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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 sp3-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 atropisomers1. Understanding the dynamics of these systems can be useful, for example, in the design of single-atropisomer drugs2 or molecular switches and motors3. 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’s 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.

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Figure 1: Stereochemical interconversion of chiral organic compounds.
Figure 2: Catalytic enantioselective bromination of N,N-diisopropyl benzamides.
Figure 3: Proposed catalytic enantioselective bromination of a two-axis, differentially substituted benzamide.
Figure 4: Experimental data describing the stereochemical behaviour of the isomeric benzamide products.
Figure 5: Energetic considerations and analysis of the stereoisomerizations.
Figure 6: Energetic considerations and analysis of racemization dynamics.

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Data deposits

Crystallographic data are deposited with the Cambridge Crystallographic Data Centre under the accession number CCDC 969575 (for 5-(X-ray)).


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We are grateful to the National Institute of General Medical Sciences of the NIH (GM-068649) for support. We also thank L. Guard for X-ray crystallography. A.J.M. was supported by the National Science Foundation Graduate Research Fellowship Program. All computational work was supported by the facilities and staff of the Yale University Faculty of Arts and Sciences High Performance Computing Center, and by the National Science Foundation under grant number CNS 08-21132, which partially funded acquisition of the facilities.

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S.J.M. and K.T.B. designed the project. K.T.B. performed the experiments. A.J.M. performed the theoretical calculations. All authors contributed to the analysis of data and composition of the manuscript.

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Correspondence to Scott J. Miller.

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The authors declare no competing financial interests.

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Barrett, K., Metrano, A., Rablen, P. et al. Spontaneous transfer of chirality in an atropisomerically enriched two-axis system. Nature 509, 71–75 (2014).

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