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Volume 84 Issue 25 | p. 13 | News of The Week
Issue Date: June 19, 2006

Triple Cascade

Asymmetric reaction constructs three new C-C bonds and four stereocenters
Department: Science & Technology
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Trifecta
Hüttl (from left), Enders, and Grondal developed an ingenious three-step domino reaction.
Credit: Photo by Wolfgang Bettray
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Trifecta
Hüttl (from left), Enders, and Grondal developed an ingenious three-step domino reaction.
Credit: Photo by Wolfgang Bettray

Some of the most elegant reactions in organic synthesis work just like an elaborate arrangement of dominos: Set up the reagents just so, and all it takes is a little catalytic push to make the pieces tumble into a far more elaborate whole. Such is the case with an ingenious new cascade reaction wherein a simple organic catalyst is the key element in the construction of a complex tetrasubstituted cyclohexene carbaldehyde (Nature 2006, 441, 861).

The three-step pathway, developed by Dieter Enders, Matthias R. M. Hüttl, and Christoph Grondal of Germany's RWTH Aachen University, was inspired by the tandem reactions that nature uses to biosynthesize complex natural products. The sequence employs two Michael-type reactions and an aldol condensation, ultimately creating three new C-C bonds and establishing four stereocenters with "high diastereoselectivity and complete enantioselectivity," according to the researchers.

Threesome
Asymmetric cascade reaction (above) creates three C-C bonds and four stereocenters.
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Threesome
Asymmetric cascade reaction (above) creates three C-C bonds and four stereocenters.

"This is an outstanding example of simple organic chemistry achieving very sophisticated results, results reminiscent of enzymatic finesse," remarks Johns Hopkins University chemistry professor Gary H. Posner.

To catalyze this carefully choreographed sequence, the Aachen group chose a simple secondary amine derived from the amino acid proline. Organocatalysts of this kind are emerging as a powerful tool in asymmetric synthesis. The small molecules are usually nontoxic and robust as well as inexpensive because they are often derived from readily available chiral compounds.

Enders, Hüttl, and Grondal think the organocatalyst plays a crucial role in all three steps of the cascade. In the first step, they believe it activates a linear aldehyde via enamine formation so that it selectively adds to a nitroalkene. Upon hydrolysis, the catalyst then forms an iminium ion with an α,β-unsaturated aldehyde, which undergoes conjugate addition with the compound formed in the first step. Finally, further catalytic enamine activation initiates an intramolecular aldol condensation to close the six-membered ring.

Although the reaction could generate 16 different stereoisomers, just two diastereomers are formed. "The reason for the high stereoselectivity is the first Michael addition, which is known to proceed with high diastereo- and enantioselectivity," the researchers explain. The resulting product presumably dictates the stereochemistry of the subsequent reactions.

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Catalytic Cycle
Cascade features (clockwise from top) an enamine-catalyzed Michael-type reaction followed by an iminium-ion-catalyzed Michael reaction and finally an enamine-catalyzed intramolecular aldol condensation. Newly formed bonds are in red.
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Catalytic Cycle
Cascade features (clockwise from top) an enamine-catalyzed Michael-type reaction followed by an iminium-ion-catalyzed Michael reaction and finally an enamine-catalyzed intramolecular aldol condensation. Newly formed bonds are in red.

"This work is a remarkable example of modern approaches for designing catalytic methods that perform multiple concurrent transformations with excellent stereoselectivity in each step," says Guillermo C. Bazan, a professor of chemistry and materials at the University of California, Santa Barbara. "The strategy is deceptively simple: Pick three readily available achiral starting materials, add a simple organocatalyst, and collect a product with four stereogenic centers. That the authors have been able to demonstrate three consecutive reactions in a single procedure shows remarkable creativity."

"I think this is the future of organic chemistry," Enders tells C&EN, "building molecules as Mother Nature does."

 
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