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

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• 作者：Seung-Yong Choi ; Philip E. Eaton ; Paul F. Hollenberg ; Katherine E. Liu ; Stephen J. Lippard ; Martin Newcomb ; David A. Putt ; Subhash P. Upadhyaya ; and Yusheng Xiong
• 刊名：Journal of the American Chemical Society
• 出版年：1996
• 出版时间：July 17, 1996
• 年：1996
• 卷：118
• 期：28
• 页码：6547 - 6555
• 全文大小：258K
• 年卷期：v.118,no.28(July 17, 1996)
• ISSN：1520-5126

文摘

Reactions of methylcubane (1) with thetert-butoxyl radical (t-BuO), withcytochrome 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 wereprepared. 2-Methylcubanecarboxylic acid(9b) is a new compound prepared from cubanecarboxylic acid.The key synthetic reactions were (1) metalation andsubsequent iodination of the 2-position of(diisopropylcarbamoyl)cubane to effect the initialfunctionalization, (2)lithium-for-iodine exchange and methylation followed by reduction togive 2-methyl-1-[(diisopropylamino)methyl]cubane, and (3) dimethyldioxirane oxidation of this amine to give9b. The known 4-methylcubanecarboxylicacid(9d) was prepared here by a route related to that employedfor 9b. Reactions of acids 9b and9d with methyllithiumgave the corresponding methyl ketones which were oxidized bym-chloroperoxybenzoic acid to provide authenticsamples of 2- and 4-methylcubanol acetates (3b and3d). Reaction of 1 witht-BuO in the presence of 2,2,5,5-tetramethylisoindole-N-oxyl radical (TMIO) at40-55 C gave mainly cube-substituted products in confirmationofthe report (Della, E. W.; Head, N. J.; Mallon, P.; Walton, J. C.J. Am. Chem. Soc. 1992, 114, 10730)that hydrogenatom abstraction by the electrophilic alkoxyl radical at lowtemperature occurs at the cubyl C-H positions. In acompetition experiment at 42 C, methylcubane was at least 3.5 timesmore reactive toward t-BuO thancyclohexane,indicating that the cubyl positions in 1 are 40 times morereactive than the methyl positions in 1 (perhydrogen)toward the alkoxyl radical. Oxidation of 1 by enzymesgave alcohol products that were converted to their acetatederivatives for identification and quantitation. Microsomalcytochrome P-450 enzymes from rat and the rat purifiedP-450 isozyme CYP2B1 hydroxylated 1 at all positions,whereas the reconstituted MMO system fromMethylococcuscapsulatus (Bath) hydroxylated 1 only at the methylposition. The differences in regioselectivity suggest thatthetransition states for hydrogen abstraction by the alkoxyl radical andfor enzyme-catalyzed hydroxylation differconsiderably. The results are consistent with a model forconcerted enzyme catalyzed hydroxylation of 1involving"side-on" approach to the C-H bond of substrate.