New Vistas In Organocatalysis

WITH THE HELP of short-lived radicals, researchers have devised a new organocatalytic route for carrying out a wide range of enantioselective additions in aldehydes. Such reactivity is unprecedented and likely to find widespread use in organic synthesis.

Aldehydes "form a big region of the reaction landscape" in organic synthesis, says chemist David W. C. MacMillan of Princeton University. But aldehydes' α position can be functionalized only by electrophiles. His team's route overcomes this limitation by allowing the addition of nucleophiles at this position, and it is enantioselective and metal-free to boot (Science, DOI: 10.1126/science.1142696). Mukund P. Sibi's group at North Dakota State University published a rendition of this strategy last month ( J. Am. Chem. Soc., DOI: 10.1021/ja069245n).

The route represents an entirely new type of asymmetric bond activation, comments organic chemist Stephen L. Buchwald of MIT. New modes of bond activation—particularly asymmetric versions—are hard to come by. Buchwald predicts that this new mode "will have a major impact on the field of organic chemistry, particularly organic synthesis."

MacMillan's team mixed an aldehyde with a chiral amine catalyst, then treated the resulting chiral enamine with a single-electron oxidant. The transient radical species that is produced can carry out a "range of enantioselective catalytic transformations not currently possible," MacMillan notes.

For example, his team used the route to enantioselectively install allyl and aryl groups at the aldehyde's α position. "These reactions haven't been shown to work with any sort of catalyst—metal, enzyme, or otherwise," MacMillan says. "That this catalyst can do these reactions at all is remarkable. That it's cheap and metal-free is even better."

The method's power will extend beyond such carbon-carbon bond-forming reactions, suggests organic chemist F. Dean Toste of the University of California, Berkeley. "This is most likely just the tip of the iceberg for what will likely be a broadly applicable concept," he says.

Sibi's demonstration that the same route can be used to α-oxidize aldehydes enantioselectively reinforces the method's broad utility. And MacMillan reports that his team soon will publish evidence that the route can also be used to carry out α-enolation and α-halogenation of aldehydes.