New chemistry technique reproduces nature’s elusive complexity

New chemistry technique reproduces nature’s elusive complexity

7:15 AM, 24th September 2012
New chemistry technique reproduces nature’s elusive complexity
Ryan A Shenvi, Senior Investigator of the study and Chemist at Scripps Research Institute.

LA JOLLA, US: Scientists at The Scripps Research Institute have shown how to synthesize in the laboratory an important set of natural compounds known as terpenes. The largest class of chemicals made by living organisms, terpenes are made within cells by some of the most complex chemical reactions found in biology.

The new technique, described in an advance online edition of the journal Nature Chemistry on September 23, 2012, mimics a crucial but obscure biochemical phenomenon that allows cells to make terpenes. The discovery may one day result in cheaper, fully synthetic versions of the cancer drug Taxol, the antimalarial compound artemisinin and hundreds of other useful terpene products.

“It’s exciting for us because we’re now making molecules that have never been made in the laboratory before, and we’ve done this by first observing what nature does,” said Ryan A Shenvi, Senior Investigator, Chemist at Scripps Research.

Many terpenes, like those in turpentine, are small, plant-made molecules that turn into vapour at relatively low temperatures and waft easily through the air. Some terpenes are more complex and are synthesized by plants and other organisms as powerful cellular defense mechanisms. “Having such strong biological functions can make them useful in medicine,” said Shenvi.

Paclitaxel (Taxol), a widely used cancer drug, is a terpene derived from the bark of the Pacific yew tree. Artemisinin, the basis for a major class of antimalarial therapy, is a terpene made by the sweet wormwood herb. But the terpene family is highly diverse and also includes vitamin A, menthol, cholesterol and steroids. Many terpenes, including Taxol and artemisinin, are made naturally in cells by processes that are complicated and hard to recreate fully using organic chemistry techniques.

In the new study, Shenvi and Sergey V Pronin, Postdoctoral Researcher, set out to recreate one of the two major terpene synthesis processes in nature. Known as tail-to-head polycyclization, this process is used by cells to make numerous complex terpenes. A crucial feature of this process is effective displacement of positive charge from one carbon atom on the structure to another, in just the right sequence.

What makes this feat so challenging for chemists to reproduce and even to analyze, is that this positively charged state in principle can slide along numerous alternative pathways on the emerging structure. Moreover, because it powerfully attracts negatively charged ions, this carbon-based positive charge, which chemists refer to as a carbocation, is inclined to snuff itself out almost immediately.

“Carbocations are notoriously tricky to include in synthetic procedures in the laboratory, because their lifetimes are so short. And yet nature has evolved tools to handle them,” said Shenvi.

Chief among these tools are cyclase enzymes, which hold terpene molecules that are under construction and use their own charged structures to protect carbocations from being quenched. Pronin and Shenvi eventually found that a type of vinyl epoxide seems to serve as a partial substitute for cyclase enzymes. As a demonstration of the power of their new technique, the chemists used it to make two different types of terpene, known as funebrene and cumacrene. These terpene compounds had never before been fully synthesized outside of living cells.

Shenvi emphasizes that this report represents merely an initial description of this new strategy and that technical obstacles still prevent its widespread use. “Once we get past these obstacles, we should be able to use this new approach to fully synthesize many other valuable compounds,” he said.

Funding for the study, “Synthesis of highly strained terpenes by non-stop tail-to-head polycyclization,” was provided by a start-up grant from the Scripps Research Institute and a grant from Eli Lilly & Co.

© WOC News

 

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