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Catalyst closes a gap in hetero Diels-Alder reaction

Powerful acid family enables cycloaddition of unactivated aldehydes and dienes

by Tien Nguyen
September 28, 2017 | A version of this story appeared in Volume 95, Issue 39

Scheme of enantioselective hetero-Diels-Alder reaction catalyzed by chiral imidodiphosphorimidates.
Chiral IDPi catalysts expand the scope of hetero Diels-Alder reactions beyond electronically biased partners.

The Diels-Alder reaction is a classic transformation that typically marries a diene (with four π electrons) and an alkene (with two π electrons) to form a six-membered ring—it’s known as a [4+2] cycloaddition. This reaction has been studied exhaustively in organic synthesis and tried in many variations, yet some reacting partner combinations remain out of reach.

Researchers led by Benjamin List at the Max Planck Institute for Kohlenforschung have now closed one of these gaps. The team has reported a method that brings together unactivated and inexpensive dienes and aldehydes for the first time in a hetero Diels-Alder reaction, a variant that trades a carbon atom in the alkene partner for a heteroatom, which is oxygen in the case of the aldehyde (J. Am. Chem. Soc. 2017, DOI: 10.1021/jacs.7b08357).

Diels-Alder reactivity is ruled by the energy gap between the two reacting partners. Chemists need to narrow this gap to drive the reaction forward, generally by modulating the reaction partners’ electronic properties through different substituent groups and/or with catalysts. For hetero Diels-Alder reactions between dienes and aldehydes, success has been limited to electronically engineered reacting partners.

By using highly acidic chiral imidodiphosphorimidate (IDPi) catalysts, List and coworkers were able to access electronically unactivated dienes and aldehydes to form dihydropyrans, which are often found in pharmaceutical and agrochemical settings. The researchers propose that the catalysts create a confined environment that enables high stereocontrol and avoids a number of acid-promoted side reactions.

Efforts to measure the new IDPi catalysts’ acidity are ongoing, but the compounds are estimated to be more acidic than an analogous IDPi compound that is reportedly the strongest chiral acid ever synthesized, according to the researchers.

“I really think this catalyst class is the most significant contribution to come from my lab,” List says. He believes the catalysts hold “enormous potential” for asymmetric synthesis because they are so active and selective.

The new class of strong IDPi acids are “extremely effective” at producing dihydropyrans in high enantiomeric excess, says Varinder Aggarwal, a synthetic chemist at the University of Bristol. Aggarwal points out that these dihydropyran products are valuable in the fragrance industry, adding that List’s lab must be “smelling pretty good.”



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