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Journal of Natural Products
ARTICLE
Scheme 1. Syntesis of 5-10a
preserved phytotoxicity to different extents, whereas a significant
decrease and/or a complete loss of activity was observed for the
derivatives 3, 4, 5, 6, 9, 10, and 12. In particular, the 1,4-dione
derivative (7) showed the same strong activity as shown by 1 on
all tested plant species. The derivative 8 was moderately toxic
(necrosis diameter <2 mm for all species tested except for tomato
leaves). Compound 11, the monoacetyl derivative of episphaer-
opsidone (2), exhibited a modest decrease in phytotoxicity in
comparison to 2, whereas its triacetyl derivative (12) was inactive
in the bioassay.
In the tomato cuttings bioassay, compounds 1, 2, 7, and 11
were active. The cuttings treated with 0.1 mg/mL sphaeropsi-
done (1) and derivative 7 showed complete wilting (leaves and
stems) within 48 h of application. Furthermore, symptoms of
phytotoxicity (stewing on stem) were also observed with deri-
vative 7 at concentration of 0.025 mg/mL. At the same concentra-
tion, sphaeropsidone (1) and its epimer (2) were inactive. Epis-
phaeropsidone (2) appeared to be less toxic than 1 in this bioassay.
The tomato cuttings showed wilting symptoms (at first only
on the stem) after four days at a concentration of 0.1 mg/mL.
Derivative 11 showed stewing on the stem at 0.1 mg/mL. None
of the other compounds caused any visible symptoms in this
bioassay at the highest concentration used.
These results allowed us to speculate on the structure-activity
relationships and on some structural features determining the
phytotoxic activity shown by each dimedone methyl ether.
The epoxy ring seems to be somehow associated with the
activity, even if it is not alone sufficient to produce the phytotoxic
effects. The marked decrease and/or the complete lack of activity
for derivatives 3, 4, 6, 10, and 12 supports this result. Considering
that some compounds preserving the epoxy ring were inactive, it
is reasonable to suppose that other features of the molecule,
other than the epoxy ring, could be important.
a Reagents and conditions: (a) Ac2O, pyridine, 80 ꢀC; (b) MnO2,
CH2Cl2, rt; (c) Li2NiBr4, THF, rt; (d) NaBH4, MeOH, rt; (e) H2, Pd
10%, MeOH, rt.
Scheme 2. Synthesis of 11 and 12a
The oxidation of the C-5 allylic hydroxy group leading to 7
seems to enhance, albeit slightly, the bioactivity of 1, whereas the
stereoselective epoxy ring-opening obtained by converting 1 into
the corresponding bromohydrin (8) reduces the bioactivity of 1.
The activity of 7 can probably be ascribed to its quinonoid nature,
and thus to its greater reactivity with nucleophiles compared to
the R,β-unsaturated carbonyl group of 1. The persistent,
although reduced, toxicity of 8 is probably due to its conversion
in vivo into 1 by an SN2 nucleophilic oxirane-forming process via
the C-6 OH group and the bromide ion being a good leaving
group. This probably did not occur in 3, as the chloride ion is a
poor nucleofuge compared to the bromide ion. However, in this
case it generated an R-oxirane ring. On the other hand, 4 is not
suitable for an SN2 nucleophilic substitution.
Both the reduction of the C-2 carbonyl group (9) and the
reduction of the olefinic double bond with the selective reductive
opening of the epoxy ring (10) led to a complete loss of activity.
The lack of toxicity exhibited by derivative 9 underlines the
important role of the C-2 carbonyl group in the biological
activity.
Furthermore, not all compounds (see derivatives 3, 4, 5, 9, and
12) preserving the olefinic Δ3 double bond were active. This
result could suggest that this feature is probably not essential for
activity. However, compounds 3, 4, 5, 9, and 12 also showed the
opening of the oxirane ring and/or the modification of other
structural features important for toxicity.
A marked loss of activity was observed with the conversion, by
acetylation, of 1 in derivative 5 and 6. It is interesting to note that
5-O-acetylsphaeropsidone (5) was inactive compared to its
a Reagents and conditions: (a) Ac2O, NaOAc, 80 ꢀC.
R-pseudoequatorial and R-pseudoaxial, respectively, and con-
sequently their geminal hydroxy group β-pseudoaxial and
β-pseudoequatorial.19 This stereochemistry is also in agreement
with a Dreiding model of 10.
Derivative 10 showed both the reduction of the olefinic
double bond and the selective reductive opening of the epoxy
ring, resulting in the 2,4-dihydroxycyclohexanone, which should
assume a half-chair conformation.
Finally, acetylation of episphaeropsidone (Scheme 2) yielded
the corresponding 5-O-acetyl derivative (11), which is the
5-epimer of 5, and the triacetyl derivative (12). The latter,
following acetylation of the C-5 hydroxy group as in 11, was
probably generated by cleavage of the epoxy ring via nucleophlic
attack of the acetoxy group at the less hindered C-1 from the
R-side and subsequent acetylation of the resulting anionic oxygen at
C-6. The configuration of 12, deduced from the coupling
constants, confirmed such a hypothesized reaction mechanism.
Two bioassays were used to investigate the phytotoxic activity
of sphaeropsidones (1, 2), their natural analogues 3 and 4, and
derivatives 5-12 as described in the Experimental Section. In the
leaf puncture bioassay, the phytotoxicity was evaluated for
Quercus ilex, Q. rubra, Q. suber, and tomato leaves. The toxicity
data in Figure 1 show that both sphaeropsidone (1) and its
epimer (2), at the concentration used, had remarkable toxicity,
causing necrotic lesions to leaves of all species tested. Among the
sphaeropsidone (1) derivatives, only compounds 7 and 8
759
dx.doi.org/10.1021/np100837r |J. Nat. Prod. 2011, 74, 757–763