Spontaneous Transfer Of Chirality In An Atropisomerically Enriched Two-Axis System

One of the most well-recognized stereogenic elements in a chiral molecule is an sp(3)-hybridized carbon atom that is connected to four different substituents. Axes of chirality can also exist about bonds with hindered barriers of rotation; molecules containing such axes are known as atropisomers(1). Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs(2) or molecular switches and motors(3). For molecules that exhibit a single axis of chirality, rotation about that axis leads to racemization as the system reaches equilibrium. Here we report a two-axis system for which an enantioselective reaction produces four stereoisomers (two enantiomeric pairs): following a catalytic asymmetric transformation, we observe a kinetically controlled product distribution that is perturbed from the system\u27s equilibrium position. As the system undergoes isomerization, one of the diastereomeric pairs drifts spontaneously to a higher enantiomeric ratio. In a compensatory manner, the enantiomeric ratio of the other diastereomeric pair decreases. These observations are made for a class of unsymmetrical amides that exhibits two asymmetric axes-one axis is defined through a benzamide substructure, and the other axis is associated with differentially N,N-disubstituted amides. The stereodynamics of these substrates provides an opportunity to observe a curious interplay of kinetics and thermodynamics intrinsic to a system of stereoisomers that is constrained to a situation of partial equilibrium

Desymmetrization of Diarylmethylamido Bis(phenols) through Peptide-Catalyzed Bromination: Enantiodivergence as a Consequence of a 2 amu Alteration at an Achiral Residue within the Catalyst

Diarylmethylamido bis­(phenols) have been subjected to peptide-catalyzed, enantioselective bromination reactions. Desymmetrization of compounds in this class has been achieved such that enantioenriched products may be isolated with up to 97:3 er. Mechanistically, the observed enantioselectivity was shown to be primarily a function of differential functionalization of enantiotopic arenes, although additional studies unveiled a contribution from secondary kinetic resolution of the product (to afford the symmetrical dibromide) under the reaction conditions. Variants of the tetrapeptide catalyst were also evaluated and revealed a striking observationenantiodivergent catalysis is observed upon changing the achiral amino acid residue in the catalyst (at the <i>i</i>+2 position) from an aminocyclopropane carboxamide residue (97:3 er) to an aminoisobutyramide residue (33:67 er) under a common set of conditions. An expanded set of catalysts was also evaluated, enabling structure/selectivity correlations to be considered in a mechanistic light

Parameterization and Analysis of Peptide-Based Catalysts for the Atroposelective Bromination of 3‑Arylquinazolin-4(3<i>H</i>)‑ones

We report the development of a method to parameterize and predict the performance of structurally flexible β-turn-containing peptide catalysts, using the atroposelective bromination of 3-arylquinazolin-4­(3<i>H</i>)-ones as a case study. The multivariate correlations obtained for tetrapeptides of two β-turn types, type I′ pre-helical and type II′ β-hairpin, indicate that although one conformer may be associated with a more dominant contribution to the observed enantioselectivity, it is possible that multiple conformers contribute to a complex transition state ensemble