Enantioenriched secondary alcohols represent an important class of molecules found in numerous intermediates, chiral building blocks, and biologically active compounds. Asymmetric reduction of prochiral ketones constitutes the most straightforward way to form these important moieties. Traditionally, stoichiometric amounts of chiral ligands were used together with an aluminium or a boron hydride to achieve high levels of enantioselectivity. Various catalytic processes have been developed in the past three decades in an effort to eliminate the use of stoichiometric amounts of chiral regents. The Corey–Bakshi–Shibata (CBS) catalyst and Noyori s ruthenium catalyst represent two of the most wellknown methods for this purpose. Both catalytic systems have been further developed by altering the ligand or by employing different metals in efforts to enhance the selectivity or improve practicality. Despite extensive research, the utilization of simple chiral Bronsted acids as precatalysts for this asymmetric process is still unknown. Chiral phosphoric acids have emerged as highly efficient and selective catalysts for a variety of transformations since their first reports, through independent studies by Akiyama and Terada. Early publications using these catalysts relied on the activation of imine electrophiles. Recently, additional discoveries have shown an ability for these catalysts to activate vinyl ether, aziridines, nitroso compounds, enones, and glyoxylates. However, general carbonyl compounds, like ketones, have not been used as substrates in the presence of chiral phosphoric acid. Recently, our group reported the first highly enantioselective allylboration of aldehydes catalyzed by a chiral phosphoric acid. Protonation of the boronate oxygen by the catalyst was proposed to rationalize both the activation and the enantioselectivity. The broadening of the limited scope of this type of activation is highly desired. Herein, we describe, to the best of our knowledge, the first example of highly enantioselective reduction of ketones catalyzed by a chiral phosphoric acid derivative. However, this chemistry is believed to differ mechanistically in comparison to our previous allyboration. The formation of a new phosphoryl catechol boronate is proposed based on preliminary spectroscopic evidence. The phosphoryl borate formed in situ is believed to act as a novel chiral bifunctional catalytic system. The reduction of acetophenone (1a) with catecholborane was chosen as the starting point for optimization of the reaction conditions. A series of binol-derived phosphoric acids were screened in toluene at room temperature in the presence of 5 molecular sieves (Table 1, entries 1–6). Catalyst P3, with a 9-anthryl group in the 3,3’-position of binol, provided the product with the highest enantioselectivity (Table 1, entry 3). Chiral N-triflyl phosphoramide P7, which is a stronger Bronsted acid than its phosphoric acid counterpart, provided the product with reverse absolute configuration and low ee (Table 1, entry 7). Further solvent
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Nov 14, 2013
Valeria Di Bussolo + 6
Open Access
