RESUMEN
Site-selective C(sp3)-H oxidation is of great importance in organic synthesis and drug discovery. γ-C(sp3)-H lactonization of free carboxylic acids provides the most straightforward means to prepare biologically important lactone scaffolds from abundant and inexpensive carboxylic acids; however, a versatile catalyst for this transformation with a broad substrate scope remains elusive. Herein, we report a simple yet broadly applicable and scalable γ-lactonization reaction of free aliphatic acids enabled by a copper catalyst in combination with inexpensive Selectfluor as the oxidant. This lactonization reaction exhibits compatibility with tertiary, benzylic, allylic, methylene, and primary γ-C-H bonds, affording access to a wide range of structurally diverse lactones such as spiro, fused, and bridged lactones. Notably, exclusive γ-methylene C-H lactonization of cycloalkane carboxylic acids and cycloalkane acetic acids was observed, giving either fused or bridged γ-lactones that are difficult to access by other methods. δ-C-H lactonization was only favored in the presence of tertiary δ-C-H bonds. The synthetic utility of this methodology was demonstrated by the late-stage functionalization of amino acids, drug molecules, and natural products, as well as a two-step total synthesis of (iso)mintlactones (the shortest synthesis reported to date).
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Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here we report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N-X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up).
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In 2001, our curiosity to understand the stereochemistry of C-H metalation with Pd prompted our first studies in Pd(II)-catalyzed asymmetric C-H activation (RSC Research appointment: 020 7451 2545, Grant: RG 36873, Dec. 2002). We identified four central challenges: 1.â poor reactivity of simple Pd salts with native substrates; 2.â few strategies to control site selectivity for remote C-H bonds; 3.â the lack of chiral catalysts to achieve enantioselectivity via asymmetric C-H metalation, and 4.â low practicality due to limited coupling partner scope and the use of specialized oxidants. These challenges necessitated new strategies in catalyst and reaction development. For reactivity, we developed approaches to enhance substrate-catalyst affinity together with novel bifunctional ligands which participate in and accelerate the C-H cleavage step. For site-selectivity, we introduced the concept of systematically modulating the distance and geometry between a directing template, catalyst, and substrate to selectively access remote C-H bonds. For enantioselectivity, we devised predictable stereomodels for catalyst-controlled enantioselective C-H activation based on the participation of bifunctional ligands. Finally, for practicality, we have developed varied catalytic manifolds for Pd(II) to accommodate diverse coupling partners while employing practical oxidants such as simple peroxides. These advances have culminated in numerous C-H activation reactions, setting the stage for broad industrial applications.
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Elevated levels of receptor tyrosine kinase-like orphan receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic peptides as binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.
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Péptidos Cíclicos , Receptores Huérfanos Similares al Receptor Tirosina Quinasa , Adulto , Humanos , Línea Celular Tumoral , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/efectos de los fármacos , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacologíaRESUMEN
Remote C-H functionalization of heterocyclic biaryls will be of great importance in synthesis and medicinal chemistry. Through adjusting the geometric relationship of the directing atom and target C-H bonds, two new catalytic templates have been developed to enable the functionalization of the more hindered ortho-C-H bonds of heterobiaryls bearing directing heteroatom at the meta- or para-positions, affording unprecedented site-selectivity. The use of template chaperone also overcomes product inhibition and renders the directing templates catalytic. The utility of this protocol was demonstrated by olefination of heterocyclic biaryls with various substituents, overriding conventional steric and electronic effects. These ortho-C-H olefinated heterobiaryls are sterically hindered and can often be challenging to prepare through aryl-aryl coupling reactions.
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1,3-Dienes are common scaffolds in biologically active natural products as well as building blocks for chemical synthesis. Developing efficient methods for the synthesis of diverse 1,3-dienes from simple starting materials is therefore highly desirable. Herein, we report a Pd(II)-catalyzed sequential dehydrogenation reaction of free aliphatic acids via ß-methylene C-H activation, which enables one-step synthesis of diverse E,E-1,3-dienes. Free aliphatic acids of varying complexities, including the antiasthmatic drug seratrodast, were found to be compatible with the reported protocol. Considering the high lability of 1,3-dienes and lack of protecting strategies, dehydrogenation of aliphatic acids to reveal 1,3-dienes at the late stage of synthesis offers an appealing strategy for the synthesis of complex molecules containing such motifs.
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With the large number of Pd(II)-catalyzed C-H activation reactions of native substrates developed in the past decade, the development of catalysts to enable the use of green oxidants under safe and practical conditions has become an increasingly important challenge. Notably, the compatibility of Pd(II) catalysts with sustainable aqueous H2O2 has been a long-standing challenge in catalysis including Wacker-type oxidations. We report herein a bifunctional bidentate carboxyl-pyridone (CarboxPyridone) ligand that enables room-temperature Pd-catalyzed C-H hydroxylation of a broad range of benzoic and phenylacetic acids with an industry-compatible oxidant, aqueous hydrogen peroxide (35% H2O2). The scalability of this methodology is demonstrated by a 1000 mmol scale reaction of ibuprofen (206 g) using only a 1 mol % Pd catalyst loading. The utility of this protocol is further illustrated through derivatization of the products and synthesis of polyfluorinated natural product coumestan and pterocarpene from phenol intermediates prepared using this methodology.
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Productos Biológicos , Peróxido de Hidrógeno , Catálisis , Hidroxilación , Ibuprofeno , Ligandos , Oxidantes , Paladio , Fenoles , Fenilacetatos , Piridonas , Temperatura , AguaRESUMEN
The development of C(sp3 )-H functionalization reactions that use common protecting groups and practical oxidants remains a significant challenge. Herein we report a monoprotected aminoethyl thioether (MPAThio) ligand-enabled ß-C(sp3 )-H lactamization of tosyl-protected aliphatic amides using tert-butyl hydrogen peroxide (TBHP) as the sole oxidant. This protocol features exceedingly mild reaction conditions, reliable scalability, and the use of practical oxidants and protecting groups. Further derivatization of the ß-lactam products enables the synthesis of a range of biologically important motifs including ß-amino acids, γ-amino alcohols, and azetidines.
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Amidas , Paladio , Amidas/química , Catálisis , Ligandos , Oxidantes , Paladio/químicaRESUMEN
Ligand-enabled Pd-catalyzed regioselective α,ß-dehydrogenation of carbonyl compounds via ß-methylene C-H activation has recently emerged as a promising transformation. Herein, we report the realization of ß,γ-dehydrogenation and subsequent vinyl C-H olefination reactions of free carboxylic acids, thus providing a unique method for the structural diversification of aliphatic acids containing α-quaternary centers through sequential functionalizations of two ß-C-H bonds and one γ-C-H bond. This tandem dehydrogenation-olefination-lactonization reaction offers a one-step preparation of ß-alkylidene-γ-lactones, which are often difficult to prepare through conventional methods, from inexpensive and abundant free aliphatic acids. A variety of free aliphatic acids, such as isosteviol and grandiflorolic acid natural products, and olefins are compatible with the reported protocol. The newly designed bidentate oxime ether-pyridone and morpholine-pyridone ligands are crucial for this tandem reaction to proceed. Notably, these ligands also enable preferential methylene C-H activation over the previously reported, competing process of methyl C-H bond olefination.
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Ácidos Grasos , Lactonas , Catálisis , Lactonas/química , Ligandos , PiridonasRESUMEN
Cross-coupling between two similar or identical functional groups to form a new C-C bond is a powerful tool to rapidly assemble complex molecules from readily available building units, as seen with olefin cross-metathesis or various types of cross-electrophile coupling1,2. The Kolbe electrolysis involves the oxidative electrochemical decarboxylation of alkyl carboxylic acids to their corresponding radical species followed by recombination to generate a new C-C bond3-12. As one of the oldest known Csp3-Csp3 bond-forming reactions, it holds incredible promise for organic synthesis, yet its use has been almost non-existent. From the perspective of synthesis design, this transformation could allow one to agnostically execute syntheses without regard to polarity or neighbouring functionality just by coupling ubiquitous carboxylates13. In practice, this promise is undermined by the strongly oxidative electrolytic protocol used traditionally since the nineteenth century5, thereby severely limiting its scope. Here, we show how a mildly reductive Ni-electrocatalytic system can couple two different carboxylates by means of in situ generated redox-active esters, termed doubly decarboxylative cross-coupling. This operationally simple method can be used to heterocouple primary, secondary and even certain tertiary redox-active esters, thereby opening up a powerful new approach for synthesis. The reaction, which cannot be mimicked using stoichiometric metal reductants or photochemical conditions, tolerates a range of functional groups, is scalable and is used for the synthesis of 32 known compounds, reducing overall step counts by 73%.
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Ácidos Carboxílicos , Técnicas de Química Sintética , Níquel , Ácidos Carboxílicos/química , Catálisis , Descarboxilación , Electroquímica , Ésteres/química , Estructura Molecular , Níquel/química , Oxidación-ReducciónRESUMEN
γ-Lactams form important structural cores of a range of medicinally relevant natural products and clinical drugs, principal examples being the new generation of immunomodulatory imide drugs (IMiDs) and the brivaracetam family. Compared to conventional multistep synthesis, an intramolecular γ-C-H amination of aliphatic amides would allow for the direct construction of valuable γ-lactam motifs from abundant amino acid precursors. Herein we report a novel 2-pyridone ligand enabled Pd(II)-catalyzed γ-C(sp3)-H lactamization of amino acid derived native amides, providing the convenient synthesis of γ-lactams, isoindolinones, and 2-imidazolidinones. C6-Substitution of the 2-pyridone ligand is crucial for the lactam formation. This protocol features the use of N-acyl amino acids, which serve as both the directing group and cyclization partner, practical and environmentally benign tert-butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and a broad substrate scope. The utility of this protocol was demonstrated through the two-step syntheses of a lenalidomide analog and brivaracetam from readily available carboxylic acids and amino acids.
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Amidas/química , Lactamas/química , Paladio/química , Catálisis , Estructura MolecularRESUMEN
Hydroxylation of aryl carbon-hydrogen bonds with transition metal catalysts has proven challenging when oxygen is used as the oxidant. Here, we report a palladium complex bearing a bidentate pyridine/pyridone ligand that efficiently catalyzes this reaction at ring positions adjacent to carboxylic acids. Infrared, x-ray, and computational analysis support a possible role of ligand tautomerization from mono-anionic (L,X) to neutral (L,L) coordination in the catalytic cycle of aerobic carbon-hydrogen hydroxylation reaction. The conventional site selectivity dictated by heterocycles is overturned by this catalyst, thus allowing late-stage modification of compounds of pharmaceutical interest at previously inaccessible sites.
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Ácidos Carboxílicos/química , Hidrógeno/química , Oxígeno/química , Paladio/química , Ácidos Heterocíclicos/química , Carbono/química , Catálisis , Enlace de Hidrógeno , Hidroxilación , Ligandos , Modelos Moleculares , Estructura Molecular , Piridinas/química , Piridonas/químicaRESUMEN
Dehydrogenative transformations of alkyl chains to alkenes through methylene carbon-hydrogen (CH) activation remain a substantial challenge. We report two classes of pyridine-pyridone ligands that enable divergent dehydrogenation reactions through palladium-catalyzed ß-methylene CH activation of carboxylic acids, leading to the direct syntheses of α,ß-unsaturated carboxylic acids or γ-alkylidene butenolides. The directed nature of this pair of reactions allows chemoselective dehydrogenation of carboxylic acids in the presence of other enolizable functionalities such as ketones, providing chemoselectivity that is not possible by means of existing carbonyl desaturation protocols. Product inhibition is overcome through ligand-promoted preferential activation of C(sp3)H bonds rather than C(sp2)H bonds or a sequence of dehydrogenation and vinyl CH alkynylation. The dehydrogenation reaction is compatible with molecular oxygen as the terminal oxidant.
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Carbono/química , Ácidos Carboxílicos/química , Técnicas de Química Sintética , Hidrógeno/química , 4-Butirolactona/análogos & derivados , 4-Butirolactona/síntesis química , 4-Butirolactona/química , Ácidos Carboxílicos/síntesis química , Catálisis , Fenómenos Químicos , Enlace de Hidrógeno , Ligandos , Estructura Molecular , Oxidación-Reducción , Oxígeno/química , Paladio/química , Piridinas/química , Piridonas/químicaRESUMEN
ABSTACT: The growing prevalence of synthetically modified proteins in pharmaceuticals and materials has exposed the need for efficient strategies to enable chemical modifications with high site-selectivity. While genetic engineering can incorporate non-natural amino acids into recombinant proteins, regioselective chemical modification of wild-type proteins remains a challenge. Herein, we use photoredox catalysis to develop a site-selective tyrosine bioconjugation pathway that incorporates bioorthogonal formyl groups, which subsequently allows for the synthesis of structurally defined fluorescent conjugates from native proteins. A water-soluble photocatalyst, lumiflavin, has been shown to induce oxidative coupling between a previously unreported phenoxazine dialdehyde tag and a single tyrosine site, even in the presence of multiple tyrosyl side chains, through the formation of a covalent C-N bond. A variety of native proteins, including those with multiple tyrosines, can successfully undergo both tyrosine-specific and single-site-selective labelling. This technology directly introduces aldehyde moieties onto native proteins, enabling rapid product diversification using an array of well-established bioorthogonal functionalization protocols including the alkyne-azide click reaction.
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Aldehídos/química , Sondas Moleculares/química , Oxazinas/química , Proteínas/química , Tirosina/química , Aminación , Catálisis/efectos de la radiación , Flavinas/química , Flavinas/efectos de la radiación , Luz , Modelos Químicos , Oxidación-ReducciónRESUMEN
Bioconjugation technologies have revolutionized the practice of biology and medicine by allowing access to novel biomolecular scaffolds. New methods for residue-selective bioconjugation are highly sought to expand the toolbox for a variety of bioconjugation applications. Herein we report a site-selective methionine bioconjugation protocol that uses photoexcited lumiflavin to generate open-shell intermediates. This reduction-potential-gated strategy enables access to residues unavailable with traditional nucleophilicity-based conjugation methods. To demonstrate the versatility and robustness of this new protocol, we have modified various proteins and further utilized this functional handle to append diverse biological payloads.
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Metionina/química , Procesos Fotoquímicos , Sitios de Unión , Catálisis , Oxidación-Reducción , Proteínas/química , Especificidad por SustratoRESUMEN
This Communication reports the first general method for rapid, chemoselective, and modular functionalization of serine residues in native polypeptides, which uses a reagent platform based on the P(V) oxidation state. This redox-economical approach can be used to append nearly any kind of cargo onto serine, generating a stable, benign, and hydrophilic phosphorothioate linkage. The method tolerates all other known nucleophilic functional groups of naturally occurring proteinogenic amino acids. A variety of applications can be envisaged by this expansion of the toolbox of site-selective bioconjugation methods.
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Péptidos/química , Serina/química , Secuencia de Aminoácidos , Aminoácidos/química , Sitios de Unión , Modelos Moleculares , Oxidación-Reducción , Oligonucleótidos Fosforotioatos/química , Fosforilación , Conformación Proteica , Ubiquitina/químicaRESUMEN
The first example of free amine γ-C(sp3)-H fluorination is realized using 2-hydroxynicotinaldehyde as the transient directing group. A wide range of cyclohexyl and linear aliphatic amines could be fluorinated selectively at the γ-methyl and methylene positions. Electron withdrawing 3,5-disubstituted pyridone ligands were identified to facilitate this reaction. Computational studies suggest that the turnover determining step is likely the oxidative addition step for methylene fluorination, while it is likely the C-H activation step for methyl fluorination. The explicit participation of Ag results in a lower energetic span for methylene fluorination and a higher energetic span for methyl fluorination, which is consistent with the experimental observation that the addition of silver salt is desirable for methylene but not for methyl fluorination. Kinetic studies on methyl fluorination suggest that the substrate and PdL are involved in the rate-determining step, indicating that the C-H activation step may be partially rate-determining. Importantly, an energetically preferred pathway has identified an interesting pyridone-assisted bimetallic transition state for the oxidative addition step in methylene fluorination, thus uncovering a potential new role of the pyridone ligand.
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Aminas/química , Hidrocarburos Fluorados/síntesis química , Paladio/química , Catálisis , Halogenación , Hidrocarburos Fluorados/química , Estructura MolecularRESUMEN
Pd(II)-catalyzed C-H lactonization of o-methyl benzoic acid substrates has been achieved using molecular oxygen as the oxidant. This finding provides a rare example of C-H oxygenation through Pd(II)/Pd(0) catalysis as well as a method to construct biologically important benzolactone scaffolds. The use of a gas mixture of 5% oxygen in nitrogen demonstrated the possibility for its application in pharmaceutical manufacturing.
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Fluorine is known to promote ortho-C-H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho-palladation intermediate and is then relayed to the meta position, leading to meta-selective C-H arylation of fluoroarenes. Deuterium experiment suggests that this meta-arylation is initiated by ortho C-H activation and the catalytic cycle is terminated by C-2 protonation. A dual-ligand system is crucial for the observed high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity.
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Carbono/química , Fluorenos/química , Hidrocarburos Aromáticos/química , Hidrógeno/química , Ligandos , Estructura MolecularRESUMEN
Saturated azacycles are commonly encountered in bioactive compounds and approved therapeutic agents. The development of methods for functionalization of the α-methylene C-H bonds of these highly privileged building blocks is of great importance, especially in drug discovery. While much effort has been dedicated toward this goal by using a directed C-H activation approach, the development of directing groups that are both general as well as practical remains a significant challenge. Herein, the design and development of novel amidoxime directing groups is described for Ir(I)-catalyzed α-C(sp3)-H alkylation of saturated azacycles using readily available olefins as coupling partners. This protocol extends the scope of saturated azacycles to piperidines, azepane, and tetrahydroisoquinoline that are incompatible with our previously reported directing group. A variety of olefin coupling partners, including previously unreactive disubstituted terminal olefins and internal olefins, are compatible with this transformation. The selectivity for a branched α-C(sp3)-alkylation product is also observed for the first time when acrylate is used as the reaction partner. The development of practical, one-step installation and removal protocols further adds to the utility of amidoxime directing groups.