Chemistry Reference
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SCHEME 19.11
In order for the rearrangement to take place, the presence of an alkoxy
group at the
a
position of the ester or, alternatively, the presence of an ortho
hydroxymethyl group in the aryl group is essential.
68
Prodrugs 42 exhibit DNA cleaving properties and cytotoxicity in vitro
indicating that the allylic rearrangement may occurr also in aqueous buffer,
without Lewis acid catalysis. Interestingly, in this case also the free alcohols
are active. In particular, for Ar
2-naphthyl, compounds with EC
50
around
1-10
m
M were obtained. They also were demonstrated to be cytotoxic on
cancer cell lines.
68
ΒΌ
19.3.2 C
YCLIC
E
NEDIYNES
F
USED WITH
A
RENES
T
HROUGH THE
D
OUBLE
B
OND
The fusion of the 10-membered enediyne ring with a benzene ring brings
about a marked decrease of the cycloaromatization rate, probably because
of the lower gain in aromatic stabilization (Scheme 19.12). Thus compound
44 is stable for more than 1 week at 37
C, undergoing appreciable Bergman
reaction only at 84
C. Moreover, the rate is dependent on the concentration
of 1,4-cyclohexadiene.
69
This fact seems to be due to a change in the rate
limiting step, with the hydrogen abstraction by the di-radical becoming the
slow one.
70
A similar behavior was shown by 45.
71
Interestingly, the corres-
ponding ketone reacted slightly faster.
SCHEME 19.12
A strong difference between hydroquinone 46 and quinone 47 has been
observed. The former is quite stable up to 100
C, whereas 47 undergoes
cycloaromatization at 55
C with a t
1/2
of 32min. This result opens the way
for conceivable hydroquinone prodrugs to be activated upon an oxidative
process.
72
Actually, despite its stability, the hydroquinone 46 induced in vitro
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