Synthesis and absolute configuration of (S)-(+)-chichimol ketone: the defensive secretion of walking stick Agathemera elegans

Article abstract of DOI:10.1016/j.tetasy.2009.02.030

The first enantioselective synthesis of chichimol ketone (4-methyl-1-hepten-3-one) is described and the absolute configuration of the main semiochemical compound is determined as having an (S)-configuration. The synthesis features the use of a ruthenium c

Full text of DOI:10.1016/j.tetasy.2009.02.030

Tetrahedron: Asymmetry 20 (2009) 1062–1064
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and absolute configuration of (S)-(+)-chichimol ketone: the
defensive secretion of walking stick Agathemera elegans
*
Marlene Espinoza-Moraga, Roxana Cornejo-Morales, Leonardo Silva Santos
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, Universidad de Talca, PO Box 747, Talca, Chile
a r t i c l e i n f o
a b s t r a c t
Article history:
The first enantioselective synthesis of chichimol ketone (4-methyl-1-hepten-3-one) is described and the
absolute configuration of the main semiochemical compound is determined as having an (S)-configura-
tion. The synthesis features the use of a ruthenium catalytic asymmetric hydrogenation reaction to intro-
duce chirality into acid 2. The synthetic chichimol ketone (S)-1 displayed a specific rotation that was in
accordance with that of the natural product, thereby supporting the (S) configuration for natural chichi-
mol ketone. To assure the correct stereochemical assignment, (S)-1 was converted in the known ketone
(S)-5: the main alarm pheromone of the ant Atta texana that is 400 times more active than its (R)-
enantiomers.
Received 4 February 2009
Accepted 10 February 2009
Available online 25 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
a,b-unsaturated acids employing Ru catalysts, followed by the addi-
tion of a vinyl Grignard to a Weinreb amide to give 1 (Scheme 1).
As part of our current interest in the use of asymmetric
hydrogenation catalysis,4 we figured out the synthesis of (S)-1 by
hydrogenation of E-2-methyl-2-pentenoic acid 2 employing (S)-
H8-BINAP-Ru(OAc)2 catalyst.5 Transition-metal-catalyzed asym-
metric hydrogenation of prochiral double bonds represents one
of the most efficient and atom economic methods for preparing
chiral compounds, and has attracted increasing attention in both
industrial production and academic research. Catalytic enantiose-
Organic synthesis has remained an important branch of chem-
istry, while chemical ecology is a new and interdisciplinary branch
of science developed since the 1970s. Chemical ecology deals with
the chemistry and biology of inter- and intraspecific interactions
among organisms, by means of semiochemicals (signal substance).
Semiochemicals are biomolecules that spread information
between individuals. The word is synonymous with ‘signal sub-
stances’ and is derived from ‘semio’ (Greek = sign). Many insects
rely on the use of chemical compounds for communication, chem-
ical signaling, and defense. In the Phasmatodea order, around 2500
species of walking stick insects are known to produce noxious
defensive secretions. However, the defensive chemistry of only a
few species to date has been elucidated.1 Insects of the genus
Agathemera (Phasmatidae) live in the Chilean Andes over 3500 m
above sea level. Under stress, the insects release a spray that can
cause temporary blindness in humans.2 The composition of chem-
icals used for defense by South American phasmids was studied by
Schmeda-Hirschmann, who reported that both the female and
male defensive secretion of Agathemera elegans are made up of 4-
methyl-1-hepten-3-one (Fig. 1).3 This compound was reported
for the first time as a natural product; however, its absolute config-
uration was not determined.
lective hydrogenation of
a,b-unsaturated carboxylic acids is a
straightforward method for the synthesis of chiral carboxylic acids,
which are important intermediates for the construction of biolog-
ically active compounds.6 Thus, (S)-3 was obtained by employing
the asymmetric Ru-hydrogenation of acid 2 in 85% yield, Scheme
2.7 The enantiomeric excess of 3 was determined after derivatiza-
tion with aniline to give the phenylamide. The phenylamide deriv-
ative of 3 was subjected to HPLC analysis by employing a chiral
Welch-01 column; the enantiomeric excess for the hydrogenation
R or S ?
Herein, we report a short approach to the synthesis of chichimol
ketone 1 (Fig. 1). The synthetic route envisioned for chichimol
ketonefeaturesthepreparationof(S)-methylalkylacids,thekeyinter-
mediate in our approach, through the asymmetric hydrogenation of
O
1
chichimol ketone
* Corresponding author. Tel.: +56 71 201575; fax: 56 71 200448.
E-mail address: lssantos@utalca.cl (L.S. Santos).
Figure 1. Agathemera elegans found in cordillera Chilean valleys and chichimol
ketone isolated as the main semiochemical.3
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.030

M. Espinoza-Moraga et al. / Tetrahedron: Asymmetry 20 (2009) 1062–1064
1063
ral acrylic acid 2. Using (S)-BINAP as a diphosphine ligand resulted
in lower enantioselectivities by 10% (86% ee) when compared with
(S)-H8-BINAP. To prevent any racemization during the following
reactions, all glassware apparatus were treated with 1.0 mL of
chlorotrimethylsilane (freshly distilled from calcium hydride),
which was removed under reduced pressure.
Next carboxylic acid (S)-3 was converted into the corresponding
Weinreb amide 4 using N,O-dimethylhydroxyamine, EDC, and
HOBt in DMF,8 as depicted in Scheme 2. The higher reactivity of
the amide allowed us to introduce the vinyl group with a Grignard
reagent at À20 °C (Scheme 2). The reaction of the Weinreb amide
(S)-4 with vinyl magnesium bromide provided enone derivative
(S)-1 in 75% yield. GC analysis using chiral Heptakis column was
performed to assure the ee of 1. The racemic standard ( )-1 was
obtained from ( )-3 to assure the reliability of the ee analysis. No
epimerization was observed in the further steps of the synthesis,
which was prevented by using TMSCl in all the glassware
employed.
O
O
OH
1
2
chichimol ketone
Scheme 1. Retrosynthetic analysis of chichimol ketone 1.
Ph2
P
Ru(OAc)2
PPh2
O
O
OH
OH
H2 (1.5 atm)
30 h, 85%
2
(S)-3, 95% ee
Herein, the correct stereochemical assignment of (S)-1 was
probed by its hydrogenation to the known ketone (S)-5. Ketone
(S)-5 is interesting due to the fact that it is 400 times more active
than its (R)-enantiomers,9 and it is the main alarm pheromone of
the ant Atta texana. Herein, (S)-5 was identified in several exocrine
glands of ants exhibiting particularly widespread taxonomic distri-
bution. Furthermore, it was identified as an alarm pheromone in
ants of the Myrmicinae subfamily,10 as a component of the defen-
sive secretion of the Leiobunum vittatum (Opiliones),11 and is also
produced by the elm bark beetles Scolytus multistriatus and Scolytus
scolytus.12 Ketone (S)-5 is a common secondary metabolite in
insects and other arthropods, which has communicatory and eco-
logical functions.13 Ketone 5 is also an interesting compound that
was described as an alarm pheromone and used to coordinate
recruitment to food sources,14 Opilionids (Arachnida) employ (S)-
5 as a defensive allomone against ants.15 Furthermore, in the inter-
action between the ant Paraponera clavata and its parasite Apo-
cephalus paraponerae (Diptera), it was discovered that (S)-5 is
useful as a kairomone, a semiochemical that disfavors the emitter
and benefits another organism.16
H
N
O
H3CO
CH3
OCH3
MgBr
N
THF, -20 oC
1 h, 75%
EDC, HOBt, Et3N
DMF, 0 oC to rt
20 h, 87%
CH3
(S)-4
O
O
Pd/C, H2
AcOEt, rt
12 h, 99%
1
(S)- , 95% ee
(S)-5, 95% ee
Scheme 2.
of 2 was determined as >95%, as depicted in Figure 2. (S)-BINAP
was also tested as a ligand in the hydrogenation of 2, but the
catalytic selectivities were not satisfactory. It was seen that (S)-
H8-BINAP is better than (S)-BINAP for the hydrogenation of prochi-
2. Conclusion
In conclusion, the first asymmetric synthesis of chichimol
ketone [4-(S)-methyl-1-hepten-3-one] is described and the abso-
lute configuration of the main semiochemical compound isolated
from A. elegans is determined to be the (S)-configuration. Our
approach to probe the absolute configuration of 1 is also useful
for the synthesis of (S)-4-methyl-3-heptanone 5, which was
obtained by catalytic hydrogenation of (S)-1 employing Pd/C in
AcOEt as solvent in 99% yield. The spectroscopic data for synthetic
(S)-5 are in accordance with described previously by other
groups.17
3. Experimental
1H and 13C NMR spectra were recorded at 400 MHz and
100 MHz, respectively, on a Bruker instrument using CDCl3 as sol-
vent and tetramethylsilane as the internal standard. Chemical
shifts (d) are reported in ppm and coupling constants (J) in Hertz.
Infrared spectra were recorded as film on KBr cells on a Nicolet
Nexus FT-IR instrument and the wavenumbers are expressed in
cmÀ1. GC analyses were recorded on Hewlett–Packard 5890 instru-
ment, and GC–MS analyses were recorded on Perkin Elmer Turbo
Mass using a fused silica capillary column, MDN-5 (Supelco),
Figure 2. HPLC analysis of phenylamide derivative of 3: (a) racemic mixture, (b)
synthesized compound. Condition: n-hexane/isopropanol = 9:1, 1.0 mL/min,
254 nm UV detector, tR = 4.65 min for (S)-enantiomer and tR = 5.88 min for (R)-
enantiomer.
30 m  0.25
lm. HRMS analyses were recorded on a Micromass
Q-Tof 1 instrument.

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M. Espinoza-Moraga et al. / Tetrahedron: Asymmetry 20 (2009) 1062–1064
3.1. (S)-2-Methylpentanoic acid 3
TLC (hexane/EtOAc, 1:1) Rf 0.45. [a]D = +15.8 (c 1.0, CHCl3), HPLC
of research activity. Universidad de Talca was also acknowledged
for financial support to M.E.M. We are also thankful to Dr. Schme-
da-Hirschmann.
condition for corresponding phenylamide derivative: chiral Welch-
01 column, n-hexane/isopropanol = 9:1, 1.0 mL/min, 254 nm UV
detector, tR = 4.65 min for (S)-enantiomer and tR = 5.88 min for
(R)-enantiomer. 1H NMR (400 MHz, CDCl3), d: 0.90 (3H, t, J = 7.1
Hz, CH3), 1.15 (3H, d, J = 6.5 Hz, CH3), 1.44–1.33 (3H, m, CH2),
1.72–1.64 (1H, m, CH2), 2.50–2.41 (1H, m, CH), 11.45 (1H, br s,
COOH). HRMS [ESI(+)-MS]: [C6H12O2+H]+ m/z calcd 117.0916,
found 117.0910.
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L.S.S. thanks FONDECYT (Project 1085308), IFS (F/4195-1), the
Organization for the Prohibition of Chemical Weapons for support