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1.
Molecules ; 29(9)2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38731527

RESUMEN

An expeditious synthesis of γ- and δ-lactams from tethered alkenyl trichloroacetamides in the presence of 5% of RuCl2(PPh3)3 is reported. In this investigation we have demonstrated that microwave activation significantly enhances reaction rates, leading to the formation of the corresponding lactams in yields ranging from good to excellent. Thus, we have been able to prepare a wide range of lactams, including indole and morphan bicyclic scaffolds, where the corresponding reactions were completely diastereoselective. This process was successfully extended to α,α-dichloroamides without affecting either their yield or their diastereoselectivity. Some of the lactams prepared in this work were evaluated for their hemolytic and cytotoxic responses. All compounds were found to be non-hemolytic at the tested concentration, indicating their safety profile in terms of blood cell integrity. Meanwhile, they exhibited interesting cytotoxicity responses that depend on both their lactam structure and cell line. Among the molecules tested, γ-lactam 2a exhibited the lowest IC50 values (100-250 µg/mL) as a function of its cell line, with promising selectivity against squamous carcinoma cells (A431) in comparison with fibroblasts (3T3 cell line).


Asunto(s)
Lactamas , Microondas , Lactamas/química , Lactamas/síntesis química , Lactamas/farmacología , Ciclización , Humanos , Catálisis , Ratones , Animales , Línea Celular Tumoral , Acetamidas/química , Acetamidas/síntesis química , Acetamidas/farmacología , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química
2.
Org Biomol Chem ; 22(2): 388-394, 2024 Jan 03.
Artículo en Inglés | MEDLINE | ID: mdl-38086711

RESUMEN

The first violet light-mediated synthesis of γ- and δ-lactams from N-alkenyl trichloroacetamides is reported in tetrahydrofuran or 2-methyltetrahydrofuran alone. These catalyst and additive-free reactions are achieved with non-anhydrous solvents and under an air atmosphere where the solvent serves as the radical initiator.

3.
Molecules ; 27(18)2022 Sep 14.
Artículo en Inglés | MEDLINE | ID: mdl-36144721

RESUMEN

Natural and synthetic ß-lactam derivatives constitute an interesting class of compounds due to their diverse biological activity. Mostly used as antibiotics, they were also found to have antitubercular, anticancer and antidiabetic activities, among others. In this investigation, six new 3,3-dichloro-ß-lactams prepared in a previous work were evaluated for their hemolytic and cytotoxic properties. The results showed that the proposed compounds have non-hemolytic properties and exhibited an interesting cytotoxic activity toward squamous cell carcinoma (A431 cell line), which was highly dependent on the structure and concentration of these ß-lactams. Among the molecules tested, 2b was the most cytotoxic, with the lowest IC50 values (30-47 µg/mL) and a promising selectivity against the tumor cells compared with non-tumoral cells.


Asunto(s)
Antineoplásicos , beta-Lactamas , Acetamidas , Antineoplásicos/química , Antineoplásicos/farmacología , Antituberculosos/farmacología , Catálisis , Línea Celular Tumoral , Cloroacetatos , Hipoglucemiantes , Microondas , beta-Lactamas/química
4.
J Org Chem ; 87(15): 10516-10522, 2022 08 05.
Artículo en Inglés | MEDLINE | ID: mdl-35862855

RESUMEN

A synthetic approach to a functionalized ABC-tricyclic framework of calyciphilline A-type alkaloids, a building block toward this class of alkaloids, is reported. The key synthetic steps involve a radical cyclization to form the hydroindole system and piperidine ring closure through a stereocontrolled aldol cyclization. The resulting alcohol allows the methyl group to be installed in the bowl-shaped azatricyclic structure; this crucial reaction takes place with configuration retention. The synthesis of azatricyclic compound I constitutes a formal synthesis of himalensine A.


Asunto(s)
Alcaloides , Aldehídos , Alcaloides/química , Ciclización , Estructura Molecular , Compuestos Policíclicos , Estereoisomerismo
5.
Org Biomol Chem ; 20(15): 3118-3123, 2022 04 13.
Artículo en Inglés | MEDLINE | ID: mdl-35333274

RESUMEN

The first blue light-mediated synthesis of γ- and δ-lactams from trichloroacetamides is reported in the presence of fac-Ir(ppy)3. Unlike previous works, these reactions are achieved under an air atmosphere with non-anhydrous solvents and even in water. Moreover, we have demonstrated that the solvent can be the hydrogen donor in the radical process which opens up new insights into these radical transformations and the reaction mechanisms involved.


Asunto(s)
Hidrógeno , Lactamas , Catálisis , Luz
6.
Org Biomol Chem ; 19(10): 2284-2301, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33625434

RESUMEN

The 5-endo-trig radical cyclization of N-benzyl-N-[(2-substituted)cycloalkenyl] trichloroacetamides (tetrasubstituted enamides) using Bu3SnH and AIBN is a reliable synthetic procedure giving access to 3a-methyl- and 3a-methoxycarbonyl enelactams. The substrate-controlled diastereoselective enolate alkylation of these enelactams resulted in the synthesis of a set of 3-substituted derivatives that upon reduction furnished polyfunctionalized cis-octahydroindoles. The latter building blocks, which embody three consecutive stereocenters at C-3, C-3a, and C-7a, were also synthesized through an initial reductive radical cyclization using (carbo-substituted)dichloroacetamides.

7.
Org Lett ; 21(14): 5757-5761, 2019 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-31264879

RESUMEN

An azapentacyclic compound with the daphenylline ACDEF ring framework was synthesized from a benzo[e]indole intermediate efficiently obtained by a 5-endo-trig radical cyclization of a bicyclic trichloroenamide. Stereocontrolled processes were used to generate the three stereogenic methine carbons in the pyrrolidine C ring including the all-carbon quaternary stereocenter at C5. Ring closure to build both seven- and five-membered rings was achieved by Friedel-Crafts reactions.

8.
Chem Commun (Camb) ; 52(97): 14031-14034, 2016 Nov 29.
Artículo en Inglés | MEDLINE | ID: mdl-27853764

RESUMEN

Radical cyclization of dichloroacetamide-tethered ketones using pyrrolidine, AIBN and TTMSS under microwave activation gave 2-azabicyclo[3.3.1]nonan-3,6-diones. In a five-minute one-pot process, after the generation of an enamine, intramolecular addition of a carbamoylchloromethyl radical, and oxidation of the α-aminoalkyl radical intermediate, the resulting iminium salt evolved to the corresponding enamine and, after a workup, to the alkylated ketone.

9.
Org Lett ; 17(15): 3860-3, 2015 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-26197207

RESUMEN

An unexpected C-C bond cleavage was observed in trichloroacetamide-tethered ketones under amine treatment and exploited to develop a new synthesis of normophans from 4-amidocyclohexanones. The reaction involves an unprecedented intramolecular haloform-type reaction of trichloroacetamides promoted by enamines (generated in situ from ketones) as counter-reagents. The methodology was applied to the synthesis of compounds embodying the 6-azabicyclo[3.2.1]octane framework.


Asunto(s)
Compuestos de Azabiciclo/síntesis química , Ciclohexanonas/química , Cetonas/química , Acetamidas/química , Compuestos de Azabiciclo/química , Cloroacetatos/química , Indicadores y Reactivos , Estructura Molecular , Estereoisomerismo
10.
Org Lett ; 17(3): 568-71, 2015 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-25607252

RESUMEN

Synthesis of the tetracyclic cores of madangamines D-F was achieved, featuring a reductive radical process from an ethoxycarbonyldichloroacetamide to build the morphan nucleus, a Mitsunobu-type aminocyclization toward the common diazatricyclic intermediate, and ring-closing metathesis reactions for the macrocyclization step leading to the 13- to 15-membered rings.


Asunto(s)
Alcaloides/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Alcaloides/química , Ciclización , Compuestos Heterocíclicos de 4 o más Anillos/química , Biología Marina , Estructura Molecular , Estereoisomerismo
11.
J Org Chem ; 79(19): 9365-72, 2014 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-25203675

RESUMEN

Intramolecular Kharasch-type additions of trichloroacetamides on anisole and enol acetates catalyzed by Grubbs' ruthenium carbenes are described. This protocol provides access to highly functionalized 2-azaspiro[4.5]decanes, morphan compounds, and the azatricyclic core of FR901483.

12.
Chem Commun (Camb) ; 48(70): 8799-801, 2012 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-22836236

RESUMEN

A novel synthetic entry to 2-azabicyclo[3.3.1]nonanes based on a copper(I)-catalyzed intramolecular coupling of amino-tethered trichloroacetamides and unsaturated nitriles, esters and alkenes, as well as enol acetates, is described. A study of the reaction conditions and the scope of the process is reported.


Asunto(s)
Alcanos/síntesis química , Compuestos de Azabiciclo/síntesis química , Cobre/química , Ciclohexenos/química , Acetamidas/química , Alquenos/química , Catálisis , Cloroacetatos/química , Ciclización , Electrones , Ésteres , Espectroscopía de Resonancia Magnética , Nitrilos , Estereoisomerismo
13.
Org Biomol Chem ; 9(9): 3180-7, 2011 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-21423929

RESUMEN

Under radical reaction conditions, two different and competitive reaction pathways were observed for N-(α-methylbenzyl)trichloroacetamides with a N-3-cyclohexenyl substituent: 1,4-hydrogen translocation and radical addition to a double bond. However, for radicals with an acyclic alkenyl side chain, the direct cyclisation process was exclusively observed. The dichotomy between translocation and direct radical cyclisation in these substrates has been theoretically studied using density functional theory (DFT) methods at the B3LYP/6-31G** computational level.


Asunto(s)
Alquenos/química , Cloroacetatos , Acetamidas , Ciclización , Radicales Libres/química , Modelos Moleculares , Estructura Molecular , Ácido Tricloroacético/síntesis química
14.
Chem Commun (Camb) ; 47(11): 3251-3, 2011 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-21274472

RESUMEN

The intramolecular reaction of secondary amines with tethered alkenes using NIS was studied, which gave insight into the kinetic vs. thermodynamic control of the iodoaminocyclization and the regioselectivity of the aziridinium ring-opening reactions, and led to functionalized piperidines.


Asunto(s)
Aminas/química , Piperidinas/química , Alquenos/química , Aminas/síntesis química , Ciclización , Deuterio/química , Cinética , Espectroscopía de Resonancia Magnética , Piperidinas/síntesis química , Termodinámica
15.
Org Biomol Chem ; 7(12): 2517-9, 2009 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-19503923

RESUMEN

The six-membered nitrogen-containing ring of the morphan scaffold, ubiquitous in natural products, is formed by an intramolecular aldol process of an aza-tethered dicarbonyl compound, leading to the first asymmetric synthesis of a morphan derivative using organocatalysis.


Asunto(s)
Aldehídos/química , Compuestos de Azabiciclo/síntesis química , Microondas , Compuestos de Azabiciclo/química , Catálisis , Glicina/análogos & derivados , Glicina/química , Cetonas/química , Prolina/química , Estereoisomerismo , Especificidad por Sustrato
17.
J Org Chem ; 73(2): 768-71, 2008 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-18095709

RESUMEN

Synthesis of the tricyclic core of madangamine alkaloids has been achieved in a 10-step sequence starting from a 4-(aminomethyl)anisole derivative. A Birch reduction and acylation with cyanoacetic acid followed by an intramolecular Michael process renders a polyfunctionalized cis-perhydroisoquinoline. A diastereoselective allylation and reduction of amide, nitrile, and ketone groups leads to a bicyclic alcohol, which undergoes aminocyclization through the nosyl derivative to the diazatricyclic ring.


Asunto(s)
Alcaloides/síntesis química , Isoquinolinas/química , Alcaloides/química , Ciclización , Compuestos Heterocíclicos de 4 o más Anillos/química , Estructura Molecular , Estereoisomerismo
18.
Org Lett ; 9(14): 2633-6, 2007 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-17550259

RESUMEN

Bishomoallylic secondary amines embodying the 2-allyl-N-benzylcyclohexylamine unit react with NIS to undergo cyclization through 6-endo processes in either the cis or trans series. Nevertheless, when the resulting cis-3-iododecahydroquinolines are treated with Al2O3, the exo derivatives evolve into octahydroindoles and the endo derivatives keep the same backbone, the configuration being retained in the generated alcohols.


Asunto(s)
Aminas/síntesis química , Ciclohexilaminas/química , Níquel/química , Quinolinas/síntesis química , Ciclización , Indicadores y Reactivos
19.
Magn Reson Chem ; 43(7): 599-601, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15924281

RESUMEN

The 1H and 13C NMR spectra of six 5-substituted 2-azabicyclo[2.2.2]octane derivatives were fully assigned by COSY and HSQC experiments.


Asunto(s)
Espectroscopía de Resonancia Magnética/métodos , Quinuclidinas/análisis , Quinuclidinas/química , Isótopos de Carbono , Espectroscopía de Resonancia Magnética/normas , Protones , Valores de Referencia
20.
J Org Chem ; 68(14): 5746-9, 2003 Jul 11.
Artículo en Inglés | MEDLINE | ID: mdl-12839475

RESUMEN

The scope and limitations of Pd(0)-catalyzed intramolecular coupling of amino-tethered vinyl halides and ketone enolates as a methodology for the synthesis of nitrogen heterocycles have been studied. This reaction constitutes a synthetic procedure to obtain bridged, condensed, and monocyclic nitrogen-containing compounds.


Asunto(s)
Aminas/química , Compuestos Heterocíclicos/síntesis química , Catálisis , Ciclización , Paladio
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