arylketone-substituted alkyl acids with DDQ. It was found
that these alkyl acids could also be converted to lactones using
DDQ in refluxing benzene (Table 3, entries 10–14). And the
six-membered ring lactone 27 was obtained in higher yield
(62%) than five-membered ring lactones (19, 21, 23, 25)
(36–58%). These racemic arylketone lactones warrant further
investigation in the future.
Finally, the antitumor activity of olean-28,13b-olide 2
against human hepatoma BEL-7402 cells, human cervical
cancer HeLa cells, and human breast cancer MCF-7 cells
was determined using MTT assays16 that showed IC50s of
2.1, 5.3, and 3.7 mM, respectively. These antiproliferative
effects are comparable to those of the positive control
CDDO–Me17 (see the ESIw, S33).
In conclusion, a novel and facile DDQ-mediated approach
to generate olean-28,13b-olides and other pentacyclic triterpen-
28,13b-olides like urs-28,13b-olide was developed, which can
be applied not only to natural rigid polycyclic systems but also
to flexible compounds. ESR spectroscopy experiments revealed
that DDQ-mediated olean-28,13b-olide formation occurred
via a radical ion mechanism, which is supported by DPPHꢀ-
promoted chemical identification. More importantly, we
obtained both direct and indirect evidence for an enol transient
intermediate in the formation of olean-28,13b-olide that
occurs via an enolization of the C12-ketone. A preliminary
biological study showed that 2 exhibits comparable in vitro
antitumor activity to CDDO–Me. Further pharmaceutical
investigations of 2 and other olean-28,13b-olides, urs-28,13b-
olides are underway, and the results will be reported in due
course.
Scheme 2 A proposed radical ion mechanism for the DDQ-mediated
formation of olean-28,13b-olide 2.
enolization of the ring C ketone could be involved in the
formation of lactone.
A battery of mechanistic information has now been acquired
that includes: (i) data obtained from DPPHꢀ-mediated reactions;
(ii) ESR spectra of the DDQ-promoted reactions; (iii) invest-
igations to determine the role of the C12-carbonyl; (iv) trapping
of a C12-enol transient intermediate; and (v) Floreancig et al.’s
recent reports showing that DDQ can induce a radical cation
intermediate on an electron-rich benzene ring or a vinyl moiety
before the a-position carbon hydrogen bond is homolytically
cleaved.13,14 Accordingly, based on the above data, we now
propose a radical ion mechanism as depicted in Scheme 2, while
a similar mechanism for quinone dehydrogenations of hydro-
aromatic to aromatic hydrocarbons was mentioned by Hofler
¨
and Ruchardt.15 In refluxing benzene, DDQ can trap an electron
Notes and references
¨
from the electron-rich enone on ring C of CDDO to produce
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–
a radical cation c and a radical anion DDQꢀ . Subsequent
homolytic cleavage of the C–H bond at the C13 position of
CDDO forms a dienol radical cation d. Then the oxygen atom
with a pair of electrons on the C28-carboxylic hydroxyl of d acts
as a nucleophile to attack the C13, followed by deprotonation to
form a lactone radical e and DDQHꢀ. The intermediate e is
subsequently oxidized by DDQHꢀ to generate cation f and
DDQH–. Finally, f is deprotonated to provide 2 and DDQH2.
To extend the potential applications of this method, we
investigated the DDQ-induced lactonization of other oleanane
and ursane compounds. As shown in Table 3, all oleanane and
ursane compounds can be converted to their corresponding
lactones except for the following three compounds: 5 without a
C12-carbonyl, 6 without a free C28-carboxyl and 15 without a
C13-H (Table 3, entries 2, 3, and 8). Expectedly, compounds
with more electron-rich a,b-unsaturation of the C12-ketone
gave higher yields (78–89%, Table 3, entries 1, 4, 5, 6, and 9) in
comparison with compound 13 without a double bond (61%,
Table 3, entry 7). All results are consistent with the proposed
radical ion mechanism. Notably, in contrast to the known
synthesis of olean-28,13b-olides, this DDQ-mediated approach
tolerates several oxidation-sensitive moieties (Table 3, entries 1
and 9).
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¨
¨
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To examine whether this methodology could be applied
not only to natural rigid polycyclic systems but also to
flexible compounds, we investigated the reactions of some
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9495–9497 9497