Late-Stage Functionalization

Challenges and opportunities:•Our definition of late-stage functionalization (LSF) resolves previous ambiguity associated with the term and should help chemists to classify reactions as LSF or not.•For LSF reactions, chemoselectivity is a requirement, whereas site selectivity is an optional yet often desired feature.•Many LSF reactions feature small-molecule catalysts or reagents. Complementary approaches are deemed necessary to address unmet selectivity challenges for the development of new LSF reactions. The term late-stage functionalization (LSF) is recent but is now frequently used in the field of organic methodology development to describe transformations on complex molecules. Such reactions include catalytic and non-catalytic reactions, C–H functionalizations, and functional-group manipulations with one or several desired products. However, explicit guidance to classify whether a reaction is a LSF or not, and why or why not, is not available. Herein, we advance a definition for LSF and highlight the requirements, features, and challenges of LSF reactions accompanied by representative examples. We aspire that our analysis will be helpful as a guiding principle in the field. The term late-stage functionalization (LSF) is recent but is now frequently used in the field of organic methodology development to describe transformations on complex molecules. Such reactions include catalytic and non-catalytic reactions, C–H functionalizations, and functional-group manipulations with one or several desired products. However, explicit guidance to classify whether a reaction is a LSF or not, and why or why not, is not available. Herein, we advance a definition for LSF and highlight the requirements, features, and challenges of LSF reactions accompanied by representative examples. We aspire that our analysis will be helpful as a guiding principle in the field. We define late-stage functionalization (LSF) as follows: LSF is a desired chemoselective transformation on a complex molecule to provide at least one analog in sufficient quantity and purity for a given purpose without the necessity for installation of a functional group that exclusively serves the purpose to enable said transformation. As chemists, we have been unable to unambiguously define molecular complexity for over half a century,1von Korff M. Sander T. Molecular complexity calculated by fractal dimension.Sci. Rep. 2019; 9: 967Crossref PubMed Scopus (9) Google Scholar yet our intuitive understanding of the term is sufficient for a meaningful definition of LSF. Although the complexity of a molecule is an intrinsic property of the chemical structure itself, it often determines the synthetic effort to make it. LSF eases this synthetic effort and can access derivatives that would be substantially more cumbersome or time consuming to access from simple molecular building blocks. As such, LSF can quickly provide access to molecules of potential value, for example, in the area of drug development or materials chemistry, that otherwise might not have been available at all or too burdensome to make.2Wencel-Delord J. Glorius F. C–H bond activation enables the rapid construction and late-stage diversification of functional molecules.Nat. Chem. 2013; 5: 369-375Crossref PubMed Scopus (1599) Google Scholar,3Cernak T. Dykstra K.D. Tyagarajan S. Vachal P. Krska S.W. The medicinal chemist's toolbox for late stage functionalization of drug-like molecules.Chem. Soc. Rev. 2016; 45: 546-576Crossref PubMed Google Scholar Both C–H functionalization reactions and functional-group manipulations can be LSFs provided that they fulfill the requirements of the definition of LSF (Scheme 1A).4Sawada S. Okajima S. Aiyama R. Nokata K.-i. Furuta T. Yokokura T. Sugino E. Yamaguchi K. Miyasaka T. Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin.Chem. Pharm. Bull. 1991; 39: 1446-1450Crossref PubMed Scopus (259) Google Scholar,5Sladojevich F. Arlow S.I. Tang P. Ritter T. Late-stage deoxyfluorination of alcohols with PhenoFluor.J. Am. Chem. Soc. 2013; 135: 2470-2473Crossref PubMed Scopus (97) Google Scholar Chemoselectivity is a requirement for LSF reactions but not sufficient; not every chemoselective reaction is a LSF. A chemoselective reaction is defined as the preferential reaction of a reagent or catalyst with one out of at least two different functional groups in a molecule and as the preferential reaction of a reagent or catalyst with one out of at least two competing molecules.6Muller P. Glossary of terms used in physical organic chemistry (IUPAC recommendations 1994).Pure Appl. Chem. 1994; 66: 1077-1184Crossref Scopus (488) Google Scholar Complex molecules commonly feature several distinct functional groups that must stay intact throughout the LSF reaction. In that sense, a high level of chemoselectivity is what matters for LSF and is sometimes referred to as functional-group tolerance. The higher the level of chemoselectivity, the more useful the LSF because it allows for a predictable reaction outcome and provides synthetically useful yields with a given valuable substrate as the limiting reagent. For example, an electrophilic aromatic bromination reaction of a complex molecule that provides a mixture of constitutional isomers of aryl bromides as the major products would be classified as LSF because aromatic C–H bonds are chemoselectively functionalized over other C–H bonds and all other functional groups. In contrast, a fluorination reaction on a complex molecule with fluorine gas that displays little chemoselectivity for either C–H bonds or functional groups leads to an unpredictable reaction outcome with multiple different products, and thus it is not suitable for LSF. It follows from the above definitions that every chemoselective functionalization of C–H bonds in complex molecules classifies as LSF, except when a required directing or activating group must be installed beforehand. Identifying transformations on functional groups in complex molecules as LSF is more subtle, and it is important to recognize the difference between LSF and functional-group-tolerant reactions on complex molecules that are not themselves LSF reactions. For example, the bioorthogonal strain-promoted 1,3-dipolar cycloaddition to form triazoles is a functional-group-tolerant reaction of immense synthetic value that can proceed on extremely complex molecules, but itself is not a LSF if both azide and alkyne must be explicitly installed on a given molecule to subsequently react in a cycloaddition. Pre-installation of any group that engages directly or indirectly in a given transformation precludes this reaction from being a LSF. Installations of azide or alkyne functionalities can proceed by LSF, although most commonly they do not.7Jewett J.C. Bertozzi C.R. Cu-free click cycloaddition reactions in chemical biology.Chem. Soc. Rev. 2010; 39: 1272-1279Crossref PubMed Scopus (1105) Google Scholar,8Sletten E.M. Bertozzi C.R. Bioorthogonal chemistry: fishing for selectivity in a sea of functionality.Angew. Chem. Int. Ed. 2009; 48: 6974-6998Crossref PubMed Scopus (1951) Google Scholar In contrast, reactions that make use of a native functional group in a complex molecule do qualify as LSF.9deGruyter J.N. Malins L.R. Baran P.S. Residue-specific peptide modification: a chemist’s guide.Biochemistry. 2017; 56: 3863-3873Crossref PubMed Scopus (204) Google Scholar, 10Vinogradova E.V. Zhang C. Spokoyny A.M. Pentelute B.L. Buchwald S.L. Organometallic palladium reagents for cysteine bioconjugation.Nature. 2015; 526: 687-691Crossref PubMed Scopus (247) Google Scholar, 11Lee H.G. Lautrette G. Pentelute B.L. Buchwald S.L. Palladium-mediated arylation of lysine in unprotected peptides.Angew. Chem. Int. Ed. 2017; 56: 3177-3181Crossref PubMed Scopus (71) Google Scholar, 12Taylor M.T. Nelson J.E. Suero M.G. Gaunt M.J. A protein functionalization platform based on selective reactions at methionine residues.Nature. 2018; 562: 563-568Crossref PubMed Scopus (85) Google Scholar, 13Garreau M. LeVaillant F. Waser J. C-terminal bioconjugation of peptides through photoredox catalyzed decarboxylative alkynylation.Angew. Chem. Int. Ed. 2019; 58: 8182-8186Crossref PubMed Scopus (48) Google Scholar For example, the chemoselective reaction of the native methionine side chains in proteins with azide containing oxaziridines to form sulfimidates is an excellent example of a LSF.14Lin S. Yang X. Jia S. Weeks A.M. Hornsby M. Lee P.S. Nichiporuk R.V. Iavarone A.T. Wells J.A. Toste F.D. Chang C.J. Redox-based reagents for chemoselective methionine bioconjugation.Science. 2017; 355: 597-602Crossref PubMed Scopus (177) Google Scholar The subsequent 1,3-dipolar cycloaddition that makes use of the azide introduced in the previous step to provide a polyethylene glycol (PEG) bioconjugate is not. While also being chemoselective and functional-group tolerant, the reaction makes use of a previously installed functional group that is directly involved in the cycloaddition, which excludes its classification as LSF as per our definition (Scheme 1B). Even the most functional-group-tolerant transformations can require introduction of functional groups through numerous steps or de novo synthesis, in that case, they cannot be classified as LSF. High functional-group tolerance is a requirement for late-stage C–H bond functionalization reactions.15Bergman R.G. Organometallic chemistry: C–H activation.Nature. 2007; 446: 391-393Crossref PubMed Scopus (1053) Google Scholar,16Hartwig J.F. Catalyst-controlled site-selective bond activation.Acc. Chem. Res. 2017; 50: 549-555Crossref PubMed Scopus (101) Google Scholar Although the definition of LSF does not require distinction between different types of C–H bonds for a C–H functionalization reaction, in practice, it often is desirable because otherwise, the requirement for product isolation in sufficient quantity and purity might not be achievable. Chemoselective aliphatic late-stage C–H bond functionalization is often achieved by methods that proceed via C–H homolysis or C–H insertion steps,17White M.C. Zhao J. Aliphatic C–H oxidations for late-stage functionalization.J. Am. Chem. Soc. 2018; 140: 13988-14009Crossref PubMed Scopus (149) Google Scholar,18Davies H.M.L. Manning J.R. Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion.Nature. 2008; 451: 417-424Crossref PubMed Scopus (1667) Google Scholar and chemoselectivity for stronger C(sp2)-H bonds is most commonly observed in reactions involving their orthogonal π-system. Pre-coordination of the arene to π-acids can account for high chemoselectivity for aromatic functionalization in reactions that involve a C–H metalation step. The late-stage C–H borylation, originally reported by Hartwig, Miyaura, Ishiyama, Maleczka, and Smith, can proceed via η2-coordination of the arene substrate to the iridium or rhodium catalyst prior to turnover limiting C–H metalation, which is consistent with the faster rate for the reaction of electron-rich arenes than for electron-poor arenes (Scheme 2A).19Boller T.M. Murphy J.M. Hapke M. Ishiyama T. Miyaura N. Hartwig J.F. Mechanism of the mild functionalization of arenes by diboron reagents catalyzed by iridium complexes. Intermediacy and chemistry of bipyridine-ligated iridium trisboryl complexes.J. Am. Chem. Soc. 2005; 127: 14263-14278Crossref PubMed Scopus (354) Google Scholar,20Saito Y. Segawa Y. Itami K. para-C-H borylation of benzene derivatives by a bulky iridium catalyst.J. Am. Chem. Soc. 2015; 137: 5193-5198Crossref PubMed Scopus (129) Google Scholar When no arene is present in the substrate or the arene is sterically encumbered, the iridium-catalyzed borylation reaction can also occur on aliphatic C–H bonds, which further highlights the importance of arene pre-coordination for chemoselective functionalization of aromatic C–H bonds.21Liskey C.W. Hartwig J.F. Iridium-catalyzed borylation of secondary C–H bonds in cyclic ethers.J. Am. Chem. Soc. 2012; 134: 12422-12425Crossref PubMed Scopus (109) Google Scholar,22Oeschger R. Su B. Yu I. Ehinger C. Romero E. He S. Hartwig J. Diverse functionalization of strong alkyl C–H bonds by undirected borylation.Science. 2020; 368: 736-741Crossref PubMed Scopus (34) Google Scholar Metal-catalyzed C–H functionalizations do not need to proceed via the formation of a metal-carbon bond between the catalyst and the substrate. The palladium-catalyzed fluorination developed by our group features a highly electrophilic triply cationic Pd(IV)-fluoride complex that chemoselectively provides aryl fluoride products (Scheme 2B).23Yamamoto K. Li J. Garber J.A.O. Rolfes J.D. Boursalian G.B. Borghs J.C. Genicot C. Jacq J. van Gastel M. Neese F. Ritter T. Palladium-catalysed electrophilic aromatic C–H fluorination.Nature. 2018; 554: 511-514Crossref PubMed Scopus (72) Google Scholar In the transition state of C–F bond formation, electrons are transferred from the arene π-system to the palladium(IV) complex, which cannot occur from energetically lower-lying electrons in aliphatic C–H bonds.24Liu W. Huang X. Cheng M.J. Nielsen R.J. Goddard W.A. Groves J.T. Oxidative aliphatic C–H fluorination with fluoride ion catalyzed by a manganese porphyrin.Science. 2012; 337: 1322-1325Crossref PubMed Scopus (372) Google Scholar,25Bume D.D. Harry S.A. Lectka T. Pitts C.R. Catalyzed and promoted aliphatic fluorination.J. Org. Chem. 2018; 83: 8803-8814Crossref PubMed Scopus (31) Google Scholar Organic electrophiles can show high chemoselectivity for aromatic C–H functionalization via electrophilic aromatic substitution (SEAr). The use of bis(methanesulfonyl) peroxide in hexafluoroisopropanol (HFIP) displays high chemoselectivity for aromatic C–H oxygenation to provide aryl mesylates (Scheme 2C). An explanation for the chemoselectivity could be the formation of charge transfer complexes between the peroxide and the arene prior to C–O bond formation, which distinguishes bis(methanesulfonyl) peroxide from other peroxides. Peroxides typically display low chemoselectivity because of the facile generation of O-centered radicals that are typically prone to undergo hydrogen atom abstraction (HAA) in preference to adding to unsaturated carbon atoms.26Börgel J. Tanwar L. Berger F. Ritter T. Late-stage aromatic C–H oxygenation.J. Am. Chem. Soc. 2018; 140: 16026-16031Crossref PubMed Scopus (31) Google Scholar Identification of radicals that add faster to the π-system of arenes than they abstract hydrogen atoms from aliphatic C–H bonds has led to useful LSF reactions for nitrogen- and carbon-centered radicals. For example, positively charged, electrophilic nitrogen-centered radicals preferentially add to arenes (Scheme 2D).27Legnani L. Prina Cerai G. Morandi B. Direct and practical synthesis of primary anilines through iron-catalyzed C–H bond amination.ACS Catal. 2016; 6: 8162-8165Crossref Scopus (79) Google Scholar,28D'Amato E.M. Börgel J. Ritter T. Aromatic C–H amination in hexafluoroisopropanol.Chem. Sci. 2019; 10: 2424-2428Crossref PubMed Scopus (37) Google Scholar The chemoselectivity for the addition of carbon-centered radicals correlates with two properties: electrophilicity and molecular geometry.29Pryor W.A. Tang F.Y. Tang R.H. Church D.F. Chemistry of the tert-butyl radical: polar character, ρ value for reaction with toluenes, and the effect of radical polarity on the ratio of benzylic hydrogen abstraction to addition to aromatic rings.J. Am. Chem. Soc. 1982; 104: 2885-2891Crossref Scopus (63) Google Scholar,30Dolbier W.R. Fluorinated free radicals.in: Chambers R.D. Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates. Springer, 1997: 97-163Crossref Google Scholar The ratio between the rate constants for addition to arenes and for HAA of benzylic C–H bonds was found to be larger for electrophilic than nucleophilic radicals.29Pryor W.A. Tang F.Y. Tang R.H. Church D.F. Chemistry of the tert-butyl radical: polar character, ρ value for reaction with toluenes, and the effect of radical polarity on the ratio of benzylic hydrogen abstraction to addition to aromatic rings.J. Am. Chem. Soc. 1982; 104: 2885-2891Crossref Scopus (63) Google Scholar A higher degree of pyramidalization of the radical was found to decrease the rate for aliphatic HAA because of increasing steric hindrance between the radical and the substrate. Furthermore, the non-planarity of the radical can provide an energetic advantage for reaching the transition state structure for addition to unsaturated carbon atoms, for which the radical needs to adopt a bent structure.30Dolbier W.R. Fluorinated free radicals.in: Chambers R.D. Organofluorine Chemistry: Fluorinated Alkenes and Reactive Intermediates. Springer, 1997: 97-163Crossref Google Scholar Thus, the electrophilic and pyramidalized trifluoromethyl radical displays high chemoselectivity for aromatic C–H bond functionalization of hetero- and carboarenes, as shown for the LSF reactions developed by the Baran and MacMillan groups, respectively (Scheme 2E).31Fujiwara Y. Dixon J.A. O’Hara F. Funder E.D. Dixon D.D. Rodriguez R.A. Baxter R.D. Herlé B. Sach N. Collins M.R. et al.Practical and innate carbon–hydrogen functionalization of heterocycles.Nature. 2012; 492: 95-99Crossref PubMed Scopus (596) Google Scholar, 32Stout E.P. Choi M.Y. Castro J.E. Molinski T.F. Potent fluorinated agelastatin analogues for chronic lymphocytic leukemia: design, synthesis, and pharmacokinetic studies.J. Med. Chem. 2014; 57: 5085-5093Crossref PubMed Scopus (28) Google Scholar, 33Nagib D.A. MacMillan D.W.C. Trifluoromethylation of arenes and heteroarenes by means of photoredox catalysis.Nature. 2011; 480: 224-228Crossref PubMed Scopus (902) Google Scholar In contrast, the more nucleophilic and planar methyl radical only adds to protonated nitrogen-containing heterocycles with chemoselectivity sufficiently high for a useful LSF.34DiRocco D.A. Dykstra K. Krska S. Vachal P. Conway D.V. Tudge M. Late-stage functionalization of biologically active heterocycles through photoredox catalysis.Angew. Chem. Int. Ed. 2014; 53: 4802-4806Crossref PubMed Scopus (302) Google Scholar Chemoselectivity is important for one type of C–H bond not only within the same molecule but also between two different molecules. For some LSF reactions, over-functionalization can be a problem if the desired mono-functionalized compound reacts faster than the substrate molecule under the reaction conditions. For example, the oxidative synthesis of phenols from C–H bonds suffers commonly from over-oxidation because phenols are generally more electron rich than the substrate molecules. The electron-withdrawing effect of the mesyl group in the above described transformation renders the arene more electron poor and thus protects it from over-oxidation. However, an additional synthetic step is necessary to remove the mesyl group to obtain phenols. Generally, it is desirable to access phenols in one step, which has been achieved with enzyme catalysts for LSF.35Ren X. Yorke J.A. Taylor E. Zhang T. Zhou W. Wong L.L. Drug oxidation by cytochrome P450BM3: metabolite synthesis and discovering new P450 reaction types.Chemistry. 2015; 21: 15039-15047Crossref PubMed Scopus (47) Google Scholar,36Genovino J. Sames D. Hamann L.G. Touré B.B. Accessing drug metabolites via transition-metal catalyzed C−H oxidation: the liver as synthetic inspiration.Angew. Chem. Int. Ed. 2016; 55: 14218-14238Crossref PubMed Scopus (54) Google Scholar The level of site selectivity, which is synonymous with positional selectivity and regioselectivity, is irrelevant for the classification of a reaction as LSF. LSF reactions can be either site selective or not, and both scenarios can be desired and useful. For example, structural optimization of lead compounds in drug discovery can benefit from quick access to various constitutional isomers, so site-unselective introduction of a substituent to access multiple constitutional isomers can be the quickest possible way to access analogs for biological testing, even if purification is difficult.3Cernak T. Dykstra K.D. Tyagarajan S. Vachal P. Krska S.W. The medicinal chemist's toolbox for late stage functionalization of drug-like molecules.Chem. Soc. Rev. 2016; 45: 546-576Crossref PubMed Google Scholar,37Moir M. Danon J.J. Reekie T.A. Kassiou M. An overview of late-stage functionalization in today’s drug discovery.Expert Opin. Drug Discov. 2019; 14: 1137-1149Crossref PubMed Scopus (44) Google Scholar It is generally acknowledged that highly site-selective C–H functionalization reactions are inherently valuable, and one set of site-selective C–H functionalization reactions to access each constitutional isomer independently is desirable. The chemists’ reaction repertoire to meet such a lofty goal is currently not sufficient, but some reactions provide single constitutional isomers based on innate substrate selectivity for a given type of reaction. If the observed constitutional isomer is the desired product, the selective transformation is of value because other isomers do not need to be separated as waste. Such highly site-selective reactions are also desired if the site of reaction is irrelevant as long as functionalization of a single site is observed. For example, bioconjugation or radiolabeling of complex substrates by LSF can provide a single molecular entity, which allows for facile purification to access well-defined material on a molecular level, whereas the site of functionalization plays less of a role. In the simplest cases, when only one site in a molecule reacts innately much faster than others in a specific reaction, site selectivity can be predictably achieved by LSF. Sites of innate selectivity for a given substrate depend on the respective reaction mechanism, and thus different sites of a molecule can be functionalized selectively by the choice of a suitable reaction, if available. Innate selectivity can correlate with the bond dissociation energy of C–H bonds for reactions that involve a C–H homolysis step. For example, benzylic C–H bonds are weaker than many other classes of C–H bonds, and thus site-selective functionalization in benzylic positions is often possible. In the benzylic radiofluorination reported by Groves et al., a benzylic radical is generated via HAA by a Mn(V)-oxo complex followed by fluorine transfer from a Mn(IV)-[18F]fluoride complex (Scheme 3A).38Huang X. Liu W. Ren H. Neelamegam R. Hooker J.M. Groves J.T. Late stage benzylic C–H fluorination with [18F]fluoride for PET imaging.J. Am. Chem. Soc. 2014; 136: 6842-6845Crossref PubMed Scopus (149) Google Scholar In other cases, the acidity differences of C–H bonds can be utilized as differentiating factor, which also includes acidification of certain C–H bonds through coordination of an available directing group to a metal in a reagent or catalyst.39Friis S.D. Johansson M.J. Ackermann L. Cobalt-catalysed C–H methylation for late-stage drug diversification.Nat. Chem. 2020; 12: 511-519Crossref PubMed Scopus (46) Google Scholar The palladium-catalyzed β-lactam formation from secondary amines present in complex molecules via C–H functionalization under CO atmosphere is enabled by amine coordination to palladium(II) prior to C–H metalation via concerted-metalation deprotonation (CMD) (Scheme 3B).40Willcox D. Chappell B.G.N. Hogg K.F. Calleja J. Smalley A.P. Gaunt M.J. A general catalytic β-C–H carbonylation of aliphatic amines to β-lactams.Science. 2016; 354: 851-857Crossref PubMed Scopus (137) Google Scholar Electronic activation of specific C–H bonds can also lead to site selectivity. For example, the conjugation of complex molecules with peptides by the use of electrophilic selenium reagents reported by Pentelute and Buchwald is site selective for the most nucleophilic aromatic position, which is located between two strongly resonance-donating hydroxy groups (Scheme 3C).41Cohen D.T. Zhang C. Fadzen C.M. Mijalis A.J. Hie L. Johnson K.D. Shriver Z. Plante O. Miller S.J. Buchwald S.L. Pentelute B.L. A chemoselective strategy for late-stage functionalization of complex small molecules with polypeptides and proteins.Nat. Chem. 2019; 11: 78-85Crossref PubMed Scopus (38) Google Scholar Innate selectivity of aromatic heterocycles for oxidative nucleophilic aromatic substitution can provide access to a single constitutional isomer, such as in the Chichibabin-type fluorination reported by the Hartwig group, in which AgF2 is employed as the oxidant to provide complex 2-fluoropyridine derivatives selectively (Scheme 3D).42Fier P.S. Hartwig J.F. Selective C–H fluorination of pyridines and diazines inspired by a classic amination reaction.Science. 2013; 342: 956-960Crossref PubMed Scopus (161) Google Scholar,43Fier P.S. Hartwig J.F. Synthesis and late-stage functionalization of complex molecules through C–H fluorination and nucleophilic aromatic substitution.J. Am. Chem. Soc. 2014; 136: 10139-10147Crossref PubMed Scopus (89) Google Scholar Functionalization can also occur in the sterically most accessible position of a given substrate. The rhodium- and iridium-catalyzed borylation and silylation reactions display site selectivity that is controlled by steric factors (Scheme 3E).19Boller T.M. Murphy J.M. Hapke M. Ishiyama T. Miyaura N. Hartwig J.F. Mechanism of the mild functionalization of arenes by diboron reagents catalyzed by iridium complexes. Intermediacy and chemistry of bipyridine-ligated iridium trisboryl complexes.J. Am. Chem. Soc. 2005; 127: 14263-14278Crossref PubMed Scopus (354) Google Scholar,44Larsen M.A. Hartwig J.F. Iridium-catalyzed C–H borylation of heteroarenes: scope, regioselectivity, application to late-stage functionalization, and mechanism.J. Am. Chem. Soc. 2014; 136: 4287-4299Crossref PubMed Scopus (218) Google Scholar,45Cheng C. Hartwig J.F. Iridium-catalyzed silylation of aryl C–H bonds.J. Am. Chem. 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Site-selective and versatile aromatic C−H functionalization by thianthrenation.Nature. 2019; 567: 223-228Crossref PubMed Scopus (106) Google Scholar The thianthrenyl group serves as versatile linchpin for follow-up cross-coupling and photoredox coupling reactions, such as C–O and C–F bond formations (Scheme 4A).47Sang R. Korkis S.E. Su W. Ye F. Engl P.S. Berger F. Ritter T. Site-selective C−H oxygenation via aryl sulfonium salts.Angew. Chem. Int. Ed. 2019; 131: 16307-16312Crossref Google Scholar,48Li J. Chen J. Sang R. Ham W.S. Plutschack M.B. Berger F. Chabbra S. Schnegg A. Genicot C. Ritter T. Photoredox catalysis with aryl sulfonium salts enables site-selective late-stage fluorination.Nat. Chem. 2020; 12: 56-62Crossref PubMed Scopus (47) Google Scholar A related example for a linchpin strategy for pyridine derivatives is the addition of triphenyl phosphine to the 4-position of in-situ-generated N-triflyl pyridinium salts reported by McNally.49Koniarczyk J.L. Hesk D. Overgard A. 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Ed. 2016; 55: 13244-13248Crossref PubMed Scopus (26) Google Scholar However, general methods that allow for the control of the reaction site are still scarce. Reagent and catalyst control to achieve site selectivity that is not dependent on substrate bias is highly desirable and constitutes an important future objective in the field. The Fe(PDP) catalyst, developed by the White group, oxygenates tertiary C–H bonds site selectively, which is predicted on the basis of innate substrate selectivity.17White M.C. Zhao J. Aliphatic C–H oxidations for late-stage functionalization.J. Am. Chem. Soc. 2018; 140: 13988-14009Crossref PubMed Scopus (149) Google Scholar,52Chen M.S. White M.C. 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Chem. 2018; 83: 3023-3033Crossref PubMed Scopus (11) Google Scholar Such a switch in site selectivity provides products that are otherwise only accessible by cumbersome procedures. However, small-molecule catalysts have only limited parameters that can be modified to achieve catalyst-controlled site selectivity, and even if achieved, the chemoselectivity requirement might not be fulfilled anymore. For example, if a secondary alcohol is the desired product, the site of functionalization can be changed from tertiary to secondary C–H bonds but chemoselectivity for the alcohol product is not observed. Furthermore, the chemo- and site selectivity for oxygenation of the less electron-rich primary C–H bonds to alcohols over more electron-rich secondary and tertiary C–H bonds present is an unsolved problem in small-molecule catalysis for LSF. Compared with small-molecule catalysts, enzymes such as cytochrome P450 enzymes (CYPs) can achieve distinct chemo- and site selectivity through specific binding of the substrate in the enzymes’ active site. For example, the oxidation of artemisinin by a naturally occurring CYP provides one diastereomer of the secondary alcohol as the major product along with minor amounts of the other epimer and oxidation at a primary position (Scheme 5B).56Zhang K. Shafer B.M. Demars M.D. Stern H.A. Fasan R. Controlled oxidation of remote sp3 C–H bonds in artemisinin via P450 catalysts with fine-tuned regio- and stereoselectivity.J. Am. Chem. Soc. 2012; 134: 18695-18704Crossref PubMed Scopus (117) Google Scholar On the basis of this reactivity, a CYP mutant of the parent enzyme was engineered by directed evolution that shows over 90% selectivity for oxidation of the primary alcohol. This example highlights the potential for enzymatic reactions for LSF to provide chemo- and site selectivity complementary to small-molecule catalysts.57Wang J.B. Li G. Reetz M.T. Enzymatic site-selectivity enabled by structure-guided directed evolution.Chem. Commun. 2017; 53: 3916-3928Crossref PubMed Google Scholar,58Arnold F.H. Directed evolution: bringing new chemistry to life.Angew. Chem. Int. Ed. 2018; 57: 4143-4148Crossref PubMed Scopus (348) Google Scholar Conformational control to induce selectivity can also be used in non-enzymatic systems: the use of supramolecular catalysts that engage in host-guest interactions, for example, is an approach in which the ligand environment of the host can provide high selectivity, distinct from what would be observed by small-molecule catalysts.59Hong C.M. Bergman R.G. Raymond K.N. Toste F.D. Self-assembled tetrahedral hosts as supramolecular catalysts.Acc. Chem. Res. 2018; 51: 2447-2455Crossref PubMed Scopus (137) Google Scholar The Bergman, Raymond, and Toste groups reported a self-assembled tetrahedral cage with gallium(III)-triscatecholate vertices that can be mixed with a rhodium-diphosphine complex to form a supramolecular catalyst for hydrogenation reactions (Scheme 5C).60Bender T.A. Bergman R.G. Raymond K.N. Toste F.D. A supramolecular strategy for selective catalytic hydrogenation independent of remote chain length.J. Am. Chem. Soc. 2019; 141: 11806-11810Crossref PubMed Scopus (31) Google Scholar The reaction of trans,trans-2,4-hexadiene-1-ol with dihydrogen catalyzed by a supramolecular catalyst leads to selective formation of the corresponding (Z)-homoallylic alcohol via 1,4-addition. A cis orientation is adopted by the substrate throughout the reaction to minimize steric clash with the walls inside the host, which leads to the obtained Z configuration of the product. Although this example is not a LSF reaction, it shows the potential for supramolecular chemistry to be used to induce selectivity for specific transformations that would otherwise be difficult to achieve and could provide a conceptual advance for the development of new LSF reactions. Here, we have provided a definition for LSF. We analyze representative examples of LSF reactions, highlight the chemoselectivity requirement, and explain strategies for achieving site selectivity, if desired. Our analysis shows that chemo- and site-selectivity challenges require a wide variety of complementary transformations to address current synthesis challenges. We anticipate that our analysis will be valuable for the development and classification of new LSF reactions that enable fast and reliable access of analogs of complex molecules in all areas of synthetic chemistry. We thank the Max-Planck-Institut für Kohlenforschung for funding.