Better Route To Hard-To-Get Isomers

A new synthetic path to atropisomers—a class of chiral compounds that includes drugs, natural products, and ligands for asymmetric catalysis—could open the door to creating a wider range of such compounds, which until now have been difficult to synthesize.

Atropisomers are stereoisomers that can be enantiomeric, owing to a steric barrier to rotation about a single bond. Examples include biaryl compounds with bulky substituents, natural products such as the antibiotic vancomycin, and BINAP, a ligand widely used as a catalyst in asymmetric synthesis.

Previous techniques for creating atropisomers relied on capturing them with selective reactions of rapidly equilibrating compounds or forging new bonds between biaryl fragments. But catalytic reactions that can produce specific atrop­iso­meric enantiomers from equilibrating racemic mixtures have not been extensively developed.

Now, synthetic chemist Scott J. Miller and coworkers Jeffrey L. Gustafson and Daniel Lim of Yale University have crafted what could prove to be a more general approach (Science 2010, 328, 1251). They designed and optimized a small-molecule tripeptide-based catalyst that trihalogenates enantiomeric but rapidly interconverting biaryl compounds stereoselectively, forming stable atropisomeric products.

The approach—which has high en­an­tio­se­lec­tiv­i­ties (enantiomeric ratios of about 95:5) and high yields (in most cases 65 to 87%)—could make a wider range of potentially useful enantiomeric compounds more accessible synthetically. Miller and coworkers also propose a possible mechanism for the reaction, enabling them to rationalize its stereochemical outcome.

The technique could lead to “selective reactions of other interconverting, axially chiral compounds, promoted by simple peptide-based catalysts,” the researchers write.

“I was mesmerized by the paper,” says T. Ross Kelly of Boston College, who has worked with atropisomers. “I never would have predicted that this would have worked”—that a small peptide-based compound would catalyze atropisomer resolution—“and I never would have tried it. The wonderful thing about basic research is sometimes you hit amazing pay dirt, and I think this is one of those cases. The technique should have lots of utility,” he says.

Jonathan Clayden of the University of Manchester, in England, who developed an earlier atropisomer synthesis method, says: “The Miller paper’s key breakthrough is conceptually simple—it uses a peptide to capture one conformation of a molecule, which is then trapped by having its rotational freedom clamped down. It’s a proof of concept which, because the catalysts are peptides, will be readily extendable to a range of substrates, I’m sure. I think this is the key advantage—potential flexibility.”

“The results are exciting and important because they provide a new way to control a very subtle form of isomerism in organic molecules,” says Samuel H. Gellman, a specialist in designed peptides at the University of Wisconsin, Madison. “Although the creation of isomerically pure biaryl compounds is very important,” until now scientists have found it extremely difficult to form one or the other enantiomer predominantly, he continues. Many scientists will be drawn to these results, Gellman says.