Regiochemical Variations in Reactions of Methylcubane with tert-Butoxyl Radical, Cytochrome P-450 Enzymes, and a Methane Monooxygenase System

Citations Over TimeTop 10% of 1996 papers

Abstract

Reactions of methylcubane (1) with the tert-butoxyl radical (t-BuO•), with cytochrome P-450 enzymes, and with a methane monooxygenase (MMO) system have been studied. For the purpose of product characterization, authentic samples of 2-methylcubyl and 4-methylcubyl derivatives were prepared. 2-Methylcubanecarboxylic acid (9b) is a new compound prepared from cubanecarboxylic acid. The key synthetic reactions were (1) metalation and subsequent iodination of the 2-position of (diisopropylcarbamoyl)cubane to effect the initial functionalization, (2) lithium-for-iodine exchange and methylation followed by reduction to give 2-methyl-1-[(diisopropylamino)methyl]cubane, and (3) dimethyldioxirane oxidation of this amine to give 9b. The known 4-methylcubanecarboxylic acid (9d) was prepared here by a route related to that employed for 9b. Reactions of acids 9b and 9d with methyllithium gave the corresponding methyl ketones which were oxidized by m-chloroperoxybenzoic acid to provide authentic samples of 2- and 4-methylcubanol acetates (3b and 3d). Reaction of 1 with t-BuO• in the presence of 2,2,5,5-tetramethylisoindole-N-oxyl radical (TMIO•) at 40−55 °C gave mainly cube-substituted products in confirmation of the report (Della, E. W.; Head, N. J.; Mallon, P.; Walton, J. C. J. Am. Chem. Soc. 1992, 114, 10730) that hydrogen atom abstraction by the electrophilic alkoxyl radical at low temperature occurs at the cubyl C−H positions. In a competition experiment at 42 °C, methylcubane was at least 3.5 times more reactive toward t-BuO• than cyclohexane, indicating that the cubyl positions in 1 are ≥40 times more reactive than the methyl positions in 1 (per hydrogen) toward the alkoxyl radical. Oxidation of 1 by enzymes gave alcohol products that were converted to their acetate derivatives for identification and quantitation. Microsomal cytochrome P-450 enzymes from rat and the rat purified P-450 isozyme CYP2B1 hydroxylated 1 at all positions, whereas the reconstituted MMO system from Methylococcus capsulatus (Bath) hydroxylated 1 only at the methyl position. The differences in regioselectivity suggest that the transition states for hydrogen abstraction by the alkoxyl radical and for enzyme-catalyzed hydroxylation differ considerably. The results are consistent with a model for concerted enzyme catalyzed hydroxylation of 1 involving “side-on” approach to the C−H bond of substrate.

Related Papers

• → Alkylation of 2-Substituted (6-Methyl-2-pyridyl)methyllithium Species with Epoxides(2008)13 cited
• → Furopyridines. XII. Reaction of 3‐bromo, 2‐phenylthio and 2‐phenylthio‐3‐bromo derivatives of furo[2,3‐b]‐, furo[3,2‐b]‐, furo[2,3‐c]‐ and furo[3,2‐c]pyridine with several alkyllithiums(1992)20 cited
• → Some observations on the pyrolysis of methyllithium(1992)3 cited
• → ChemInform Abstract: Alkylation of 2‐Substituted (6‐Methyl‐2‐pyridyl)methyllithium Species with Epoxides.(2009)
• → ChemInform Abstract: Some Observations on the Pyrolysis of Methyllithium.(1992)