Summary: Researchers have successfully created a synthetic version of a small molecule found in a recently discovered sea sponge that appears to have therapeutic benefits for Parkinson’s disease.
Organic chemists at UCLA have created the first synthetic version of a molecule recently discovered in a sea sponge that may have therapeutic benefits for Parkinson’s disease and similar disorders. The molecule, known as lissodendoric acid A, appears to counteract other molecules that can damage DNA, RNA and proteins and even destroy whole cells.
And in an interesting twist, the research team used an unusual, long-neglected compound called a cyclic allene to control a crucial step in the chain of chemical reactions needed to produce a usable version of the molecule in the lab — an advance they say could prove advantageous in developing other complex molecules for pharmaceutical research.
Their findings are published in the journal Science.
“The vast majority of medicines today are made by synthetic organic chemistry, and one of our roles in academia is to establish new chemical reactions that could be used to quickly develop medicines and molecules with intricate chemical structures that benefit the world,” said Neil Garg, UCLA’s Kenneth N. Trueblood Professor of Chemistry and Biochemistry and corresponding author of the study.
A key factor complicating the development of these synthetic organic molecules, Garg said, is called chirality, or “handedness.” Many molecules — including lissodendoric acid A — can exist in two distinct forms that are chemically identical but are 3D mirror images of each other, like a right and left hand. Each version is known as an enantiomer.
When used in pharmaceuticals, one enantiomer of a molecule may have beneficial therapeutic effects while the other may do nothing at all — or even prove dangerous. Unfortunately, creating organic molecules in the laboratory often yields a mixture of both enantiomers, and chemically removing or reversing the unwanted enantiomers adds difficulties, costs and delays to the process.
To address this challenge and quickly and efficiently produce only the enantiomer of lissodendoric acid A that is found almost exclusively in nature, Garg and his team employed cyclic allenes as an intermediate in their 12-step reaction process. First discovered in the 1960s, these highly reactive compounds had never before been used to make molecules of such complexity.
“Cyclic allenes,” Garg said, “have largely been forgotten since their discovery more than half a century ago. This is because they have unique chemical structures and only exist for a fraction of a second when they are generated.”
The team discovered that they could harness the compounds’ unique qualities to generate one particular chiral version of cyclic allenes, which in turn led to chemical reactions that ultimately produced the desired enantiomer of the lissodendoric acid A molecule almost exclusively.
While the ability to synthetically produce an analog of lissodendoric acid A is the first step in testing whether the molecule may possess suitable qualities for future therapeutics, the method for synthesizing the molecule is something that could immediately benefit other scientists involved in pharmaceutical research, the chemists said.
“By challenging conventional thinking, we have now learned how to make cyclic allenes and use them to make complicated molecules like lissodendoric acid A,” Garg said. “We hope others will also be able to use cyclic allenes to make new medicines.”
Co-authors of the research were UCLA doctoral students Francesca Ippoliti (now a postdoctoral scholar at the University of Wisconsin), Laura Wonilowicz and Joyann Donaldson (now of Pfizer Oncology Medicinal Chemistry); UCLA postdoctoral researchers Nathan Adamson and Evan Darzi (now CEO of the startup ElectraTect, a spinoff from Garg’s lab); and Daniel Nasrallah, a UCLA assistant adjunct professor of chemistry and biochemistry.
About this Parkinson’s disease research news
Original Research: Closed access.
“Total synthesis of lissodendoric acid A via stereospecific trapping of a strained cyclic allene” by Neil Garg et al. Science
Total synthesis of lissodendoric acid A via stereospecific trapping of a strained cyclic allene
Small rings that contain allenes are unconventional transient compounds that have been known since the 1960s.
Despite being discovered around the same time as benzyne and offering a number of synthetically advantageous features, strained cyclic allenes have seen relatively little use in chemical synthesis.
We report a concise total synthesis of the manzamine alkaloid lissodendoric acid A, which hinges on the development of a regioselective, diastereoselective, and stereospecific trapping of a fleeting cyclic allene intermediate.
This key step swiftly assembles the azadecalin framework of the natural product, allows for a succinct synthetic endgame, and enables a 12-step total synthesis (longest linear sequence; 0.8% overall yield).
These studies demonstrate that strained cyclic allenes are versatile building blocks in chemical synthesis.