organic synthesis provides opportunities to transform drug ... · organic synthesis in academia...

PersPectivehttps://doi.org/10.1038/s41557-018-0021-z

© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

1Medicinal Sciences, Pfizer, Inc. Eastern Point Road, Groton, CT, USA. 2UCB, Slough, Berkshire, UK. 3GSK Medicines Research Centre, Stevenage, UK. 4Astex Pharmaceuticals, Cambridge, UK. 5Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland. 6Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. 7Medicinal Sciences, Pfizer, Inc., Cambridge, MA, USA. 8Present address: BenevolentBio, London, UK. 9Present address: GSK, Stevenage, UK. *e-mail: [email protected]

Breakthrough synthesis research, pioneered in universities and applied in industrial drug-discovery laboratories, has revo-lutionized drug design. Consider, for example, the impact of

asymmetric synthesis and metal-catalysed cross-coupling reac-tions. Today these processes are routine for medicinal chemists but prior to the fundamental academic research some drugs could not easily be manufactured in an enantiopure fashion and it was not possible to rapidly explore structure–activity relationships associ-ated with many C–C bond-forming reactions that are widespread today. However, synthetic methodology still limits the compounds that medicinal chemists can design and make experimentally. The timelines required by industry for compound delivery determine whether synthetically complex compounds are practically acces-sible. Organic synthesis is certainly not a solved problem as many significant challenges remain. Furthermore, experimental synthesis represents the most time-consuming aspect of medicinal chemistry so improvements there, along with in silico predictions and com-pound design, have great potential to increase efficiency and reduce the cost of preparing novel molecules. There is therefore good potential for scientific and financial return on investments made in fundamental organic synthesis research.

In the past few years, chemists in drug-discovery laboratories have enthusiastically applied recent developments in photoredox chemistry1–3, new catalysts for cross-coupling reactions, direct C–H bond activation and late-stage functionalization towards the prep-aration of drug-like molecules4. These new chemistries have dra-matically increased the chemical space accessible to drug-discovery project teams in a timely manner. There is clear evidence that new synthetic methodology published by academics can spark the phar-maceutical industry to make and explore structures that were previ-ously inaccessible.

We believe that industry is keen to respond rapidly to new synthetic chemistry, and this is especially feasible when it has

been designed with industrial application in mind; that is, when it addresses key retrosynthetic disconnections for drug discovery and is applicable to substrates with drug-like structural features (discussed in more detail below). We highlight in particular the requirement for syntheses that tolerate nitrogen heteroatoms and (unprotected) polar functional groups common in drug molecules. Key benefits in future methodological advances to allow more rapid industry take-up are summarized in Box 1.

The value–synthesis trajectoryThe investment in the synthesis of an individual molecule or class of molecules in industry is generally linked to the relevance of the biological design hypothesis and also the stage of development of the drug-discovery project, as illustrated in Fig. 1a. Significant syn-thetic resource is also justified for individual compounds if there is a strong and specific biological design hypothesis, such as a structure-based design utilizing a protein X-ray crystal structure.

In the initial stages of drug-discovery projects, small quantities (approximately 2–20 mg) of hundreds or thousands of molecules are designed, synthesized, characterized and tested in vitro. Value increases when biological activity is achieved and compounds are selected for in vivo evaluation, which typically requires ~0.1–1 g quantities. At this stage, increased resources are applied to individ-ual compound synthesis. Further evaluation of the biological pro-file and progression to safety assessment studies calls for additional investment in synthesis and the demands on chemistry change; methods need to be robust, scalable and safe. Figure 1a shows another value increase when a drug candidate is selected for clini-cal evaluation, which often involves its synthesis being scaled-up to ≥ 1 kg quantities. The compound may be handed over to pro-cess chemistry experts at this stage where extensive synthetic route optimization may be undertaken — but ideally a scalable route will already have been defined through the joint efforts of discovery and

Organic synthesis provides opportunities to transform drug discoveryDavid C. Blakemore1, Luis Castro2, Ian Churcher3,8, David C. Rees4*, Andrew W. Thomas5, David M. Wilson6 and Anthony Wood7,9

Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceu-tical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of trans-formational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional discon-nections, more C–H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic hetero-cyclic ring synthesis, C–X or C–C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis plan-ning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

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PersPective NaTure CHemiSTry

development chemists. The process-chemistry development phase is critical but beyond the scope of this discussion5,6.

Industry–academia collaborationsChemists in industry continue to rely on the creativity and innovation of the academic community, both to discover new synthetic meth-ods7,8 and to train students in organic synthesis. Industry–academia collaboration can come in many forms, including joint studentships and publications, strategic alliances, joint funding applications, sabbaticals, consultancies and secondments. Strategic alliances between multiple academics and/or industrial companies include the Merck Catalysis Center at Princeton University (https://chem-istry.princeton.edu/research-facilities/merck-catalysis-center), the US Center For Selective C–H Functionalization (http://www.nsf-cchf.com/index.html), the Dial-a-Molecule network8, pharma-ceutical company training9 and PhD programmes with Universities, scientific internships10, 11,12, and the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine at the University of Oxford involving ten industrial partners and 100 PhD students (http://www.oxfordsynthesiscdt.ox.ac.uk/). Recently, sabbaticals and secondments where academic scientists are able to spend time working in industry laboratories and vice versa have also been encouraged (https://royalsociety.org/grants-schemes-awards/grants/industry-fellowship/). These kinds of interactions, now sup-ported by many companies, offer a unique way of sharing knowl-edge and raising awareness of the issues, challenges and problems faced by industry.

The culture within the pharmaceutical industry has changed dra-matically in the last decade; collaborations, research alliances and consortia are now much more strategically important (see Fig. 1b). We would like to see even more scientific interactions between aca-demics, drug-discovery chemists, commercial compound vendors and equipment manufacturers. For example, a ‘road-testing’ forum could encourage feedback from industry to academia and vice versa on the application of newly discovered synthetic methodologies to the synthesis of drug-like molecules (http://generic.wordpress.soton.ac.uk/dial-a-molecule/). Sharing experiences about which industry-relevant reagents and monomer sets are compatible with new methods, and equally importantly their limitations, could help to lower the barrier for industry to utilize novel synthetic transfor-mations and new reactivity paradigms.

We emphasize the increasing opportunities for multi-institute pre-competitive consortia that allow many-to-many interactions and larger groups of — often interdisciplinary — teams to tackle significant challenges such as machine-assisted synthesis, late stage functionalization, biomacromolecule-compatible synthesis and application of artificial intelligence in synthesis. The identi-fication of ‘grand challenges’ for synthetic chemistry (such as the

Dial-a-Molecule network) might mobilize the community and gen-erate significant new funding, as has been the case in other scien-tific disciplines, with for example the Large Hadron Collider and the Human Genome Project.

significant synthetic challengesAmines, nitrogen heterocycles and unprotected polar groups. From an industry perspective, the most common challenge for any new synthetic method is its level of tolerance to the polar functional groups and nitrogen heteroatoms found in biologi-cally active molecules. Drug molecules typically contain a num-ber of often densely clustered, polar functional groups such as bases, weak protic acids, amides, amines, alcohols, hydrogen-bond donors or acceptors, and nitrogen-containing heterocycles (Fig. 2a). These polar groups are specifically designed to confer high-affinity binding interactions with proteins and drug-like physicochemical properties. A key message is that the most com-monly used reactions in early stage drug-discovery projects will be those with the broadest scope in terms of compatibility of the reaction conditions towards substrates and products containing functional groups of the type shown in Fig. 2. Conversely, new published methods that are not exemplified with substrates bear-ing a range of these functionalities are less easily adopted without further experimental validation11,12.

Syntheses involving nitrogen-containing compounds are well known to require protecting groups but this adds additional steps. As an example, the Suzuki–Miyaura coupling on tetrahydropyrazolo[3,4-c]pyridines works well when both nitrogens are protected but fails when either is left unprotected (Fig. 3a)13.

Palladium-mediated aryl C–N bond-forming reactions, also known as Buchwald–Hartwig cross-couplings, are widely used. However, polar five-membered ring amino-heterocycles can be challenging substrates. For example, 1,3-oxazole-2-amines have proven difficult and the coupling with 2,4-chloropyridine pro-ceeds in less than 3% yield (Fig. 3b)14. A long-standing solution to this problem has been to first couple methyl 2-amino-1,3-ox-azole-5-carboxylate, hydrolyse and decarboxylate (Fig. 3b). This strategy has been shown to work with a number of substrates, but it would be desirable to enable this transformation in a sin-gle step rather than taking a circuitous route through carboxyl-ate intermediates and decarboxylation. It is noteworthy that, since this work-around solution was published, the Buchwald group discovered a new ligand that enables the successful cou-pling of this heterocycle without requiring the incorporation of a carboxylate group15.

The challenge that polar functional groups can bring to impor-tant reaction types can be seen in an industry analysis of 2,149 metal-catalysed C–N bond-forming reactions performed in the

Box 1 | Key messages for organic synthesis when it comes to drug discovery

Organic synthesis is a rate-limiting factor in drug discovery. The timelines required in industry determine whether complex molecules are practically accessible; continued investment in in-novative academic research is required.

Academic research. By driving the discovery of novel organic synthesis, academic research opens up new areas of chemistry for industry to apply to transformational medicines. Industry–academia alliances should be broadened to facilitate translating academic innovation to drug discovery.

Specific functionalities. Drug molecules typically contain amines and N-heterocycles as well as unprotected polar groups, which present significant synthesis challenges. More synthetic methods are needed which tolerate these functionalities.

Reporting data. Journals, authors and referees all have a role to play to ensure that new methods fully disclose the substrate scope and functional-group tolerance.Non-traditional disconnections. New reactions are needed, such as: more C–H bond activation and late-stage functionalization; stereoselectively substituted aliphatic heterocyclic ring synthesis; C–X and C–C bond formation.

Syntheses compatible with biomacromolecules. These will be increasingly needed as the fields of small synthetic molecules and protein/RNA/oligosaccharides converge.

New technologies. Machine-assisted synthesis for example, and artificial intelligence for synthesis planning, have the potential to revolutionize drug discovery.

NATuRe CheMIsTRy | VOL 10 | APRIL 2018 | 383–394 | www.nature.com/naturechemistry384

https://chemistry.princeton.edu/research-facilities/merck-catalysis-center

https://chemistry.princeton.edu/research-facilities/merck-catalysis-center

http://www.nsf-cchf.com/index.html

http://www.nsf-cchf.com/index.html

http://www.oxfordsynthesiscdt.ox.ac.uk/

https://royalsociety.org/grants-schemes-awards/grants/industry-fellowship/

https://royalsociety.org/grants-schemes-awards/grants/industry-fellowship/

http://generic.wordpress.soton.ac.uk/dial-a-molecule/

http://generic.wordpress.soton.ac.uk/dial-a-molecule/



PersPectiveNaTure CHemiSTry

synthesis of highly functional drug leads16. Of the reactions exam-ined, 55% failed to deliver any products and the authors noted that these failures could result in compound sets enriched in hydropho-bic molecules less likely to become successful drug candidates. In a related analysis, it has been reported that more polar products in parallel synthesis reactions fail more often in synthesis17.

In the early stages of drug discovery, chemistry to make wide ranges of analogues in a parallel or array format is often used through a highly diverse set of reagents or ‘monomers’ (building blocks) covering a wide range of chemical space. The use of mono-mer sets can represent a significant functional-group tolerability challenge to synthetic methods18,19. A selection of amine building blocks that have been incorporated into project compounds within

the pharmaceutical industry are shown in Fig. 2b. New methods that are able to use reagents such as these are of high value to drug-discovery chemists.

One potential solution to the problems that polar functionality brings is the use of experimental techniques to rapidly determine and optimise reaction scope. For example, a ‘robustness screen’ to efficiently assess functional-group compatibility by use of vari-ous additives20,21, high-throughput nanomole-scale screening16 or experimentation22 to identify optimal catalysts and reaction condi-tions can be highly effective.

Good aqueous solubility is a property often associated with suc-cessful drugs — but these polar, drug-like molecules with good aqueous solubility often have poor solubility in the apolar organic solvents used for most synthetic methodologies. Molecules lacking polar functional groups tend to be lipophilic and dissolve in organic solvents, presenting more options for synthetic manipulation and purification but consequently have poor solubility in aqueous sys-tems making them less attractive for drug discovery.

Journals, authors and referees all have a critical role to play to encourage reports of novel methodology to disclose their substrate scope and functional-group tolerance. Describing the experimen-tal outcomes from a range of representative substrates bearing the groups highlighted in Fig. 2 is strongly encouraged and will expedite the application of newly published synthesis by industry. Clearly, achieving broad substrate scope is a very significant challenge and new reactions are always going to have limitations in scope — but papers that highlight both strengths and current limitations of methodology are most valuable to industry. Without this informa-tion, industry practitioners are left wondering whether groups such as unprotected amines, alcohols, or heterocycles are incompatible with the chemistry or have simply not been tried.

C–H bond activation and late-stage functionalization. In terms of key strategic areas for industry, increasing interest has been paid to chemical transformations capable of directly modifying an exist-ing bioactive molecule into a closely related analogue utilizing late-stage functionalization and C–H bond activation and encouraging progress has been made4,23–34. The advantage of this approach is that it is no longer necessary to initiate a new synthetic route for each target. However, the remaining challenge is to regiochemically functionalize a structurally complex polar molecule in a predict-able way. Methodology that allows selective addition of for example methyl, fluoro or other small groups on each position of a (unpro-tected) lead molecule would be widely used in industry, although we recognize that this represents a significant scientific challenge for synthetic chemistry. A related challenge is to discover new reac-tions that regioselectively activate each individual C–H bond in het-erocycles within biologically active molecules.

Introduction of fluorine substituents can modulate metabolism, binding affinity and the electronic properties of drug molecules. Considerable progress has been made in fluorination over the past few years35–41 however C–H fluorination of aromatic hetero-cycles remains a challenge. A typical example where this could be advantageous can be found in the synthesis of a number of fluo-rine-containing inhibitors of aggrecanases (a family of extracellular proteolytic enzymes) described by Shiozaki and co-workers42. In this important synthesis, fluorine has been introduced as part of the pyridine starting material before being taken through five steps to arrive at the requisite compound (Fig. 3c). In this case the ability to regioselectively introduce fluorine at different positions of the scaffold at the end of the synthesis would generate novel analogues even more efficiently. Ideally we would like to see a comprehensive toolkit that would allow the selective fluorination of any position in the most commonly used aromatic systems and sp3 carbon atoms43 allowing rapid structure–activity relationship exploration as illus-trated in Fig. 4a.

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Fig. 1 | Molecule–value relationship in drug discovery and organic synthesis. a, The effective value of a molecule increases significantly as it moves closer to becoming a marketed drug. Particular inflection points include demonstration of biological activity, selection for clinical study and progress through clinical development. The investment in the synthesis of a molecule in industry is linked to the relevance of the biological design hypothesis as well as the stage of development of the drug-discovery project. b, Academic research drives the discovery of novel synthesis, opening up new areas of chemistry for industry to apply to transformational medicines. Industry–academia alliances are increasingly important and should be broadened to facilitate translating academic innovation to drug discovery. Collaborations include strategic alliances between multiple academics and/or industrial companies, multi-institute precompetitive consortia, sabbaticals, consultancies, in-kind support as well as traditional direct funding and joint studentships. The term industry includes global pharmaceutical and small biotechnology companies, contract research organizations, equipment manufacturers and compound vendors.





A second hypothetical example, limited by synthetic methodol-ogy available today, is the selective addition of small groups such as Me, OMe, CH2OH, NH2, OH, CF3, CHF2 to each position of a complex molecule. Consider, for example, if a structure like the drug aripiprazole (Fig. 2a) was identified as a lead. Progress on late-stage functionalization of aripiprazole has been made — recent publications describe C–H silylation followed by conversion into a CF3 group on the dichlorophenyl ring44,45, and oxidation of the piperazine ring to form a diketopiperazine46. A room-temperature photoredox-catalysed method for C–H hydroxymethylation of drug-like heteroaromatic bases has been devised and recently pub-lished47, illustrating industry’s current interest in this area.

The growing field of fragment-based drug discovery (FBDD) — in which low-molecular-weight moieties (∼ 150 Da) that bind to biologically important macromolecules are identified then opti-mized — is benefiting from recent C–H bond functionalization research. In many cases X-ray crystallographic studies suggest specific C–H bonds where introduction of additional substituents would be expected to give improved biological activity. For exam-ple, the piperazine-containing fragment (Fig. 3d) binds to the X-linked inhibitor of apoptosis protein (XIAP) — an anti-cancer drug target — and was elaborated into a lead molecule using struc-ture-based design and growing from two C–H positions on the piperazine ring48. Preparation of the methoxymethyl derivative in

Fig. 3d required a new synthetic sequence but if direct and selec-tive derivatization of the N-substituted piperazine precursor had been possible, this project would have been significantly expedited. Today, C–H bond functionalization is a general synthetic challenge for the elaboration of fragments49,50.

White has demonstrated the value of iron-based catalysts in both oxidizing and aminating remote aliphatic C–H bonds51–58 and has applied this methodology to the remote functionalization of a range of natural products. Until recently the limitation of this methodol-ogy from a drug-discovery perspective was its inability to tolerate the presence of nitrogen-containing heterocycles. White has demon-strated a potential solution to this issue59. In other advances, Groves has utilized manganese porphyrins to selectively halogenate aliphatic C–H bonds60–63. Recently, an electrochemical method to remotely oxidize aliphatic C–H bonds looks to have potential broad scope in allowing functionalization of pharmaceutically relevant molecules64.

Late-stage functionalization of the drug Prozac was recently pub-lished by MacMillan’s laboratory. N–Boc-protected Prozac (where Boc is tbutyl carbamate) was alkylated selectively at the methyl position with simple alkyl bromide electrophiles to access a small library of alkylated products through polarity-match-based selective C–H alkylation65.

Increased synthetic flexibility using aliphatic heterocyclic rings. Piperazines, pyrrolidines, tetrahydropyrans and other aliphatic

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Fig. 2 | Drug molecules typically feature a number of groups — often clustered — that present significant synthetic challenges. a, Examples of drug molecules containing amines and N-heterocycles as well as other unprotected polar groups (circled in red) that present significant synthetic challenges. More reactions are needed that tolerate these functionalities. b, A selection of amine building blocks that have been incorporated into project compounds within the pharmaceutical industry. Journals, authors and referees are encouraged to consider these moieties when disclosing the substrate scope and functional group tolerance of new synthetic methods.





heterocyclic rings are present in many drugs but it is often chal-lenging to make small, selective structural modifications to these fragments within biologically active leads. New ways to access ste-reoselectively substituted derivatives are needed when optimizing biological activity or for structure–activity relationship studies, either by substitutions onto existing aliphatic rings or by new ring synthesis from aliphatic precursors (Fig. 4b)11,66–70. For example, leads with a piperidine ring are common but obtaining all possible analogues substituted with a single methyl or methoxy group is suf-ficiently challenging that these may be overlooked or only made towards the end of a project.

The concept of introducing a functional handle onto an ali-phatic ring system is a powerful way of yielding molecules with increased biological activity or suitable for subsequent derivatiza-tion. Significant progress in this area has been made recently. Amongst the notable examples, the use of iridium-mediated boryla-tion has been extended from aromatic systems to aliphatic variants by Hartwig to allow the functionalization of cyclopropanes and ali-phatic heterocycles71. The resulting boronate species can be further elaborated in multiple ways.

The metal-catalysed C–C bond forming revolution. Metal cata-lysed C–C bond forming reactions are hugely important in drug discovery72 and are discussed in detail here to illustrate some of the challenges that still exist today for practitioners in industry.

Amongst the most commonly used variants are the Suzuki–Miyaura coupling (SMC)73, the Negishi coupling and key C–N bond forming reactions74–77 such as the Buchwald–Hartwig coupling,

Chan–Lam coupling and Ullmann coupling78. Although all of these reactions are used routinely by industry, challenges still remain. For example, the choice of ligand in these reactions has a significant impact on the chances of success: factors influencing this are subtle but challenging couplings might be due to a difficult oxidative addi-tion into a carbon–halogen bond, the presence of other function-alities or chelating groups in the coupling partner. A wide range of ligand classes have been developed to address this issue and these include electron-rich, sterically hindered ligands79–81, bis-phosphine chelating ligands and N-heterocyclic carbene ligands. With such a wide range of options, reaction screening and high throughput experimentation22,82 is used to identify optimal conditions for chal-lenging reactions.

One of the key challenges for carbon-carbon coupling reactions is to access motifs with increased three-dimensional shape83. For example, conformational twists induced by ortho-substituted (and particularly ortho, ortho′ -disubstituted) biaryls confer 3D nature but these constitute the synthetically least-tractable targets, making this an area where improved catalysts could have a big contribution. With the success of the SMC reaction in generating biraryl motifs, a variant allowing routine sp3–sp2 and sp3–sp3 couplings — ideally in an enantioselective manner84–86 — is both highly desirable and could fundamentally change the motifs being generated.

With the environmental sustainability of chemistry in mind, an area with potential to impact on coupling methodologies in the coming years is the use of surfactants such as TPGS-750-M to drive reactions in water through micelles. This technology has been successfully applied to Suzuki–Miyaura couplings87–89, Lipshutz–

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Fig. 3 | syntheses involving nitrogen-containing compounds and late-stage functionalizations. a, Suzuki–Miyaura coupling of protected nitrogen containing heterocycles. Xphos, 2-dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl; DME, dimethylether. b, A circuitous C–N bond-forming route to couple 1,3-oxazol-2-amine in high yield, which requires a decarboxylation step. Xantphos, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; dba, dibenzylideneacetone; NMP, N-methyl-2-pyrrolidone. c, The synthesis of fluoro-containing aggrecanase inhibitors involved introducing the fluorine atom on the starting material. d, Fragment and corresponding lead with new binding groups (methyl and methoxymethyl) replacing two C–H bonds, which required a new synthetic sequence as direct C–H of the piperazine moiety is not accessible.





Negishi cross–coupling90 and extended to a range of other reaction types such as SNAr (ref. 91) suggesting that the local concentration increases that can be achieved could be of benefit across a wide range of reaction types.

Although the majority of SMC reactions are carried out using palladium catalysts, there is increasing interest in the use of non-precious metals. The use of nickel is attractive in terms of both cost92,93 and increased reactivity relative to palladium but there are potential concerns over toxicity of nickel salts94 and the abil-ity to carry out these key bond disconnections using iron and copper are of interest from a scalability, cost-saving and green chemistry perspective.

The synthesis of flurbiprofen95 (Fig. 5a) illustrates the potential of nickel in cross-coupling reactions with a site-selective enolate cross-coupling followed by a nickel-catalysed Suzuki–Miyaura reac-tion on the sulfamate moiety. Notably, the sulfamate proved unreac-tive under palladium-catalysed conditions. Nickel has found utility in other sp2–sp3 and sp3–sp3 coupling reactions. Many impressive advances have been made including significant progress in enanti-oselective couplings and the development of photoredox and reduc-tive cross-couplings1–3,96–119.

Photoredox catalysis has been rapidly adopted in the pharma-ceutical industry. Excellent examples of progress in this area include the use of alcohols activated with oxalyl chloride (Fig. 5b)1 and alkyl halides (Fig. 5c)120 as precursors in sp3–sp2 couplings. The ability to

leverage the large alkyl alcohol set for this coupling is significant as a wide range of these derivatives are readily available or accessible relative to the less stable halo derivatives. Photoredox methods are also now starting to enable some impressive non-traditional reac-tions with for example the Minisci approach to allow the coupling of alkyl ethers and heterocycles (Fig. 5d)121.

Complementary to photoredox catalysis, a new mode of cross-electrophile coupling reactivity has been developed. The coupling of alkyl acid derivatives with aryl and heteroaryl organozinc122,123 or organoboron species124,125 and the ability to couple aryl halides with alkyl halides126–128 have proven possible (Fig. 5e). These cross-electrophile couplings are an excellent illustration of the new reac-tivity that nickel catalysis accesses, opening up new disconnections and allowing the use of readily available reactants such as carboxylic acid derivatives for key reactions. The examples shown are particu-larly striking: the first shows the use of a 4-bromophenyl boronic acid in a coupling with a piperidine 4-carboxylic acid derivative (thus giving a product with a further coupling handle); the second shows that reductive couplings with protected 4-bromopiperidine can work for the challenging 3-pyridyl bromide coupling partner.

Electrochemical nickel-based couplings are starting to emerge129 hinting of the value that this technology may have in the future130.

The need to further expand C–C bond forming reactions. A hypothetical stereocontrolled sp2–sp3 coupling would enable

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R = Alkyl group

Fig. 4 | hypothetical transformations that would overcome some of the synthetic challenges outlined. a, Hypothetical selective fluorination of heteroaromatic and aliphatic C–H positions in aggrecanase inhibitors, which would avoid having to start with a fluorinated precursor as illustrated in Fig. 3c. b, Novel stereo- and chemoselective aliphatic ring synthesis would enable the evaluation of an increased variety of drug-like molecules; R and R1 are C, N, O-based substituents (see examples of the desired groups in Fig. 2). c, A stereocontrolled sp2–sp3 coupling would enable rapid variation of the p-fluorophenyl ring of paroxetine. d, Hypothetical sp3–sp3 coupling in the presence of unprotected polar functional groups. e, Hypothetical regioselective N-alkylation of heterocyclic ring positions. f, Hypothetical replacement of a C with an N atom in a ring. SDM, site-directed mutagenesis.





rapid variation of the p-fluorophenyl ring of paroxetine (Fig. 4c). Although C–C bond forming disconnections of this type are known (for example, Fig. 5e, and a recent publication on site selective C–H arylation of aliphatic amines131), the presence of an unprotected secondary amine and polar functional groups make this more challenging.

As noted above, there have been many impressive advances in sp2–sp3 and sp3–sp3 couplings in the last few years. However, enanti-oselective couplings of aliphatic heterocycles and couplings of mol-ecules containing free amines, for example, remain a challenge, as shown generically in Fig. 4d. As such, additional methodologies to enable sp2–sp3 and sp3–sp3 couplings across a greater range of potential

drug-like scaffolds are highly desired. As a recent example, Fig. 5f shows a selective sp3 photoredox C–H alkylation using polarity matched hydrogen atom transfer65.

Orthogonal functionalization of multiple heteroatoms of simi-lar reactivity. In polyfunctional molecules, well understood rules of regio- and chemoselectivity determine accessible products and to divert from this typically requires extensive protecting group strategies. If new methods, conditions and reagents that allow less reactive centres or disfavoured reaction outcomes to be accessed, new molecules hitherto difficult to prepare efficiently could be pre-pared. As an example, Fig. 4e shows a polyfunctional substrate for

c

O Br

NBr

NiCl2.dtbbpy (0.5 mol%)Ir[dF(CF3)ppy]2(dtbbpy)PF6 (1 mol%)

TTMSS, Na2CO3

RT, 34 W blue LED (80% yield)

d

O O

N

N

Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2 mol%)Na2S2O8, TFA

MeCN/H2O, 23 °C26 W CFL (62% yield)

O

O

O

O

eNBoc

O

O N

O

O

Cl

Cl

Cl

Cl

B Br

HO

HO

(3 equiv.)

O

N

NiCl2.6H2O (20 mol%), Et3N (10 equiv.)1,4-dioxane/DMF (10:1), 75 °C (61% yield)

N N

NBoc Br

(20 mol%)

NBoc

N

NBoc Br

N

Br (1.1 equiv.)

NiCl2.glyme (10 mol%), Phenanthroline (20 mol%)4-Ethylpyridine (50 mol%), NaBF4 (50 mol%)

Mn (2 equiv.), MeOH, 60 °C (45% yield)

fN Br

+N

BocN

Boc

1 mol% [Ir], 2 mol% [Ni]10 mol% quinuclidine

K2CO3, MeCN/H2OBlue LED

Ni(bipy)Br2

Mn, TFA, DMF50 °C (70% yield)

aOSO2NMe2

F

I

Cl

O

OMe OSO2NMe2

F

O

OMe

1. PhB(OH)2, NiCl2(PCy)3, K3PO4, toluene, 130 °C

2. H2SO4, 1,4-dioxane84% yield (2 steps)

Ph

F

O

OH

Flurbiprofenb

O

O

O

OH

NBoc

OH

NBoc (No purification)

Oxalyl chlorideNBoc

O

HNiBr2.dtbbpy (5 mol%)Ir[dFppy]2(dtbbpy)PF6 (1 mol%)

5:1 dioxane/THP:DMSO CsHCO3

4h, 70 °C, 34 W blue LED (61% yield)

Br

H

O

N

Fig. 5 | Metal-catalysed C–C bond-forming reactions. a, Synthesis of flurbiprofen using nickel-mediated coupling approach; bipy, bipyridine. b, sp2–sp3 coupling using photoredox with alcohol derivatives illustrated with Boc-piperidinol. Oxalyl chloride, (COCl)2; dtbbpy, 4,4’-di-tert-butyl-2,2’-dipyridyl; dFppy, 2-(2,4-difluorophenyl)pyridine. c, Reductive coupling using photocatalysis. RT, room temperature; dF(CF3)ppy, 2-(2,4-Difluorophenyl)-5-(trifluoromethyl)pyridine; TTMSS, tris(trimethylsilyl)silane; LED, light-emitting diode. d, Photoredox Minisci approach to aliphatic ether functionalization. CFL, compact fluorescent lamp. e, Examples of sp2–sp3 coupling with nickel. f, sp3–sp3 coupling with protected amine.





N-alkylation which can give rise to five monoalkylation products; reagent systems which regioselectively furnish each of these would be desirable.

Novel ways to expand utility of potentially unstable functional-ity. Consider an approach to prepare a set of Sildenafil analogues (Fig. 6a). If we wished to vary the sulfonamide amine, we would need an effective way to access a number of sulfonyl halides but many of these may be unstable. So, the generation of aryl sulfinates in situ19,132 allows a much wider range of sulfonamides to be pre-pared than might be possible if specific intermediates needed to be isolated and stored.

A further example of the in situ use of potentially unstable inter-mediates is the alkylation of amines using alcohols and ‘hydrogen-borrowing’ redox approaches133 (Fig. 6b). This reaction makes use of readily available alcohols, avoids the potentially unstable alkyl halides or aldehydes frequently used to achieve this transforma-tion and has the potential to be a powerful and versatile method. A complementary approach has been developed using biocatalysis to convert alcohols to enantiopure amines. A dual-enzyme hydro-gen-borrowing cascade utilizing an alcohol dehydrogenase and an amine dehydrogenase plus ammonium as the nitrogen source con-verts primary and secondary alcohols into the corresponding (R)-amines with high enantiomeric excess134.

Flow chemistry also offers many examples where reactive inter-mediates are produced in situ and immediately used135.

Natural products. Natural products have a long and successful his-tory as medicines. It has been estimated that almost 50% of anti-cancer drugs launched between the 1940s and 2014 are based on, or inspired by, natural products or semi-synthetic structures136 and there is re-emerging interest in natural products for disrupt-ing protein–protein interactions and for phenotypic screening137,138. The synthesis of natural products and their analogues to elucidate biological structure–activity relationships presents challenges for organic synthesis including C–H bond activation and late-stage functionalization. A recent example of a synthetic transformation leading to more substantial modifications is an unexpectedly selec-tive reaction of hexahydro-Diels–Alder benzynes with structurally complex natural products139. Fully synthetic routes to natural prod-ucts that provide structures not accessible by traditional semi-syn-thetic approaches are desirable, for example the convergent synthesis of macrolide antibiotics from simple chemical building blocks140.

Moonshot synthesis. Methodology to selectively make single atom exchanges to organic molecules has the potential to revolutionize

medicinal chemistry strategies but this technology is in its infancy and is included here as an example of a ground-breaking disconnec-tion without expecting near-term success.

For example, in Fig. 4f a carbon atom is replaced with nitrogen in a heterocyclic ring. This hypothetical transformation might require use of a thiazolyl ‘nucleophile’ together with a thienyl ‘leaving group’ or else a ring opening and re-closing with a distant connection to the Dimroth rearrangement of amino substituted triazoles in which endocyclic and exocyclic nitrogen atoms switch place.

The challenge here is (i) to switch an atom within a cyclic system and (ii) to exchange a carbon for a heteroatom. Related challenges include more flexible variants of other well-known atom insertion/deletion reactions such as Baeyer–Villiger oxidation, Beckmann rearrangement, Arndt–Eistert homologations and Schmidt reaction for converting ketones into the corresponding amides by adding a nitrogen atom, or the Curtius rearrangement of carboxylic acids into amines141 with the removal of one carbon atom.

Biomacromolecule-compatible synthesis. As biology and chem-istry continue to converge, there is an increasing need for chemis-tries that can be carried out in the presence of biomacromolecules. For example the synthesis of antibody– or peptide–drug conjugates and DNA-tagged libraries for hit identification. Chemistry in the presence of proteins, DNA and cells typically requires compatibil-ity with a myriad of functionality, much of which has the potential to be strongly nucleophilic or Lewis basic. Protic/aqueous solvents are also frequently required to solubilize reactants and use of strong acids, bases, redox-active reagents and potent nucleophiles or elec-trophiles is rarely well tolerated.

A specific example is DNA-encoded libraries (DELs), used to generate millions to trillions of small molecules to assess as hits for novel drug targets (Fig. 7a). The generation of DEL libraries is dependent on chemistry that can be performed in the presence of a DNA tag and ideally works reliably in water. Other practical con-siderations such as the poor acid stability142,143 of DNA must also be addressed. These limitations impact the design and synthesis of such libraries; broadening the diversity of chemistry that is compatible with aqueous systems and a DNA tag will help DEL library design-ers to explore a greater range of novel cores and to design libraries.

An increasing range of new approaches to selectively modulate biological systems seek to use conjugates of a small, synthetic mol-ecule with a biomacromolecule, frequently a protein (for example, antibody drug conjugate) or dendrimer. Chemistry that allows the ligation of these moieties, especially onto native peptide residues, is thus highly desirable. Linkers need to have the ability to che-moselectively react at both ends. A common problem is that one

a

N

NHN

N

O

EtO

BrNH

NN

N

O

EtO

SN

O O

R1

R2

Sildenafil: NR1R2 = piperazine N-Me

1. K2S2O5, NaO2CH, Pd(OAc)2

PPh3, Phen, TBAB, DMSO, 70 °C

2. R1R2NH, NBSDMSO/THF, 0 to 23 °C

Examples of R1R2NH: HN HN O

HN H2N H2N CF3

b

NH

N

OH

O

H

H

HNR2

‘Hydrogen-borrowing redox catalyst’

NH

N

NR2

O

H

H

Fig. 6 | In situ use of potentially unstable intermediates. a, Synthesis of sildenafil analogues using amine monomers. TBAB, tetrabutylammonium bromide; DMSO, dimethyl sulfoxide; Phen, 1,10-phenanthroline; NBS, N-bromosuccinimide; THF, tetrahydrofuran; R1 and R2 are alkyl groups. b, ‘Hydrogen-borrowing’ methodology to convert alcohols into tertiary amines. R, alkyl group.





end of the linker can be attached to a drug molecule in organic sol-vents, whereas the other end requires attachment to a biomolecule (protein, antibody, etcetera) in aqueous media. The ‘click’ reaction between suitable cycloaddition partners (for example, azide/tetra-zine with acetylene/1,3-dipolarophile) has found extensive use as it is bioorthogonal and thus permits good tolerance to biomacro-molecules in aqueous (biological) media. It does however require the introduction of a suitable reactive centre that, in the case of pro-teins, requires introduction of non-native residues.

Selective chemical modification of proteins is currently mainly limited to a few amino acid side-chains owing to challenges of chemo- and regioselectivity and novel approaches to bioconjuga-tion are sought. Research in this area has led to the discovery of native chemical tagging of C–H bonds in heteroaromatic rings using an azide containing sulfinate reagent144 (Fig. 7b) to allow subse-quent click-mediated ligation. Similarly, organometallic palladium reagents can now be used for cysteine bioconjugation (Fig. 7c)145.

Further work is needed in this area and novel, chemoselective transformations of a single amino acid residue, among several reac-tive amino acids (carboxylic acid, amides, amines, alcohols and thiols), will significantly impact synthetic biology and drug dis-covery. More broadly, development of methods that can be carried out under conditions compatible with biomacromolecules will find increasing usage as the fields of small, synthetic molecules and pro-tein/RNA/oligosaccharides converge.

New technologiesMachine-assisted synthesis. One reason that the machine-assisted synthesis of biomacromolecules has been so successful is the high yielding, reproducible chemistries that are used (that is, formation

of amides, phosphodiester linkages and anomeric centres in carbo-hydrates). Drug molecules typically require a much broader range of synthetic transformations, all of which would need to be efficient and compatible with a single synthesis platform. Much progress has been made by academic groups allowing specific chemical transfor-mations to be automated or included in flow sequences — see the work of Ley146 & Jamison147 for example — but, given the number of discrete chemical reactions that may be required, it remains a significant challenge to devise automated synthesis without exten-sive and lengthy optimization. One approach to overcoming this problem is the work of Burke which focuses on the use of a highly versatile reaction, the Suzuki cross coupling148 to enable synthesis of a range of molecules with diverse architectures. More demonstra-tions of small sets of reactions towards automation would further validate this potentially exciting approach. In this example a unique solvent solubility profile of reagents and intermediates was used to develop simple purification protocols without a need for extensive chromatography. Achieving efficient and rapid purification remains a significant hurdle and collaboration between synthetic chemists and analytical chemists is required to address this issue.

To enable new syntheses to be more compatible with automa-tion, the methods should be designed and evaluated not only in round-bottomed flasks but also in the vials and flow cells, which will increasingly become commonplace within machine-assisted synthesis. Methods that are designed with this application in mind are likely to be applied in industry. To enable this, closer working between synthetic chemists and robotic scientists and engineers is highly encouraged. Similarly, for these kinds of advances to find wide application in the field, the engineering needs to be accessible through commercial organizations that can package new automated

b

a

N

NH

H

CN

O

MeON

NOMe

ClCl

N

NH

Linker

CN

O

MeON

NOMe

ClCl

2. mAb-acetylene derivative‘Click’ reaction

mAb

mAb Monoclonal antibody

1. NaO2SCF2(CH2)6N3

Drug-H (Bosutinib)

c

Ln Pd

Ar

X

Biomolecule

SH

Amino acid side chains

Biomolecule

S

Amino acid side chains

Ar

CoreStep 1

Reagents ACore

A

Step 2

Reagents B

Step 3Reagents C

Core

A

B

Core

A

B

C

Steps 1,2 and 3 ideally compatible with aqueous media

Short DNA fragments

Fig. 7 | syntheses compatible with biomacromolecules are increasingly important. a, Synthesis of DNA-encoded libraries requires a series of chemical transformations (here represented by the grafting of functionalities A, B and C) that are efficient in the presence of large oligonucleotides as well as compatible with enzymatic processes for ligating an additional piece of DNA at each step to encode the library. This process represents a particular challenge for traditional synthetic chemistry. b, Bioconjugation by chemical tagging a C–H bond in bosutinib. c, Organometallic reagents such as palladium complexes can promote cysteine bioconjugation. Ar, aromatic group; X, halide.





chemical methods into specific pieces of equipment or alternatively, through services provided by new companies.

Artificial intelligence for synthesis planning. Reaction prediction is a major challenge for organic synthesis. There is a resurgence of interest based in part on the availability of enormous, publically accessible databases containing chemical reactions and syntheses in a machine-readable format149. Current research is underway to devise algorithms that learn from published synthesis examples and hence aim to predict the outcome of new transformations. This would be facilitated by ways to incentivize publishing of negative data; that is, reactions that do not work. Molecular descriptors based on physicochemical properties may be able to characterize reagents whilst neural networks that utilize known reaction mechanisms may assist the prediction of reaction outcomes150. Recently a collection of over one-million chemical reactions has been gathered by applying text mining to published patent data151. This is being used to vali-date a computational fingerprint method to classify and then predict chemical reactions. In another recent study, a database of 3.5 million published reactions has been utilised to construct a machine-learn-ing model for retrosynthesis and reaction prediction152.

ConclusionIn this Perspective, we have set out to highlight a range of specific challenges, which, if successfully addressed, would allow new chem-ical methods to better facilitate the synthesis of drug molecules. In many cases, encouraging progress towards these goals has been accomplished and we are pleased to highlight a number of excit-ing recent advances. Key themes and challenges are summarized in Box 1. If academic and industry chemists can together tackle these scientific challenges, it will have a tremendous impact on the pace of drug-discovery research in both the academic and industrial sec-tors. The ultimate positive impact of future advances in synthetic methodology will be on human health, the improvement of which is likely to rely heavily on chemistry in all its various guises.

Received: 5 April 2017; Accepted: 25 December 2017; Published online: 22 March 2018

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AcknowledgementsWe thank D. Dixon (University of Oxford) and S. Marsden (University of Leeds) for commenting on the manuscript. We also thank T. McGuire and F. Goldberg (AstraZeneca), C. Johnson (Astex) and N. Fadeyi (Pfizer) for help in preparing the manuscript, and A. Davey for assistance with the graphical abstract.

Author contributionsThe authors contributed jointly to the writing of this paper.

Additional informationReprints and permissions information is available at www.nature.com/reprints.

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