Angewandte
Chemie
prostaglandin E synthase 1 (mPGES-1; anti-inflammatory
2
[
20a]
[20b]
activity)
and for induction of apoptosis in cancer cells.
In our test systems,
[20]
myrtucommulone A isolated from
myrtle and synthetic myrtucommulone A showed almost
identical activity (Table 1).
Table 1: IC50 values [mm] for suppression of mPGES-1 and EC50 values for
induction of apoptosis for synthetic and natural myrtucommulone A (1),
synthetic 13, derivatives 11a and 11b, and myrtucommulone analogues.
Compound
mPGES-1 Inhibition
Induction of apoptosis
IC50 [mm]
EC50 [mm]
synthetic 1
natural 1
0.7
1.0
3.1
3.2
1
1
1
1
2
1a + 11b
>100
0.6
>100
1.3
3
8
9
0
1.8
1.0
0.4
0.8
n.d.
n.d.
[
[
a]
a]
[a] n.d.: not determined.
Scheme 5. Syntheses of myrtucommulone F (13) and myrtucommu-
lone C (16). a) 3, piperidine, CH Cl , RT, 15 min; b) HCl/NH Cl; c) 12,
2
2
4
NaH (2 equiv), THF, RT, 3 h, quantitative; d) 2, NaH (2 equiv), THF,
RT, 3 h, quantitative; e) pTsOH, benzene, reflux, 1 h, 96%.
With our strategy we could synthesize myrtucommu-
lone A (1), myrtucommulone F (13), and myrtucommulone C
16) as mixtures of all stereoisomers. Starting with known
(
(
Scheme 3) under basic conditions myrtucommulone C (16)
compounds, the synthesis consists of only one step (acid-
catalyzed reaction) or two steps (base-catalyzed reaction).
Research to determine the absolute configuration of natural 1
and to develop a synthesis of enantiomerically pure 1 and
further analogues is in progress.
[5]
was obtained, which was recently isolated by Shaheen et al.
(
to vary all three building blocks to synthesize myrtucommu-
lone analogues (Scheme 6).
Scheme 5).Through the strategy presented here it is possible
We determined the efficiency of the synthetic myrtucom-
mulones A and F, and some for inhibition of microsomal
Experimental Section
10: Syncarpic acid (1.1 g, 6 mmol) was suspended in dichloromethane
(20 mL) in a 250 mL round-bottom flask. Piperidine (1.2 mL, 2 equiv,
12 mmol) and isobutyraldehyde (822 mL, 1.5 equiv, 9 mmol) were
added to this stirred suspension. After 10 min. the reaction mixture
was concentrated to dryness (20 Torr, 408C). The residue was
dissolved in dichloromethane and this solution was stirred vigorously
for 15 min with 1n HCl, which had been saturated with NH Cl. The
4
phases were separated and the organic layer was dried over MgSO4.
The drying agent was removed by filtration and the solvent was
removed under reduced pressure. The crude product was filtered
through a 5 cm thick pad of silica gel (petroleum ether/acetone 2:1 (v/
v)), the eluent was removed by evaporation. The crude product was
pure enough to use in the next step and was dissolved in THF (c =
ꢀ
1
1
molL ) under N2.
: Sodium hydride (100 mg, 2 mmol, 2 equiv, 60% in mineral oil)
1
was washed two or three times in a dry 50 mL round-bottom flask
under N , each time with roughly 5 mLTHF. The remaining pure NaH
2
was suspended in 5 mL THF. Isobutyryl phloroglucinol (196 mg,
1
mmol, 1 equiv) was added to this suspension, and the mixture was
stirred for 5 min at room temperature prior to addition of the solution
of the Michael acceptor 10. Stirring was continued for 3 h, and then
the reaction mixture was quenched with saturated aqueous NH Cl
4
and extracted with diethyl ether. The organic extracts were dried over
MgSO , the drying agent was removed by filtration, and the volatiles
4
Scheme 6. Syntheses of the myrtucommulone analogues 18–20. a) 3,
piperidine, CH Cl , RT, 15 min; b) HCl/NH Cl; c) 2, NaH (2 equiv),
were removed evaporation. The crude product was purified by flash
chromatography (silica gel, petroleum ether/acetone 3:2 (v/v), R =
2
2
4
f
THF, RT, 3 h, quantitative; d) acetyl phloroglucinol, NaH (2 equiv),
THF, RT, 3 h, 96%; e) isovaleraldehyde, piperidine, CH Cl , RT, 15 min.
0.13). Yield: 665 mg myrtucommulone A (quant.) as a pale yellow
solid. Melting range: 150–1808C. Synthetic and natural myrtucom-
[
21]
2
2
Angew. Chem. Int. Ed. 2010, 49, 2045 –2049
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim