Benjamin List
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Interview
Both humans and chemical compounds can be divided
into the left- and right-handed versions, but for
humans, the benefits of one over the other are mostly
limited to a few positions in baseball. For chiral
molecules, as they’re known, which come in
mirror-image versions like right and left
hands—sugars, for instance, or amino acids or
drugs—the functional difference between a
compound and its mirror-image can be night and day. In
pharmaceuticals, one might cure your headache while the
other might be toxic, so the synthesis of compounds
that come only in one form or the other—either
all right-handed or all left—is fundamental to
the industry.
Through the turn of this century, chemists relied on two methods of
asymmetric catalysis to make their chiral compounds. One used
transition-metal complexes, the other relied on naturally occurring enzymes
known as biocatalysts to do the trick. In March 2000, the German chemist
Benjamin List published a report in the Journal of the American
Chemical Society demonstrating the ease of creating chirally pure
compounds using an organic molecule—the amino acid proline. In doing
so, List effectively launched the field of organic asymmetric catalysis and
propelled himself to the front ranks of hot chemistry. His 2000 JACS
paper has now been cited nearly 700 times (see
table below, paper #1) and is just one of more than
20 of his reports published in the last decade that have accumulated more
than 100 citations each. During 2008, his 10 Hot Papers published over the
preceding two years earned him a spot in this publication's annual roundup
of hot authors, as reported in the previous issue
(March/April 2009).
List, 41, did his undergraduate work in chemistry at the Free
University of Berlin, graduating in 1993, and obtained his doctorate
from the University of Frankfurt in 1997. He spent the next six years
at the Scripps Research Institute in La Jolla, California, before
returning to Germany in 2003 to become a group leader (associate
professor) and, since 2005, a director (full professor) at the
Max-Planck-Institut für Kohlenforschung (Coal Research) in
Mülheim an der Ruhr, and an honorary professor at the University
of Cologne.
List spoke to
Science Watch from his Max Planck
office.
How would you describe the importance to the
pharmaceutical industry of asymmetric reactions and the synthesis
of chiral compounds?
The most important answer is that pharmaceuticals are often
chiral. That means you have two mirror-image-like molecules, and most
of the time, in fact, only one has a specific activity. The other
enantiomer—the mirror image—is either inactive or, even
worse, possibly toxic. This is a very common situation, and the number
of chiral drugs nowadays is increasing. Indeed, the majority of
pharmaceuticals may now be chiral. Drug agencies demand the testing of
these agents individually, each enantiomer, and you’re required
to make the pure enantiomer. This is what motivates the interest in
making chiral enantiomerically pure compounds.
What prompted your own interest in using
asymmetric catalysis to make chiral compounds?
"People are realizing that organic catalysis is
effectively a new field," says Benjamin
List of the Max-Planck-Institut für
Kohlenforschung in Mülheim an der Ruhr,
Germany.
When I was a Ph.D. student I worked in natural-product synthesis.
My Ph.D. supervisor Prof. Mulzer had a strong background in asymmetric
synthesis. When I was doing my doctorate, the state of the art was
something called chiral auxiliaries: you introduce chirality or
asymmetry into the system by attaching an auxiliary to your substrate,
then conducting the reaction and cleaving it off afterward. But this
required several chemical operations and the use of a large amount of
the auxiliary. In asymmetric catalysis, all you need is a tiny amount
of your source of chirality, which is then amplified. Catalysis is
basically a tool—it's like a hammer. You have one hammer, but you
can hammer a million nails into the wall with it and the hammer remains
unchanged. That’s effectively what your catalyst does in a
reaction; that’s the beauty of it, and that’s why I wanted
to work in it.
What made you think that organic asymmetric
catalysis was even a viable possibility, and how did you first
approach the problem?
When I became an assistant professor in 1999 at Scripps, I had to
figure out what my line of work was going to be. My training had been
in hardcore organic synthesis, but I had worked as a post-doc with
biocatalysts—catalytic antibodies. Catalytic antibodies can be
programmed for effectively any chemical reaction you want. I was
fortunate at the time because I was working with these wonderful
catalytic antibodies. Not all biocatalysts are superactive, but the one
I was working with was really powerful. And these catalytic antibodies
catalyze the intermolecular aldol reaction, which is important for the
synthesis of chiral compounds. These enzymes have a special mechanism
which involves so-called enamines, which are formed as covalent bonds
between the catalyst and the substrate. Enamines are the key
intermediate in this catalysis. Enamines have also been used by
chemists in organic synthesis—most notably by Prof. Gilbert Stork
and others—so this was a place where nature and chemical design
came together. But chemists rarely used these enamines the way nature
does, as catalytic intermediates—which is a much more beautiful
way of doing things.
My plan in 1999 was to design small organic molecules called amines
that could catalyze the intermolecular aldol reaction, effectively
mimicking enzymes with their active site amino group. These
wouldn’t be proteins, which are big molecules, but small,
easy-to-use molecules that would also catalyze this reaction and would
do it using the same mechanism. That was how I got started, but I also
remembered that back in the 1970s two industrial groups had
independently realized that certain intramolecular aldol reactions
could be catalyzed with exactly the kind of thing that I had in
mind—a small chiral organic molecule with an amino group. What
they used as a catalyst was the amino acid proline. At the time I
assumed that this wouldn’t really work—that somebody must
have tried it in the almost 30 years since these two industrial groups
had reported it. So before I even got to trying out all the molecules I
had designed, I tried proline and it did the job pretty
well—representing, in fact, the state of the art in the field.
Why was this such a big deal?
All of a sudden, one of the most interesting transformations in
asymmetric catalysis—the direct asymmetric intermolecular aldol
reaction—could be carried out with a simple, nontoxic, readily
available organic catalyst: proline. This discovery started to make
people realize that the poorly understood intramolecular aldol reaction
was not an exotic isolated example, but that there might be a general
principle behind it. This principle is now called enamine catalysis and
has inspired literally hundreds of publications.
How did your research and the field itself evolve
after the 2000 paper?
We became part of this movement of pushing enamine catalysis,
assuring that this really is a general strategy for asymmetric
catalysis, that you can catalyze various different reactions using this
principle. There are now several dozen groups around the world working
with this catalysis principle, and they’ve also begun to explore,
as we have, other areas of organic catalysis that, like enamine
catalysis, might not have been appreciated before as being really
general.
Can you give us a simple example of one of these
other areas?
One thing we tried to do later was develop reactions that utilize
organic catalysis to hydrogenate organic compounds. This was something
people had thought was impossible for a long time.
Hydrogenation—the addition of the element of hydrogen, two H
atoms, to an organic substrate—is ubiquitous in chemistry and in
the pharmaceutical industry; all living organisms also use
hydrogenations.
For some reason everybody thought that if you did hydrogenation, if you
transferred these hydrogen atoms and did it asymmetrically, you’d
have to use a metal—either as a reagent or as a catalyst, using a
transition metal like palladium or platinum. I gave a talk back in 2001
where I was challenged: someone in the audience said, okay, this
intermolecular aldol reaction is nice, but can you do something really,
really challenging, like a metal-free hydrogenation reaction? Again I
took my inspiration from nature. How does nature hydrogenate its
substrate? And nature very rarely uses hydrogen. We use it because
it’s cheap and nice to deal with, but it has a little drawback:
it’s a gas and can be explosive. That’s a bit of risk when
you work with hydrogen. What nature does is to use organic co-factors,
dihydropyridines, which can donate hydrogen, but not in the form of
elemental hydrogen, H2. It's done indirectly.
Highly
Cited Papers by
Benjamin List and Colleagues,
Published Since
2000 (Ranked
by total citations)
Rank
Papers
Cites
1
B. List, et al.,
"Proline-catalyzed direct
asymmetric aldol reactions," J.
Am. Chem. Soc., 122(10):
2395-6, 2000.
665
2
B. List, "Proline-catalyzed
asymmetric reactions,"
Tetrahedron, 58(28):
5573-90, 2002.
523
3
J. Seayad, B. List, "Asymmetric
organocatalysis," Org.
Biomolec. Chem., 3(5): 719-24,
2005.
389
4
B. List, "The direct catalytic
asymmetric three-component Mannich
reaction," J. Am. Chem.
Soc., 122(38): 9336-7, 2000.
309
5
B. List, et al., "The
proline-catalyzed direct asymmetric
three-component Mannich reaction:
Scope, optimization, and
application to the highly
enantioselective synthesis of
1,2-amino alcohols," J. Am.
Chem. Soc., 124(5): 827-33,
2002.
So back in 2004, we came up with a solution to this: the first
completely metal-free catalytic hydrogenation of an olefin (this is the
carbon-carbon double-bond-containing molecule), which is another word
for alkene. Nature uses these dihydropyridines, and we also used a very
simple dihydropyridine, an organic compound that can donate hydrogen to
organic substrates. Again, it was known for a long time what these
molecules did, but no one had tried to use them for asymmetric
catalysis. They’re very rarely used in catalysis at all. Over the
years, we and other groups have taken to using this same compound in
other reactions—reducing imines, for instance, which is another
very important class of organic compounds. The produced chiral amines
are ubiquitous in chiral drugs, so this was a very important
development.
Has the pharmaceutical industry picked up on all
these developments?
Yes, heavily, especially in the synthesis of drug candidates. The
industry, however, has been notoriously slow in picking up these new
methods for manufacturing. In fact, they often prefer to synthesize
enantiomer-pure compounds using a method that’s even more
old-fashioned than the chiral auxiliary method. What they do is make a
mixture of two enantiomers, by any means, and then separate off the
wrong one and burn it or, ideally, at least recycle it and convert it
to something useful. This, unfortunately, is still the most common
method used in the pharmaceutical industry for making chiral,
enantiomer-pure molecules. And this is why we’ve been working so
hard to push asymmetric catalysis and make it more industry friendly.
For both environmental and economic reasons, it’s not exactly
ideal to throw away half your product.
Why do you think the industry is so averse to more
modern methods?
One reason that comes immediately to mind is that there’s
always a delay in integrating academic research into industrial
contexts. Sometimes just scaling up is difficult. Sometimes the
catalysts are not commercially available, or are considered too
expensive or are too hard to make. Sometimes the technique is not yet
sufficiently reliable. The situation, however, is changing now.
Transition-metal catalysis has recently entered the pharmaceutical
industry; biocatalysis, with enzymes, is now being used. And organic
catalysis, the third pillar of asymmetric catalysis, will probably
enter the industry soon enough because it's often easier to use and can
be less expensive than the other two methods.
If you have a sophisticated organic molecule that requires 15 steps to
make, it may indeed be more expensive. But there are many organic
catalysts that are very easy to make and commercially available.
Proline is a perfect example. You can isolate it from natural sources
in large quantities. It’s nontoxic and inexpensive. If for some
reason you want to recycle it, that can be done easily. This, of
course, is an ideal case. Organic catalysts can typically be made in
one or two steps. There are some very famous organic catalysts made
from amino acids. Others you can make from sugars in a couple of steps.
Those have the potential for being used industrially, because
they’re so easy and inexpensive and often recyclable. On other
hand, there are transition-metal catalysts that are expensive, but
they’re so active that the price is not so important. In
industry, the only thing that ultimately matters is the cost of the
process.
So how would you describe the state of the science
of organic asymmetric catalysis circa 2009, and its prospects for
the future?
It’s a good time to look back. The field is now almost ten
years old. In the beginning, there was already this perception in the
community of chemists that somehow there would always be big drawbacks
with organic catalysis. The scope might not be so large, and you might
always have to use relatively large amounts of catalyst, and
there’d be other drawbacks on top of that. Meanwhile,
transition-metal catalysis is very efficient, and it works for hundreds
of reactions. So, nowadays, the old perception is starting to change.
People are realizing that organic catalysis is effectively a new field.
While it has a long history, the activity was almost negligible over
the entire last century. People are now starting to appreciate that
there’s a tremendous amount of development going on—that
you can find really, really active organic catalysts that are highly
enantioselective. I think this is something that very few would ever
have thought possible. My vision is that in another ten years chemists
will be using biocatalysts; they’ll be using transition-metal
catalysts, and they’ll certainly be using organic catalysts more
and more.
The beauty of all this is that in nature, in living organisms, almost
half of all enzymes come with a metal ion in the active site of the
enzyme, and remaining enzymes are metal free. So nature already is
using an equal measure of both metal-containing catalysts and organic
catalysts. I predict the same thing will happen in synthetic chemistry.
We’ll also be using organic molecules more and more for
catalysis, and I have very little doubt that there will be industrial
processes utilizing organic asymmetric catalysis as well.