Aromaticity as a cornerstone of heterocyclic chemistry.

Quantitative measures of aromaticity for mono-, bi-, and tricyclic penta- and hexaatomic heteroaromatic ring systems and their interrelationships.

Publisher Summary This chapter discusses aromaticity of heterocycles. At a time when the validity of the concept of aromaticity is questioned, increasingly, it seems appropriate to review various definitions in common use and to survey their applications in heterocyclic chemistry. From a qualitative viewpoint the characteristics of an aromatic compound are easy to define. A compound is said to be aromatic if it is cyclic and unsaturated with an enhanced stability over simple olefinic compounds. The characteristic aromatic reactivity of the type described is clearly a matter of degree and is difficult to assess quantitatively. From a simple consideration of pyridine, which reacts less readily with electrophiles but more readily with nucleophiles at the ring carbon atoms than does benzene, it soon becomes apparent that attempts to discuss even relative aromatic character using kinetic criteria is fraught with difficulties; this is apart from the fundamental objection that chemical reactivity is not solely a function of ground-state stability.

Aromaticity of Heterocycles

Naphthalenic lignan lactone 3a (L-702,539), a potent and selective 5-lipoxygenase (5-LO) inhibitor, is extensively metabolized at two different sites:  the tetrahydropyran and the lactone rings. Early knowledge of the metabolic pathways triggered and directed a structure−activity relationship study aimed toward the improvement of metabolic stability in this series. The best modifications discovered, i.e., replacement of the lactone ring by a nitrile group, replacement of the tetrahydropyran ring by a 6,8-dioxabicyclo[3.2.1]octanyl moiety, and replacement of the pendant phenyl ring by a 3-furyl ring, were incorporated in a single molecule to produce inhibitor 9ac (L-708,780). Compound 9ac inhibits the oxidation of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid by 5-LO (IC50 = 190 nM) and the formation of leukotriene B4 in human polymorphonuclear leukocytes (IC50 = 3 nM) as well as in human whole blood (IC50 = 150 nM). The good inhibitory profile shown by naphthalenenitrile 9ac is accompanied by an ...

Dioxabicyclooctanyl Naphthalenenitriles as Nonredox 5-Lipoxygenase Inhibitors: Structure−Activity Relationship Study Directed toward the Improvement of Metabolic Stability

L.N. Ferguson

Papers

On the aromatic character of 4-pyrones☆