RESUMO
The [5-6-7] azatricyclic ABC core, found in several Daphniphyllum alkaloids, has been synthesized through a novel route involving ring expansion of a perhydroindolone to afford the AC ring system and a radical B ring closure as key steps. The level of functionalization of the reported octahydro-1,7-ethanocyclohepta[b]pyrroles suggests that they can serve as valuable building blocks in this alkaloid field. Also reported is the first synthesis of homomorphans by the ring enlargement of 2-azabicyclo[3.3.1]nonanes.
RESUMO
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.
RESUMO
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).
Assuntos
Lactamas , Micro-Ondas , Lactamas/química , Lactamas/síntese química , Lactamas/farmacologia , Ciclização , Humanos , Catálise , Camundongos , Animais , Linhagem Celular Tumoral , Acetamidas/química , Acetamidas/síntese química , Acetamidas/farmacologia , Estrutura Molecular , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/químicaRESUMO
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.
Assuntos
Alcaloides , Aldeídos , Alcaloides/química , Ciclização , Estrutura Molecular , Compostos Policíclicos , EstereoisomerismoRESUMO
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.
Assuntos
Hidrogênio , Lactamas , Catálise , LuzRESUMO
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.
Assuntos
Antineoplásicos , beta-Lactamas , Acetamidas , Antineoplásicos/química , Antineoplásicos/farmacologia , Antituberculosos/farmacologia , Catálise , Linhagem Celular Tumoral , Cloroacetatos , Hipoglicemiantes , Micro-Ondas , beta-Lactamas/químicaRESUMO
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.
RESUMO
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.
RESUMO
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.
Assuntos
Alcenos/química , Cloroacetatos , Acetamidas , Ciclização , Radicais Livres/química , Modelos Moleculares , Estrutura Molecular , Ácido Tricloroacético/síntese químicaRESUMO
A gamma-carboline series of cysLT(1) receptor antagonists has been prepared. Some of the compounds show good potencies both, in vitro and in vivo, compared to the standard compounds.
Assuntos
Carbolinas/química , Química Farmacêutica/métodos , Antagonistas de Leucotrienos/síntese química , Receptores de Leucotrienos/química , Administração Oral , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/farmacologia , Desenho de Fármacos , Cobaias , Humanos , Concentração Inibidora 50 , Antagonistas de Leucotrienos/farmacologia , Modelos Químicos , Relação Estrutura-Atividade , Fatores de TempoRESUMO
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.
Assuntos
Aldeídos/química , Compostos Azabicíclicos/síntese química , Micro-Ondas , Compostos Azabicíclicos/química , Catálise , Glicina/análogos & derivados , Glicina/química , Cetonas/química , Prolina/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
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.
RESUMO
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.
Assuntos
Aminas/síntese química , Cicloexilaminas/química , Níquel/química , Quinolinas/síntese química , Ciclização , Indicadores e ReagentesRESUMO
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.
RESUMO
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.
Assuntos
Compostos Azabicíclicos/síntese química , Cicloexanonas/química , Cetonas/química , Acetamidas/química , Compostos Azabicíclicos/química , Cloroacetatos/química , Indicadores e Reagentes , Estrutura Molecular , EstereoisomerismoRESUMO
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.
Assuntos
Alcaloides/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Alcaloides/química , Ciclização , Compostos Heterocíclicos de 4 ou mais Anéis/química , Biologia Marinha , Estrutura Molecular , EstereoisomerismoRESUMO
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.
Assuntos
Alcanos/síntese química , Compostos Azabicíclicos/síntese química , Cobre/química , Cicloexenos/química , Acetamidas/química , Alcenos/química , Catálise , Cloroacetatos/química , Ciclização , Elétrons , Ésteres , Espectroscopia de Ressonância Magnética , Nitrilas , EstereoisomerismoRESUMO
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.
Assuntos
Aminas/química , Piperidinas/química , Alcenos/química , Aminas/síntese química , Ciclização , Deutério/química , Cinética , Espectroscopia de Ressonância Magnética , Piperidinas/síntese química , TermodinâmicaRESUMO
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.