Catalytic Asymmetric Access to Structurally Diverse N-Alkoxy Amines via a Kinetic Resolution Strategy DOI Creative Commons
Min Cao, Zehua Wang,

Fangao Hou

et al.

JACS Au, Journal Year: 2024, Volume and Issue: 4(5), P. 1935 - 1940

Published: May 14, 2024

Chiral

Language: Английский

Rhodium‐Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of 1,3‐Dipolar Nitrones DOI

Liren Xu,

Tilong Yang, Hao Sun

et al.

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(14)

Published: Feb. 17, 2024

Abstract Owing to their distinctive 1,3‐dipolar structure, the catalytic asymmetric hydrogenation of nitrones hydroxylamines has been a formidable and longstanding challenge, characterized by intricate enantiocontrol susceptibility N−O bond cleavage. In this study, transfer were accomplished with tethered TsDPEN‐derived cyclopentadienyl rhodium(III) catalyst (TsDPEN: p ‐toluenesulfonyl‐1,2‐diphenylethylene‐1,2‐diamine), reaction proceeds via novel 7‐membered cyclic transition state, producing chiral up 99 % yield >99 ee. The practical viability methodology was underscored gram‐scale reactions subsequent transformations. Furthermore, mechanistic investigations DFT calculations also conducted elucidate origin enantioselectivity.

Language: Английский

Citations

9
Recent advances on catalytic asymmetric hydrogenation of oximes and oxime ethers DOI
Bin Lü, Jianchao Yu, Xumu Zhang

et al.

Tetrahedron Letters, Journal Year: 2024, Volume and Issue: 136, P. 154914 - 154914

Published: Jan. 21, 2024

Language: Английский

Citations

4
Reductive Amination of Carbonyl C–C Bonds Enables Formal Nitrogen Insertion DOI
Charis Amber, Lucas Göttemann,

Richard Steele

et al.

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

Given its relevance across numerous fields, reductive amination is one of the oldest and most widely used methods for amine synthesis. As a cornerstone synthetic chemistry, it has largely remained unchanged since discovery over century ago. Herein, we report mechanistically driven development complementary reaction, which reductively aminates C-C σ-bond carbonyls, not carbonyl C-O π-bond, generating value-added linear cyclic 3° amines in modular fashion. Critical to our success were mechanistic insights that enabled us modulate resting state borane catalyst, minimize deleterious disproportionation hydroxylamine nitrogen source, control migratory selectivity key nitrenoid reactive intermediate. Experiments support reaction occurring through amination/reductive Stieglitz cascade, via ketonitrone, can be interrupted under catalyst generate valuable

Language: Английский

Citations

4
Catalytic Reduction of Aromatic Nitro Compounds to Phenylhydroxylamine and Its Derivatives DOI Creative Commons
Ming‐Lung Yu,

Dachen Ouyang,

Liqiang Wang

et al.

Molecules, Journal Year: 2024, Volume and Issue: 29(18), P. 4353 - 4353

Published: Sept. 13, 2024

Phenylhydroxylamine and its derivates (PHAs) are important chemical intermediates. Phenylhydroxylamines mainly produced via the catalytic reduction of aromatic nitro compounds. However, this method prefers to generate thermodynamically stable amine. Thus, designing suitable systems, especially catalysts selectively convert compounds PHAs, has received increasing attention but remains challenging. In review, we initially provide a brief overview various strategies employed for synthesis focusing on reducing Subsequently, an in-depth analysis is presented process, encompassing discussions catalysts, reductants, hydrogen sources, comprehensive assessment merits drawbacks systems. Furthermore, concise provided regarding progress made in comprehending mechanisms involved process Finally, main challenges prospects PHAs' production outlined.

Language: Английский

Citations

3
Discovery of a Hydroxylamine-Based Brain-Penetrant EGFR Inhibitor for Metastatic Non-Small-Cell Lung Cancer DOI Creative Commons
Jarvis Hill, Robert M. Jones, David Crich

et al.

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(22), P. 15477 - 15492

Published: Nov. 7, 2023

Metastases to the brain remain a significant problem in lung cancer, as treatment by most small-molecule targeted therapies is severely limited efflux transporters at blood–brain barrier (BBB). Here, we report discovery of selective, orally bioavailable, epidermal growth factor receptor (EGFR) inhibitor, 9, that exhibits high penetration and potent activity osimertinib-resistant cell lines bearing L858R/C797S exon19del/C797S EGFR resistance mutations. In vivo, 9 induced tumor regression an intracranial patient-derived xenograft (PDX) murine model suggesting it potential lead for localized metastatic non-small-cell cancer (NSCLC) driven activating mutant EGFR. Overall, demonstrate underrepresented functional group medicinal chemistry, trisubstituted hydroxylamine moiety, can be incorporated into drug scaffold without toxicity commonly surmised accompany these units, all while maintaining biological molecular weight creep common optimization campaigns.

Language: Английский

Citations

8
Oxidative Syntheses of N,N-Dialkylhydroxylamines DOI

Daniel Barriault,

Huy M. Ly, Meredith A. Allen

et al.

The Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 89(12), P. 8767 - 8772

Published: May 30, 2024

Despite the wide utility of hydroxylamines in organic synthesis, relatively few are commercially available, and there is a need for direct, efficient, selective methods their synthesis. Herein, we report two complementary to accomplish direct oxidation secondary amines using UHP as an oxidant. The first method uses 2,2,2-trifluoroethanol (TFE) large excess amine. Isolation hydroxylamine products enabled by salt formation, recovery amine demonstrated. second hexafluoroacetone additive highlighted 1:1 stoichiometry between oxidant

Language: Английский

Citations

2
Reductive amination of carbonyl C–C bonds enables formal nitrogen insertion DOI Creative Commons

Charis Amber,

Lucas Goettemann,

Ryan P. Steele

et al.

Published: July 24, 2024

Given its ubiquity in various biological and physical processes1–3, the reductive amination of ketones aldehydes is one oldest most widely used methods for amine synthesis4. As a cornerstone synthetic chemistry, it has largely remained unchanged since discovery over century ago5. Herein, we report mechanistically-driven development complementary reaction, which reductively aminates C–C σ-bond attached to carbonyls, not carbonyl C–O π-bond, generating value-added linear cyclic 3° amines modular fashion. Critical success this endeavor were mechanistic insights that enabled us modulate resting state borane catalyst, minimize deleterious disproportionation hydroxylamine nitrogen source, control migratory selectivity key nitrenoid reactive intermediate. Experimental evidence support reaction occurring through amination/stepwise Stieglitz cascade, via ketonitrone, can be interrupted under catalyst-control generate valuable N,N-disubstituted hydroxylamines. The method reported herein enables net transformations would otherwise require lengthy sequences using pre-existing technologies. This highlighted by application two-step protocol formal insertion single atom into core framework abundant hydrocarbon feedstocks, site-selective late-stage complex molecules, diversity-oriented synthesis isomeric from precursor, transposition different positions within heterocycle.

Language: Английский

Citations

2
Atypical N-Alkyl to N-Noralkoxy Switch in a Dual cSRC/BCR-ABL1 Kinase Inhibitor Improves Drug Efflux and hERG Affinity DOI Creative Commons
Jarvis Hill, Robert M. Jones, David Crich

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2023, Volume and Issue: 14(12), P. 1869 - 1875

Published: Dec. 5, 2023

We describe an atypical amine bioisostere, the trisubstituted hydroxylamine, that upon incorporation into approved dual cSRC/BCR-ABL1 kinase inhibitor yields 9, a compound retains potent biological activity and couples it with improved drug efflux hERG affinity at expense of only 2 atomic mass unit increase in molecular weight. Contrary to common expectation for hydroxylamines medicinal chemistry, 9 is well tolerated vivo lacks mutagenicity genotoxicity so often ascribed lesser substituted hydroxylamines. A matched pair (MMP) analysis suggests beneficial properties conferred by N-alkyl N-noralkoxy switch arises from reduction basicity piperazine unit. Overall, these results lend additional support use as bioisosteres groups are not involved key polar interactions.

Language: Английский

Citations

2
Rhodium‐Catalyzed Asymmetric Hydrogenation and Transfer Hydrogenation of 1,3‐Dipolar Nitrones DOI

Liren Xu,

Tilong Yang, Hao Sun

et al.

Angewandte Chemie, Journal Year: 2024, Volume and Issue: 136(14)

Published: Feb. 17, 2024

Abstract Owing to their distinctive 1,3‐dipolar structure, the catalytic asymmetric hydrogenation of nitrones hydroxylamines has been a formidable and longstanding challenge, characterized by intricate enantiocontrol susceptibility N−O bond cleavage. In this study, transfer were accomplished with tethered TsDPEN‐derived cyclopentadienyl rhodium(III) catalyst (TsDPEN: p ‐toluenesulfonyl‐1,2‐diphenylethylene‐1,2‐diamine), reaction proceeds via novel 7‐membered cyclic transition state, producing chiral up 99 % yield >99 ee. The practical viability methodology was underscored gram‐scale reactions subsequent transformations. Furthermore, mechanistic investigations DFT calculations also conducted elucidate origin enantioselectivity.

Language: Английский

Citations

0
Catalytic Asymmetric Access to Structurally Diverse N-Alkoxy Amines via a Kinetic Resolution Strategy DOI Creative Commons
Min Cao, Zehua Wang,

Fangao Hou

et al.

JACS Au, Journal Year: 2024, Volume and Issue: 4(5), P. 1935 - 1940

Published: May 14, 2024

Chiral

Language: Английский

Citations

0