Influence of the methyl group in isoprene epoxides on reactivity compared to butadiene epoxides: Biological significance

Abstract

Reactions of the epoxides of 1,3-butadiene and isoprene (2-methyl-1,3-butadiene) with oxygen, nitrogen and sulfur nucleophiles have been compared to enable a better molecular understanding of the relative human toxicities of these epoxides. Hydrolysis of rac.-ethenyloxirane in (¹⁸O)water gave 77% (2-¹⁸O)but-3-ene-1,2-diol and 23% (1-¹⁸O)but-3-ene-1,2-diol. The R:S ratio for but-3-ene-1,2-diol from hydrolysis of (S)-ethenyloxirane was 75:25. Hence, hydrolysis of ethenyloxirane occurs by competing S_N2 attack at C-2 and C-3 in 3:1 ratio, with no S_N1 component. Hydrolysis of rac.-2-ethenyl-2-methyloxirane gave 2-hydroxy-2-methylbut-3-en-1-ol (73%) and 27% of a 2:1 mixture of the E- and Z-isomers of 4-hydroxy-2-methylbut-2-en-1-ol. In (¹⁸O)water (2-¹⁸O)2-hydroxy-2-methylbut-3-en-1-ol was obtained. Formation of these products occurs via S_N1 ionisation to resonance-stabilised allylic cations which are captured by water. Reaction of rac.-ethenyloxirane with l-valine methyl ester gave diastereoisomeric adducts from S_N2 attack of the valine amino at both C-2 (substituted position) and C-3 of the oxirane. The corresponding reaction of rac.-2-methyl-2-ethenyloxirane gave diastereoisomeric adducts, (R, S)- and (S, S)-N-(2-hydroxy-2-methyl-3-buten-1-yl)-l-valine methyl ester, from S_N2 attack of the valine amino solely at C-3. Reactions of rac.-2-ethenyl-2-methyloxirane with cysteine derivatives occurred at C-2 in neutral polar media (S_N1 reaction) or at C-3 in basic media (S_N2), whereas for ethenyloxirane products arose from attack at both C-2 and C-3. Reaction of meso-butadiene diepoxide (meso-2,2'-bioxirane) with l-valine methyl ester gave mainly 2:1 adducts, dimethyl 2,2'-(((2R,3S)-2,3-dihydroxybutane-1,4-diyl)bis(azanediyl))-(2S,2'S)-bis(3-methyl-butanoates), whereas 2-methyl-2,2'-bioxirane gave a mixture of 1:1 [methyl 2-(3,4-dihydroxy-3-methylpyrrolidin-1-yl)-3-methylbutanoates] and 2:1 adducts. Meso-2,2'-bioxirane reacted with N-acetylcysteine methyl ester in methanol to afford meso-thiolane-3,4-diol, by elimination of N-acetyldehydroalanine methyl ester from a precursor cyclic adduct. Similarly, 2-methyl-2,2'-bioxirane gave solely 3-methylthiolane-3,4-diols. Thus, the methyl group of isoprene has a subtle effect on the reactivity of its epoxides relative to those of butadiene and therefore, in the context of their toxicology, could abrogate crosslinking of nitrogen functions in biomolecules related to mutagenicity and carcinogenicity.

Keywords: Butadiene; Epoxide; Isoprene; Metabolites; Mutagenicity; Reaction mechanisms.