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.

Unmodified Aldehydes

Another novel aspect of the reaction is that one can use unmodified aldehyde substrates, without preactivating them.

In any given chemical reaction, the products and reactants will carry out side reactions if at all possible. After all, in reactions like the one the Barbas team made, the molecules are all in a pot being stirred together for hours. If any of the molecules in the pot can react, they probably will—the thermodynamic equivalent of Murphy's law.

The aldehydes that were used in one of the sets of experiments are particularly prone to the problem of side reactions. Aldehydes normally serve as electrophiles (electron acceptors) as opposed to being nucleophiles (electron donors). But in this case, to form the proper products, the aldehydes need to be nucleophiles.

"Aldehydes are difficult to use, usually," says Assistant Professor Fujie Tanaka.

This difficulty is usually overcome by pre-modifying the substrates through complicated protection and deprotection steps whereby certain parts of the molecules are made unaccessible to other molecules in the solution. Then these molecules must be deprotected later, to remove the protecting chemicals. This process is complicated, though, requiring many additional steps and chemicals that are sometimes toxic.

However, by using the naturally occurring amino acid L-proline, the problem of using aldehydes as nucleophiles is overcome easily, because the proline converts the aldehydes into nucleophilic enamines for the reaction. This is the only known way to use unmodified aldehyde donors in synthesis without using complicated protection and deprotection steps.

What the team discovered was a method for pre-activating the aldehydes in the pot with proline and transferring its inherent chirality onto the product molecules. Proline, as a naturally occurring amino acid, is a chiral compound, and the stereochemistry of the proline catalyst is preserved in the amino acid products—so L-proline makes L-amino acids, and D-proline makes D-amino acid products.

This use of unmodified aldehydes is completely unprecedented. And the use of proline to catalyze an intermolecular reaction is also innovative.

Making Proline-Catalysis History

The concept starts with antibody-catalyzed reactions the sort of which Barbas' group has been carrying out for years. Several years ago, Barbas designed with his colleagues the first commercially available catalytic antibody, 38C2, which can be made to bind certain markers on a cancer cell and catalyze reactions there. And for several years he has pioneered the use of different catalytic antibodies in organic reactions.

The inspiration for this particular study came when Barbas read about a group of researchers in the 1970s who used proline to catalyze an intramolecular reaction to make an important molecule used in the synthesis of steroids. Barbas thought about doing the same sort of reaction with one of his catalytic antibodies.

"In 1997, we looked at catalyzing the same reaction with an antibody," says Barbas. "We found that the catalytic antibody that we developed could do the same reaction as proline was doing via a reaction mechanism analogous to proline."

That stimulated further explorations of proline, as well as antibodies, in catalysis. Since the two share a common mechanism, what works for the one might also work for the other. If the proline could catalyze one type of reaction, then a similar antibody might also be able to catalyze it.

So the project grew in the last few years, and Barbas recruited others who were interested in antibody-catalyzed reactions.

Environmentally Benign

One of the greatest potential industrial advantages of the new synthesis is that it uses a naturally occurring amino acid as a catalyst, making it environmentally friendly. It is also easy to get the reactants and they are cheap and easy to handle.

"[There are] many types of high selectivity reactions are out there, but this [one uses] no metal compounds and no modified aldehydes," says Watanabe.

"We're using a food supplement to substitute for toxic metals, which most chemists are using to catalyze [this type of] reaction," says Barbas.

The reaction also makes use of aldehydes as nucleophiles without having to carry out protection and deprotection steps, many of which rely on chemicals that also contain toxic metals that must then be disposed of after the reaction.

"In ecological terms, you don't waste metals, and you don't have to heat up or cool down the reactions," says Betancort.

"And," adds Cordova, "you can do it in almost any solvent [including] those that are environmentally benign."

Finally, another tantalizing aspect of the research is that it raises the possibility of a prebiotic role for proline in early evolution, because of its ability to effectively form other amino acids of the same chirality.



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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.