Total synthesis of myrtucommulone A

Article abstract of DOI:10.1002/anie.200903906

(Chemical Equation Presented) In a one-step conversion, commercially available or known compounds are connected to form myrtucommulone A, an anti-inflammatory and apoptosis-inducing substance from the common myrtle Myrtus communis (see scheme). This strategy can be used, as well to prepare myrtucommulone libraries.

Full text of DOI:10.1002/anie.200903906

Angewandte
Chemie
DOI: 10.1002/anie.200903906
Natural Product Synthesis
Total Synthesis of Myrtucommulone A**
Hans Mꢀller, Michael Paul, David Hartmann, Volker Huch, Dagmar Blaesius, Andreas Koeberle,
Oliver Werz, and Johann Jauch*
Dedicated to Prof. Dr. Volker Schurig on the occasion of his 70th birthday
[
8]
Myrtucommulone A (1; Figure 1) was first described in 1974
total synthesis of myrtucommulone A (1), myrtucommu-
lone F (13), myrtucommulone C (16), and three analogues
thereof. Based on the constitutional symmetry of 1 the
retrosynthetic disconnection shown in Scheme 1 seems rea-
sonable. It should be possible to synthesize 1 from isobutyryl
phloroglucinol (2), isobutyraldehyd (3), and syncarpic acid (4)
by Kashman and co-workers as a substance found in the
common myrtle Myrtus communis L. These authors also
[1a]
[
9]
in one step.
Isobutyryl phloroglucinol (2) is readily available through
Friedel–Crafts acylation of phloroglucinol (5) in 70–80%
[
10]
yield (Scheme 2).
Syncarpic acid (4) is described in the
Figure 1. Myrtucommulone A (1).
reported that 1 is highly active against Gram-positive
[1b]
[2]
bacteria. Three years later Lounasmaa and co-workers
isolated myrtucommulone A from other members of the
myrtacea family. After that, interest in myrtle died down until
[
3]
2
002 when Appendino and co-workers re-examined extracts
of this Mediterranean shrub and described additional myrtu-
[
4]
commulones and their anti-oxidative properties. Shaheen
[
5]
et al. recently isolated the myrtucommulones C to E and
other natural products from Myrtus communis. Quinn and co-
[6]
workers examined extracts from Corymbia scabrida and
could identify 1 and the myrtucommulones F to I.
We became interested in the myrtucommulones when it
was reported that these compounds show very significant anti-
inflammatory activity as well as highly selective apoptosis-
inducing activity. For detailed studies of the pharmacolog-
ical activities of these compounds it seemed reasonable to
develop a synthetic strategy leading to myrtucommulone A
[7]
Scheme 1. Retrosynthetc disconnection of 1 into isobutyryl phlorogluci-
nol (2), isobutyraldehyde (3), and syncarpic acid (4).
(1) and the other myrtucommulones. Here, we report on our
[
*] H. Mꢀller, M. Paul, D. Hartmann, Prof. Dr. J. Jauch
Universitꢁt des Saarlandes, Organische Chemie II
Postfach 15 11 50, 66041 Saarbrꢀcken (Germany)
Fax: (+49)681-3026-4301
E-mail: j.jauch@mx.uni-saarland.de
Dr. V. Huch
Universitꢁt des Saarlandes
Anorganische und Allgemeine Chemie, Saarbrꢀcken (Germany)
D. Blaesius, Dr. A. Koeberle, Prof. Dr. O. Werz
Pharmazeutisches Institut, Universitꢁt Tꢀbingen (Germany)
[
**] We are grateful to the Universitꢁt des Saarlandes for generous
Scheme 2. Synthesis of 2 and 4. a) Acetyl chloride, AlCl , CS /nitro-
3
2
support of this project.
benzene, reflux, 70%; b) isobutyric chloride, AlCl , CS /nitrobenzene,
3
2
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200903906.
reflux, 70%; c) MeI, NaOMe, MeOH, reflux 12 h, 85%; d) 2n HCl,
reflux, 4 h, 95%.
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Communications
[11]
literature and is also available from 5 (Scheme 2). Accord-
ing to reference [11a] 5 is acetylated to give acetyl phloro-
glucinol (6), which is methylated to provide the tetramethyl
derivative 7 and finally deacetylated under acidic conditions.
Reactions of syncarpic acid (4) with aldehydes were
[
12]
[13]
described by Crow and co-workers, by Baltas et al., and
[
14]
also by Andrꢀ-Barrꢁs and co-workers. According to these
authors, syncarpic acid reacts under acidic conditions with
aldehydes such as 3 to give compound 8. To avoid this side
reaction, we treated 4 with 3 to obtain the Mannich base 9 , in
[
12]
analogy to the report by Crow et al.
Compound 9 was
converted in situ into myrtucommulone A (1) through the
action of anhydrous toluenesulfonic acid (alternatively with
trifluoroacetic acid) in approximately 35% yield (yields
ranged from 15 to 45%) (Scheme 3, steps b–d). In this
synthesis a Mannich reaction (!9), an elimination (!10),
and two acid catalyzed Friedel–Crafts alkylations take place
consecutively in one reaction flask.
Scheme 4. Synthesis of pentacyclic derivatives from myrtucommu-
lone A (1). a) pTsOH, benzene, reflux, 1 h, 95%.
thetic 1 from acetone to obtain crystals suitable for X-ray
[
19]
analysis
(Figure 2). The X-ray structure confirmed our
structure determination that was based on the NMR spectra
of the pentacyclic derivatives 11a and 11b.
Scheme 3. Synthesis of myrtucommulone A (1). a) 3, HCl; b) 3, piper-
idine, CH Cl , RT, 10 min.; c) pTsOH, CH Cl , RT, 10 min.; d) add 2,
2
2
2
2
then reflux, 24 h, 35%; e) HCl/NH Cl, isolate 10 as crude product;
4
f) 2, NaH (2 equiv), THF, RT, 3 h, quantitative.
The rather low yield of 1 under acidic conditions is a
consequence of dehydration to give the pentacyclic derivative
1
1 (Scheme 4). Therefore we decided to carry out the Friedel–
[
15]
Crafts alkylation under basic conditions, since this should
not result in 11. Running the Friedel–Crafts alkylation under
basic conditions required removal of the acid and isolation of
1
0 as a crude product prior to reaction with 2, which had been
deprotonated with two equivalents of NaH in THF. With this
modification, the synthesis of 1 is complete within three hours
at room temperature in quantitative yield after chromato-
graphic purification (Scheme 3, steps b, e, and f).
Figure 2. X-ray structure of myrtucommulone A (1); ellipsoids at the
50% probability level.
Determination of the structure of 1 directly by NMR
[16]
spectroscopy was extremely difficult. Therefore we treated
our synthetic compound with toluenesulfonic acid to effect
cyclization and dehydration (Scheme 4). We obtained the
pentacyclic derivatives 11a and 11b, which were separated by
preparative HPLC and characterized by NMR spectroscopy.
The first eluting 11a was the racemate while the second
eluting 11b was the meso compound. Therefore, our synthetic
The same synthetic strategy was applied to the starting
compounds syncarpic acid (4), isobutyraldehyd (3), and
hexanoyl phloroglucinol (12) to prepare myrtucommulone F
[6]
(13), which was recently described by Quinn et al.
(Scheme 5). By variation of the equivalents of 10 and 2 it
was possible to monoalkylate 2 to yield 14, which was
converted into 15 by acid-catalyzed cyclization and dehydra-
tion. When 15 was treated again with the Michael acceptor 10
1
is a mixture of three stereoisomers, one pair of enantiomers
[
18]
and one meso form. Additionally, we recrystallized syn-
2
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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
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Communications
mulone show identical NMR spectra (see the Supporting Informa-
tion).
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Gorrichon, Tetrahedron Lett. 2001, 42, 2465 – 2468; b) V. Bernat,
C. Andrꢀ-Barrꢁs, M. Baltas, N. Saffon, H. Vial, Tetrahedron
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Received: July 16, 2009
Published online: February 12, 2010
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Keywords: alkylation · apoptosis · Michael addition ·
.
natural products · total synthesis
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[
16] Myrtucommulone A (1) is a complex mixture of different
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13
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[
[
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other methods.
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[
[
17] Conditions for preparative HPLC: HPLC setup (Sykam; pump
S1521 and detector S3210); column: Macherey–Nagel Nucleo-
dur 100 5C-18 ec, 250 mm length and 21 mm inner diameter;
[
[
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ꢀ1
eluent: methanol/water 90:10; flow: 25 mLmin ; room temper-
ature; detection at 210, 254, and 283 nm; retention times
t (11a) = 10.07 min; t (11b) = 12.58 min. (see the Supporting
R
R
Information). Interestingly, only linear pentacyclic derivatives
formed. Angular derivatives could not be detected.
18] The ratio between 11a and 11b is 54:46 (see the Supporting
Information). The double Friedel–Crafts alkylation occurs with
low-level simple diastereoselectivity in favor of the chiral
myrtucommulone A. To our knowledge, this is the first example
of a double intermolecular Friedel–Crafts alkylation, in which a
benzylic stereogenic center influences the configuration of the
newly formed stereogenic center in meta position (see also the
Supporting Information and A. J. Lampkins, O. Abdul-Rahim,
R. K. Castellano, J. Org. Chem. 2006, 71, 5815—5818); Diaste-
reoselective Friedel–Crafts alkylations with chiral alkylating
reagents have been studied. See for example: a) A. C. Silvanus,
S. J. Heffernan, D. J. Liptrot, G. Kociok-Kꢂhn, B. I. Andrews,
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[
8] J. Jauch, International Patent PCT/EP 2009/006226, 2009.
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[19] X-ray analysis of 1: C38
H
52
O
10, bright yellow crystals, M
r
=
ꢀ
1
ꢀ
667.79 gmol ; triclinic, space group P1: a = 10.494(1), b =
12.436(1), c = 14.305(2) ꢄ, a = 81.755(7), b = 89.403(7), g =
75.669(7)8, V= 1789.5(4) ꢄ , Z = 2, m(MoKa) = 1.239 mm , T=
120 K, F(000) = 718. Data were collected on a Bruker-AXS
X8Apex diffractometer. 47122 reflections up to 2qmax = 608 were
3
ꢀ1
2
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Chemie
registered, of which 10236 independent reflections were used for
all calculations. The structure was solved by direct methods and
thase 1 was analyzed in the microsomal preparation of inter-
leukion-1b-stimulated A549 lung epithelial carcinoma cells. See:
A. Koeberle, U. Siemoneit, U. Bꢃhring, H. Northoff, S. Laufer,
W. Albrecht, O. Werz, J. Pharmacol. Exp. Ther. 2008, 326, 975 –
982. The induction of apoptotic cell death of human promyelo-
cytic leukemia cells (HL-60) was analyzed after 24 h incubation
by MTT assay. See Ref. [7b].
[
22]
anisotropically refined with all non-hydrogen atoms.
The
hydrogen atoms were treated as rigid groups with idealized
geometry at their carbon atoms. The isopropyl groups C12 and
C26 are disordered according to the potential isomers and were
refined at split-atom positions. The refinement with I > 2s(I)
resulted in a final R1 = 0.058, wR2 = 0.15. CCDC 640674 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[21] Recrystallization from methanol yields an amorphous powder
with a melting point of 183–1858C; Ref. [1]: 185–1868C. Natural
1, which was not recrystallized from methanol, also showed a
melting range from 150–1808C.
[22] G. M. Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112 – 122.
[
20] The catalytic transformation of prostaglandin H to pro-inflam-
2
matory prostaglandin E2 by microsomal prostaglandin E2 syn-
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