A peptide-catalysed bromination provides access to an important class of chiral compounds in high enantiomeric purity.
Atropisomerism is a type of stereoisomerism that results from restricted rotation around a single bond, and is most frequently observed in biaryl compounds. It is often exploited in the construction of chiral ligands for asymmetric catalysis — such as the ligand BINAP — and is also found in nature, an example being the antibiotic natural product vancomycin. There are, however, few ways to prepare compounds of this type in a stereoselective fashion. Now, Scott Miller and co-workers from Yale University have reported1 a dynamic kinetic resolution of biaryl compounds using a stereoselective electrophilic bromination.
Dynamic kinetic resolution works by converting one enantiomer of a starting material to product much more quickly than the other. Simultaneously, the starting material is rapidly racemized. In the case of atropisomerism, racemization only requires rotation around a single bond, so with judicious choice of starting material this can occur thermally at relatively low temperature. Provided the rotational barrier for the product is higher — so that the product does not racemize under the same conditions — then a dynamic kinetic resolution is possible. Miller and co-workers identified just such a substrate in some 3-aryl-substituted phenols.
Bromination of these phenols was found to be catalysed by simple amides, and an asymmetric variant was soon identified using peptide-derived catalysts that Miller and colleagues have shown to be useful for a wide range of other transformations. The explanation of the observed reactivity given by Miller and co-workers should also assist in identifying other atropisomeric substrates that can be resolved in this fashion.
References
Gustafson, J. L., Lim, D. & Miller S. J. Dynamic kinetic resolution of biaryl atropisomers via peptide-catalyzed asymmetric bromination. Science 328, 1251–1255 (2010).
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Davey, S. Resolving rotamers. Nature Chem (2010). https://doi.org/10.1038/nchem.766
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DOI: https://doi.org/10.1038/nchem.766