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Biological Chemistry

New Helper For Bulky Amino Acids

Asymmetric Synthesis: Stripped-down small-molecule catalyst improves synthesis of key chiral intermediates

by Carmen Drahl
October 19, 2009 | A version of this story appeared in Volume 87, Issue 42

It takes a palette of 20 amino acids to make the thousands of proteins inside cells, but chemists have a knack for wanting more than what nature's own inventions have to offer. And now, with the invention of a new and improved catalyst, chemists have a more efficient means for making bulky nonnatural amino acids for the synthesis of chiral ligands and pharmaceuticals.

Chemists already have reliable catalytic and enzymatic approaches to choose from when making amino acids. But it remains tough to access optically pure forms of nonnatural amino acids bearing bulky quaternary alkyl side chains. Harvard University chemist Eric N. Jacobsen's team had previously developed chiral thiourea-containing catalysts for the asymmetric version of the Strecker synthesis, a 150-year-old process that yields amino acids, to plug that accessibility gap. But the catalysts took eight steps to make, and the synthesis required hazardous cyanide sources.

Now Jacobsen, graduate student Stephan J. Zuend, and coworkers have addressed those limitations with a simplified thiourea that can be made in three steps (Nature, DOI: 10.1038/nature08484). The new organocatalyst "doesn't have as many moving parts and is stable to harsher conditions," Jacobsen explains. "We can isolate and reuse it without affecting its activity," he adds.

The chemistry works on product scales of more than 10 g and employs easy-to-handle cyanide sources such as KCN. The team has applied for a patent on the catalyst and anticipates that the method will be amenable to larger—even industrial—scale production.

Although a kilogram-scale run has yet to be realized, the team has made major improvements to their procedure, says Richard M. Kellogg, an organic chemist and codirector of Syncom, a contract research organization in the Netherlands with expertise in Strecker chemistry. The reaction accepts a wide variety of substrates and uses lower catalyst loadings than were previously required, yet it produces excellent yields and nearly uniform, high optical purities, he says.

The effort is "a beautiful translation of Jacobsen's early pioneering work in this area into a reaction that's practical and manageable," adds Carlos F. Barbas III, who studies organocatalysis at Scripps Research Institute.



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