Recently, we conducted a summit with key
opinion leaders to assess the state of field and
to identify areas of research in synthetic methods
that would have critical impact in the pharma-
ceutical industry. Key unsolved problems in syn-
thetic chemistry included selective saturation
and functionalization of heteroaromatics, concise
synthesis of highly functionalized, constrained
bicyclic amines, and C-H functionalization for the
synthesis ofa,a,a-trisubstituted amines. Other
areas, such as selective functionalization of bio-
molecules and synthesis of noncanonical nucleo-
sides, were identified as emerging areas of high
potential impact. We envision that partnerships
between the pharmaceutical industry and lead-
ing academic groups in the field hold great
promise to spur the invention of disruptive syn-
thetic chemistry to address these areas.
The most intriguing idea to emerge from the
discussion was the concept of molecular editing,
which would entail insertion, deletion, or ex-
change of atoms in highly functionalized com-
pounds at will and in a highly specific fashion.
Many innovations discussed above possess ele-
ments of this aspirational goal; however, a truly
general method of this type would substantially
changethepaceofdrugdiscoveryandreduce
constraints on compound design. Figure 7 pro-
spectively illustrates how analogs of a complex
lead scaffold might be accessed via site selective
C-H functionalization, heteroaromatic reduction,
ring expansion, or ring contraction. The power to
modify this scaffold directly and specifically not
only avoids a potentially lengthy synthesis of
analogs, but also removes any limitation of
molecular design imposed by synthetic hurdles.
We anticipate that breakthroughs in the area of
molecular editing will improve the pace and quality
of molecule invention, enabling the introduction
of new and important medicines at a faster rate.
Outlook
Synthetic chemistry has historically been a power-
ful force in the discovery of new medicines and is
now poised to have an even greater impact to
accelerate the pace of drug discovery and expand
the reach of synthetic chemistry beyond the tra-
ditional boundaries of small-molecule synthesis.
New methods of synthesis can greatly expand
the rate of molecule generation while also provid-
ing opportunities to routinely synthesize complex
molecules in the course of drug discovery. Manip-
ulation of biomolecules either as catalytic reagents
(i.e., engineered enzymes) or as substrates for site-
specific modulation is becoming more accessible
and creating new opportunities for producing novel
therapeutic entities. Academic research continues
to be an important venue for producing novel
reactivity, and rapid application of new methods
has the potential to further drive molecule inven-
tion in drug discovery. New technologies such as
HTE, automation, and new analytical methods
are accelerating the discovery of new reaction
methods. Further, integration of computational
reaction modeling with the vast quantities of
experimental data generated by nanoscale HTE
has the potential to build more informative mod-
els that can predict successful reaction condi-
tions or even discover new reactions. The field of
predictive chemical synthesis remains nascent,
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via machine-learning processes are likely to ex-
pand in the coming years. Continued investment
in synthetic chemistry and chemical technologies
has the promise to advance the field closer to a
state where exploration of chemical space is
unconstrained by synthetic complexity and is
only limited by the imagination of the chemist.
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