Tetrahedron report number 221

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 α4β2 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 α4β2 nAChR affinity and the desired in vivo dopaminergic profile.

Varenicline: An α4β2 Nicotinic Receptor Partial Agonist for Smoking Cessation

Insofar as one of the fundamental objectives of organic synthesis is the construction of complex molecules from simpler ones, the importance of synthetic efficiency becomes immediately apparent and has been well-recognized.1 The increase in molecular complexity2 that necessarily accompanies the course of a synthesis provides a guide (and a measure) of synthetic efficiency. As a goal, one would like to optimally match the change in molecular complexity at each step with reactions of comparable synthetic complexity. Thus, the creation of many bonds, rings, and stereocenters in a single transformation is a necessary (though not sufficient) condition for high synthetic efficiency. The ultimate, perfect match would constitute single-step syntheses. More realistically, especially in view of the desire for general synthetic methods, the combination of mulScott E. Denmark was born in New York in 1953. He obtained an S.B. degree from MIT in 1975 and carried out research with Daniel Kemp and Richard Holm. His graduate studies at the ETH-Zurich with Albert Eschenmoser culminated with the D. Sc. Tech. degree in 1980. That same year he joined the faculty of the University of Illinois at UrbanasChampaign and was promoted to full professor in 1987. In 1991 he was named the Reynold C. Fuson Professor of Chemistry. His research interests are primarily in the invention of new synthetic reactions, structure and reactivity of organoelement reagents, and the origin of stereocontrol in fundamental carbon−carbon bond forming reactions.

Tandem [4+2]/[3+2] Cycloadditions of Nitroalkenes.

Diels-Alder reactions of azadienes

Publisher Summary The first step toward unravelling the mechanism of an enzyme-catalyzed reaction is to specify the mechanisms available for the reaction concerned. Many of these reactions are not observed when the relevant groups are allowed to come together in bimolecular processes in aqueous solution. For mechanistic work involving intermolecular reactions, it is necessary to use activated substrates. An attractive alternative is to study intramolecular reactions. These are generally faster than the corresponding intermolecular processes. Thus, groups like carboxyl and imidazole are involved at the active sites of many enzymes hydrolyzing aliphatic esters and amides. Therefore, mechanistic studies of intramolecular reactions play an important part in elucidating the chemistry of the groups involved in enzyme catalysis and in defining the mechanisms available for particular reactions.

Effective Molarities for Intramolecular Reactions

Proton magnetic resonance spectra of some norbornane derivatives having double bonds and (or) a benzene ring in the skeleton were studied Differences in the chemical shifts between the bridge meth

N.m.r. studies of bridged ring systems: ii. unusual magnetic deshielding effect on the bridge methylenes of norbornadiene and benzonorbornadiene

Solvolysis of endo-anti-Tricyclo[3.2.1.02,4]octan-8-yl p-Nitrobenzoate and Two Routes to Tricyclo[5.1.0.04,8]octane Derivatives

Solvolyses of aryldineopentylcarbinyl, aryl-tert-butylneopentylcarbinyl, and aryldi-tert-butylcarbinyl p-nitrobenzoates. Effects of the bulky alkyl groups at the reaction center and substituents in the aryl ring

N.m.r. studies of bridged ring systems. i. carbon-hydrogen spin coupling constants in bicyclo[2,2,1]heptane derivatives

Transient 8,8-dimethylisobenzofulvene (5) was generated by thermal decomposition of two materials; one is formally an adduct of cyclopentadienone with 9-isopropylidenebenzonorbornadiene (6), and the other an adduct of 3,6-di(2′-pyridyl)-S-tetrazine with 6. The former was prepared by cycloaddition of 6 to tetrachlorodimethoxycyclopentadiene followed by dechlorination giving a ketal, then hydrolysis of the ketal function. Generation without any trapping reagent instantaneously yielded one kind of dimer of a stereospecific structure. In the presence of dimethyl maleate, dimethyl 9-isopropylidenebenzonorbornene-exo,cis-2,3-dicarboxylate and its endo-cis isomer were formed. In the presence of dimethyl fumarate, the trans isomer was obtained. Trapping with tropone led to a 1 : 1 adduct resulting from participation of the exocyclic C2–C8 double bond in 5. All attempts to isolate 5 or prepare a stable metal complex of 5 by conventional means were unsuccessful.

Hiroshi Tanida

Papers

N.m.r. studies of bridged ring systems: ii. unusual magnetic deshielding effect on the bridge methylenes of norbornadiene and benzonorbornadiene

Solvolysis of endo-anti-Tricyclo[3.2.1.02,4]octan-8-yl p-Nitrobenzoate and Two Routes to Tricyclo[5.1.0.04,8]octane Derivatives

Solvolyses of aryldineopentylcarbinyl, aryl-tert-butylneopentylcarbinyl, and aryldi-tert-butylcarbinyl p-nitrobenzoates. Effects of the bulky alkyl groups at the reaction center and substituents in the aryl ring

N.m.r. studies of bridged ring systems. i. carbon-hydrogen spin coupling constants in bicyclo[2,2,1]heptane derivatives

Generation and Cycloaddition of 8,8-Dimethylisobenzofulvene