ABSTRACT
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.
Subject(s)
Benzene Derivatives/chemistry , Benzene Derivatives/chemical synthesis , Computer Simulation , Hydrocarbons, Halogenated/chemistry , Kinetics , Lithium/chemistry , Magnetic Resonance Spectroscopy/methods , Models, Chemical , Molecular Structure , Organometallic Compounds/chemistry , Solvents/chemistryABSTRACT
[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.
Subject(s)
Molecular Probes , Nicotine/analogs & derivatives , Receptors, Nicotinic/chemistry , Crystallography, X-Ray , Models, Molecular , Nicotine/chemical synthesis , StereoisomerismABSTRACT
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.
Subject(s)
Piperidines/chemistry , Piperidines/pharmacology , Receptors, Nicotinic/metabolism , Smoking Cessation/methods , Animals , Cyclization , Molecular Structure , Piperidines/classification , Rats , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Alkaloids/pharmacology , Carbon/chemistry , Dopamine/metabolism , Nicotinic Agonists/pharmacology , Nucleus Accumbens/drug effects , Receptors, Nicotinic/chemistry , Alkaloids/chemistry , Animals , Azocines/chemistry , Azocines/pharmacology , Nicotinic Agonists/chemistry , Quinolizines/chemistry , Quinolizines/pharmacology , Rats , Receptors, Nicotinic/metabolism , Smoking Cessation , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Benzazepines/chemical synthesis , Nicotinic Agonists/chemical synthesis , Quinoxalines/chemical synthesis , Receptors, Nicotinic/drug effects , Smoking Cessation/methods , Animals , Benzazepines/chemistry , Benzazepines/pharmacology , Cell Line , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Humans , In Vitro Techniques , Nicotinic Agonists/chemistry , Nicotinic Agonists/pharmacology , Oocytes/drug effects , Oocytes/physiology , Quinoxalines/chemistry , Quinoxalines/pharmacology , Radioligand Assay , Rats , Receptors, Nicotinic/physiology , Varenicline , Xenopus laevisABSTRACT
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.
Subject(s)
Benzene Derivatives/chemical synthesis , Bridged Bicyclo Compounds/chemical synthesis , Lithium/chemistry , Benzene Derivatives/chemistry , Kinetics , Magnetic Resonance Spectroscopy/methods , Organometallic Compounds/chemistryABSTRACT
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.
