Collaboration as a Key to Advance Capabilities for Earth-Abundant Metal Catalysis

Organic Process Research & Development, Год журнала: 2023, Номер 27(7), С. 1160 - 1184

Опубликована: Март 20, 2023

Earth-abundant metal (EAM) catalysis can have profound impact in the pharmaceutical industry terms of sustainability and cost improvements from replacing precious metals like palladium as well harnessing differential reactivity first-row that allows for novel transformations to enable more efficient routes clinical candidates. The strategy building these capabilities within process group at Bristol Myers Squibb is described herein, with general plan a reaction screening platform, demonstrating scalability, increasing mechanistic understanding catalyst activation. development catalytic utilizing nickel, cobalt, iron while highlighting importance collaboration internal external groups advance EAM our portfolio. challenges benefits working transition metals, including metrics implementation catalysis, such cost, mass intensity, commercial availability catalysts ligands, are discussed.

Язык: Английский

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Ligand-Enabled C–H Hydroxylation with Aqueous H₂O₂at Room Temperature

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(39), С. 18109 - 18116

Опубликована: Сен. 22, 2022

With the large number of Pd(II)-catalyzed C–H activation reactions native substrates developed in past decade, development catalysts to enable use green oxidants under safe and practical conditions has become an increasingly important challenge. Notably, compatibility Pd(II) with sustainable aqueous H2O2 been a long-standing challenge catalysis including Wacker-type oxidations. We report herein bifunctional bidentate carboxyl-pyridone (CarboxPyridone) ligand that enables room-temperature Pd-catalyzed hydroxylation broad range benzoic phenylacetic acids industry-compatible oxidant, hydrogen peroxide (35% H2O2). The scalability this methodology is demonstrated by 1000 mmol scale reaction ibuprofen (206 g) using only 1 mol % Pd catalyst loading. utility protocol further illustrated through derivatization products synthesis polyfluorinated natural product coumestan pterocarpene from phenol intermediates prepared methodology.

Язык: Английский

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Palladium-Catalyzed [3 + 2] Annulation of Aromatic Amides with Maleimides through Dual C–H Activation

Organic Letters, Год журнала: 2023, Номер 25(13), С. 2190 - 2195

Опубликована: Март 26, 2023

A palladium-catalyzed [3 + 2] annulation of substituted aromatic amides with maleimides providing tricyclic heterocyclic molecules in good to moderate yields through weak carbonyl chelation is reported. The reaction proceeds via a dual C-H bond activation where the first takes place selectively at benzylic position followed by second meta afford five-membered cyclic ring. An external ligand Ac-Gly-OH has been used succeed this protocol. plausible mechanism proposed for reaction.

Язык: Английский

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Synthesis of 1,3-Dienes via Ligand-Enabled Sequential Dehydrogenation of Aliphatic Acids

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(24), С. 13003 - 13007

Опубликована: Июнь 7, 2023

1,3-Dienes are common scaffolds in biologically active natural products as well building blocks for chemical synthesis. Developing efficient methods 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 free aliphatic acids via β-methylene C–H activation, which enables one-step E,E-1,3-dienes. Free varying complexities, including antiasthmatic drug seratrodast, were found to be compatible with reported protocol. Considering high lability and lack protecting strategies, reveal at late stage offers an appealing strategy complex molecules containing such motifs.

Язык: Английский

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Palladium-Catalyzed Cascade Reactions for Synthesis of Heterocycles Initiated by C(sp3)–H Functionalization

Catalysts, Год журнала: 2025, Номер 15(1), С. 72 - 72

Опубликована: Янв. 14, 2025

Heterocycles are widely present in natural products, pharmaceuticals, and organic functional materials. In heterocycle synthesis, Pd-catalyzed cascade C–H functionalization has been regarded as one of the most powerful approaches due to its advantages terms high atom efficiency readily available starting this review, we will briefly introduce major advances palladium-catalyzed C(sp3)–H activation annulation for constructing different types heterocycles through inter- intramolecular pathways from 2010 2023.

Язык: Английский

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Unified approaches in transition metal catalyzed C(sp³)–H functionalization: recent advances and mechanistic aspects

Chemical Society Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Direct alteration of unactivated C–H bonds organic building blocks.

Язык: Английский

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Rh(III)-Catalyzed Enaminone-Directed C–H Coupling with Diazodicarbonyls for Skeleton-Divergent Synthesis of Isocoumarins and Naphthalenes

Organic Letters, Год журнала: 2022, Номер 24(42), С. 7850 - 7855

Опубликована: Окт. 19, 2022

Diversity-oriented synthesis is tremendously useful for expanding the explorable chemical space but restricted by limited available toolbox of skeleton-diversification chemistry. We report herein Rh(III)-catalyzed coupling enaminones and diazodicarbonyls skeleton-divergent isocoumarins naphthalenes. The diazodicarbonyl ring size pH dependence skeleton-forming process demonstrates achievement both substrate- reagent-controlled skeletal diversity generation in a single type system. An intriguing C–C bond cleavage reactivity critical enabling facile synthetic access to isocoumarins.

Язык: Английский

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Access to unsaturated bicyclic lactones by overriding conventional C(sp3)–H site selectivity

Nature Chemistry, Год журнала: 2023, Номер 15(11), С. 1626 - 1635

Опубликована: Авг. 10, 2023

Transition metal catalysis plays a pivotal role in transforming unreactive C-H bonds. However, regioselective activation of distal aliphatic bonds poses tremendous challenge, particularly the absence directing templates. Activation methylene bond presence methyl is underexplored. Here we show to form unsaturated bicyclic lactones. The protocol allows reversal general selectivity activation. Computational studies suggest that reversible followed by β-hydride elimination generate Pd-coordinated cycloalkene undergoes stereoselective C-O cyclization, and subsequent provide broad generality this reaction has been highlighted via dehydrogenative lactonization mid macro ring containing acids along with olefination olefin allyl alcohol. method substantially simplifies synthesis important lactones are features natural products as well pharmacoactive molecules.

Язык: Английский

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Synthesis of β,γ-Unsaturated Aliphatic Acids via Ligand-Enabled Dehydrogenation

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(38), С. 20951 - 20958

Опубликована: Сен. 12, 2023

α,β-Dehydrogenation of aliphatic acids has been realized through both enolate and β-C–H metalation pathways. However, the synthesis isolated β,γ-unsaturated via dehydrogenation not achieved to date. Herein, we report ligand-enabled β,γ-dehydrogenation abundant inexpensive free acids, which provides a new synthetic disconnection as well versatile platform for downstream functionalization complex molecules at remote γ-sites. A variety including acyclic cyclic systems with ring sizes from five-membered macrocyclic, undergo efficient dehydrogenation. Notably, this protocol features good chemoselectivity in presence more accessible α-C–H bonds excellent regioselectivity fused bicyclic scaffolds. The utility demonstrated by late-stage series bioactive terpene natural products Further β,γ-double bond allows installation covalent warheads, epoxides, aziridines, β-lactones, into product scaffolds, are valuable targeted drug discovery.

Язык: Английский

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Nondirected Pd-Catalyzed C–H Perdeuteration and meta-Selective Alkenylation of Arenes Enabled by Pyrazolopyridone Ligands

ACS Catalysis, Год журнала: 2023, Номер 13(7), С. 4042 - 4052

Опубликована: Март 16, 2023

The development of ligands and the elucidation their roles in catalytic cycle are key to achieving high efficiency selectivity nondirected transition-metal-catalyzed C–H functionalization. In particular, careful ligand design can enable functionalization previously inaccessible substrate positions, which lead regiodivergent transformations common reactants. this study, a series pyrazolopyridone (PzPyOH) that be easily prepared single step was developed for Pd-catalyzed perdeuteration meta-selective alkenylation arenes. system, 2-pyridone moiety incorporated function as an internal base, facilitating cleavage rendering activation reversible, even at challenging sp2 bonds, thus enabling perdeuteration. addition, reversible bonds implies site is determined during migratory insertion reaction, thereby preferentially functionalizing meta-positions rather than typically more reactive ortho- para-positions anisole derivatives. Further, electronic structural properties pyrazole provide flexibility binding Pd, facile coordination alkene coupling partner alkenylation. process, hydrogen bonding between pyridone acetate crucial stabilize intermediates, allowing different types modes, including L,L- L,X-type bidentate monodentate binding. Kinetic computational studies support proposed mechanisms alkenylation, findings reveal factors functionalization, will useful further pyrazole- pyridone-containing transition metal catalysis.

Язык: Английский

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