Regioselective aliphatic C–H functionalization using frustrated radical pairs

Nature, Год журнала: 2023, Номер 619(7970), С. 514 - 520

Опубликована: Июль 5, 2023

Язык: Английский

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Palladium (II)‐Catalyzed C−H Activation with Bifunctional Ligands: From Curiosity to Industrialization

Angewandte Chemie International Edition, Год журнала: 2024, Номер 63(19)

Опубликована: Фев. 29, 2024

Abstract In 2001, our curiosity to understand the stereochemistry of C−H metalation with Pd prompted first studies in Pd(II)‐catalyzed asymmetric activation (RSC Research appointment: 020 7451 2545, Grant: RG 36873, Dec. 2002). We identified four central challenges: 1. poor reactivity simple salts native substrates; 2. few strategies control site selectivity for remote bonds; 3. lack chiral catalysts achieve enantioselectivity via metalation, and 4. low practicality due limited coupling partner scope use specialized oxidants. These challenges necessitated new catalyst reaction development. For , we developed approaches enhance substrate–catalyst affinity together novel bifunctional ligands which participate accelerate cleavage step. site‐selectivity introduced concept systematically modulating distance geometry between a directing template, catalyst, substrate selectively access bonds. devised predictable stereomodels catalyst‐controlled enantioselective based on participation ligands. Finally, have varied catalytic manifolds Pd(II) accommodate diverse partners while employing practical oxidants such as peroxides. advances culminated numerous reactions, setting stage broad industrial applications.

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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One-Step Synthesis of β-Alkylidene-γ-lactones via Ligand-Enabled β,γ-Dehydrogenation of Aliphatic Acids

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(28), С. 12924 - 12933

Опубликована: Июль 8, 2022

Ligand-enabled Pd-catalyzed regioselective α,β-dehydrogenation of carbonyl compounds via β-methylene C–H activation has recently emerged as a promising transformation. Herein, we report the realization β,γ-dehydrogenation and subsequent vinyl olefination reactions free carboxylic acids, thus providing unique method for structural diversification aliphatic acids containing α-quaternary centers through sequential functionalizations two β-C–H bonds one γ-C–H bond. This tandem dehydrogenation–olefination–lactonization reaction offers one-step preparation β-alkylidene-γ-lactones, which are often difficult to prepare conventional methods, from inexpensive abundant acids. A variety such isosteviol grandiflorolic acid natural products, olefins compatible with reported protocol. The newly designed bidentate oxime ether-pyridone morpholine-pyridone ligands crucial this proceed. Notably, these also enable preferential methylene over previously reported, competing process methyl bond olefination.

Язык: Английский

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Carboxylic Acid Directed γ-Lactonization of Unactivated Primary C–H Bonds Catalyzed by Mn Complexes: Application to Stereoselective Natural Product Diversification

Journal of the American Chemical Society, Год журнала: 2022, Номер 144(42), С. 19542 - 19558

Опубликована: Окт. 13, 2022

Reactions that enable selective functionalization of strong aliphatic C–H bonds open new synthetic paths to rapidly increase molecular complexity and expand chemical space. Particularly valuable are reactions where site-selectivity can be directed toward a specific bond by catalyst control. Herein we describe the catalytic site- stereoselective γ-lactonization unactivated primary in carboxylic acid substrates. The system relies on chiral Mn activates aqueous hydrogen peroxide promote intramolecular lactonization under mild conditions, via carboxylate binding metal center. exhibits high enables oxidation γ-C–H even presence intrinsically weaker priori more reactive secondary tertiary ones at α- β-carbons. With substrates bearing nonequivalent bonds, factors governing have been uncovered. Most remarkably, manipulating absolute chirality catalyst, methyl groups gem-dimethyl structural units rigid cyclic bicyclic acids achieved with unprecedented levels diastereoselectivity. Such control has successfully exploited late-stage natural products such as camphoric, camphanic, ketopinic, isoketopinic acids. DFT analysis points rebound type mechanism initiated 1,7-HAT from bound substrate highly MnIV-oxyl intermediate, deliver carbon radical lactonizes through transfer. Intramolecular kinetic deuterium isotope effect 18O labeling experiments provide support this mechanistic picture.

Язык: Английский

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Transannular C–H functionalization of cycloalkane carboxylic acids

Nature, Год журнала: 2023, Номер 618(7965), С. 519 - 525

Опубликована: Май 31, 2023

Язык: Английский

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Dual-Ligand Catalyst for the Nondirected C–H Olefination of Heteroarenes

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(14), С. 8198 - 8208

Опубликована: Март 28, 2023

Pd(II)-catalyzed nondirected C-H functionalization of heteroarenes is a significant challenge for the following reasons: poor reactivity electron-deficient heterocycles and unproductive coordination Lewis basic nitrogen atoms. Existing methodologies using palladium catalysis often employ large excess heterocycle substrates to overcome these hurdles. Despite recent advances in arenes that allow them be used as limiting reagents, reaction conditions are incompatible with heteroarenes. Herein we report dual-ligand catalyst enables olefination without substrate. In general, use 1-2 equiv was sufficient obtain synthetically useful yields. The rationalized by synergy between two types ligands: bidentate pyridine-pyridone ligand promotes cleavage; monodentate substrate acts second form cationic Pd(II) complex has high affinity arenes. proposed cooperation supported combination X-ray, kinetics, control experiments.

Язык: Английский

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Regio-controllable [2+2] benzannulation with two adjacent C(sp ³ )–H bonds

Science, Год журнала: 2023, Номер 380(6645), С. 639 - 644

Опубликована: Май 11, 2023

Regiocontrol in traditional cycloaddition reactions between unsaturated carbon compounds is often challenging. The increasing focus modern medicinal chemistry on benzocyclobutene (BCB) scaffolds indicates the need for alternative, more selective routes to diverse rigid carbocycles rich C(sp

Язык: Английский

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Converting Non‐strained γ‐Valerolactone and Derivatives into Sustainable Polythioesters via Isomerization‐driven Cationic Ring‐Opening Polymerization of Thionolactone Intermediate

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(14)

Опубликована: Фев. 9, 2023

Abstract This contribution reports the efficient conversion of γ‐valerolactone and its derivatives, abundant but unexplored renewable feedstocks, into sustainable degradable polythioesters via establishment first isomerization‐driven ring‐opening polymerizations (IROPs) corresponding thionolactone intermediates. The key to this success relies on development a new simple robust [Et 3 O] + [B(C 6 F 5 ) 4 ] − cationic initiator which possesses high activity, exclusive selectivity, living nature, broad scope thionolactones. A complete inversion configuration during IROP enantiopure γ‐thionovalerolactone is also disclosed, affording isotactic semicrystalline ( T m =87.0 °C) with mechanical property compared well representative commodity polyolefins. formation highly crystalline supramolecular stereocomplex enhanced thermal =117.6 has been revealed.

Язык: Английский

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Highly Enantioselective Catalytic Lactonization at Nonactivated Primary and Secondary γ-C–H Bonds

Journal of the American Chemical Society, Год журнала: 2023, Номер 145(32), С. 18094 - 18103

Опубликована: Авг. 4, 2023

Chiral oxygenated aliphatic moieties are recurrent in biological and pharmaceutically relevant molecules constitute one of the most versatile types functionalities for further elaboration. Herein we report a protocol straightforward general access to chiral γ-lactones via enantioselective oxidation strong nonactivated primary secondary C(sp3)–H bonds readily available carboxylic acids. The key enabling aspect is use robust sterically encumbered manganese catalysts that provide outstanding enantioselectivities (up >99.9%) yields 96%) employing hydrogen peroxide as oxidant. resulting immediate interest preparation inter alia natural products recyclable polymeric materials.

Язык: Английский

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