A catalyst for axial chirality

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ResearchBlogging.orgAxial-chirality or atropisomerism is a very useful property as demonstrated by various chiral catalysts containing BINOL, BINAP and similar groups, but not only there. Many important natural products like e.g. the antibiotic Vancomycin are also atropisomers, which makes this property a very important aspect of stereoselective chemical synthesis. Which is extremely difficult to achieve synthetically with sufficient enantiomeric excesses. I personally always considered it next to impossible, except in special cases, when, for example, one configuration is enforced over the other by the shape of the rest of the molecule.

However, it seems that I’m wrong and that there is a way. Recently a group around Jeffrey L. Gustafson from Yale made some interesting progress in that direction. They report a tripeptide catalyst that mediates highly enantioselective electrophilic bromination of aromatic rings. The significance for atropisomerism stems from the fact that bromine atoms next to a biaryl single bond effectively prevent rotation around this bond if another functional group is present at the other ring.

So what they do is, they start with a substituted biphenyl that in principle exhibits axial chirality, but has such a low rotation barrier that it rapidly interconverts. Such a product was triple-brominated with NBS, which led to an axial-chiral compound with a rotation barrier of about 30 kJ/mol, enough to prevent racemisation at room temperature.

Of course just using NBS yields a racemic mixture so what’s needed to promote one enantiomer over the other is a chiral catalyst. There are few things as proudly chiral as peptides, and since lewis bases are known to catalyse bromination reactions, that’s where Gustafson et al. started. The first peptide turned out encouraging. It needs mentioning that they cheated a little, that is, they didn’t just tune the catalyst for maximum efficiency, but in between modified the substrate to fit the reaction best. However, in the end they came up with a combination of substrate and catalyst that produced a 97:3 enantiomeric ratio. I find that rather impressive, especially for a proof of concept.

There are a few limits to this reaction scheme, but all in all it turns out to be rather versatile. As the authors show it tolerates several different (and synthetically important) substituents like nitro groups or fluorine, and of course this is just the start. I for one wait expectantly for the first atropisomer-selective total synthesis of a natural product.

Gustafson, J., Lim, D., & Miller, S. (2010). Dynamic Kinetic Resolution of Biaryl Atropisomers via Peptide-Catalyzed Asymmetric Bromination Science, 328 (5983), 1251-1255 DOI: 10.1126/science.1188403

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