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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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