with both catalysts present. For example, the
combination of single-electron transfer–based
decarboxylation with nickel-activated electro-
philes has provided a general method for the
cross-coupling of sp^2 -sp^3 and sp^3 -sp^3 bonds.
This method establishes a new way of thinking
about the carboxylic acid functional group as a
masked cross-coupling precursor, expanding the
synthetic opportunities for a functional group
that is ubiquitous in chemical feedstocks ( 34 ).
Furthermore, leveraging synergistic catalysis
with photoredox has resulted in the discovery of
milder conditions for C-O ( 35 ) and C-N cross-
couplings, allowing application of these methods
to more pharmaceutically relevant substrates
( 36 ). The concise synthesis of the antiplatelet
drug tirofiban ( 37 ) is an excellent example of how
the pharmaceutical industry can readily use this
methodology to facilitate drug discovery and
development. As research continues to surge in
this field, additional breakthroughs are antici-
pated, and these will likely change how mole-
cules are designed and built.
Intersection of synthetic chemistry
with biomolecules
Biopolymers including proteins, nucleic acids,
and glycans have evolved to achieve exquisite
selectivity and function in a highly complex en-
vironment. These properties are of great interest
to the pharmaceutical industry not only from a
target perspective, but also from a therapeutic
perspective. The success of monoclonal antibodies,
peptides, and RNA-based therapies attests to the
power that nature’splatformsoffertoourindus-
try and patients. Recent advances in merging the
fields of synthetic and biosynthetic chemistry have
sought to harness these molecules and to expand
useful manipulation of biomolecules in three dis-
tinct ways: as catalysts for novel and selective
transformations, as conjugates through innovative
bio-orthogonal chemistry, and in the development
of novel and improved therapeutic modalities.
Biocatalysis
Historically, the broad adoption of biocatalysis
was held back by a limited availability of robust
enzymes, a relatively small scope of reactions,
and the long lead time required to optimize a
biocatalyst through protein engineering ( 38 ).
The invention of a recombinant engineered
Merck/Codexistransaminasebiocatalystforthe
commercial manufacture of sitagliptin (Januvia)
has inspired the broader application of bio-
transformations in the pharmaceutical indus-
try ( 39 ). Tremendous advances have been made
in molecular biology, bioinformatics, and pro-
tein engineering, enabling the development of
biocatalysts with desired stability, activity, and
exquisite selectivity. The impact of this area of
research is exemplified by the 2018 Nobel Prize
in Chemistry, recognizing Frances Arnold“for
the directed evolution of enzymes.”As a result,
biocatalysis has become more prevalent as a
tool in drug discovery, as a valuable method for
drug metabolite synthesis, and as a tool to enable
rapid analog synthesis for SAR ( 40 ). For example,
in 2013, the important discovery that cyclic gua-
nosine monophosphate–adenosine monophos-
phate (2′,3′-cGAMP) is the endogenous agonist
of STING, a protein involved in the activation
of innate immune cells, triggered an intense
interest in the synthesis of cyclic dinucleotide
(CDN) analogs ( 41 ). Typically, the total synthesis
of CDNs by purely chemical transformations
requires long linear sequences and results in a
time-consuming and low-yielding process. The
optimization of STING agonists was greatly
facilitated by the realization that the endoge-
nous enzyme cGAS, responsible for the in vivo
production of 2′,3′-cGAMP, could be engineered
and harnessed for the biocatalytic production
of non-natural CDNs (Fig. 3). The cyclization of
various nucleotide triphosphate derivatives in
a single biosynthetic step considerably reduced
the cycle time and increased the yield of CDN
synthesis, inspiring the design of novel agonists
and the generation of SAR in this class ( 42 ).
The continued investment in biocatalysis will
lead to innovative solutions for unsolved prob-
lems in synthetic chemistry in both the dis-
covery and development arenas. This will be
driven by increased speed of protein engineer-
ing, access to enzymes with a variety of natural
and even unnatural ( 43 ) catalytic activities, and
the implementation of biocatalytic cascade catal-ysis to efficiently build complex chemical matter
from simple starting materials ( 44 ).Bio-orthogonalchemistry
Achieving selective reactions with biopolymers
such as proteins presents a host of unique chal-
lenges to the synthetic chemistry community;
proteins have multiple reactive centers, charged
residues, higher-order structure, and are usually
handled in an aqueous environment. Nonethe-
less, the opportunity to create improved conju-
gates as therapies and imaging agents, or to
inducecovalentinteractionstoidentifyprotein
targets, represents important value to therapeu-
tic drug discovery.
Methods for selective conjugation to biomole-
cules have undergone major synthetic evolution
over the past 20 years. The discovery and devel-
opment of a suite of click reactions has served
as a powerful and broadly applied tool in protein
bioconjugation ( 45 ). This highly bio-orthogonal
and biocompatible reaction offers a powerful al-
ternative to heterogeneous conjugation to sur-
face lysines or engineered cysteines, and spurred
the development of complementary expression
technologies that could incorporate unnatural
elements or recognition tags into biopolymers.
This evolution in conjugation chemistry is best
evidenced in the field of antibody-drug conju-
gates (ADCs): The first generation of ADCs were
heterogeneous conjugates, whereas those of the
second generation are now almost entirely ho-
mogeneous, with growing evidence that the site
ofconjugationisanimportantdeterminantof
overall ADC performance ( 46 ).
The development of additional bio-orthogonal
chemistries that can lead to selective reaction
with biomolecules, particularly without the re-
quirement for engineering a recognition ele-
ment into the biomolecule, is an important new
frontier for synthetic impact. Two recent exam-
ples of synthetic innovation suggest this toolset
is expanding for proteins. In many cases, having
the ability to conjugate at either the N or C ter-
minus of a wild-type protein should avoid un-
intended disruption of its function or secondary
structure. The development of selective N-terminal
conjugation chemistry ( 47 ) and complementaryCamposet al.,Science 363 , eaat0805 (2019) 18 January 2019 3of8
Fig. 3. Biocatalytic synthesis of novel cyclic dinucleotides.
RESEARCH | REVIEW
on January 19, 2019^http://science.sciencemag.org/Downloaded from