Enantio‐ and Diastereoselective Synthesis of Chiral Tetrasubstituted α‐Amino Allenoates Bearing a Vicinal All‐Carbon Quaternary Stereocenter with Dual‐Copper‐Catalysis

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(31)

Опубликована: Июнь 1, 2023

The skeletons of chiral tetrasubstituted allenes bearing a vicinal all-carbon quaternary stereocenter are importance but still challenging to synthesize. Herein, we report enantio- and diastereoselective γ-additions 1-alkynyl ketimines with dual-copper-catalysis under mild conditions, affording α-amino allenoates in high yields (up 99 % yield) excellent enantioselectivities ee) diastereoselectivities >20 : 1 dr). Importantly, the stereodivergent synthesis products was realized by asymmetric γ-addition reaction Grignard reagent promoted epimerization. Moreover, dual-copper-catalyzed reactions were smoothly applied gram-scale adopted introduce allenyl moieties into bioactive molecules. Mechanistic experiments density functional theory (DFT) calculations demonstrated that catalyzed double copper catalysts.

Язык: Английский

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Desymmetrization of Geminal Difluoromethylenes using a Palladium/Copper/Lithium Ternary System for the Stereodivergent Synthesis of Fluorinated Amino Acids

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(47)

Опубликована: Окт. 10, 2023

Fluorinated amino acids and related peptides/proteins have been found widespread applications in pharmaceutical agricultural compounds. However, strategies for introducing a C-F bond into an enantioselective manner are still limited no such asymmetric catalysis strategy has reported. Herein, we successfully developed Pd/Cu/Li ternary system stereodivergent synthesis of chiral fluorinated acids. This method involves sequential desymmetrization geminal difluoromethylenes allylic substitution with acid Schiff bases via Pd/Li Pd/Cu dual activation, respectively. A series non-natural bearing allylic/benzylic fluorine motif easily synthesized high yields excellent regio-, diastereo-, enantioselectivities (up to >20 : 1 dr >99 % ee). density functional theory (DFT) study revealed the F-Cu interaction substrate Cu catalyst significantly influence stereoselectivity.

Язык: Английский

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Copper‐Catalyzed Chemoselective Asymmetric Hydrogenation of C=O Bonds of Exocyclic α,β‐Unsaturated Pentanones

Angewandte Chemie International Edition, Год журнала: 2023, Номер 62(35)

Опубликована: Июнь 12, 2023

A highly chemoselective earth-abundant transition metal copper catalyzed asymmetric hydrogenation of C=O bonds exocyclic α,β-unsaturated pentanones was realized using H2 . The desired products were obtained with up to 99 % yield and 96 ee (enantiomeric excess) (99 ee, after recrystallization). corresponding chiral allylic pentanol can be converted into several bioactive molecules. mechanism investigated via deuterium-labelling experiments control experiments, which indicate that the keto-enol isomerization rate substrate is faster than also show Cu-H complex only catalyze chemoselectively reduction carbonyl group. Computational results multiple attractive dispersion interactions (MADI effect) between catalyst bulky substituents play important roles stabilize states reduce generation by-products.

Язык: Английский

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Bimetallic Ru/Ru‐Catalyzed Asymmetric One‐Pot Sequential Hydrogenations for the Stereodivergent Synthesis of Chiral Lactones

Advanced Science, Год журнала: 2024, Номер 11(23)

Опубликована: Март 21, 2024

Abstract Asymmetric sequential hydrogenations of α ‐methylene γ ‐ or δ ‐keto carboxylic acids are established in one‐pot using a bimetallic Ru/Ru catalyst system, achieving the stereodivergent synthesis all four stereoisomers both chiral and ‐lactones with two non‐vicinal carbon stereocenters high yields (up to 99%) excellent stereoselectivities >99% ee >20:1 dr). The compatibility Ru systems is investigated detail, it found that basicity reaction system plays key role hydrogenation processes. protocol can be performed on gram‐scale low loading 11000 S/C) resulting products allow for many transformations, particularly several intermediates useful preparation drugs natural products.

Язык: Английский

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Enantio‐ and Diastereoselective Synthesis of Chiral Tetrasubstituted α‐Amino Allenoates Bearing a Vicinal All‐Carbon Quaternary Stereocenter with Dual‐Copper‐Catalysis

Angewandte Chemie, Год журнала: 2023, Номер 135(31)

Опубликована: Июнь 1, 2023

Abstract The skeletons of chiral tetrasubstituted allenes bearing a vicinal all‐carbon quaternary stereocenter are importance but still challenging to synthesize. Herein, we report enantio‐ and diastereoselective γ‐additions 1‐alkynyl ketimines with dual‐copper‐catalysis under mild conditions, affording α‐amino allenoates in high yields (up 99 % yield) excellent enantioselectivities ee ) diastereoselectivities >20 : 1 dr ). Importantly, the stereodivergent synthesis products was realized by asymmetric γ‐addition reaction Grignard reagent promoted epimerization. Moreover, dual‐copper‐catalyzed reactions were smoothly applied gram‐scale adopted introduce allenyl moieties into bioactive molecules. Mechanistic experiments density functional theory (DFT) calculations demonstrated that catalyzed double copper catalysts.

Язык: Английский

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Photocatalytic Reductive Azaarenylation of Cyclopropanes via Consecutive Photo‐induced Electron Transfer: A Facile Route to α‐Quaternary Azaarenes^†

Chinese Journal of Chemistry, Год журнала: 2024, Номер 42(23), С. 3035 - 3040

Опубликована: Июль 30, 2024

Comprehensive Summary α‐Azaarene quaternary carbon centers are prevalent in drug molecules, making the development of efficient synthetic approaches great interest. Herein, we describe an unprecedented method for constructing α‐all‐carbon carbon‐centered azaarenes by employing photocatalytic reductive coupling various 2,2‐disubstituted cycloproarylketones with readily available cyanoazaarenes. The reaction proceeds high efficiency, displaying excellent compatibility functional groups and demonstrating chemo‐ regioselectivity. Mechanistic investigations suggest that consecutive photo‐induced electron transfer (ConPET) plays a crucial role formation photocatalyst greater reducing capability, ultimately enabling direct conversion unreactive π‐bonds under mild transition‐metal‐free conditions.

Язык: Английский

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Copper‐Catalyzed Chemoselective Asymmetric Hydrogenation of C=O Bonds of Exocyclic α,β‐Unsaturated Pentanones

Angewandte Chemie, Год журнала: 2023, Номер 135(35)

Опубликована: Июнь 12, 2023

Abstract A highly chemoselective earth‐abundant transition metal copper catalyzed asymmetric hydrogenation of C=O bonds exocyclic α,β‐unsaturated pentanones was realized using H 2 . The desired products were obtained with up to 99 % yield and 96 ee (enantiomeric excess) (99 ee, after recrystallization). corresponding chiral allylic pentanol can be converted into several bioactive molecules. mechanism investigated via deuterium‐labelling experiments control experiments, which indicate that the keto‐enol isomerization rate substrate is faster than also show Cu−H complex only catalyze chemoselectively reduction carbonyl group. Computational results multiple attractive dispersion interactions (MADI effect) between catalyst bulky substituents play important roles stabilize states reduce generation by‐products.

Язык: Английский

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Desymmetrization of Geminal Difluoromethylenes using a Palladium/Copper/Lithium Ternary System for the Stereodivergent Synthesis of Fluorinated Amino Acids

Angewandte Chemie, Год журнала: 2023, Номер 135(47)

Опубликована: Окт. 10, 2023

Abstract Fluorinated amino acids and related peptides/proteins have been found widespread applications in pharmaceutical agricultural compounds. However, strategies for introducing a C−F bond into an enantioselective manner are still limited no such asymmetric catalysis strategy has reported. Herein, we successfully developed Pd/Cu/Li ternary system stereodivergent synthesis of chiral fluorinated acids. This method involves sequential desymmetrization geminal difluoromethylenes allylic substitution with acid Schiff bases via Pd/Li Pd/Cu dual activation, respectively. A series non‐natural bearing allylic/benzylic fluorine motif easily synthesized high yields excellent regio‐, diastereo‐, enantioselectivities (up to >20 : 1 dr >99 % ee). density functional theory (DFT) study revealed the F−Cu interaction substrate Cu catalyst significantly influence stereoselectivity.

Язык: Английский

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Synergistic Li/Li Bimetallic System for the Asymmetric Synthesis of Antituberculosis Drug TBAJ-587

The Journal of Organic Chemistry, Год журнала: 2023, Номер 88(11), С. 7601 - 7606

Опубликована: Май 1, 2023

TBAJ-587, an analogue of the antituberculosis drug bedaquiline (BDQ), bearing a diarylquinoline skeleton retains high bacterial potency, is less toxic, and has better pharmacokinetic profile than parent molecule, which entered phase I clinical trials. In contrast to its fascinating bioactivity, however, highly efficient synthesis this molecule still unsolved challenge. Herein, first asymmetric TBAJ-587 based on synergistic Li/Li bimetallic system reported. The product could be obtained in excellent yield 90% enantiomeric ratio (er) 80:20. Furthermore, reaction conducted 5 g scale, was with 99.9:0.1 er after simple recrystallization. realization protocol will greatly aid demand for production.

Язык: Английский

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Development of a Continuous Flow Process for the Efficient Preparation of Anti-Tuberculosis-Specific Drug TBAJ-876

Organic Process Research & Development, Год журнала: 2024, Номер 28(5), С. 1869 - 1876

Опубликована: Фев. 14, 2024

Previously, the first asymmetric synthesis of anti-tuberculosis agent TBAJ-876 had been successfully achieved using a synergistic Li/Li catalysis approach, yielding excellent results on 5 g scale. However, scaling up process presents significant challenges due to its poor repeatability and safety concerns associated with commercial scale use organolithium reagents. In this paper, we describe design, development, scale-up continuous flow for TBAJ-876. Notably, our not only allowed us synthesize at 100 reaction scale, an achievement unattainable through batch processing, but it also significantly reduced time, ensuring robustness, efficiency, scalability. This method provides viable pathway large-scale industrial production compounds, such as

Язык: Английский

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