Polyhydroxylated compounds such as carbohydrates, glycerols and diols play an important role in biological chemistry and are useful synthetic intermediates to access chiral building blocks. In this regard, enantioselective desymmetrization by direct monofunctionalization of prochiral diols is a powerful strategy to prepare valuable synthetic intermediates in high optical purity. However, unlike 1,2-meso diols, catalytic methods for desymmetrization of prochiral 1,3-diols are scarce and limited to acylation. Thus, a general strategy for the enantioselective desymmetrization of prochiral 1,3-diols substrates by other functionalization remains an important challenge in organic synthesis. In this context, boronic acid catalysis (BAC) has emerged as an attractive method for diol activation by utilizing the dynamic covalent interactions of boronic acids with hydroxy groups of diols to enhance the nucleophilicity of oxygen through the formation of tetrahedral adducts. Through a screen of different organoboron compounds, 9-hydroxy-9,10-boroxarophenanthrene, was found to catalyze the monofunctionalization of diols with good yields. Using the boroxarophenanthrene motif as core, a binaphthyl-based chiral catalyst was rationally designed and applied in the enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient conditions. It is revealed by the X-ray crystal structure of a complex of boroxarophenanthrene and diol that nucleophilic activation occurs through a defined chair-like 6-membered intermediate. The optimal catalyst features a large aryloxytrityl group that effectively shields one of the two prochiral hydroxy groups on the intermediate, and an ortho-methyl group on the boroxarophenanthrene unit strategically placed to mitigate an undesirable competing conformation of the reactive intermediate. Using the optimal catalyst, monoalkylated products with enantiomeric ratios up to 96:4 were obtained from a wide range of 2-aryl-1,3-propanediols.

Enantioselective desymmetrization of 2-aryl-1,3-propanediols by direct <i>O</i>-alkylation using a rationally designed chiral hemiboronic acid catalyst

ACS Fall 2021

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Enantioselective desymmetrization of 2-aryl-1,3-propanediols by direct O-alkylation using a rationally designed chiral hemiboronic acid catalyst