Catalysis Made Easy

By Jason Socrates Bardi


Join we together, for the public good.

——William Shakespeare, Henry VI, Part 2

Synthetic reactions can be noteworthy for their originality, using chemicals in ways nobody has done before, for their simplicity, making compounds easier than anybody has ever done, or for their selectivity, combining molecules to preferentially form one stereoisomer over another.

Or reactions can be noteworthy for being original, easy, and selective. And those are just the sort of reactions that interest a team of chemists at The Scripps Research Institute (TSRI), led by Carlos Barbas, professor in the Department of Molecular Biology and investigator in the TSRI Skaggs Institute for Chemical Biology.

Using novel aldehyde chemistry and the amino acid proline as a catalyst, members of the team were able to selectively synthesize a number of compounds, including novel functionalized amino acids and derivatives of those compounds, which are useful pharmaceutically.

"We have taken L-proline and we can use that to make a whole family of other, optically pure amino acids using very simple chemistry," says Barbas, who holds the Janet and Keith Kellogg II Chair in Molecular Biology.

"The products would be quite valuable synthetically, because they can be converted into b-lactams and [other] antibiotics or unusual amino acids, which are common to HIV protease inhibitors," he adds.

Add, Stir, and Extract

"Our concept is operationally simple—it's a stir and mix approach," says Barbas' former research associate Wolfgang Notz. "[And it] allows us to synthesize highly stereospecifically functionalized amino acids."

In fact, nothing could be simpler: take a few common chemicals off the shelf—imines, aldehydes, and ketones—and throw them into a pot with a benign organic solvent, like EtOAc, and the amino acid proline, and stir for a few hours at room temperature.

"You can start a reaction in the morning, and in the afternoon [isolate the product]," says Assistant Professor Guofu Zhong, who made several compounds using the methodology. "Some reactions take a couple of hours, and some go overnight."

"In some cases, you just run your filtrate through a column and you get your product," says Armando Cordova.

"And," adds Juan Betancort, who studied the intermediates in the reactions and did some synthetic manipulations of the final products to compare them with other, known structures. "We got high enantioselectivity and high yield."

Enantioselectivity is a very important consideration in industrial chemistry because nature itself is chiral. All the basic molecules of life—proteins, DNA, and carbohydrates—are chiral molecules. The subunits from which they are made have non-superimposeable mirror image "enantiomers," which are like right and left hands. Without the correct enantiomeric subunit, many of these basic chemicals of life will not function. Likewise, many drugs must also be of correct chirality in order to function. Indeed, in some cases, the wrong enantiomer can be toxic.

Pharmaceuticals and other commercially produced chemicals usually must be enantiomerically pure to be safe. While a drug, for instance, may return our bodies to good health, its enantiomer may be pure poison. Selectivity is important in chemical synthesis because often synthetic reactions will produce a racemic mixture—composed of pairs of (various) enantiomeric forms, and separating the right one out later may be expensive, difficult, or impossible.

The synthesis enables access to functional amino acids and novel amino acids with very high selectivity, in excess of 99 percent of the desired enantiomer, and yields around 80 percent—the amount of product generated from starting material.

"This reaction should have a high impact [in the field]," says Shin-ichi Watanabe.


Next Page | Making Proline-Catalysis History

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Professor Carlos Barbas III, Janet and Keith Kellogg II Chair in Molecular Biology and Investigator in The Skaggs Institute of Chemical Biology. Photo by Biomedical Grpahics.


Assistant Professor Guofu Zhong (left), and former Research Associate Wolfgang Notz.


Research Associates Shin-ichi Watanabe (left), and Armando Córdova.


Assistant Professor Fujie Tanaka (left), and Research Associate Juan M. Betancort. Photo by Kevin Fung.