Reactions of muconaldehyde isomers with nucleophiles including tri-O-acetylguanosine: Formation of 1,2-disubstituted pyrroles from reactions of the (Z,Z)-isomer with primary amines

Abstract

(Z,Z)-Muconaldehyde reacts with primary amines, including valine and lysine (epsilon-amino), to afford N-substituted-2-(oxoethyl)pyrroles, which were reduced with sodium borohydride to the more stable N-substituted-2-(hydroxyethyl)pyrroles. The formation of the pyrrole aldehydes was performed in a variety of solvents including aqueous methanol. With tri-O-acetylguanosine, the putative pyrrole aldehyde derived from reaction at NH2 condenses with N-1 (guanine component) to afford a bicyclic adduct: 4,5-dihydro-5-hydroxy-10-beta-D-tri-O- acetylribosylpyrrolo[1',2':3,4]pyrimido[1,2-a]purin-7(10H)-one (5a). This was hydrolyzed to 4,5-dihydro-5-hydroxy-10-beta-D- ribosylpyrrolo[1',2':3,4]pyrimido[1,2-a]purin-7(10H)-one (5b). The structures of 5a and 5b were primarily based on NMR evidence and comparison with 4,5-dihydro-5-hydroxy-9-methylpyrrolo[1',2':3,4]pyrimido[2,1-b] pyrimidin-7-one (7), obtained from reacting (Z,Z)-muconaldehyde with 2-amino-4-hydroxy-6-methylpyrimidine. (E,Z)-Muconaldehyde also reacted with primary amines to give N-substituted-2-(oxoethyl)pyrroles, whereas (E,E)-muconaldehyde gave bis-imines. The results described are discussed in the context of the carcinogenicity of benzene.

Chemistry of muconaldehydes of possible relevance to the toxicology of benzene.

“…The material obtained was identical with previously prepared as by 'H NMR (10). Reaction of(ZZ)-Muconaldebyde with 2-Amino-4-hydroxy-6-methylpyrimidine 3a to Afford 4,5-Dihydro-5-hydroxy-8methylpyrrolo[l',2':3,4]pyrimido[2, 1-b]pyrimidine-6-one 3b.…”

“…This may explain the observation that conversion of (Z,Z)into (E,Z)-muconaldehyde is faster at higher pH. The cyclization process shown certainly occurs in basic methanol because the the cis-and transisomers of 2-(2'-hydroxyethyl)-5-methoxy-2,5-dihydrofuran were isolated after borohydride reduction (10). Further information on the isomerizations of (Z,Z)into (E,Z)and (E,E)-muconaldehyde in water and aqueous buffers is given in the sections on reactions of (Z,Z)-muconaldehyde with nucleosides.…”

Dimethyldioxirane Converts Benzene Oxide/Oxepin into (Z,Z)-Muconaldehyde and sym-Oxepin Oxide: Modeling the Metabolism of Benzene and Its Photooxidative Degradation

“…There is ample evidence to indicate that enals of the muconaldehyde type are potentially carcinogenic (). Indeed, metabolically produced muconaldehydes are candidates for explaining the carcinogenicity of benzene ( , ). Thus, attempts to elucidate the complex toxicology of benzene () are focused on the roles of the isomeric muconaldehydes 2a − c ( , ), as well as the metabolites benzene oxide ( 1a ) ( , ) and 1,2- and 1,4-benzoquinone ().…”

“…Indeed, metabolically produced muconaldehydes are candidates for explaining the carcinogenicity of benzene ( , ). Thus, attempts to elucidate the complex toxicology of benzene () are focused on the roles of the isomeric muconaldehydes 2a − c ( , ), as well as the metabolites benzene oxide ( 1a ) ( , ) and 1,2- and 1,4-benzoquinone (). We have shown that ( Z,Z )-muconaldehyde ( 2a ) and ( E,Z )-muconaldehyde ( 2b ) can form cyclic adducts with the DNA bases adenine and guanine ().…”

Enantiopure arene dioxides: chemoenzymatic synthesis and application in the production of trans-3,4-dihydrodiols

“…3 Oxepine epoxide 8 and Z,Z-muconaldehyde have been implicated in DNA adduct formation and possibly the carcinogenicity of benzene (Scheme 1). 4 Evidence that arene dioxides can be formed in eucaryotic systems is provided by the isolation of the anti-naphthalene dioxide 9 as a liver metabolite of naphthalene, 5 and the synbenzene dioxide 10 as a fungal metabolite. 6 Following earlier studies of remote site epoxidation of arene oxide derivatives of polycyclic arenes using DMD, 7 we have extended this method to the synthesis of anti-arene dioxides in mono-and polycyclic arenes.…”