Two Students, Two Prizes, Two Promising Futures
By Jason Socrates
Bardi
"If
I have seen further... it is by standing upon the shoulders
of Giants."
—Sir
Isaac Newton, Letter to Robert Hooke, 1675
Last summer, Scott Wolkenberg and Anthony Jon Roecker, two
students in The Scripps Research Institute (TSRI) Department
of Chemistry, applied for fellowships in organic chemistry
sponsored by the American Chemical Society (ACS). After a
nationwide competition, the ACS chose them both to receive
these prestigious fellowships.
From Upstate New York to Southern California
Scott Wolkenberg came to Professor Dale Boger's group in
the summer of 1998, driving west from Ithaca, New York, soon
after he completed undergraduate work at Cornell University.
In the years since he joined the laboratory, he has become
an important part of the group, even helping with day-to-day
duties as a de facto manager.
"Each person has responsibilities that they take on for
the group as a whole, and Scott assigns them to people," says
Boger.
But Wolkenberg's primary work is in the science he is doing
at TSRI. One of his research projects is the total synthesis
of the molecule cytostatin, a linear molecule with a polyene
portion and several asymmetric centers with an alcohol unit
and a ring on one side.
Some targets for total synthesis are interesting because
of the inherent beauty and complexity of their chemical structure,
and some are interesting because of what they do. "We are
really interested in [the molecule] because of its biological
activity," says Wolkenberg.
This target has anti-cancer properties through an unknown
mechanism. Most likely, Boger and Wolkenberg believe, cytostatin
inhibits an enzyme that is linked to cancer, a protein phosphatase
called 2B, which removes the phosphate groups from other proteins
involved in cell cycle signaling and adhesion. If the phosphatase
removes the phosphates from adhesion molecules, then cells
can pick up and move, and this is exactly what you don't want
if the cells are cancerous—like criminals who suddenly
find the prison doors flung wide open.
That cytostatin discourages this sort of behavior is exactly
what makes the molecule such an alluring target. If you can
use cytostatin to disrupt the cell adhesion process, perhaps
you can prevent metastasis. The target is particularly promising
because it is rare for protein phosphatase inhibitors to be
specific, which is one of the properties of cytostatin.
Wolkenberg is also asking basic questions about the underlying
biology, such as "what is responsible for protein phosphatase
inhibition?" and "how does the inhibitor interact with the
enzyme?" He is also looking for structural analogues to the
natural product in the hopes of improving its activity against
the enzyme, its potency as an anti-tumor agent, and its stability.
Stability is of particular concern. The inhibitor is part
of a class of molecules that includes another structure completed
by Boger's group a few years ago—pursued as an anti-tumor
agent by the National Cancer Institute until recently when
trials were halted due to doubts about the stability of the
sample.
From the Midwest to the West Coast
Anthony Jon Roecker, or "A.J." as he is affectionately known,
is in his third year in the laboratory of Department of Chemistry
chair K.C. Nicolaou, whom he joined after completing his undergraduate
work at Ohio State University. He got the idea to apply for
the fellowship from Nicolaou himself, who brought him the
application.
"A.J. impressed me from the very beginning. It was only
a matter of time, I thought, before his successes will bring
him recognition," says Nicolaou. "So when I was invited to
nominate a student for an ACS fellowship, his name came to
mind."
At the moment, Roecker is working on studies leading towards
the total synthesis of azadirachtin, a potent insect pesticide
that comes from the plant Azadirichta indica, commonly
known as the neem tree. This natural product is a popular
insecticide because it only attacks molting insects and does
not affect mammals, making it a tantalizing target for chemists.
Taking the substance from the source trees is problematic
because of the difficulty and expense of separating this chemical
from the rest of the components of the tree's seed kernel.
Yet, despite years of attempts, chemists have never been able
to synthesize the chemical because it has a central bond between
two quaternary carbons, one of the hardest bonds to form in
organic synthesis.
"Its demonic molecular architecture has been challenging
synthetic chemists for decades," says Nicolaou. "A.J.'s contributions
address the thorniest problem posed by this structure: he
found a way to construct the crowed bond connecting the two
domains of the molecule."
This approach differs from the fruitless path that has been
followed by many other synthetic chemists who have tried to
synthesize the molecule in the last 20 years. Most of them
attempted to make two highly advanced portions of the molecule
and then bring them together at a later stage in the synthesis
to form the quaternary center.
"[The difficulty] inspires you to become creative and go
to the literature and find ways that haven't been explored,"
says Roecker.
Roecker, Nicolaou, and other laboratory members working
on the project are trying to generate the bond in advance
and utilize the resulting compound as a precursor upon which
the outside of the molecule can be built.
"We're trying some novel chemistry to try to generate systems
that contain this quaternary center," says Roecker. "We've
had some success that hopefully [the work] will be coming
out soon."
The New Diels
Another project that Wolkenberg is involved with is working
out the details for a type of synthetic methodology, a technique
that, once established, can become a tool for synthetic chemists
everywhere.
The particular methodology Wolkenberg is working on arises
out of the long-standing interest of the group, the heterocyclic
Diels–Alder reaction.
An ordinary Diels–Alder reaction takes a compound containing
a diene—conjugated four carbon chains with two doubly
bonded carbons connected by a single bond—and combines
it with a molecule containing a two-carbon doubly bound "–ene."
Under suitable conditions, the six pi-orbital electrons in
the two molecules react in such a way that the two molecules
join and form a new, cyclic compound.
This type of reaction, which is called a cycloaddition,
is a powerful tool for organic synthesis, since ring structures
are a common feature in many target molecules and dienes are
required motifs within precursor molecules. The Diels–Alder
reaction can simplify certain synthetic problems and help
shortcut synthetic pathways, allowing sometimes complicated
ring structures to be built in a single step.
For many years, though, the reaction was limited to carbon,
but the reaction becomes an even more powerful tool of organic
synthesis when it is expanded to include other, "hetero" atoms
like nitrogen and oxygen.
The heterocyclic Diels–Alder reaction, a powerful synthetic
methodology Boger has studied in detail for many years, does
just that, using as a precursor a compound containing a ring
of heteroatoms. The heteroatoms are important because the
non-carbons act as local electrophiles and draw electron density
from the ring, leaving it less electron-rich than the corresponding
all-carbon ring.
The cyclic system with which Wolkenberg works is a 5-membered
ring with two carbons, two nitrogens, and an oxygen. The work,
like many chemistry projects, is highly collaborative, and
Wolkenberg is working with graduate students Gordon Wilkie
and Danielle Soenen and research associates Greg Elliott,
Brian Blagg, Michael Miller.
"We're first defining its scope, and then we have in mind
a couple applications for that methodology in natural products'
total synthesis," says Boger.
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