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Total synthesis of lissodendoric acid A comes via highly reactive cyclic allenes

Chemists lasso the unruly compounds for enantioselective synthesis of complex natural product

by Leigh Krietsch Boerner
January 26, 2023 | A version of this story appeared in Volume 101, Issue 4


Two pieces of a yellow sea sponge on a blue background.
Credit: Vladimir B. Krasokhin
Lissodendoric acid A is made by the sea sponge Lissodendoryx florida.

Organic chemists are always looking for new ways to stick carbon atoms together, and Neil Garg and coworkers at the University of California, Los Angeles, have found an unlikely method. The group figured out how to control highly reactive cyclic allenes and put them to work building the core of lissodendoric acid A (shown below), an alkaloid compound that might be useful as a treatment for Parkinson’s disease (Science 2023, DOI: 10.1126/science.ade0032). Using a well-known cycloaddition reaction, the team created a short-lived cyclic allene that locked in a specific stereochemistry. This approach has promise as an important tool that synthetic chemists can use to build complex scaffolds while controlling the stereochemistry of the desired molecule.

The structure for lissodendoric acid A, which has three stereocenters.

Garg’s lab had previously used cyclic allenes to make a single enantiomer of a much smaller compound, but this was the first time the researchers put the method into practice to make a complicated molecule. This work is also the first published total synthesis of lissodendoric acid A, which comes from the marine sponge Lissodendoryx florida and belongs to a family of compounds known to have biological activity. Overall, the 12-step method uses low temperatures, forms two carbon-carbon bonds, and makes nearly 80% of the enantiomer the scientists want.

The trick to this short total synthesis was building in a lot of structural complexity in one step, Garg says. To achieve this, the researchers designed a cyclic allene precursor that would ultimately give them the isomer of lissodendoric acid A that they wanted. They first reduce the allene precursor using a chiral catalyst, which selectively creates mainly one isomer of an unstable cyclic allene intermediate. This short-lived allene is quickly grabbed by a pyrone to form the central core of the alkaloid through a Diels-Alder reaction. Getting the isomer that they wanted was challenging, Garg says, but making the right cyclic allene was crucial in building structural complexity and is ultimately what enabled such a short total synthesis.

Using strained cyclic allenes in total synthesis is rare, Garg says. Allenes have three carbons and two double bonds. When in cyclic form, these bonds are put under an enormous amount of ring strain, usually making cyclic allenes too reactive to control.

That difficulty made the use of the compounds for enantioselective synthesis previously unthinkable, says Nuno Maulide, an organic chemist at the University of Vienna. Garg’s approach “opens far-ranging perspectives for the investigation and application of these unusual intermediates. These are species literally “jam-packed” with ring strain,” he says.

In an email, organic chemist Richmond Sarpong of the University of California, Berkeley, calls the synthesis “elegant” and says that using small-ring cyclic allenes for an enantioselective synthesis is a surprising development.

Garg says he hopes this work convinces chemists that strained cyclic allenes are useful synthetic building blocks and that they shouldn’t avoid the compounds.



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