prochiral substrates by the chiral catalyst system. This premise makes it difficult for the reaction to achieve high enantioselectivity.
To obtain a large number of chiral molecules containing two or three similar substituents by direct asymmetric catalysis remains a challenge, which hinders the development of asymmetric catalysis and the related fields.
In a study published in Nature Communications, the research group led by Prof. FANG Xingqiang from Fujian Institute of Research on the Structure of Matter (FJIRSM) of the Chinese Academy of Sciences reported the new strategy of kinetic resolution of auxiliary adjacent alcohols (KRA*) that can be used to solve the above difficulties.
KRA* features the combination of diastereoselective secondary alcohol synthesis and the following kinetic resolution, and in the process, the hydroxy group serves as a kinetic resolution auxiliary group.
Using this strategy, the researchers obtained a large variety of optically enriched tertiary alcohols, epoxides, esters, ketones, hydroxy ketones, epoxy ketones, β-ketoesters, and tetrasubstituted methane analogs with two, three, and four spatially and electronically similar groups. Currently, the strategy is the optimal solution that can complement the inability caused by direct asymmetric catalysis in getting chiral molecules with challenging fully substituted stereocenters.
After obtaining a large number of enantioenriched molecules with quaternary and tetrasubstituted stereocenters and secondary alcohol units, the auxiliary hydroxyl groups can be transformed through oxidation or removal to obtain the types of molecules. The readily transformable feature of the OH group makes further transformations simple. Through easily operable oxidation conditions or removal reactions, they prepared a series of tetrasubstituted molecules with similar steric hindrance and electronic properties.
Besides the OH-oxidation and removal reactions, the enantiopure substances obtained in this study can also participate in a series of useful transformations, such as ring-opening, formal replacement of OH by NH2 group, cycloaddition, epoxidation, formal Friedel-Crafts alkylation, and formal synthesis of serotonin antagonist.
This study shows a general scope in accessing enantioenriched molecules with various tetrasubstituted carbon stereocenters, including those with two, three, and even four sterically and electronically unbiased substituents. A detailed survey has shown that a vast majority of the products obtained via KRA* in this study cannot be obtained using either direct asymmetric catalysis or starting from enantiopure chiral chemicals.
Featured image: Inspiration for the development of KRA*. © Shengtong Niu et al.
Reference: Niu, S., Zhang, H., Xu, W. et al. Access to enantioenriched compounds bearing challenging tetrasubstituted stereocenters via kinetic resolution of auxiliary adjacent alcohols. Nat Commun 12, 3735 (2021). https://doi.org/10.1038/s41467-021-23990-4
Provided by Chinese Academy of Sciences