Zhenghu Xu, Tyler Buechler, K. Wheeler
Mar 8, 2010
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Influential Citations
19
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Journal
Chemistry
Abstract
Imidazolidin-4-ones, and compounds of similar structure, constitute a widespread structural motif in natural products and pharmaceuticals. Imidazolidin-4-one derivatives have shown a range of biological activities, such as antimalarial activity, antiproliferative activity for melanoma, and so forth. Imidazolidin-4-ones have also been widely used in peptidomimetics, as chiral auxiliaries for the synthesis of amino acids and other important compounds, as an important chiral building block in the total synthesis of natural products, and, most recently, as organocatalysts for iminium-based reactions. Even though other methods are available, the general synthetic approach to imidazolidin-4-ones is through condensation of protected amino acids or peptides with carbonyl compounds followed by intramolecular cyclization. This reaction can be catalyzed by an acid or a base. Despite the presence of chiral center(s) in the amino acids/peptides, the diastereoselectivity of the formation of imidazolidin-4-ones is low. Furthermore, N1-unsubstituted imidazolidin-4-ones are unstable and readily undergo hydrolysis under acidic and neutral conditions. Given the importance of this class of compounds, a stereoselective synthesis of stabilized imidazolidin-4-ones is desirable. Aza-Michael additions have grown into an important strategy for constructing C N bonds. These additions typically occur under basic conditions, but Lewis acids and organocatalysts have also been shown to catalyze aza-Michael additions. In contrast, Brønsted acid catalyzed aza-Michael additions, in particular intermolecular addition of simple amines, are very rare. Herein, we report the highly diastereoselective formation of stable imidazolidin-4-one derivatives through a three-component reaction based on a Brønsted acid catalyzed, remote-group-directed dynamic kinetic aza-Michael addition. N1-unsubstituted imidazolidin-4-ones can be stabilized by non-stereoselective formation of a salt or by acylation. 6b, 19] We are interested in N1 alkylation through aza-Michael addition, which can provide a stable tertiary amine and, at the same time, introduce a new functional group (a carbonyl group) to the structural motif that could open up the compound to wider reaction possibilities. For simple secondary amines there will be competition between iminium activation and aza-Michael addition under acidic conditions (Scheme 1), and iminium formation is generally favored. We