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Shifting carbonyls means synthesis shortcut

Highly selective method moves group over in 1-pot reaction

by Leigh Krietsch Boerner
November 9, 2021


Researchers shift a carbonyl on dihydrotestosterone acetate to make a testosterone analog in a one-pot, two-step treaction using alkynyl triflate, then a palladium-norbornene cocatalyst, amine, and a hydronium ion.

Being able to shuffle functional groups on a molecule is something organic chemists would love to do, but it is not straightforward to do in the lab. A new synthesis designed by Guangbin Dong and coworkers at the University of Chicago makes such a move possible. The team found a way to selectively shift carbonyl groups to neighboring carbons on cyclic alkanes in a one-pot reaction (Science, 2021, DOI: 10.1126/science.abl7854). The relocation is highly selective and works in the presence of a number of functional groups, including electron withdrawing groups, electron donating groups, esters, olefins, and cyano groups.

To relocate a carbonyl group, scientists have to remove it from one carbon and install it on another, which normally requires harsh conditions and several steps.“There’s no simple organic reaction that allows you to just delete and add one,” Dong says. Instead, the team took advantage of a palladium and norbornene-amide cocatalyst system to nudge the carbonyl over to the adjacent carbon. The bulky norbornene blocks reactions on other parts of the molecule, and the catalysts drive a temporary amine addition as an intermediate step to shift the carbonyl group. This type of functional-group shift can be useful in drug discovery to help scientists understand structure-function relationships, Dong says. Chemists often try to vary the position of a carbonyl to test its effect, which has traditionally required a new synthesis for each carbonyl location. “With our method, you can shift it to the other position to generate a new analog easily without redesigning the synthetic route,” Dong says. Using their new approach, the group made more than 50 chemical compounds, including a testosterone analog (shown) and precursors to potential diabetes and cholesterol drugs. “We can reduce the step count, and also increase the yields and selectivity,” Dong says.

This reaction strategy is both unprecedented and highly innovative, says Qiu Wang, a bioorganic chemist at Duke University. The function of ketones is very important in organic synthesis, and Dong’s method is likely to have a transformative impact on the synthesis of structurally complex natural products and bioactive compounds, she says.

Dong says he hopes the reaction will be useful for medicinal chemists. “People doing synthesis can be able to think about using a simple carbonyl shift to quickly access some intermediates” and other useful compounds, he says.



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