Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Abstract Chiral functionalized piperidine and lactone heterocycles are widely spread in natural products drug candidates with promising pharmacological properties. However, there remains no general asymmetric methodologies that enable rapid assemble both critical biologically important units into one three-dimensional chiral molecule. Herein, we describe a straightforward relay strategy for the construction of enantioenriched bridged piperidine-γ-butyrolactone skeletons incorporating three skipped stereocenters via allylic alkylation aza -Prins cyclization/lactonization sequences. The excellent enantioselectivity control allylation simplest precursor is enabled by synergistic Cu/Ir-catalyzed protocol; success can be attributed to pivotal role ester substituent, which acts as preferential intramolecular nucleophile terminate intermediacy piperid-4-yl cation species. resulting bridged-heterocyclic show impressive preliminary biological activities against panel cancer cell lines.

Language: Английский

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

Advanced Science, Journal Year: 2024, Volume and Issue: 11(23)

Published: March 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.

Language: Английский

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Stereodivergent Synthesis of Enantioenriched α-Deuterated α-Amino Acids via Cascade Cu(I)-Catalyzed H–D Exchange and Dual Cu- and Ir-Catalyzed Allylation

Organic Letters, Journal Year: 2022, Volume and Issue: 24(30), P. 5562 - 5567

Published: July 21, 2022

A one-pot Cu-mediated H–D exchange with inexpensive heavy water as the deuterium source, followed by Cu- and Ir-catalyzed stereodivergent allylic alkylation, has been developed, providing efficient access to enantioenriched α-deuterium-labeled α-amino acids from readily available glycine imine esters in a high yield excellent stereoselectivity. High enrichment, exquisite regioselectivity, precise stereoselectivity control, operationally convenient procedures make this protocol appealing for preparation of highly synthetically useful α-deuterated acids.

Language: Английский

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Bimetallic Catalysis in Stereodivergent Synthesis

Angewandte Chemie, Journal Year: 2022, Volume and Issue: 134(45)

Published: Aug. 2, 2022

Abstract Bimetallic catalysis has emerged as an efficient strategy for the development of new chemical reactions. Importantly, this also provides a simple and powerful platform stereodivergent synthesis, whereby all possible stereoisomers products bearing two stereocenters can be easily prepared from same set starting materials. In Minireview, allylic substitution, propargylic hydrofunctionalization, annulation based on bimetallic been summarized. It is expected that more catalytic systems will developed applied synthesis valuable molecules.

Language: Английский

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Electron-rich benzofulvenes as effective dipolarophiles in copper(i)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides

Chemical Science, Journal Year: 2023, Volume and Issue: 14(20), P. 5460 - 5469

Published: Jan. 1, 2023

A series of benzofulvenes without any electron-withdrawing substituents were employed as 2π-type dipolarophiles for the first time to participate in Cu(i)-catalyzed asymmetric 1,3-dipolar cycloaddition (1,3-DC) reactions azomethine ylides. An intrinsic non-benzenoid aromatic characteristic from serves a key driving force activation electron-rich benzofulvenes. Utilizing current methodology, wide range multi-substituted chiral spiro-pyrrolidine derivatives containing two contiguous all-carbon quaternary centers formed good yield with exclusive chemo-/regioselectivity and high excellent stereoselectivity. Computational mechanistic studies elucidate origin stereochemical outcome chemoselectivity, which thermostability these products is major factor.

Language: Английский

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Palladium-catalyzed asymmetric [4 + 3] cycloaddition of acyclic α,β-unsaturated imines with trimethylenemethane donors: access to chiral non-fused azepines

Organic Chemistry Frontiers, Journal Year: 2024, Volume and Issue: 11(8), P. 2326 - 2331

Published: Jan. 1, 2024

An efficient approach for the construction of non-fused azepines in good yields with high enantioselectivity via Pd-catalyzed asymmetric [4 + 3] cycloaddition was developed.

Language: Английский

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Bridged-Type Selective Intramolecular Nitrone–Alkene Cycloaddition: Computational Chemistry-Inspired Regioselectivity Control

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 4, 2025

A regioselective intramolecular nitrone-alkene cycloaddition for synthesizing oxazabicyclo ring-fused indoles is reported. Computational studies guided the development of optimal conditions using In(OTf)3 as a Lewis acidic reagent. This method demonstrates broad substrate scope, forming seven- and eight-membered carbocycles with various substituents, provides versatile route to complex nitrogen-containing scaffolds potential applications in medicinal chemistry total synthesis biologically active compounds.

Language: Английский

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Dual Cu/Ir Catalyzed Asymmetric Allylation and Pictet‐Spengler Cyclization: Stereodivergent Access to Chiral Indole Fused 9‐Azabicyclo[4.2.1]nonanes^†

Chinese Journal of Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 24, 2025

Comprehensive Summary Nitrogen‐containing bridged‐heterocycles and indoles are key subunits of many natural products pharmacologically active molecules. We herein present a bimetallic Cu/Ir catalyzed asymmetric allylation ketimine esters ( E )‐4‐indolyl allyl carbonates followed by acid‐promoted Pictet‐Spengler cyclization sequences, enabling stereodivergent synthesis chiral indole fused 9‐azabicyclo[4.2.1]nonanes containing an eight‐membered ring with one tertiary two quaternary stereogenic centers. This one‐pot sequential protocol features step economy, good substrate tolerance, excellent stereoselective control.

Language: Английский

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Stereodivergently asymmetric synthesis of chiral phosphorus compounds by synergistic combination of ion-pair catalyst and base

Science China Chemistry, Journal Year: 2022, Volume and Issue: 65(12), P. 2500 - 2511

Published: Oct. 9, 2022

Language: Английский

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Dispersion Interactions in Asymmetric Induction for Constructing Vicinal Stereogenic Centers

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(22), P. 3260 - 3270

Published: Oct. 30, 2023

ConspectusVicinal stereogenic centers are prevalent structural motifs of primary functional relevance in natural products and bioactive molecules. The quest for the rapid controllable construction vicinal stands as a frontier endeavor asymmetric organic synthesis. Over past decade, stereodivergent synthesis has been intensely researched within realm bimetallic catalysis, aiming at establishing novel transition-metal dual-catalytic reactions that efficiently generate all stereochemical combinations multichiral molecules from identical starting materials, thus offering new opportunities toward complexity building diversity-oriented chiral compound library generation. In this Account, we summarize our recent advancements computational investigations allylic alkylation, an important reaction class heavily studied purpose constructing centers. Our discussions focus on synergistic catalysis syntheses α,α-disubstituted α-amino acids cascade allylation/cyclization enantiomerically enriched indole-containing heterocycles. We describe series studies converge molecular mechanism induction copper-azomethine ylide, nucleophile holds widespread utility is characterized by distinctive, sterically biased surrounding enveloping prochiral center. Notably, revealed attacks site allylmetal species significantly favored dispersion attraction one face (-PPh2) but blocked steric repulsion associated distortions opposite (oxazoline), therefore up multimodal highly robust face-selective stereoinduction. showcase how suite systematic analyses generates precise atomistic insights into number systems relevance. also discuss same methodologies can be applied to intermediates with shared interaction patterns, including rhodium-Josiphos catalyst hydrogenation create two continuous stereocenters. selectivity-controlling migratory insertion step, models unveiled ligand-substrate -PPh2 side hindered -PtBu2 side. These noncovalent interactions along distal ligand-auxiliary enable strictly oriented three-dimensional analysis effects competing pathways highlights certain interaction-level similarities between PHOX-type Josiphos-type ligands induction. summary, Account underscores foundational significance broad applicability nonbonded inductions envisage employed these will shift paradigm interaction-based rational design.

Language: Английский

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