Dynamic Kinetic Resolution-Based Asymmetric Transfer Hydrogenation of Racemic 2-Substituted Quinolines

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

The synthesis of chiral tetrahydroquinolines (THQs) has garnered significant interest from medicinal chemists due to their frequent presence as pharmacophores in bioactive compounds. While existing synthetic methods have primarily focused on THQs with single or multiple endocyclic centers, the selective construction both endo- and exo-cyclic centers remains a challenge that requires further development. This study introduces dynamic kinetic resolution (DKR)-based transfer hydrogenation racemic 2-substituted quinolines, which yields structurally novel consecutive excellent stereoselectivities (59 examples, generally >20:1 dr >90% ee, up three stereocenters). Our approach offers mechanistically method for asymmetric transformation electron-deficient aromatic N-heterocycles presents an innovative way expand N-heterocycle chemical space chemistry.

Language: Английский

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Rhodium-Catalyzed Homogeneous Asymmetric Hydrogenation of Naphthol Derivatives

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 29, 2025

Due to their strong aromaticity and difficulties in chemo-, regio-, enantioselectivity control, asymmetric hydrogenation of naphthol derivatives 1,2,3,4-tetrahydronaphthols has remained a long-standing challenge. Herein, we report the first example homogeneous catalyzed by tethered rhodium-diamine catalysts, affording wide array optically pure high yields with excellent enantioselectivities (up 98% yield >99% ee). Mechanistic studies experimental computational approaches reveal that fluorinated solvent 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) plays vital roles control reactivity selectivity, 1-naphthol is reduced via cascade reaction pathway, including dearomative tautomerization, 1,4-hydride addition, 1,2-hydride addition sequence. A novel synergistic activation mode was proposed which HFIP assists both hydrogen molecule presence base, situ-generated fleeting keto tautomer immediately trapped Rh(III)-H species before it escapes from cage. This protocol provides straightforward practical pathway for synthesis key intermediates several chiral drugs. Particularly, Nadolol, drug treatment hypertension, angina pectoris, congestive heart failure, certain arrhythmias, enantioselectively synthesized time.

Language: Английский

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Enantioselective Synthesis of α‐Hydroxy Allyl Ketones via BINAP‐CuH‐Catalyzed Hydroacylation

Angewandte Chemie, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Catalytic hydrocupration of unsaturated carbon‐carbon bonds to generate organometallic nucleophiles has recently become an attractive alternative conventional stoichiometric reagents in the stereoselective synthesis. Herein, we have developed efficient and economical method synthesize enantiopure α ‐hydroxy allyl ketones via a copper hydride (CuH)‐catalyzed hydroacylation alkoxyallenes, significant advancement given scarcity reports on such scaffolds literature. DFT calculations reveal that this reaction proceeds through nucleophilic attack kinetically favourable Z ‐selective allyl‐copper intermediate acid anhydrides six‐membered chair‐like transition state, stabilized by strongly non‐covalent interactions ultimately leads high level enantioselectivities using simple BINAP ligand. This successfully overcomes challenges over‐reduction carbonyl functionality presence CuH‐complex, olefin isomerization highly enolizable ‐stereocenter, which can lead erosion enantioselectivities, making our strategy desirable. The exhibits wide range substrate scope including symmetrical as well carbonic with both aromatic, aliphatic substitutions. In addition, ‐substituted provide exclusive syn α,α′ ‐disubstituted excellent enantiomeric ratios, where allylation occurs one carbonyls containing matched α‐ stereocenter, confirmed mechanistic studies.

Language: Английский

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Enantioselective Synthesis of α‐Hydroxy Allyl Ketones via BINAP‐CuH‐Catalyzed Hydroacylation

Angewandte Chemie International Edition, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

Abstract Catalytic hydrocupration of unsaturated carbon‐carbon bonds to generate organometallic nucleophiles has recently become an attractive alternative conventional stoichiometric reagents in the stereoselective synthesis. Herein, we have developed efficient and economical method synthesize enantiopure α ‐hydroxy allyl ketones via a copper hydride (CuH)‐catalyzed hydroacylation alkoxyallenes, significant advancement given scarcity reports on such scaffolds literature. DFT calculations reveal that this reaction proceeds through nucleophilic attack kinetically favourable Z ‐selective allyl‐copper intermediate acid anhydrides six‐membered chair‐like transition state, stabilized by strongly non‐covalent interactions ultimately leads high level enantioselectivities using simple BINAP ligand. This successfully overcomes challenges over‐reduction carbonyl functionality presence CuH‐complex, olefin isomerization highly enolizable ‐stereocenter, which can lead erosion enantioselectivities, making our strategy desirable. The exhibits wide range substrate scope including symmetrical as well carbonic with both aromatic, aliphatic substitutions. In addition, ‐substituted provide exclusive syn α,α′ ‐disubstituted excellent enantiomeric ratios, where allylation occurs one carbonyls containing matched α‐ stereocenter, confirmed mechanistic studies.

Language: Английский

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Catalytic Asymmetric Transfer Hydrogenation of β,γ-Unsaturated α-Diketones

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

Asymmetric transfer hydrogenation (ATH) has been recognized as a highly valuable strategy that allows access to enantioenriched substances and widely applied in the industrial production of drug molecules. However, despite great success ATH ketones, efficient, regio- stereoselective on enones remains underdeveloped. Moreover, optically pure acyloins 1,2-diols are both extremely useful building blocks organic synthesis, medicinal chemistry, materials science, but concise asymmetric approaches allowing different types have scarcely discovered. We report this paper first efficient readily accessible β,γ-unsaturated α-diketones. The protocol affords four fashion. synthetic value work showcased by divergent synthesis related natural products. systematic mechanistic studies density functional theory (DFT) calculations illustrated origin reactivity divergence, revealed roles aromatic aliphatic substituents substrates, provided range unique rationales not disclosed ATH-related studies.

Language: Английский

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