REVIEW SUMMARY◥

ORGANIC CHEMISTRY

The importance of synthetic chemistryin the pharmaceutical industryKevin R. Campos*, Paul J. Coleman*, Juan C. Alvarez, Spencer D. Dreher,Robert M. Garbaccio, Nicholas K. Terrett, Richard D. Tillyer,Matthew D. Truppo, Emma R. Parmee

BACKGROUND: Over the past century, inno-vations in synthetic chemistry have greatlyenabled the discovery and development of im-portant life-changing medicines, improvingthe health of patients worldwide. In recentyears, many pharmaceutical companies havechosen to reduce their R&D investment inchemistry, viewing synthetic chemistry moreas a mature technology and less as a driver ofinnovation in drug discovery. Contrary to thisopinion, we believe that excellence and inno-vation in synthetic chemistry continue to becritical to success in all phases of drug discov-ery and development. Moreover, recent devel-opments in new syntheticmethods, biocatalysis,chemoinformatics, and reaction miniaturiza-tion have the power to accelerate the pace andimprove the quality of products in pharma-ceutical research. Indeed, the application ofnew synthetic methods is rapidly expandingthe realm of accessible chemical matter formodulating a broader array of biological tar-gets, and there is a growing recognition thatinnovations in synthetic chemistry are chang-ing the practice of drug discovery. We identifysome of the most enabling recent advancesin synthetic chemistry as well as opportunities

that we believe are poised to transform thepractice of drug discovery and development inthe coming years.

ADVANCES: Over the past century, innova-tions in synthetic methods have changed theway scientists think about designing andbuilding molecules, enabling access to moreexpansive chemical space and to moleculespossessing the essential biological activityneeded in future investigational drugs. In or-der for the pharmaceutical industry to con-tinue to produce breakthrough therapies thataddress global health needs, there remains acritical need for invention of synthetic trans-formations that can continue to drive newdrug discovery. Toward this end, investmentin research directed toward syntheticmethodsinnovation, furthering the nexus of syntheticchemistry and biomolecules, and developingnew technologies to accelerate methods dis-covery is essential. One powerful example ofan emerging, transformative syntheticmethodis the recent discovery of photoredox catal-ysis, which allows one to harness the energy ofvisible light to accomplish synthetic trans-formations on drug-like molecules that were

previously unachievable. Furthermore, recentbreakthroughs in molecular biology, bioinfor-matics, and protein engineering are drivingrapid identification of biocatalysts that possessdesirable stability, unique activity, and exquis-ite selectivity needed to accelerate drug dis-covery. Recent developments in the mergingfields of synthetic and biosynthetic chemis-try have sought to harness these moleculesin three distinct ways: as biocatalysts for

novel and selective trans-formations, as conjugatesthrough innovative bio-orthogonal chemistry, andin the development of im-proved therapeutic mod-alities. The development

of high-throughput experimentation andanalytical tools for chemistry has made itpossible to execute more than 1500 simul-taneous experiments at microgram scale in1 day, enabling the rapid identification of suit-able reaction conditions to explore chemicalspace and accelerate drug discovery. Finally,advances in computational chemistry andmachine learning in the past decade are de-livering real impact in areas such as new cat-alyst design, reaction prediction, and even newreaction discovery.

OUTLOOK:These advances position syntheticchemistry to continue to have an impact onthe discovery and development of the nextgeneration of medicines. Key unsolved prob-lems in synthetic chemistry with potentialimplications for drug discovery include se-lective saturation and functionalization ofheteroaromatics; concise synthesis of highlyfunctionalized, constrained bicyclic amines;and C-H functionalization for the synthesisof a,a,a-trisubstituted amines. Other areas,such as site-selective modification of bio-molecules and synthesis of noncanonical nu-cleosides, are emerging as opportunities ofhigh potential impact. The concept of mo-lecular editing, whereby one could selectivelyinsert, delete, or exchange atoms in highlyelaborated molecules, is an area of emerginginterest. Continued investment in syntheticchemistry and chemical technologies throughpartnerships between the pharmaceutical in-dustry and leading academic groups holdsgreat promise to advance the field closer to astate where exploration of chemical space isunconstrained by synthetic complexity andonly limited by the imagination of the chem-ist, enabling the discovery of the optimal chem-ical matter to treat disease faster than everbefore.▪

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The list of author affiliations is available in the full article online.*Corresponding author. Email: kevin_campos@merck.com(K.R.C.); paul_coleman@merck.com (P.J.C.)Cite this article as K. R. Campos et al., Science 363, eaat0805(2019). DOI: 10.1126/science.aat0805

Evolution of synthesis as a driver of innovation in drug discovery. Past, present, andfuture advances in synthetic chemistry are poised to transform the practice of drug discoveryand development.

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REVIEW◥

ORGANIC CHEMISTRY

The importance of synthetic chemistryin the pharmaceutical industryKevin R. Campos1*, Paul J. Coleman1*, Juan C. Alvarez1, Spencer D. Dreher1,Robert M. Garbaccio1, Nicholas K. Terrett1, Richard D. Tillyer2,Matthew D. Truppo2, Emma R. Parmee1

Innovations in synthetic chemistry have enabled the discovery of many breakthroughtherapies that have improved human health over the past century. In the face of increasingchallenges in the pharmaceutical sector, continued innovation in chemistry is required todrive the discovery of the next wave of medicines. Novel synthetic methods not only unlockaccess to previously unattainable chemical matter, but also inspire new concepts as to howwe design and build chemical matter. We identify some of the most important recentadvances in synthetic chemistry as well as opportunities at the interface with partnerdisciplines that are poised to transform the practice of drug discovery and development.

Over the past century, innovations in syn-thetic chemistry have greatly enabled thediscovery and development of importantlife-changing medicines, improving thehealth of patients worldwide. In recent

years, many pharmaceutical companies havechosen to reduce their R&D investment in chem-istry, viewing synthetic chemistry more as a ma-ture technology and less as a driver of innovationin drug discovery (1–3). Contrary to this opinion,we believe that excellence and innovation in syn-thetic chemistry continues to be critical to successin all phases of drug discovery and development.Moreover, recent developments in new syntheticmethods, biocatalysis, chemoinformatics, and re-action miniaturization have the power to accel-erate the pace and improve the quality of productsin pharmaceutical research. The application ofnew synthetic methods is rapidly expanding therealm of accessible chemical matter for modulat-ing a broader array of biological targets, and thereis a growing recognition that innovations in syn-thetic chemistry are changing the practice of drugdiscovery (4, 5). Here, we identify some of themost enabling recent advances in synthetic chem-istry as well as opportunities that we believe arepoised to transform the practice of drug discov-ery and development in the coming years.The pharmaceutical sector is currently facing

multiple challenges: an increasing focus on com-plex diseases with unknown causal biology, arapidly changing and highly competitive land-scape, and substantial pricing pressures frompatients and payers. In this challenging envi-ronment, drug discovery scientists must selectbiological targets of relevance to human disease

and find safe and effective therapeutic moleculesthat appropriately modulate those targets. Thecurrent toolbox of synthetic methods and com-mon chemical starting materials provides ac-cess to chemical space (6) that can be efficientlyexplored andmined to identify a suitable ligandand subsequently pursue studies of that prelim-inary lead compound toward its potential devel-opment as a successful drug. Brown andBoströmhave noted that a historical overreliance on justa few robust synthetic transformations (amidebond formation, sp2-sp2 C-C cross-coupling, andSNAr reactions) has biased the output of manydrug discovery efforts, leading to narrow samplingof chemical space (7). In other cases, the lack ofany reasonable method of synthesis has, at mini-mum, hampered thorough evaluation of chem-ical space or, at worst, prevented it completely.Conversely, the discovery of breakthrough syn-

thetic methods can truly transform the process

of drug discovery. Innovation in synthetic chem-istry provides opportunity to gain more rapidaccess to biologically active, complexmolecularstructures in a cost-effective manner that canchange the practice of medicine. An outstandingexample of the transformative power of syntheticchemistry in drug discovery is the application ofcarbenoid N-H insertion chemistry to the syn-thesis of b-lactam antibiotics (8). In the 1950s,the synthesis of antibiotics such as penicillinrepresented a formidable challenge to medicinalchemists, and broad exploration of structure-activity relationships (SAR) within this class ofcompounds was hindered by a lack of goodmeth-ods of synthesis for these chemically sensitivestructures. Indeed, the first chemical synthesis ofpenicillin took nearly a decade of dedicated ef-fort to achieve (9) despite an intensive effort acrossmultiple laboratories. This lack of synthetic ac-cessibility prevented thorough evaluation of struc-turally related antibiotics that might have abroader spectrum of activity and an improvedresistance profile. The application of intramo-lecular N-H carbenoid insertion chemistry (Fig. 1)to these structures provided a disruptive solutionto the preparation of these fused b-lactams. Thissynthetic method was applied to the preparationof numerous natural and synthetic anti-infectives,including thienamycin (10), which subsequent-ly led to the discovery and industrial manufac-ture of the antibiotic imipenem. In this example,synthesis enabled design, opening access to pre-viously unattainable molecules of high therapeu-tic value.The development of targeted medicines for

the treatment of chronic hepatitis C infection, aglobal health challenge (11), illustrates anotherkey advance that innovative synthetic chemistryhas contributed to drug discovery in recent years.The design and synthesis of hepatitis C virus(HCV) NS3/4a protease inhibitors represents aformidable challenge for medicinal chemists be-cause the active site of this protease has a shallow,open binding site, and the enzyme possesses bothgenotypic andmutational diversity. Early studies

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1Global Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033,USA. 2Janssen Research & Development LLC, Spring House,PA 19477, USA.*Corresponding author. Email: kevin_campos@merck.com (K.R.C.);paul_coleman@merck.com (P.J.C.)

Fig. 1. Synthetic method innovations enable discovery of important anti-infectives, imipenemand vaniprevir.

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of peptide-based inhibitors and subsequentmolecular modeling suggested that construc-tion of large, macrocyclic enzyme inhibitorscould provide favorable ligand-protein bindingand potent inhibition of this essential viral pro-tease (12). The relatively flat and featurelessprotein surface requires a large ligand to gainsufficient binding affinity, while constrainedmacrocyclic ligands minimize the entropic costof inhibitor binding. The application of ring-closingmetathesis chemistry (13) has been trans-formative in the synthesis of many HCV NS3/4aprotease 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 relatedmacrocycles, allowingrapid assembly of complex bioactive moleculesand broad exploration of SAR to address a rangeof properties.In the two examples described above, the dis-

covery of new synthetic pathways changed theway scientists thought about designing and build-ing molecules, which broadened the accessiblechemical space and thereby furnished moleculespossessing the biological activity required in fu-ture drug candidates. The ability of the pharma-ceutical industry to discover molecules to treatunmet medical needs and deliver them to pa-tients efficiently in the face of an increasinglychallenging regulatory landscape is dependenton continued invention of transformative, syn-theticmethodologies. Toward this end, investmentin research directed toward synthetic methodsinnovation, furthering the nexus of syntheticchemistry and biomolecules, and developing newtechnologies to accelerate methods discovery isabsolutely essential. Pertinent examples in thesethree areas are reviewed below.

Synthetic methods innovation

Over the past 20 years, several scientists have beenrecognized with the Nobel Prize for the inventionof synthetic methodologies that have changedthe way chemists design and build molecules.Each of these privileged methods—asymmetrichydrogenation, asymmetric epoxidation, olefinmetathesis, and Pd-catalyzed cross-couplings—have broadly influenced the entire field of syn-thetic chemistry, but they have also enabled newdirections in medicinal chemistry research. Ofparticular interest are new synthetic methodsthat enable medicinal chemists to control reac-tivity in complex, drug-likemolecules, access non-obvious vectors for SAR development, and rapidlyaccess new chemical space or unique bond for-mations. Recently, there have been several re-ported methods in these categories that havebeen rapidly adopted by medicinal chemists asa result of their practicality and broad utility.Owing to the diverse biological activity of

nitrogen-containing compounds, the discoveryof Pd-catalyzed and Cu-catalyzed cross-couplingreactions of amines and aryl halides to form C-Nbonds resulted in the rapid implementation ofthese synthetic methods in the pharmaceutical

industry (20). The methodology addressed anunsolved problem to quickly and predictably ac-cess aromatic and heteroaromatic amines fromsimple precursors, and as a result it was rapidlyadopted by medicinal chemists. Further devel-opment of these methodologies by process chem-istry groups for scale-up has resulted in optimizedligands and precatalysts, as well as generallyreliable protocols that have further advanced theapplication of this methodology in discoveryprograms. Consequently, aromatic C-N bonds arecommon features in pharmaceutical compounds(21), highlighting the tremendous impact thatcontrolled construction of C-N bonds in aromaticcompounds has had on medicinal chemistry pro-grams. The next frontier is development of reliablemethods to accomplish Csp3-N couplings (22).As the development of transitionmetal–catalyzed

processes has advanced, application of cutting-edge methods to the predictable activation ofC-H bonds for functionalization of complex leadstructures can enable novel vector elaborations,changing the way analogs are prepared (23). Inparticular, late-stage selective fluorination andtrifluoromethylation of C-H bonds in an efficient,high-yielding, and predictable fashion permitsthe modification of lead compounds to give ana-logs that potentially possess greater target affi-nity and metabolic stability without resorting tode novo synthesis. Methodological advances haveenabled preparation of fluorinated analogs of leadstructures under either nucleophilic or electro-philic conditions (24). One promising recent exam-ple shows that electrophilic aromatic fluorinationcan occur undermild conditionswith a palladiumcatalyst and an electrophilic fluorine source suchas N-fluorobenzenesulfonimide (NFSI) (25). Inaddition, trifluoromethylation of a structurallydiverse array of drug discovery candidates usingzinc sulfinates, in the presence of iron(III) acetyl-acetonate, generated analogs with improvedmeta-

bolic properties (26). Visible-light photoredoxcatalysis has been also been applied to thepractical, direct trifluoromethylation of het-eroarenes (27).Adoption of photoredox catalysis in the phar-

maceutical industry has been rapid, owing tothe practicality of the process, the tolerance tofunctional groups in drug-like candidates, andthe activation of nonconventional bonds in drug-like molecules (28). Application of photoredoxcatalysis to the Minisci reaction was reported,enabling the facile and selective introduction ofsmall alkyl groups into a variety of biologicallyactive heterocycles such as camptothecin (29).Photoredox catalysis has also been used for thedirect and selective fluorination of leucine methylester to afford g-fluoroleucine methyl ester with adecatungstate photocatalyst and NFSI (Fig. 2).Numerous processes have been reported to accessg-fluoroleucinemethyl ester, a critical fragment ofthe late-stage drug candidate odanacatib; how-ever, this method enables the most direct andefficientmethod to access this key building blockin the fewest operations from a commodity feed-stock (30).More recently, photoredox catalysiswasused to generate diazomethyl radicals, equivalentsof carbyne species, which induced site-selectivearomatic functionalization in a diverse array ofdrug-like molecules (31). This represents thelatest of a series of very diverse, practical, andpotentially 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 accomplishpreviously unimaginable reactivity under verymild conditions (32, 33), even more remarkabletransformations are being reported via synergis-tic catalysis, where both the photocatalyst and aco-catalyst are responsible for distinct steps ina mechanistic pathway that is only accessible

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Fig. 2. Synthetic methods with potential to enable drug discovery.

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with both catalysts present. For example, thecombination of single-electron transfer–baseddecarboxylation with nickel-activated electro-philes has provided a general method for thecross-coupling of sp2-sp3 and sp3-sp3 bonds.This method establishes a new way of thinkingabout the carboxylic acid functional group as amasked cross-coupling precursor, expanding thesynthetic opportunities for a functional groupthat is ubiquitous in chemical feedstocks (34).Furthermore, leveraging synergistic catalysiswith photoredox has resulted in the discovery ofmilder conditions for C-O (35) and C-N cross-couplings, allowing application of these methodsto more pharmaceutically relevant substrates(36). The concise synthesis of the antiplateletdrug tirofiban (37) is an excellent example of howthe pharmaceutical industry can readily use thismethodology to facilitate drug discovery anddevelopment. As research continues to surge inthis field, additional breakthroughs are antici-pated, and these will likely change how mole-cules are designed and built.

Intersection of synthetic chemistrywith biomolecules

Biopolymers including proteins, nucleic acids,and glycans have evolved to achieve exquisiteselectivity and function in a highly complex en-vironment. These properties are of great interestto the pharmaceutical industry not only from atarget perspective, but also from a therapeuticperspective. The success of monoclonal antibodies,peptides, and RNA-based therapies attests to thepower that nature’s platforms offer to our indus-try and patients. Recent advances in merging thefields of synthetic and biosynthetic chemistry havesought to harness these molecules and to expanduseful manipulation of biomolecules in three dis-tinct ways: as catalysts for novel and selectivetransformations, as conjugates through innovativebio-orthogonal chemistry, and in the developmentof novel and improved therapeutic modalities.

Biocatalysis

Historically, the broad adoption of biocatalysiswas held back by a limited availability of robustenzymes, a relatively small scope of reactions,

and the long lead time required to optimize abiocatalyst through protein engineering (38).The invention of a recombinant engineeredMerck/Codexis transaminase biocatalyst for thecommercial manufacture of sitagliptin (Januvia)has inspired the broader application of bio-transformations in the pharmaceutical indus-try (39). Tremendous advances have been madein molecular biology, bioinformatics, and pro-tein engineering, enabling the development ofbiocatalysts with desired stability, activity, andexquisite selectivity. The impact of this area ofresearch is exemplified by the 2018 Nobel Prizein Chemistry, recognizing Frances Arnold “forthe directed evolution of enzymes.” As a result,biocatalysis has become more prevalent as atool in drug discovery, as a valuable method fordrugmetabolite synthesis, and as a tool to enablerapid 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 agonistof STING, a protein involved in the activationof innate immune cells, triggered an intenseinterest in the synthesis of cyclic dinucleotide(CDN) analogs (41). Typically, the total synthesisof CDNs by purely chemical transformationsrequires long linear sequences and results in atime-consuming and low-yielding process. Theoptimization of STING agonists was greatlyfacilitated by the realization that the endoge-nous enzyme cGAS, responsible for the in vivoproduction of 2′,3′-cGAMP, could be engineeredand harnessed for the biocatalytic productionof non-natural CDNs (Fig. 3). The cyclization ofvarious nucleotide triphosphate derivatives ina single biosynthetic step considerably reducedthe cycle time and increased the yield of CDNsynthesis, inspiring the design of novel agonistsand the generation of SAR in this class (42).The continued investment in biocatalysis willlead to innovative solutions for unsolved prob-lems in synthetic chemistry in both the dis-covery and development arenas. This will bedriven by increased speed of protein engineer-ing, access to enzymes with a variety of naturaland even unnatural (43) catalytic activities, andthe implementation of biocatalytic cascade catal-

ysis to efficiently build complex chemical matterfrom simple starting materials (44).

Bio-orthogonal chemistry

Achieving selective reactions with biopolymerssuch as proteins presents a host of unique chal-lenges to the synthetic chemistry community;proteins have multiple reactive centers, chargedresidues, higher-order structure, and are usuallyhandled in an aqueous environment. Nonethe-less, the opportunity to create improved conju-gates as therapies and imaging agents, or toinduce covalent interactions to identify proteintargets, represents important value to therapeu-tic drug discovery.Methods for selective conjugation to biomole-

cules have undergone major synthetic evolutionover the past 20 years. The discovery and devel-opment of a suite of click reactions has servedas a powerful and broadly applied tool in proteinbioconjugation (45). This highly bio-orthogonaland biocompatible reaction offers a powerful al-ternative to heterogeneous conjugation to sur-face lysines or engineered cysteines, and spurredthe development of complementary expressiontechnologies that could incorporate unnaturalelements or recognition tags into biopolymers.This evolution in conjugation chemistry is bestevidenced in the field of antibody-drug conju-gates (ADCs): The first generation of ADCs wereheterogeneous conjugates, whereas those of thesecond generation are now almost entirely ho-mogeneous, with growing evidence that the siteof conjugation is an important determinant ofoverall ADC performance (46).The development of additional bio-orthogonal

chemistries that can lead to selective reactionwith biomolecules, particularly without the re-quirement for engineering a recognition ele-ment into the biomolecule, is an important newfrontier for synthetic impact. Two recent exam-ples of synthetic innovation suggest this toolsetis expanding for proteins. In many cases, havingthe 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 secondarystructure. Thedevelopmentof selectiveN-terminalconjugation chemistry (47) and complementary

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Fig. 3. Biocatalytic synthesis of novel cyclic dinucleotides.

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application of decarboxylative alkylation chem-istry to the C terminus of a protein substrate (48)offer new insights into achieving bio-orthogonaland highly site-selective conjugation with com-plex biomolecules (Fig. 4). These reactions takeadvantage of local differences in basicity andionization potential respectively and, in doing so,leverage the complexity that biopolymers offer.

Synthetic innovation andtherapeutic modalities

As these advances in synthetic, biorthogonal, andbiosynthetic chemistry merge, so too do our capa-bilities to improve therapeutic modalities in the

space between synthetic small molecules andexpressed largemonoclonal antibodies. Peptides,oligonucleotides, and bioconjugates have been ad-vanced particularly for biological targets deemed“undruggable” by small-molecule and antibodyplatforms. Advances in these chemistries inspirenew platforms and improve the breadth of bio-logical targets that we can address. Two exam-ples of innovation in therapeutic modalitiesthrough synthetic and biosynthetic chemistry aredescribed below, althoughmany others are beinginvented in academic and industrial settings.In the first case, it has longbeenappreciated that

a critical element of the success of oligonucleotide-

based therapies was the introduction of phos-phorothioates into the oligo backbone, whichafforded improved stability to biologicalmatricesas well as improved membrane permeabilityto aid with cytosolic delivery. Although theseand other improvements in stability and de-livery have advanced the field and enablednovel therapeutics to enter the clinic, manyoligo-based therapies require high doses toovercome barriers to delivery, and their use islimited by their toxicity. Further improvementsin stability and potency of the oligonucleotideshould contribute to a widening of the ther-apeutic index and dose lowering. Interesting-ly, the chemistry used to introduce stabilizingphosphorothioates leaves each center as a mix-ture of two P-stereoisomers. Therefore, mostclinical phosphorothioate-containing oligos thathave 20 base pairs are, in reality, a large mixtureof stereoisomers (219), each with different po-tency and stability characteristics. The ability tocontrol phosphorothioate chemistry through anoxazaphospholidine approach by Wada and col-leagues (49) led to a practical and scalable plat-form (50) for stereopure antisense oligonucleotidesthat demonstrate preclinical superiority to thecorresponding stereomixtures.Within the peptide arena, there has been a

growing recognition that cyclic peptides offerimproved starting points for drug discovery pro-grams relative to their linear counterparts, largelydue to improvements in entropic cost for bindingand proteolytic stability. Early display platformsdeveloped to discover cyclic peptides relied ondisulfide formation, and more recently on post-translational introduction of bis-electrophiles

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Fig. 4. Bio-orthogonal reactivity with proteins at N and C termini.

Fig. 5. High-throughput experimentation to accelerating reaction discovery.

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that can cyclize peptides with two cysteine resi-dues (51). Through combined application of aribozyme biocatalyst to enable unnatural aminoacid incorporation into peptides, and then bio-orthogonal chemistry for cysteine cyclizationthrough that unnatural amino acid, the Suga labhas developed an improved mRNA display plat-form (52) that has demonstrated tremendous po-tential to identify peptide ligands for challengingtargets. The merging of chemical synthesis andbiosynthesis within a common platform inspiresfurther exploration of cyclic peptide modality; theintroduction of selection pressures and forcedevolution into this platform begins to resembleaspects of natural product generation that hashistorically inspired both organic synthesis anddrug discovery.

Technologies to accelerate innovationHigh-throughput experimentation

Given the need to invent and rapidly delivermedicines to patients, the pharmaceutical indus-try must invest in capabilities with the potentialto radically accelerate the discovery and indus-trialization of transformative synthetic method-ologies. High-throughput screening in biology

has been the foundation of hit discovery fordecades, and in recent years, the pharmaceu-tical industry has strategically invested in thecreation of high-throughput experimentation(HTE) tools for chemistry that enable scientiststo test experimental hypotheses with hundreds ofarrayed experiments (53). In the same time framerequired for traditional single-reaction evalua-tion, the different parameters that determinereaction outcome, discrete variables (catalysts,reagents, solvents, additives), and continuousvariables (temperatures, concentrations, stoi-chiometries) can be holistically explored in par-allel (54). As a result, the synthetic chemist nowhas access to exponentially larger amounts ofexperimental data than ever before. One recentexample of the use of end-to-end HTE in processdevelopment was the discovery and develop-ment of an organo-catalyzed, enantioselective,aza-Michael reaction for the commercial man-ufacture of the antiviral letermovir (Fig. 5) (55).In this work, a series of efficient synthetic path-ways were envisioned by chemists and keytransformations were evaluated in parallel usingHTE. The emergence of an H-bonding catalysismechanism was initially discovered with mod-

erate enantioselectivity and low conversion usingchiral phosphoric acids. Rapid evaluation of alarge number of diverse scaffoldswithH-bondingcapability in this transformation resulted in thediscovery of an efficient and highly selective bis-sulfonamide catalyst. Further HTEwork enabledthe mechanistic understanding of the transfor-mation, leading to optimization of both the cat-alyst structure and definition of optimal processingconditions. In this studyand inmanyothers (56,57),novel bond-forming reactions were conceived byscientists, discovered throughHTE, and then rap-idly industrialized for the commercial manufac-ture of late-stage drug candidates.HTE tools have also begun to have an impact

in drug discovery (58). As new catalytic methodsemerge that redefine which bonds can be forged,the breadth of the resulting substrate scope ispoorly understood, as most test substrates com-monly demonstrated in the literature are simpleand not representative of the complex func-tionality common in drug candidates. Pre-dosed,reaction-specific HTE screening kits, contain-ing a lab’s most successful and general catalystsystems, are used in discovery chemistry labsto enable the rapid identification of reaction

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Fig. 6. Application of computational modeling to new catalyst design.

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conditions that work for these complex substrates.Additionally, HTE has recently been leveragedto benchmark emerging methods against dif-ferent catalytic procedures through the cre-ation of arrays of complex, drug-like substratesknown as informer libraries (59) or throughaddition of diverse molecular fragments thatcan disrupt catalysis (60, 61). The use of thesediagnostic methods allows exploration of therelationship between reaction types and diversecomplex substrate structures, thus enablingsynthetic practitioners tomake better decisionsabout which synthetic methods to prioritize intheir problem-solving. Additionally, miniatur-ization of HTE to nanomole scale—for example,by automated nanomole-scale batch (62) andflow (63) approaches—now enables the executionof more than 1500 simultaneous experimentsat microgram scale in 1 day for rapid identifi-cation of suitable reaction conditions to explorechemical space and accelerate drug discovery.This capability is augmented by advances inrapid high-throughput analytics, such as MISER(multiple injections in a single experimental run)and MALDI (matrix-assisted laser desorption/ionization) mass spectrometry techniques (64),which have enabled the analysis of as many as1536 reactions in very short time frames. Finally,nanomoleHTE can also expedite the preparationof diverse, complex arrays ofmolecules and, whencoupled directly with biological testing, can rad-ically alter how drug discovery is performed (65).

Computational methods

The use of computer-assisted methods to guidesynthetic chemistry is emerging as an importantcomponent in the practice of drug discovery.Advances in computational chemistry and ma-chine learning in the past decade are deliveringreal impact in areas such as new catalyst design(66) or showing considerable promise in otherssuch as reaction prediction (67). The applicationof deep learning methods has the potential touncover new chemical reactions, expanding theaccess to new pharmaceutical chemical matter.Granda et al. (68) have reported promising resultstoward this end. By combining automated syn-thesis with machine learning, they reported thediscovery of four chemical transformations withdifferentiated novelty.Recently, computer-guided design has been

successfully applied to the preparation of cat-alysts that provide asymmetric control of a cy-cloisomerization reaction (69). Computationalmethodswere used to evaluate the catalytic path-way of a previously unknown reaction, leadingto the hypothesis that the electronics of the cat-alyst ligand influence both the rate and stereo-selectivity of the transformation. Application ofquantum methods such as density functionaltheory (DFT) provided optimal ligand designswithmarkedly enhanced rate and selectivity overthe original ligand. A second example where theuse of computational methods aided in the de-sign of a superior catalyst is reported in the syn-thesis of a pronucleotide (ProTide, Fig. 6) (70).Achieving selective phosphoramidation of a nu-

cleoside at the 5′hydroxyl over the 3′hydroxylwithstereocontrol at the phosphorus center is highlychallenging. A combination of mechanistic studiesusing a variety of chiral catalysts and DFT calcula-tions of a proposed transition state further informedby experimental observations led to the rationaldesign of a dimeric phosphoramidation catalystwithan improved rateandexcellent stereoselectivity.Despite these successes, the process for ratio-

nal computational design of a catalyst is arduous,requiring the modeling of multiple mechanisticpathways and refinement of numerousmoleculesand transition states. A program for automatingmuch of this process has been reported (71), andthe advancement of such methods as well as thecontinual increase in processing power will drivefurther use of these tools in the future.The application of machine learning to syn-

thetic problems has also generated considera-ble interest and excitement. One area of activeresearch is the use of algorithms for syntheticroute planning to a target molecule (72, 73).Segler et al. combined Monte Carlo tree searchand three neural networks to identify potentialsynthetic routes (74). The success of the approachwas qualitatively evaluated through a double-blind A/B test, where 45 chemistry studentsshowednopreference betweenmachine-suggestedsynthetic routes versus literature routes for repre-sentative target molecules. Machine learning hasadditionally been applied to forward reactionprediction (75). Neural networks were used topredict the major product of a reaction using analgorithm that assigns a probability and rank topotential products. Additionally, machine learn-ing was used to successfully predict the perform-

ance of a single reaction, a Buchwald-Hartwigamination, against multiple variables: reactants,catalysts, bases, and additives (76). Application ofmachine learning holds considerable promise forsynthetic optimization of targets far exceedingthose described herein, toward predicting routes,main products, side products, and optimal con-ditions, among others. The continued advance-ment of these methods leverages the wealth ofpublic information in the scientific and patentliterature as well as within pharmaceutical insti-tutions. The quality, breadth, depth, and densityof the datawithin the domain of the predictions iscritical for driving toward high-accuracy models.Inclusion of examples of both successful and un-successful transformations is alsohighly important.HTE is a highly attractive, complementary tech-nology for augmenting existing datasets bygenerating model-suitable data, maximizing in-formation content through careful design of exper-iments and capacity to deliver large volumes ofdata in a rapid and cost-effective manner.

Future directions

As we have discussed, breakthroughs in syn-thetic chemistry have proven to be the inspi-ration for the discovery and development of newmedicines of important therapeutic value.Despitethemany advances described above, the pace andbreadth of molecule design is still constrainedbecause of unsolved problems in synthetic chem-istry. Many opportunities still remain to advancethe field, such that synthetic chemistrywill neverconstrain compound design or program pace,and should actually inspire access to unchartedchemical space in the pharmaceutical industry.

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Fig. 7. Molecular editing to enable drug discovery.

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Recently, we conducted a summit with keyopinion leaders to assess the state of field andto identify areas of research in syntheticmethodsthat would have critical impact in the pharma-ceutical industry. Key unsolved problems in syn-thetic chemistry included selective saturationand functionalization of heteroaromatics, concisesynthesis of highly functionalized, constrainedbicyclic amines, and C-H functionalization for thesynthesis of a,a,a-trisubstituted amines. Otherareas, such as selective functionalization of bio-molecules and synthesis of noncanonical nucleo-sides, were identified as emerging areas of highpotential impact. We envision that partnershipsbetween the pharmaceutical industry and lead-ing academic groups in the field hold greatpromise 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 trulygeneral method of this type would substantiallychange the pace of drug discovery and reduceconstraints on compound design. Figure 7 pro-spectively illustrates how analogs of a complexlead scaffold might be accessed via site selectiveC-H functionalization, heteroaromatic reduction,ring expansion, or ring contraction. The power tomodify this scaffold directly and specifically notonly avoids a potentially lengthy synthesis ofanalogs, but also removes any limitation ofmolecular design imposed by synthetic hurdles.We anticipate that breakthroughs in the area ofmolecular editingwill improve the pace andqualityof molecule invention, enabling the introductionof 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 isnow poised to have an even greater impact toaccelerate the pace of drug discovery and expandthe reach of synthetic chemistry beyond the tra-ditional boundaries of small-molecule synthesis.New methods of synthesis can greatly expandthe rate of molecule generation while also provid-ing opportunities to routinely synthesize complexmolecules 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 accessibleand creatingnewopportunities for producingnoveltherapeutic entities. Academic research continuesto be an important venue for producing novelreactivity, and rapid application of newmethodshas the potential to further drivemolecule inven-tion in drug discovery. New technologies such asHTE, automation, and new analytical methodsare accelerating the discovery of new reactionmethods. Further, integration of computationalreaction modeling with the vast quantities ofexperimental data generated by nanoscale HTEhas the potential to buildmore informativemod-

els that can predict successful reaction condi-tions or even discover new reactions. The field ofpredictive chemical synthesis remains nascent,but opportunities to build prognostic algorithmsvia machine-learning processes are likely to ex-pand in the coming years. Continued investmentin synthetic chemistry and chemical technologieshas the promise to advance the field closer to astate where exploration of chemical space isunconstrained by synthetic complexity and isonly limited by the imagination of the chemist.Advancements in synthetic chemistry are certainto remain highly relevant to the mission of in-venting new medicines to improve the lives ofpatients worldwide.

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ACKNOWLEDGMENTS

We thank M. Kress, J. Hale, L.-C. Campeau, D. Schultz, S. Krska,D. DiRocco, and A. Walji for their critical review of the manuscript;C. T. Liu for preparation of Fig. 1; and D. MacMillan, R. Sarpong,M. Gaunt, F. Arnold, and G. Dong for their participation in theDisruptive Chemistry Summit at Merck. The authors declare nocompeting financial interests.

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The importance of synthetic chemistry in the pharmaceutical industry

Tillyer, Matthew D. Truppo and Emma R. ParmeeKevin R. Campos, Paul J. Coleman, Juan C. Alvarez, Spencer D. Dreher, Robert M. Garbaccio, Nicholas K. Terrett, Richard D.

DOI: 10.1126/science.aat0805 (6424), eaat0805.363Science 

, this issue p. eaat0805Scienceapproaches are just coming into focus.methods optimization from small-scale discovery to large-scale production, and complementary machine-learningreactions to selectively modify proteins for conjugation. High-throughput techniques are also poised to accelerate catalysts stimulated by visible light, enzymes engineered for versatility beyond their intrinsic function, and bio-orthogonalthe advantages that have come from recent innovations in synthetic methods. In particular, they highlight small-molecule

review some ofet al.Chemical synthesis plays a key role in pharmaceutical research and development. Campos Synthetic innovation in drug development

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