February 27, 2012 - IMM@BUCT

COVER STORY
DABBLING IN FLUORINE
With their latest synthetic methods, ORGANIC CHEMISTS
help tackle challenges in fluorine chemistry
STEPHEN K. RITTER , C&EN WASHINGTON
THERE’S A SHAKE-UP taking place in
fluorine chemistry. Synthetic organic
chemists who don’t normally mess with
fluorine are stepping in with their toolbox
of synthetic methods to broaden the range
of fluorination reactions.
Behind the trend are pharmaceutical and
agricultural chemical companies, which
need fluorine in their bioactive compounds
to keep metabolism in check, facilitate
delivery to a target, or improve binding
to that target. But fluorine’s hard-tohandle
notoriety has limited these
companies to using simple fluorinated
starting reagents, constraining
their ability to crank
out new lead compounds that
could benefit from a wellplaced
fluorine group.
Enter the organic chemists,
who have already used
O
HO
cross-coupling reactions, which were the
basis of the 2010 Nobel Prize in Chemistry,
to fundamentally shift how companies
conduct new-molecule discovery. Crosscoupling
and other reactions are allowing
discovery chemists to more efficiently
create the complex molecular frameworks
they need. Now discovery chemists want to
use the same strategies to more efficiently
install fluorine in molecules—to do fluorinations
with less fuss. The contributions
of synthetic organic chemists are greatly
easing the work of discovery chemists
handling fluorine chemistry, although in
one key area—practical catalytic fluorinations—success
still is elusive.
Fluorine chemists are feeling chagrined
by the invasion of their turf, although they
acknowledge that this is one case where
having too many cooks in the kitchen is a
good thing. Chemists in industry are ecstatic
because they suddenly are gaining access
to new ways of getting fluorine into their
molecules, likely accelerating the discovery
process. All the kinks haven’t yet been
worked out, but the new dynamic is already
leading to a burst of synthetic advances.
“The benefit of adding one, two, or three
F
F
H
Fluticasone (component of
GlaxoSmithKline’s Seretide)
Atorvastatin (Pfizer’s Lipitor)
3 out of 10
best-selling drugs in
2011 contain fluorine
HO
O
OH
H 3 C
N
S
N
O
N
OH
CH3
Rosuvastatin (AstraZeneca’s Crestor)
WWW.CEN-ONLINE.ORG 10 FEBRUARY 27, 2012
O
F
F
fluorines into a molecule has definitely
been recognized by mainstream synthetic
organic chemists,” says William R. Dolbier
Jr. , a seasoned fluorine chemist at the University
of Florida. “This trend is playing out
because researchers at pharmaceutical and
agrochemical companies are interested
in finding truly useful ways to get fluorine
into organic molecules—methods
that are catalytic, inex-
F
O
S
O
OH
OH
H
N N
H
pensive, easy to use, and have high yields.”
Dolbier’s group is known for using
the reducing agent tetrakis(dimethylamino)ethylene,
or TDAE, with fluorinated
precursors such as CF 3 I to generate
in situ fluorinated carbanions that
effectively add CF 3 groups to molecules.
His team also developed trimethylsilyl
2-(fluorosulfonyl)-2,2-difluoroacetate,
or TFDA. This reagent has extended the
scope of synthetic difluorocarbene chemistry,
enabling the construction of difluorocyclopropane
substituents, for example.
Dolbier has mixed feelings about the
influx of fluorine newcomers. One reservation
he has is that some of them are not
scrupulous about referencing relevant earlier
work. However, he understands how such
lapses can happen. Much like the new crop
of organic chemists engaging in fluorine
research, Dolbier also was an organic chemist
before he started making forays into
OH
O
fluorine chemistry in the 1970s.
Because fluorine chemistry is
OH
an esoteric field, Dolbier says
he sometimes found himself
“rediscovering the wheel”
as a consequence of not being fully aware of
the fluorine literature.
“There is one part of you that wants
to tell the newcomers: ‘Hey, stay
out of our field. Leave the fluorine
chemistry to us. We can do it,’ ”
Dolbier says. “On the other hand, we have
to recognize that they are bringing in the
methodologies they use with nonfluorinated
compounds and adapting them to
fluorine chemistry to create great new reagents.
They are making novel, worthwhile
contributions to the field.”
LIKE DOLBIER, fluorine veteran G. K. Surya
Prakash of the University of Southern California
(USC) also has mixed feelings about
the new developments. “Chemists who are
doing leading organic and organometallic
chemistry and traditionally develop methodologies
for drug discovery and natural
product synthesis have realized there is a
bonanza by focusing on fluorine chemistry,”
Prakash says. “Fluorine has become a
driving force—it’s the new kingpin of drug
discovery.”
Prakash is a little disappointed, however,
that some of the new results are being
touted as though fluorine chemistry is
something new. “Still,” he adds, “it’s a pretty
good thing for the field that an energetic
wave of organic chemists is joining in and
developing new methodologies.”
Prakash is best known for his work with