Organocatalytic Asymmetric N-Sulfonyl Amide C-N Bond Activation

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Amides are fundamentally important functional groups in organic chemistry, having a wide variety of applications in chemistry, biochemistry, and material science. The amide bond forming reactions rank as the most frequently executed reaction in the synthesis of active pharmaceutical ingredients, synthetic intermediates, and synthetic polymers in chemical industry. In comparison of the tremendous progress made in the construction of amide bonds, breaking the C-N bond of an amide using synthetic chemistry seems much more difficult due to its poor electrophiles. This situation has improved since Grag’ seminal work in 2015 that nickel-catalyzed cleavage of amide C–N bonds. These metal catalysis systems developed by Grag and some other groups are very useful to activate amide bond, providing unique approaches for various invaluable chemical transformations. So far, however, there are still several unsolved challenges in the cleavage transformation of amide bonds: (i)  most reactions depend on transition metal catalysis; (ii) urgent need for stereoselective transformation; (iii) does not meet the requirements of atomic economic chemistry, the removed amino moiety is not well used, and is discarded as a by-product in most reactions.

We embarked on a search for organocatalytic solutions to solve the challenging problem of amide bond activation based on our understanding of organocatalysis. Configurationally labile biaryl lactams attracted our attention because of its enhanced reactivity by torsional strain. We hope the amide C-N bond can be activated and cleaved in a stereoselective attack manner with the assistance of organocatalyst. Notably, if alcohol is used as a nucleophile,  this catalytic strategy can provide a conceptually new and practical approach to a structurally diverse set of axially chiral biaryl amino acids. Unlike well studied centrally chiral amino acids, there have been fewer reports on the synthesis and application of axially chiral amino acids, although their derivatives are frequently found in natural products and bioactive compounds. Before our initial attempt, we mainly considered two key problems: (i) because of  the resonance stability of the amide bond, the intrinsic torsional strain of the substrate is probably not enough to activate the secondary amide C-N bond. The introduction of electron-withdrawing groups (e.g., N-Ts, N-Boc, N-Cbz etc) into nitrogen atom is worthy of careful investigation. (ii) the selected organocatalyst not only be able to control the stereoselectivity of the reaction, but also be efficient to enhance the activity of the amides to a certain extent.

After careful reaction design and catalyst evaluation, we successfully addressed direct organocatalytic asymmetric activation of amide C–N bond under exceptionally mild reaction conditions. We use this methodology to convert configurationally labile biaryl lactams to a structurally diverse set of axially chiral biaryl amino acids in high yields with excellent enantioselectivities, which is a challenging and underdeveloped transformation. Mechanism studies and density functional theory calculations demonstrated that the cooperative effects of the bifunctional moieties of the Cinchona-alkaloid-derived thiourea catalyst ensure the transformation with excellent results.

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Guanjie Wang

PhD, Nanjing Tech University