RESUMO
The key elimination step for the formation of 3-substituted and 3,6-disubstituted benzynes from 2-haloaryllithiums displays a pronounced solvent-dependent regioselectivity. All 2-haloaryllithiums with electron withdrawing groups in the 6 position are shown by 6Li and 13C NMR spectroscopic studies to be monomers in THF. DFT computational studies implicate trisolvates. Rate studies reveal that LiF eliminates via monomer-based pathways requiring THF dissociation whereas LiCl eliminates via nondissociative pathways. Elimination to form 3-chloro- and 3-fluorobenzyne from 2-chloro-6-fluorophenyllithium displays a pronounced solvent-dependent regioselectivity that is traced to competing solvent-dissociative and nondissociative dissociative pathways for the elimination of LiCl and LiF, respectively.
Assuntos
Derivados de Benzeno/química , Derivados de Benzeno/síntese química , Simulação por Computador , Hidrocarbonetos Halogenados/química , Cinética , Lítio/química , Espectroscopia de Ressonância Magnética/métodos , Modelos Químicos , Estrutura Molecular , Compostos Organometálicos/química , Solventes/químicaRESUMO
[Structure: see text] The development of a concise enantioselective synthesis of nicotinic alkaloid 1 is presented. The route features the synthesis and use of a "stable" aliphatic triflate 21 in an alkylation step to generate Heck precursor 24 and an enantioselective cyclization to establish a compound with the key [3.2.1]-bicyclic core, 29.
Assuntos
Sondas Moleculares , Nicotina/análogos & derivados , Receptores Nicotínicos/química , Cristalografia por Raios X , Modelos Moleculares , Nicotina/síntese química , EstereoisomerismoRESUMO
3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Receptores Nicotínicos/metabolismo , Abandono do Hábito de Fumar/métodos , Animais , Ciclização , Estrutura Molecular , Piperidinas/classificação , Ratos , Relação Estrutura-AtividadeRESUMO
Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.
Assuntos
Benzazepinas/síntese química , Agonistas Nicotínicos/síntese química , Quinoxalinas/síntese química , Receptores Nicotínicos/efeitos dos fármacos , Abandono do Hábito de Fumar/métodos , Animais , Benzazepinas/química , Benzazepinas/farmacologia , Linhagem Celular , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Humanos , Técnicas In Vitro , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Quinoxalinas/química , Quinoxalinas/farmacologia , Ensaio Radioligante , Ratos , Receptores Nicotínicos/fisiologia , Vareniclina , Xenopus laevisRESUMO
The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
Assuntos
Alcaloides/farmacologia , Carbono/química , Dopamina/metabolismo , Agonistas Nicotínicos/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores Nicotínicos/química , Alcaloides/química , Animais , Azocinas/química , Azocinas/farmacologia , Agonistas Nicotínicos/química , Quinolizinas/química , Quinolizinas/farmacologia , Ratos , Receptores Nicotínicos/metabolismo , Abandono do Hábito de Fumar , Relação Estrutura-AtividadeRESUMO
The key elimination step for the formation of 3-chloro- and 3-fluorobenzyne from 2-chloro-6-fluorophenyllithium displays a pronounced solvent-dependent regioselectivity. 6Li and 13C NMR spectroscopic studies on 2-chloro-6-fluorophenyllithium reveal a single monomeric aryllithium, suggested by DFT computational studies to be a trisolvate. Rate studies indicate that the elimination of LiCl and LiF proceeds via trisolvated and disolvated monomers, respectively.
Assuntos
Derivados de Benzeno/síntese química , Compostos Bicíclicos com Pontes/síntese química , Lítio/química , Derivados de Benzeno/química , Cinética , Espectroscopia de Ressonância Magnética/métodos , Compostos Organometálicos/químicaRESUMO
Noncoordinating solvents permit the halogen-metal exchange-induced formation of benzyne (aryne) from di- and trihalobenzene precursors in the presence of cyclopentadiene to give 1,4-dihydro-1,4-methano-naphthalenes. Studies with mixed halide precursors and nonacidic Diels-Alder diene traps reveal that ethereal and hydrocarbon solvents influence the halide leaving group facility, resulting in a reversal of 3-halobenzyne regioselectivity.