of peptide-based inhibitors and subsequent
molecular modeling suggested that construc-
tion of large, macrocyclic enzyme inhibitors
could provide favorable ligand-protein binding
and potent inhibition of this essential viral pro-
tease ( 12 ). The relatively flat and featureless
protein surface requires a large ligand to gain
sufficient binding affinity, while constrained
macrocyclic ligands minimize the entropic cost
of inhibitor binding. The application of ring-
closing metathesis chemistry ( 13 ) has been trans-
formative in the synthesis of many HCV NS3/4a
protease inhibitors of varying ring sizes and com-
plexity, including six approved drugs: simeprevir
( 14 ), paritaprevir ( 15 ), vaniprevir ( 16 ), grazoprevir
( 17 ), voxilaprevir ( 18 ), and glecaprevir ( 19 ). Ring-
closing metathesis chemistry enabled the dis-
covery of these and related macrocycles, allowing
rapid assembly of complex bioactive molecules
and broad exploration of SAR to address a range
of properties.
In the two examples described above, the dis-
covery of new synthetic pathways changed the
way scientists thought about designing and build-
ing molecules, which broadened the accessible
chemical space and thereby furnished molecules
possessing the biological activity required in fu-
ture drug candidates. The ability of the pharma-
ceutical industry to discover molecules to treat
unmet medical needs and deliver them to pa-
tients efficiently in the face of an increasingly
challenging regulatory landscape is dependent
on continued invention of transformative, syn-
thetic methodologies. Toward this end, investment
in research directed toward synthetic methods
innovation, furthering the nexus of synthetic
chemistry and biomolecules, and developing new
technologies to accelerate methods discovery is
absolutely essential. Pertinent examples in these
three areas are reviewed below.
Synthetic methods innovation
Over the past 20 years, several scientists have been
recognized with the Nobel Prize for the invention
of synthetic methodologies that have changed
the way chemists design and build molecules.
Each of these privileged methods—asymmetric
hydrogenation, asymmetric epoxidation, olefin
metathesis, and Pd-catalyzed cross-couplings—
have broadly influenced the entire field of syn-
thetic chemistry, but they have also enabled new
directions in medicinal chemistry research. Of
particular interest are new synthetic methods
that enable medicinal chemists to control reac-
tivity in complex, drug-like molecules, access non-
obvious vectors for SAR development, and rapidly
access new chemical space or unique bond for-
mations. Recently, there have been several re-
ported methods in these categories that have
been rapidly adopted by medicinal chemists as
a result of their practicality and broad utility.
Owing to the diverse biological activity of
nitrogen-containing compounds, the discovery
of Pd-catalyzed and Cu-catalyzed cross-coupling
reactionsofaminesandarylhalidestoformC-N
bonds resulted in the rapid implementation of
these synthetic methods in the pharmaceutical
industry ( 20 ). The methodology addressed an
unsolved problem to quickly and predictably ac-
cess aromatic and heteroaromatic amines from
simple precursors, and as a result it was rapidly
adopted by medicinal chemists. Further devel-
opment of these methodologies by process chem-
istry groups for scale-up has resulted in optimized
ligands and precatalysts, as well as generally
reliable protocols that have further advanced the
application of this methodology in discovery
programs. Consequently, aromatic C-N bonds are
commonfeaturesinpharmaceuticalcompounds
( 21 ), highlighting the tremendous impact that
controlled construction of C-N bonds in aromatic
compounds has had on medicinal chemistry pro-
grams. The next frontier isdevelopment of reliable
methods to accomplish Csp^3 -N couplings ( 22 ).
As the development of transition metal–catalyzed
processes has advanced, application of cutting-
edge methods to the predictable activation of
C-H bonds for functionalization of complex lead
structures can enable novel vector elaborations,
changing the way analogs are prepared ( 23 ). In
particular, late-stage selective fluorination and
trifluoromethylation of C-H bonds in an efficient,
high-yielding, and predictable fashion permits
the modification of lead compounds to give ana-
logs that potentially possess greater target affi-
nity and metabolic stability without resorting to
de novo synthesis. Methodological advances have
enabled preparation of fluorinated analogs of lead
structures under either nucleophilic or electro-
philic conditions ( 24 ). One promising recent exam-
ple shows that electrophilic aromatic fluorination
can occur under mild conditions with a palladium
catalyst and an electrophilic fluorine source such
asN-fluorobenzenesulfonimide (NFSI) ( 25 ). In
addition, trifluoromethylation of a structurally
diverse array of drug discovery candidates using
zinc sulfinates, in the presence of iron(III) acetyl-
acetonate, generated analogs with improved meta-bolic properties ( 26 ). Visible-light photoredox
catalysis has been also been applied to the
practical, direct trifluoromethylation of het-
eroarenes ( 27 ).
Adoption of photoredox catalysis in the phar-
maceutical industry has been rapid, owing to
the practicality of the process, the tolerance to
functional groups in drug-like candidates, and
the activation of nonconventional bonds in drug-
like molecules ( 28 ). Application of photoredox
catalysis to the Minisci reaction was reported,
enabling the facile and selective introduction of
small alkyl groups into a variety of biologically
active heterocycles such as camptothecin ( 29 ).
Photoredox catalysis has also been used for the
direct and selective fluorination of leucine methyl
ester to affordg-fluoroleucine methyl ester with a
decatungstate photocatalyst and NFSI (Fig. 2).
Numerous processes have been reported to access
g-fluoroleucine methyl ester, a critical fragment of
the late-stage drug candidate odanacatib; how-
ever, this method enables the most direct and
efficient method to access this key building block
in the fewest operations from a commodity feed-
stock ( 30 ). More recently, photoredox catalysis was
used to generate diazomethyl radicals, equivalents
of carbyne species, which induced site-selective
aromatic functionalization in a diverse array of
drug-like molecules ( 31 ). This represents the
latest of a series of very diverse, practical, and
potentially impactful uses of photoredox tech-
niques to assemble libraries of drug-like scaf-
folds for screening.
Although the preceding examples highlight
the power of photoredox catalysis to accomplish
previously unimaginable reactivity under very
mild conditions ( 32 , 33 ), even more remarkable
transformations are being reported via synergis-
tic catalysis, where both the photocatalyst and a
co-catalyst are responsible for distinct steps in
a mechanistic pathway that is only accessibleCamposet al.,Science 363 , eaat0805 (2019) 18 January 2019 2of8
Fig. 2. Synthetic methods with potential to enable drug discovery.RESEARCH | REVIEW
on January 19, 2019^http://science.sciencemag.org/Downloaded from