Reactions of
methylcubane (
1) with the
tert-butoxyl radical (
t-BuO
mages/entities/bull.gif">), withcytochro
me P-450 enzy
mes,and with a
methane
monooxygenase (MMO) syste
m have been studied.For the purpose of product characterization,authentic sa
mples of 2-
methylcubyl and 4-
methylcubyl derivatives wereprepared. 2-Methylcubanecarboxylic acid(
9b) is a new co
mpound prepared fro
m cubanecarboxylic acid.The key synthetic reactions were (1)
metalation andsubsequent iodination of the 2-position of(diisopropylcarba
moyl)cubane to effect the initialfunctionalization, (2)lithiu
m-for-iodine exchange and
methylation followed by reduction togive 2-
methyl-1-[(diisopropyla
mino)
methyl]cubane, and (3) di
methyldioxirane oxidation of this a
mine to give
9b. The known 4-
methylcubanecarboxylicacid(
9d) was prepared here by a route related to that e
mployedfor
9b. Reactions of acids
9b and
9d with
methyllithiu
mgave the corresponding
methyl ketones which were oxidized by
m-chloroperoxybenzoic acid to provide authenticsa
mples of 2- and 4-
methylcubanol acetates (
3b and
3d). Reaction of
1 with
t-BuO
mages/entities/bull.gif"> in the presence of 2,2,5,5-tetra
methylisoindole-
N-oxyl radical (TMIO
mages/entities/bull.gif">) at40-55
![](/i<font color=)
mages/entities/deg.gif">C gave
mainly cube-substituted products in confir
mationofthe report (Della, E. W.; Head, N. J.; Mallon, P.; Walton, J. C.
J. Am. Chem. Soc. 1992,
114, 10730)that hydrogenato
m abstraction by the electrophilic alkoxyl radical at lowte
mperature occurs at the cubyl C-H positions. In aco
mpetition experi
ment at 42
![](/i<font color=)
mages/entities/deg.gif">C,
methylcubane was at least 3.5 ti
mes
more reactive toward
t-BuO
mages/entities/bull.gif"> thancyclohexane,indicating that the cubyl positions in
1 are
![](/i<font color=)
mages/entities/ge.gif">40 ti
mes
morereactive than the
methyl positions in
1 (perhydrogen)toward the alkoxyl radical. Oxidation of
1 by enzy
mesgave alcohol products that were converted to their acetatederivatives for identification and quantitation. Microso
malcytochro
me P-450 enzy
mes fro
m rat and the rat purifiedP-450 isozy
me CYP2B1 hydroxylated
1 at all positions,whereas the reconstituted MMO syste
m fro
mMethylococcuscapsulatus (Bath) hydroxylated
1 only at the
methylposition. The differences in regioselectivity suggest thatthetransition states for hydrogen abstraction by the alkoxyl radical andfor enzy
me-catalyzed hydroxylation differconsiderably. The results are consistent with a
model forconcerted enzy
me catalyzed hydroxylation of
1involving"side-on" approach to the C-H bond of substrate.