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New radical route to chiral quaternary carbons reported

New reaction could provide an easier path to the important stereocenters

by Stu Borman
April 14, 2016 | A version of this story appeared in Volume 94, Issue 16

CORRECTION: This story was updated on April 21, 2016, to clarify that the method described was not the first radical-based route to chiral quaternary carbon centers. The method is the first route involving radical conjugate addition, not the first radical route of any kind.

Many natural products, pharmaceuticals, and other biologically active molecules feature chiral carbon atoms attached to four other carbons. Chemists can synthesize these quaternary stereocenters using organometallic reagents that add carbon groups to conjugated carbonyl compounds. These reagents, however, are expensive and hard to generate, can cause problematic side reactions, and don’t always work well at crowded carbon centers.

Reaction scheme shows how organocatalyst makes possible radical conjugate addition reaction to create quaternary products.
R is a carbon-based group, X is an anion, PC is a photocatalyst, PC* is a light-activated version, and PCred is a reduced form.

Now researchers report a new radical route to quaternary carbon stereocenters, offering a possibly easier way to form the important chiral groups.

Chemists previously have tried using radical-based conjugate addition reactions to form chiral quaternary centers because, compared with organometallic reagents, radicals are cheaper and easier to produce, readily add carbons to sterically congested carbon sites, and cause less-problematic side reactions. But these radical reactions have not worked. For example, amine-catalyzed radical conjugate additions have been hampered by the formation of an unstable radical cation intermediate.

Paolo Melchiorre of the Institute of Chemical Research of Catalonia and coworkers have now found a way around that problem. In their amine-catalyzed reaction, they trap the unstable radical and prevent its breakdown. The result is the first enantioselective, catalytic, radical conjugate addition to generate quaternary carbon stereocenters (Nature 2016, DOI: 10.1038/nature17438).

In the reaction, an organocatalyst’s amine group reacts with an enone starting material to produce a chiral iminium cation. A nucleophilic radical carbon group then adds to the molecule’s carbon-carbon double bond, forming an unstable radical intermediate. A redox-active carbazole group on the organocatalyst immediately reduces the unstable intermediate, preventing it from breaking down. The reduced intermediate then tautomerizes, changing how its atoms are connected, to form a species that is further reduced and hydrolyzed, yielding the quaternary product and releasing the original organocatalyst. A separate photocatalyst both creates the nucleophilic radical and catalyzes the final reduction.

“Since this method provides a convenient route to quaternary stereocenters with the potential of excellent functional group tolerance, I envision a wide range of applications,” comments radical-conjugate-addition expert Steven L. Castle of Brigham Young University. Although the study demonstrated its use on a limited range of substrates, “it should be possible to extend the scope to encompass a broader range.”



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