Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
J Org Chem ; 89(11): 8208-8219, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38764429

ABSTRACT

A conceptual strategy for a formal α-alkylation of α-methylene ketones was developed. Diverse 1° and 2° alkyl substituents were generated in the α-position of various ketones via synthesis of enaminone (step 1) and treatment with organomagnesium (step 2) with subsequent catalytic hydrogenation (step 3, 1° alkyl) or organocopper reagents (step 4, 2° alkyl). Tolerance toward ester, Boc-protected amine, and α-fluoro-substituted ketone moieties was demonstrated. The suitability of the method for late-stage natural product modification was shown.

2.
Org Lett ; 26(22): 4808-4812, 2024 Jun 07.
Article in English | MEDLINE | ID: mdl-38804566

ABSTRACT

This work highlights stellane's cage stability and derivatization opportunities. A diverse range of building blocks were synthesized using modern synthesis protocols to demonstrate stellane's reactivity and chemical tolerance across different reaction systems, proving its promise as a bioisosteric scaffold. It can be utilized in scaffold-based molecular design and is superior in terms of topological precision compared to existing ortho isosteres, as well as monosubstituted benzene mimetics, holding the potential to become a robust platform for future medicinal chemistry studies.

3.
J Am Chem Soc ; 146(22): 15464-15472, 2024 06 05.
Article in English | MEDLINE | ID: mdl-38780539

ABSTRACT

Molecules bearing fluorine are increasingly prevalent in pharmaceuticals, agrochemicals, and functional materials. The cyanodifluoromethyl group is unique because its size is closer than that of any other substituted difluoromethyl group to the size of the trifluoromethyl group, but its electronic properties are distinct from those of the trifluoromethyl group. In addition, the presence of the cyano group provides synthetic entry to a wide range of substituted difluoromethyl groups. However, the synthesis of cyanodifluoromethyl compounds requires multiple steps, highly reactive reagents (such as DAST, NSFI, or IF5), or specialized starting materials (such as α,α-dichloroacetonitriles or α-mercaptoacetonitriles). Herein, we report a copper-mediated cyanodifluoromethylation of aryl and heteroaryl iodides and activated aryl and heteroaryl bromides with TMSCF2CN. This cyanodifluoromethylation tolerates an array of functional groups, is applicable to late-stage functionalization of complex molecules, yields analogues of FDA-approved pharmaceuticals and fine chemicals, and enables the synthesis of a range of complex molecules bearing a difluoromethylene unit by transformations of the electron-poor CN unit. Calculations of selected steps of the reaction mechanism by Density Functional Theory indicate that the barriers for both the oxidative addition of iodobenzene to [(DMF)CuCF2CN] and the reductive elimination of the fluoroalkyl product from the fluoroalkyl copper intermediate lie in between those of [(DMF)CuCF3] and [(DMF)CuCF2C(O)NMe2].

4.
Int J Mol Sci ; 25(7)2024 Mar 22.
Article in English | MEDLINE | ID: mdl-38612396

ABSTRACT

Acid-sensing ion channels (ASICs) play a key role in the perception and response to extracellular acidification changes. These proton-gated cation channels are critical for neuronal functions, like learning and memory, fear, mechanosensation and internal adjustments like synaptic plasticity. Moreover, they play a key role in neuronal degeneration, ischemic neuronal injury, seizure termination, pain-sensing, etc. Functional ASICs are homo or heterotrimers formed with (ASIC1-ASIC3) homologous subunits. ASIC1a, a major ASIC isoform in the central nervous system (CNS), possesses an acidic pocket in the extracellular region, which is a key regulator of channel gating. Growing data suggest that ASIC1a channels are a potential therapeutic target for treating a variety of neurological disorders, including stroke, epilepsy and pain. Many studies were aimed at identifying allosteric modulators of ASIC channels. However, the regulation of ASICs remains poorly understood. Using all available crystal structures, which correspond to different functional states of ASIC1, and a molecular dynamics simulation (MD) protocol, we analyzed the process of channel inactivation. Then we applied a molecular docking procedure to predict the protein conformation suitable for the amiloride binding. To confirm the effect of its sole active blocker against the ASIC1 state transition route we studied the complex with another MD simulation run. Further experiments evaluated various compounds in the Enamine library that emerge with a detectable ASIC inhibitory activity. We performed a detailed analysis of the structural basis of ASIC1a inhibition by amiloride, using a combination of in silico approaches to visualize its interaction with the ion pore in the open state. An artificial activation (otherwise, expansion of the central pore) causes a complex modification of the channel structure, namely its transmembrane domain. The output protein conformations were used as a set of docking models, suitable for a high-throughput virtual screening of the Enamine chemical library. The outcome of the virtual screening was confirmed by electrophysiological assays with the best results shown for three hit compounds.


Subject(s)
Amiloride , Benzamidines , Humans , Molecular Docking Simulation , Acid Sensing Ion Channels , Pain
5.
Chem Rec ; 24(2): e202300300, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38063808

ABSTRACT

Actual problems of development of catalysts for hydrogenation of heterocyclic compounds by hydrogen are summarized and discussed. The scope of review covers composites of nanoparticles of platinum group metals and 3d metals for heterogeneous catalytic processes. Such problems include increase of catalyst activity, which is important for reduction of precious metals content; development of new catalytic systems which do not contain metals of platinum group or contain cheaper analogues of Pd; control of factors which make influence on the selectivity of the catalysts; achievement of high reproducibility of the catalyst's performance and quality control of the catalysts. Own results of the authors are also summarized and described. The catalysts were prepared by decomposition of Pd0 and Ni0 complexes, pyrolysis of Ni2+ and Co2+ complexes deposited on aerosil and reduction of Ni2+ in pores of porous support in situ. The developed catalysts were used for hydrogenation of multigram batches of heterocyclic compounds.

6.
Chemistry ; 29(70): e202302454, 2023 Dec 14.
Article in English | MEDLINE | ID: mdl-37731162

ABSTRACT

Herein, we present previously unavailable C(sp3 )-rich polycyclic hydrocarbon scaffolds that have the potential to become valuable tools in medicinal chemistry and crop science as saturated bioisosteres of benzenoids. We have developed a scalable protocol (up to 50 g from a single synthetic run) for the synthesis of tricyclo[3.3.0.03,7 ]octane (bisnoradamantane or stellane) 1,5-dicarboxylic acid derivatives. X-ray crystallographic analysis of the stellane 1,5-dicarboxylic acid dimethyl ester has revealed that this scaffold is an optimal saturated isostere for ortho-disubstituted benzene where substituents exhibit in-plane topology. The synthetic protocol is based on the oxidative cyclization of dimethyl octahydropentalene-2,5-dicarboxylate (DMOD) through lithiation followed by I2 oxidation. The reaction outcome is determined by the stereochemistry of the substrate. While the endo,endo cis-DMOD, exclusively gives the "unwanted" Claisen cyclization product, the exo,endo cis- and exo,exo cis- stereoisomers afford the desired stellane 1,5-dicarboxylic acid dimethyl ester quantitatively. DFT computations have revealed that the reaction proceeds via the dianion of dimethyl octahydropentalene-2,5-dicarboxylate, which undergoes SET oxidation by I2 to form a radical anion. The subsequent cyclization followed by a second SET oxidation gives the desired stellane derivative.

7.
Org Lett ; 12(19): 4372-5, 2010 Oct 01.
Article in English | MEDLINE | ID: mdl-20795656

ABSTRACT

An efficient two-step multigram synthesis of the previously unknown 3-benzyl-3-azabicyclo[3.1.1]heptan-6-one is described. The compound is shown to be a promising building block for further selective derivatization of the cyclobutane ring providing novel conformationally restricted piperidine derivatives.


Subject(s)
Benzyl Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Heptanes/chemical synthesis , Crystallography, X-Ray , Models, Molecular , Molecular Structure
SELECTION OF CITATIONS
SEARCH DETAIL
...