14429-16-4Relevant academic research and scientific papers
Discovery of tert-amine-based RORγt agonists
Qiu, Ruomeng,Yu, Mingcheng,Gong, Juwen,Tian, Jinlong,Huang, Yafei,Wang, Yonghui,Xie, Qiong
, (2021/07/26)
The nuclear receptor retinoic acid receptor-related orphan receptor gamma-t (RORγt) is a transcription factor regulating Th17 cell differentiation and proliferation from naive CD4+ T cells. Since Th17 cells have demonstrated the antitumor efficacy by eliciting remarkable activation of CD8+ T cells, RORγt agonists could be applied as potential small molecule therapeutics for cancer immunotherapy. Based on the previously reported RORγt agonist 1 and its resolved co-crystal structure, a series of new tertiary amines were designed, synthesized and biologically evaluated, yielding optimal moieties with improved chemical properties and biological responses. The combination of these optimal moieties resulted in identification of novel RORγt agonists such as 8b with further elevated RORγt agonism responses at a target-based level as well as in cell-based assays, which provided some structural knowledge for further optimization of RORγt agonists as small molecule therapeutics for cancer immunotherapy.
A practical catalytic reductive amination of carboxylic acids
Andrews, Keith G.,Denton, Ross M.,Hirst, David J.,Stoll, Emma L.,Tongue, Thomas,Valette, Damien
, p. 9494 - 9500 (2020/10/02)
We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.
A proton-responsive annulated mesoionic carbene (MIC) scaffold on IR complex for proton/hydride shuttle: An experimental and computational investigation on reductive amination of aldehyde
Bera, Jitendra K.,Daw, Prosenjit,Din Reshi, Noor U.,Ehmann, Kira R.,H?lscher, Markus,Leitner, Walter,Pandey, Pragati
, p. 3849 - 3863 (2020/11/23)
A Cp*Ir(III) complex (1) bearing a proton-responsive hydroxy unit on an annulated imidazo[1,2-a][1,8]naphthyridine based mesoionic carbene scaffold was synthesized by two different synthetic routes. The molecular structure of 1 revealed an anionic lactam form of the ligand. The acid?base equilibrium between the lactam-lactim tautomers on the ligand scaffold was examined by 1H NMR and UV?vis spectra. The pKa of the appendage ?OH group in the lactim form of 1 was estimated to assess the proton transfer property of the catalyst. The catalytic efficacy of 1 for reductive amination of aldehyde was evaluated by utilizing three different hydrogen sources: molecular H2iPrOH/KOtBu combination, and HCOOH/Et3N (5:2) azeotropic mixture. The HCOOH/Et3N (5:2) azeotropic mixture rotocol was found to be the best amon the three different h dro enation methods. Catalyst 1 hydrogenates imines chemoselectively over carbonyls under the reaction conditions. A range of aldehydes was reductively aminated to the corresponding secondary amines using the HCOOH/Et3N (5:2) azeotropic mixture. Further, catalyst 1 showed high efficiency for the reduction of a wide variety of N-heterocyclic imine derivatives. The lactam-lactim tautomerization of the ligand system is proposed for direct hydrogenation, whereas only the lactam form operates in the strongly basic medium (iPrOH/KOtBu). Under HCOOH/Et3N (5:2) conditions, the lactam scaffold is not protonated; rather, an outer-sphere hydride transfer from formate to the Ir is proposed, which is supported by 1H NMR and DFT calculations. Finally, ligand-promoted hydride transfer from metal-hydride to the protonated imine affords the corresponding amine. A close agreement between the experimentally estimated and computed thermodynamic/kinetic parameters gives credence to the metal-ligand cooperative mechanism for the imine hydrogenation reaction using the HCOOH/Et3N (5:2) azeotropic mixture.
High-Throughput Screening of Reductive Amination Reactions Using Desorption Electrospray Ionization Mass Spectrometry
Cooks, R. Graham,Ferreira, Christina R.,Li, Yangjie,Logsdon, David L.,Paschoal Sobreira, Tiago Jose,Thompson, David H.
supporting information, p. 1647 - 1657 (2020/10/26)
This study describes the latest generation of a high-throughput screening system that is capable of screening thousands of organic reactions in a single day. This system combines a liquid handling robot with desorption electrospray ionization (DESI) mass spectrometry (MS) for a rapid reaction mixture preparation, accelerated synthesis, and automated MS analysis. A total of 3840 unique reductive amination reactions were screened to demonstrate the throughputs that are capable with the system. Products, byproducts, and intermediates were all monitored in full-scan mass spectra, generating a complete view of the reaction progress. Tandem mass spectrometry experiments were conducted to verify the identity of the products formed. The amine and electrophile reactivity trends represented in the data match what is expected from theory, indicating that the system accurately models the reaction performance. The DESI results correlated well with those generated using more traditional mass spectrometry techniques like liquid chromatography-mass spectrometry, validating the data generated by the system.
Design, synthesis and identification of N, N-dibenzylcinnamamide (DBC) derivatives as novel ligands for α-synuclein fibrils by SPR evaluation system
Chen, Yan-Fei,Bian, Jiang,Zhang, Peng,Bu, Lu-Lu,Shen, Yan,Yu, Wen-Bo,Lu, Xiu-Hong,Lin, Xin,Ye, De-Yong,Wang, Jian,Chu, Yong
, (2020/02/22)
PET imaging of α-synuclein (α-syn) deposition in the brain will be an effective tool for earlier diagnosis of Parkinson's disease (PD) due to α-syn aggregation is the widely accepted biomarker for PD. However, the necessary PET radiotracer for imaging is clinically unavailable until now. The lead compound discovery is the first key step for the study. Herein, we initially established an efficient biologically evaluation system well in high throughput based on SPR technology, and identified a novel class of N, N-dibenzylcinnamamide (DBC) compounds as α-syn ligands through the assay. These compounds were proved to have high affinities against α-syn aggregates (KD D) has been acquired, indicating its potential as a new lead compound for developing PET radiotracer.
Electrochemical, Iodine-Mediated α-CH Amination of Ketones by Umpolung of Silyl Enol Ethers
Strehl, Julia,Hilt, Gerhard
supporting information, p. 5968 - 5972 (2020/08/12)
The electrochemical, oxidative Umpolung reaction of silyl enol ethers utilizing simple iodide salts for the synthesis of α-amino ketones is described. The products were isolated in excellent yields of up to 100percent, and various functionalized starting materials were accepted in an undivided electrochemical cell design. Moreover, a sensitivity assessment to ensure an improved reproducibility of the reaction and cyclic voltammetry experiments were performed to postulate a plausible reaction mechanism on their basis.
Metal-Organic Capsules with NADH Mimics as Switchable Selectivity Regulators for Photocatalytic Transfer Hydrogenation
Wei, Jianwei,Zhao, Liang,He, Cheng,Zheng, Sijia,Reek, Joost N. H.,Duan, Chunying
, p. 12707 - 12716 (2019/09/04)
Switchable selective hydrogenation among the groups in multifunctional compounds is challenging because selective hydrogenation is of great interest in the synthesis of fine chemicals and pharmaceuticals as a result of the importance of key intermediates. Herein, we report a new approach to highly selectively (>99%) reducing C=X (X = O, N) over the thermodynamically more favorable nitro groups locating the substrate in a metal-organic capsule containing NADH active sites. Within the capsule, the NADH active sites reduce the double bonds via a typical 2e- hydride transfer hydrogenation, and the formed excited-state NAD+ mimics oxidize the reductant via two consecutive 1e- processes to regenerate the NADH active sites under illumination. Outside the capsule, nitro groups are highly selectively reduced through a typical 1e- hydrogenation. By combining photoinduced 1e- transfer regeneration outside the cage, both 1e- and 2e- hydrogenation can be switched controllably by varying the concentrations of the substrates and the redox potential of electron donors. This promising alternative approach, which could proceed under mild reaction conditions and use easy-to-handle hydrogen donors with enhanced high selectivity toward different groups, is based on the localization and differentiation of the 2e- and 1e- hydrogenation pathways inside and outside the capsules, provides a deep comprehension of photocatalytic microscopic reaction processes, and will allow the design and optimization of catalysts. We demonstrate the advantage of this method over typical hydrogenation that involves specific activation via well-modified catalytic sites and present results on the high, well-controlled, and switchable selectivity for the hydrogenation of a variety of substituted and bifunctional aldehydes, ketones, and imines.
Compound capable of being strongly bound with alpha-synuclein aggregate, and preparation method and use of compound
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Paragraph 0027; 0029-0031; 0111-0113, (2019/08/30)
The invention belongs to the technical field of medicine, and relates to a compound with a structural general formula I, and a preparation method and use of the compound. In the formula I, R1 is selected from phenyl, substituted phenyl, pyridyl and pyrimidinyl, and i is selected from 0 to 2, and is an integer; R2 is selected from alkyl, phenyl, substituted phenyl and 5-6-membered aromatic heterocyclic rings, and m is selected from 0 to 5, and is an integer; and R3 is selected from phenyl and substituted phenyl, and n is selected from 0 to 3, and is an integer. The compound comprises a cis-isomer, a trans-isomer or a mixture of the cis-isomer and the trans-isomer of the compound with the formula I structure. The compound can be strongly bound to an alpha-synuclein aggregate, can be used asan imaging tracer for the image technology such as PET, SPECT and the like, or can be used for preparing an imaging tracer and a composition containing the imaging tracer, the compound can be used forparticularly detecting Parkinson's disease or neurological disorders associated with the misfolding and aggregation of alpha-synuclein, and the compound has very good application prospects.
Expanding Water/Base Tolerant Frustrated Lewis Pair Chemistry to Alkylamines Enables Broad Scope Reductive Aminations
Fasano, Valerio,Ingleson, Michael J.
supporting information, p. 2217 - 2224 (2017/02/18)
Lower Lewis acidity boranes demonstrate greater tolerance to combinations of water/strong Br?nsted bases than B(C6F5)3, this enables Si?H bond activation by a frustrated Lewis pair (FLP) mechanism to proceed in the presence of H2O/alkylamines. Specifically, BPh3has improved water tolerance in the presence of alkylamines as the Br?nsted acidic adduct H2O–BPh3does not undergo irreversible deprotonation with aliphatic amines in contrast to H2O–B(C6F5)3. Therefore BPh3is a catalyst for the reductive amination of aldehydes and ketones with alkylamines using silanes as reductants. A range of amines inaccessible using B(C6F5)3as catalyst, were accessible by reductive amination catalysed by BPh3via an operationally simple methodology requiring no purification of BPh3or reagents/solvent. BPh3has a complementary reductive amination scope to B(C6F5)3with the former not an effective catalyst for the reductive amination of arylamines, while the latter is not an effective catalyst for the reductive amination of alkylamines. This disparity is due to the different pKavalues of the water–borane adducts and the greater susceptibility of BPh3species towards protodeboronation. An understanding of the deactivation processes occurring using B(C6F5)3and BPh3as reductive amination catalysts led to the identification of a third triarylborane, B(3,5-Cl2C6H3)3, that has a broader substrate scope being able to catalyse the reductive amination of both aryl and alkyl amines with carbonyls.
A General and Selective Rhodium-Catalyzed Reduction of Amides, N-Acyl Amino Esters, and Dipeptides Using Phenylsilane
Das, Shoubhik,Li, Yuehui,Lu, Liang-Qiu,Junge, Kathrin,Beller, Matthias
supporting information, p. 7050 - 7053 (2016/05/19)
This article describes a selective reduction of functionalized amides, including N-acyl amino esters and dipeptides, to the corresponding amines using simple [Rh(acac)(cod)]. The catalyst shows excellent chemoselectivity in the presence of different sensitive functional moieties. A selective reduction of functionalized amides, including N-acyl amino esters and dipeptides, to the corresponding amines using simple [Rh(acac)(cod)] is described (see scheme). The catalyst shows excellent chemoselectivity in the presence of different sensitive functional moieties. Even the selective reduction of a secondary amide bond in the presence of a ketone is possible.
