Identification and assignment of the absolute configuration of biologically active methyl-branched ketones from limnephilid caddis flies

Article abstract of DOI:10.1002/1099-0690(200108)2001:16<3175::AID-EJOC3175>3.0.CO;2-4

Glands of the 4th and 5th abdominal stemite of the caddis flies Potamophylax latipennis, Potamophylax cingulatus, and Glyphotaelius pellucidus contain (S)-4-methyl-3-heptanone (4a), (4S,6S)-4,6-dimethyl-3-octanone (4b), and (4S,6S)-4,6-dimethyl-3-nonanone (4c). As shown by gas chromatography coupled with electrophysiological recordings, these ketones elicit a strong response in the insects' antennae. The structural assignment of the compounds was achieved on the basis of mass spectra, enantioselective synthesis, and gas chromatography on a chiral stationary phase.

Full text of DOI:10.1002/1099-0690(200108)2001:16<3175::AID-EJOC3175>3.0.CO;2-4

FULL PAPER
Identification and Assignment of the Absolute Configuration of Biologically
Active Methyl-Branched Ketones from Limnephilid Caddis Flies
Jan Bergmann,[a] Christer Löfstedt,[b] Vladimir D. Ivanov,[c] and Wittko Francke*[a]
Dedicated to Prof. Dr. Peter Köll on the occasion of his 60th birthday
Keywords: Ketones / Structure elucidation / Asymmetric synthesis / Caddis flies / Natural products
Glands of the 4th and 5th abdominal sternite of the caddis
flies Potamophylax latipennis, Potamophylax cingulatus, and
Glyphotaelius pellucidus contain (S)-4-methyl-3-heptanone
(4a), (4S,6S)-4,6-dimethyl-3-octanone (4b), and (4S,6S)-4,6-
coupled with electrophysiological recordings, these ketones
elicit a strong response in the insects’ antennae. The struc-
tural assignment of the compounds was achieved on the ba-
sis of mass spectra, enantioselective synthesis, and gas chro-
dimethyl-3-nonanone (4c). As shown by gas chromatography matography on a chiral stationary phase.
Introduction
analysis by gas chromatography with electroantennographic
detection (GC-EAD)[6] showed two compounds eliciting a
response of the male antennae.
Caddis flies (Trichoptera) are phylogenetically considered
as the sister order of butterflies and moths (Lepidoptera).[1]
Recent investigations showed, that primitive moths of the
family Eriocraniidae and caddisflies exhibit similarities in
physiology, morphology, and systems of chemical commun-
ication. While more advanced lepidopteran species produce
sex pheromones containing long-chain unsaturated acetates,
aldehydes, and primary alcohols in glands located near the
ovipositor, caddis flies and eriocraniid moths possess glands
in the 4th and 5th abdominal segment where they mainly
produce unbranched, short-chain methylketones and
methylcarbinols.[2Ϫ4] However, in the limnephilid caddis fly,
Hesperophylax occidentalis, a branched ketone, 6-methyl-3-
nonanone with an unknown stereochemistry, was reported
to be the sex-pheromone.[5] In the present paper we describe
the identification of similar branched compounds in three
other species of the family Limnephilidae, Potamophylax la-
tipennis, Potamophylax cingulatus, and Glyphotaelius pellu-
cidus.
Upon GC-MS analysis of the extracts, the two EAD-act-
ive main components and one additional minor compound
could be identified. They showed similar mass spectra and,
therefore, were believed to be structurally related. The mass
spectra of these compounds were characterised by a prom-
inent m/z ϭ 86 fragment, suggesting the compounds to rep-
resent 4-ketones or 3-ketones with methyl branching in po-
sition 2 or 4, as this fragment is the result of a typical
McLafferty rearrangement at the carbonϪoxygen double
bond. The base peak at m/z ϭ 57 results from an α-cleavage
relative to the carbonyl carbon, indicating a 3-ketone and
excluding, at the same time, the structure of a 2-methyl-3-
alkanone (which would have yielded m/z ϭ 71). Thus, the
compounds were likely to represent 4-methyl-3-ketones. A
comparison of mass spectral data[7] and gas chromato-
graphic retention times using a synthetic sample proved the
first eluting compound to be 4-methyl-3-heptanone (4a).
The two remaining ketones, with molecular ions of m/z ϭ
156 and 170, respectively, were proposed to be 4,6-dimethyl-
3-octanone (4b) and 4,6-dimethyl-3-nonanone (4c) based on
a comparison of the retention times of singly and doubly
branched 3-alkanones. Further structural proof was ob-
tained by coinjection with synthetic samples. The mass
spectrum of 4c is shown in Figure 1.
Results and Discussion
Preliminary electroantennographic (EAG) recordings
carried out on male antennae showed an activity with the
extracts of females of both Potamophylax species. Further
The assignment of the absolute configurations of the
compounds was achieved by gas chromatography using a
modified cyclodextrin, octakis-(6-O-methyl-2,3-di-O-pen-
tyl)-γ-cyclodextrin, as the stationary phase. Enantiomers
and diastereomers could be well separated. The natural
products were shown to have (4S)- and (4S,6S)-configura-
tion, respectively (see Figure 2). Both racemic and enantio-
pure material for comparison was obtained synthetically,
as described below.
[a]
Institute of Organic Chemistry, University of Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax: (internat.) ϩ 49-40/428383834
E-mail: francke@chemie.uni-hamburg.de
[b]
Department of Ecology, Ecology Building, Lund University,
Sölvegatan 37, 223 62 Lund, Sweden
[c]
Department of Entomology, Faculty of Biology, St. Petersburg
State University,
Universitetskaya nab. 7/9, 199034 St. Petersburg, Russia
Eur. J. Org. Chem. 2001, 3175Ϫ3179
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0816Ϫ3175 $ 17.50ϩ.50/0
3175

J. Bergmann, C. Löfstedt, V. D. Ivanov, W. Francke
FULL PAPER
elicit responses of the male antennae in EAD experiments.
While in males both are major components, females pro-
duce less 4,6-dimethyl-3-octanone (4b). The biological func-
tion of these ketones is still unknown. The role of these
compounds in intraspecific communication is presently un-
der investigation.
Synthesis of Racemic Ketones
Racemates of the ketones 4 were obtained by using the
dimethylhydrazone method introduced by Corey and En-
ders.[8] The dimethylhydrazone 2 of 3-pentanone (1) was al-
kylated with the respective alkyl halides and the product 3
cleaved by reaction with sodium periodate (Scheme 1).
Figure 1. Mass spectrum of 4,6-dimethyl-3-nonanone (4c)
Scheme 1. Synthesis of racemic ketones 4aϪc
Enantioselective Synthesis of the Ketones
The (S) configuration at C-4 was generated by enantiose-
lective alkylation of the SAMP hydrazone 5 of 3-pentanone
(1), according to the method of Enders et al.[9] (S)-4-
Methyl-3-heptanone [(S)-4a], showing an enantiomeric ex-
cess of 97%, was synthesized as described previously.[10] In
the case of the dimethylketones, the (S)-configuration in po-
sition 6 of the final product was introduced with the alkylat-
ing agent. (S)-1-Bromo-2-methylbutane (9b), used for the
synthesis of (4S,6S)-4,6-dimethyl-3-octanone [(4S,6S)-4b]
was obtained by bromination of commercially available (S)-
2-methylbutan-1-ol (8b) by the method of Wijnberg et al.[11]
Figure 2. Gas chromatographic determination of the absolute con-
figurations of compounds 4aϪc in females of Potamophylax spp.;
additional peaks in the chromatograms of the extracts represent
components which are different from the ketones described here; (S)-2-Methylpentan-1-ol (8c), necessary for the synthesis of
for conditions see Exp. Sect.
(4S,6S)-4,6-dimethyl-3-nonanone [(4S,6S)-4c], was pro-
duced by Wittig reaction of [(R)-3-hydroxy-2-methylpro-
Extracts of male P. latipennis contain (S)-4-methyl-3-hep- pyl]triphenylphosphonium bromide (6) with acetaldehyde,
tanone (4a), but not the dimethylketones. An analysis of followed by catalytic hydrogenation of the resulting mixture
Glyphotaelius pellucidus extracts showed that both males of (E)- and (Z)-(S)-2-methyl-3-penten-1-ol (7). The alcohol
and females produce (4S,6S)-4,6-dimethyl-3-octanone (4b) 8c was subsequently converted into the corresponding
and (4S,6S)-4,6-dimethyl-3-nonanone (4c), and that both bromide 9c as described above (Scheme 2).
3176
Eur. J. Org. Chem. 2001, 3175Ϫ3179

Biologically Active Methyl-Branched Ketones from Limnephilid Caddis Flies
FULL PAPER
Scheme 2. Enantioselective synthesis of 4c
Branched ketones similar to those described here have
also been identified in other insects.[12] (S)-4-Methyl-3-hep-
tanone (4a) is the typical alarm pheromone of many Atta
ants[13] and has also been found in daddy long legs (Leiobu-
num spp.; Arachnida: Opiliones) along with (6E)-4,6-di-
methyl-6-octen-3-one (‘‘leiobunone’’).[14] Although the en-
antiomers of leiobunone have been synthesized, the abso-
lute configuration of the natural product is still un-
known.[15] The branched ketones 4b and 4c were previously
identified from the desert wasp Dasymutilla occidentalis, but
again, the absolute configuration could not be deter-
mined.[16] The biological significance of all these com-
pounds is unknown. Another doubly branched ketone, 4,6-
dimethyl-4-octen-3-one (‘‘manicone’’), was identified as an
alarm pheromone from Manica ants,[17] and was found to
have a (4E,6S)-configuration.[18]
As for the biosynthesis of the compounds identified here,
methyl branching in the ketones is presumably introduced
by replacement of an acetate (malonate) by a propanoate
(or methylmalonate) unit along a polyketide route. This is
depicted in Scheme 3, where [X], [Y], and [Z] are activators.
The ethylketone moiety might be formed from a pro-
panoate unit entering in the last condensation step in a
‘‘head-to-head’’ coupling. Subsequent loss of a carbon
atom through decarboxylation would yield the 3-alkanone
structure.[19] Accordingly, (S)-4-methyl-3-heptanone (4a)
would be derived from condensation of three propanoate
units, while the biosynthesis of (4S,6S)-4,6-dimethyl-3-oc-
tanone (4b) would start with an acetate unit, followed by
elongation with three propanoates. In a further step, the
ketones can be reduced to the corresponding branched 3-
alkanols, which we found in another caddis fly species, Lim-
nephilus lunatus (to be published).
Scheme 3. Possible pathways for the biosynthesis of the methyl-
branched ketones 4aϪc
Experimental Section
Caddis flies were collected in 1997 and 1998 at locations near
Lund, Sweden. Extracts were prepared by dissecting the 4th and
5th abdominal sternite and extracting them for 30 min. in a small
amount (usually 10Ϫ30 µL) of dichloromethane. Extracts were sub-
sequently analysed by injecting a 1 µL sample into a gas chromato-
graph (HewlettϪPackard 5890) coupled to a mass spectrometer
(VG70Ϫ250SE), or concentrated and then submitted to GC-MS
analysis.
Eur. J. Org. Chem. 2001, 3175Ϫ3179
3177

J. Bergmann, C. Löfstedt, V. D. Ivanov, W. Francke
FULL PAPER
All syntheses were carried out under argon. Solvents were distilled
prior to use and dried according to standard procedures. For col-
umn chromatography, Merck silica gel (0.040Ϫ0.063 mm) was
sphane (2.63 g, 10 mmol), and 2-methylpentan-1-ol (815 mg,
8.0 mmol) yielded 1.04 g (78 %) of rac-9c. Ϫ 1H NMR (400.1 MHz,
3
2
CDCl3): δ ϭ 3.40 (dd, J1a,2 ϭ 5.1, J1a,1b ϭ 9.7 Hz, 1 H, H-1a),
3
2
used. Mass spectra were recorded by using a combination GC8008/ 3.32 (dd, J1b,2 ϭ 6.1, J1b,1a ϭ 9.7 Hz, 1 H, H-1b), 1.86Ϫ1.75 (m,
MD800 (Fisons) equipped with fused silica capillaries coated with
DB5 (30 m ϫ 0.25 mm ID; programmed from 60 to 300 °C at 5
1 H, H-2), 1.47Ϫ1.16 (m, 4 H, H-3,4), 1.01 (d, 3J2Ј,2 ϭ 6.6 Hz, 3 H,
H-2Ј), 0.91 (t, 3J5,4 ϭ 7.1 Hz, 3 H, H-5). Ϫ 13C NMR (100.6 MHz,
°C/min.) or 60% octakis-(6-O-methyl-2,3-di-O-pentyl)-γ-cyclodex- CDCl3): δ ϭ 41.8 (Ϫ), 37.0 (Ϫ), 35.0 (ϩ), 20.0 (Ϫ), 18.8 (ϩ), 14.4
trin in OV1701 (25 m ϫ 0.25 mm ID; programmed from 40 to 120 (ϩ). Ϫ MS (70 eV): m/z ϭ 39 (23), 41 (58), 42 (20), 43 (100), 55
°C at 2 °C/min.). NMR spectra were recorded with a Bruker (11), 57 (6), 69 (5), 71, (9), 85 (55), 93 (1), 95 (1), 121 (1), 123 (1),
AMX400 using TMS as the internal standard. Optical rotatory
values were obtained with a PerkinϪElmer 341 in 10 cm cuvettes
at 20 °C.
164 (0.2) [Mϩ], 166 (0.2) [Mϩ].
rac-4,6-Dimethyl-3-nonanone (rac-4c): According to the procedure
described above for rac-4b, 2 (3.60 g, 28 mmol), and rac-9c (4.60 g,
28 mmol) were reacted and, after oxidative cleavage, yielded 1.68 g
(35 %) of rac-4c. Ϫ 1H NMR (400.1 MHz, CDCl3): δ ϭ 2.70Ϫ2.57
(m, 1 H, H-4), 2.54Ϫ2.37 (m, 2 H, H-2), 1.72Ϫ1.64 (m, 1 H, H-6),
1.47Ϫ1.19 (m, 6 H, H-5,7,8), 1.05 (d, J ϭ 7.1 Hz, 3 H, H-4Ј), 1.04
(d, J ϭ 6.1 Hz, 3 H, H-6Ј), 0.87 (t, J ϭ 7.6 Hz, 3 H), 0.86 (t, J ϭ
7.6 Hz, 3 H). Ϫ 13C NMR (100.6 MHz, CDCl3): δ ϭ 215.6 (o),
43.9 (ϩ), 40.8 (Ϫ), 34.2 (Ϫ), 30.3 (ϩ), 20.0 (Ϫ), 19.9 (Ϫ), 17.4 (ϩ),
16.3 (ϩ), 14.3 (ϩ), 7.8 (ϩ). Ϫ MS (70 eV): m/z ϭ 41 (29), 43 (47),
55 (13), 57 (100), 69 (5), 71 (31), 86 (49), 87 (4), 99 (4), 113 (2), 127
(1), 141 (1), 155 (1), 170 (1) [Mϩ].
1-Bromo-2-methylbutane (rac-9b): Bromine (1.51 mL, 29 mmol)
was added slowly to a solution of triphenylphosphane (7.60 g,
29 mmol) in 25 mL dry dichloromethane at 0 °C. Subsequently, 2-
methylbutan-1-ol (8b; 3.11 mL, 29 mmol) was added dropwise at
the same temperature. After 1 h the mixture was allowed to warm
to room temperature, most of the dichloromethane was distilled
off, and 20 mL pentane was added. The solution was stored for
about 12 h in the refrigerator to allow the produced triphenylphos-
phane oxide to precipitate. The white precipitate was filtered off,
carefully washed with pentane, and the filtrate was concentrated.
The residue was distilled to yield 2.41 g (55 %) of a colorless liquid.
1
(S)-1-Bromo-2-methylbutane [(S)-9b]: The synthesis was essentially
the same as for rac-9b. Bromine (1.51 mL, 29 mmol), triphenylpho-
sphane (7.60 g, 29 mmol), and (S)-2-methylbutan-1-ol (8b; 3.11
mL, 29 mmol) yielded 2.41 g (55 %) of (S)-9b. Same NMR and MS
data as for rac-9b, [α]D ϭ ϩ3.8 (c ϭ 5.0, CHCl3) (ref.:[20] ϩ3.74).
bp760 ϭ 118 °C. Ϫ H NMR (400.1 MHz, CDCl3): δ ϭ 3.40 (dd,
J ϭ 9.7, J ϭ 5.1 Hz, H-1a), 3.34 (dd, J ϭ 9.7, J ϭ 6.1 Hz, H-1b),
1.76Ϫ1.67 (m, 1 H, H-2), 1.53Ϫ1.44 (m, 1 H, H-3), 1.34Ϫ1.23 (m,
1 H, H-3), 1.01 (d, J ϭ 6.6 Hz, 3 H, H-2Ј), 0.91 (t, J ϭ 7.6 Hz, 3
H, H-4). Ϫ 13C NMR (100.6 MHz, CDCl3): δ ϭ 41.1 (Ϫ, C1), 36.8
(ϩ, C2), 27.6 (Ϫ, C3), 18.4 (ϩ), 11.3 (ϩ). Ϫ MS (70 eV): m/z ϭ 39
(25), 41 (63), 42 (19), 43 (49), 53 (6), 55 (36), 56 (10), 57 (35), 69
(4), 70 (4), 71 (100), 72 (5), 93 (3), 95 (3), 107 (2), 109 (2), 121 (6),
123 (6), 150 (3) [Mϩ].
(4S,6S)-4,6-Dimethyl-3-octanone [(4S,6S)-4b]: To a stirred solution
of diisopropylamine (1.30 mL, 9 mmol) in 50 mL dry diethyl ether
was added butyllithium (1.6  solution in hexane; 5.65 mL,
9 mmol) at 0 °C. After 15 min. of additional stirring, 3-pentanone-
SAMP-hydrazone (5; 1.76 g, 9 mmol) in 10 mL dry diethyl ether
was added dropwise. The mixture was stirred at 0 °C for 4 h, then
cooled to approx. Ϫ110 °C (pentane/liq. nitrogen), and (S)-9b
(1.40 g, 9 mmol) was added dropwise. The mixture was stirred for
about 12 h and allowed to warm to room temperature. It was then
poured into a mixture of 150 mL diethyl ether/30 mL water and
extracted three times with 20 mL portions of diethyl ether. The
combined organic extracts were washed with 30 mL water, dried
with anhydrous magnesium sulfate, and concentrated. The crude
product was dissolved in 40 mL dry dichloromethane, cooled to
Ϫ60 °C, and ozone was passed through the solution until it turned
green. It was then warmed to room temperature, and the solvent
was distilled off. The residue was chromatographed on silica (hex-
ane/ethyl acetate, 50:1) to yield 356 mg (26 %) of (4S,6S)-4b. Same
NMR and MS data as for rac-4b. Ϫ [α]D ϭ ϩ21.0 (c ϭ 1.3, hex-
ane), ee (chiral GC) ϭ 98 %. Ϫ HR-MS: calcd. 156.1514; found
156.1517.
rac-4,6-Dimethyl-3-octanone (rac-4b): To a stirred solution of diiso-
propylamine (1.16 mL, 8 mmol) in 100 mL dry tetrahydrofuran was
added butyllithium (1.6  solution in hexane; 5.00 mL, 8 mmol) at
0 °C and the mixture stirred for 15 min. Subsequently, 3-pen-
tanone-dimethylhydrazone (2; 1.03 g, 8 mmol) was added, and the
mixture was stirred for an additional 2 h at the same temperature.
The solution was then cooled to Ϫ78 °C and, rac-9b (1.20 g,
8 mmol) was added. This mixture was stirred for about 12 h and
then allowed to warm to room temperature. It was then poured
into a mixture of 150 mL water and 50 mL dichloromethane, and
the layers were separated. The aqueous layer was extracted three
times with 50 mL portions of dichloromethane. The combined or-
ganic layers were washed with brine, dried with anhydrous magnes-
ium sulfate, and concentrated. The residue was dissolved in 50 mL
of methanol and 10 mL of 1 phosphate buffer (pH 7), and
30 mmol of sodium periodate in 80 mL water was added. This mix-
ture was stirred for 3 h. The precipitate was filtered off and washed
with dichloromethane. The filtrate was extracted with dichlorome-
thane, and the combined organic layers were washed with brine,
dried and concentrated. The residue was chromatographed on silica
(2S)-2-Methyl-3-penten-1-ol (7): To a suspension of [(R)-3-hydroxy-
2-methylpropyl]triphenylphosphonium
bromide
(6;
10.0 g,
24,1 mmol) in 100 mL dry tetrahydrofuran, was added butyllithium
(1.6  solution in hexane; 30.0 mL, 48 mmol) at Ϫ25 °C. After
stirring for 10 min., freshly distilled acetaldehyde (2.00 mL,
35.5 mmol) was added at the same temperature. The reaction mix-
ture was then allowed to warm to room temperature. Subsequently,
100 mL of saturated aqueous ammonium chloride was added, and
the mixture was extracted three times with 50 mL portions of a 1:1
(v/v) pentane/diethyl ether mixture. The combined organic extracts
were dried with magnesium sulfate and concentrated under reduced
pressure. The precipitated triphenylphosphane oxide was filtered
off and washed carefully with pentane. The filtrate was again con-
1
(hexane/ethyl acetate, 50:1) to yield 540 mg (44 %) of rac-4b. Ϫ H
NMR (400.1 MHz, CDCl3): δ ϭ 2.69Ϫ2.60 (m, 1 H, H-4),
2.54Ϫ2.36 (m, 2 H, H-2), 1.74Ϫ1.65 (m, 1 H, H-6), 1.37Ϫ1.24 (m,
4 H, H-5,7), 1.04 (pseudo-t, 6 H, H-4Ј,6Ј), 0.90Ϫ0.83 (m, 6 H, H-
1,8). Ϫ 13C NMR (100.6 MHz, CDCl3): δ ϭ 216.0 (o), 43.9 (ϩ),
40.4 (Ϫ), 34.2 (Ϫ), 32.3 (ϩ), 22.7 (Ϫ), 19.3 (ϩ), 17.4 (ϩ), 14.1 (ϩ),
7.8 (ϩ). Ϫ MS (70 eV): m/z ϭ 39 (11), 41 (27), 43 (7), 55 (14), 57
(100), 71 (2), 86 (23), 99 (2), 127 (1), 156 (0.1) [Mϩ].
1-Bromo-2-methylpentane (rac-9c): This synthesis was essentially
the same as for rac-9b. Bromine (0.53 mL, 10 mmol), triphenylpho-
3178
Eur. J. Org. Chem. 2001, 3175Ϫ3179

Biologically Active Methyl-Branched Ketones from Limnephilid Caddis Flies
FULL PAPER
centrated under reduced pressure, and the crude product was chro-
matographed on silica gel (pentane/diethyl ether, 3:1), yielding
1.27 g (53 %) of 7 as a mixture of stereoisomers. Ϫ 1H NMR
(400.1 MHz, CDCl3): δ ϭ 5.69Ϫ5.51 (m, 2 H, H-4), 5.28 (dd, 1 H,
H-3trans) J ϭ 15.3, J ϭ 7.6, 5.17 (pseudo-t, 1 H, H-3cis), 3.55Ϫ3.43
(m, 2 H, H-1), 3.39Ϫ3.31 (m, 2 H, H-1), 2.82Ϫ2.67 (m, 1 H, H-2),
2.38Ϫ2.24 (m, 1 H, H-2), 1.68 (t, 6 H, H-5), 0.98 (t, 6 H, H-2Ј). Ϫ
MS: m/z ϭ 39 (27), 41 (100), 42 (8), 43 (10), 53 (8), 55 (10), 57 (6),
58 (4), 67 (10), 69 (63), 70 (9), 71 (6), 82 (8), 100 (3) [Mϩ].
der chemischen Industrie for financial support. V. I. was supported
by grants from RFFI and the Russian University Program.
[1]
H. H. Ross, Ann. Rev. Entomol. 1967, 12, 169Ϫ206.
C. Löfstedt, B. S. Hansson, E. Petersson, P. Valeur, A. Rich-
[2]
ards, J. Chem. Ecol. 1994, 20, 153Ϫ170.
J. Bergmann, C. Löfstedt, V. D. Ivanov, W. Francke, Proceed-
[3]
ings of the 10th International Symposium on Trichoptera, Pots-
dam, Germany, 2000.
M. V. Kozlov, J. Zhu, P. Philipp, W. Francke, E. L. Zvereva, B.
[4]
S. Hansson, C. Löfstedt, J. Chem. Ecol. 1996, 22, 431Ϫ454.
(S)-2-Methyl-1-pentanol (8c): Compound 7 (1.20 g, 12.0 mmol) in
20 mL hexane was hydrogenated for 3.5 h at 35 bar with palladium
on charcoal (10 % Pd) as catalyst. The reaction mixture was filtered
through silica gel (diethyl ether), dried with anhydrous magnesium
[5]
L. B. Bjostad, D. K. Jewett, D. L. Brigham, J. Chem. Ecol.
1996, 22, 103Ϫ121.
[6]
H. Arn, E. Städler, S. Rauscher, Z. Naturforsch. 1975, 30c,
722Ϫ725.
sulfate, and concentrated to give 860 mg (70 %) of 8c. Ϫ [α]D
ϭ
[7]
F. W. McLafferty, D. B. Stauffer, The Wiley/NBS Registry of
Ϫ8.2 (c ϭ 1.48, CHCl3) {ref.:[21] Ϫ13 (c ϭ 1.08, CHCl3, 578 nm)}.
Mass Spectral Data, J. Wiley & Sons, New York, 1989.
1
3
[8]
Ϫ H NMR (400.1 MHz, CDCl3): δ ϭ 3.51 (dd, J1a,2 ϭ 5.6 Hz,
E. J. Corey, D. Enders, Tetrahedron Lett. 1976, 3Ϫ6.
3
2
2J1a,1b ϭ 10.6 Hz, 1 H, H-1a), 3.42 (dd, J1b,2 ϭ 6.6 Hz, J1b,1a
ϭ
[9]
D. Enders, in Asymmetric Synthesis Vol. 3 (Ed.: J. D. Mor-
10.6 Hz, 1 H, H-1b), 1.69Ϫ1.58 (m, 1 H, H-2), 1.44Ϫ1.31 (m, 4 H,
H-3,4), 0.95Ϫ0.86 (m, 6 H, H-2Ј,5) - 13C NMR (100.6 MHz,
CDCl3): δ ϭ 68.5 (Ϫ), 35.5 (Ϫ), 35.4 (ϩ), 20.1 (Ϫ), 16.6 (ϩ), 14.3
(ϩ). Ϫ MS: m/z ϭ 39 (17), 41 (41), 42 (21), 43 (100), 53 (3), 55
(33), 56 (26), 57 (5), 59 (2), 69 (31), 70 (33), 71 (35), 84 (9), 85 (1),
102 (0.1) [Mϩ].
rison), Academic Press, New York 1984, pp. 275Ϫ339.
[10]
D. Enders, H. Kipphardt, P. Fey, Org. Synth. 1987, 65,
183Ϫ202.
[11]
J. B. P. A. Wijnberg, P. G. Wiering, H. Steinberg, Synthesis
1981, 901Ϫ903.
W. Francke, S. Schulz, in, Comprehensive Natural Products
Chemistry, Vol. 8 (Eds.: D. Barton, K. Nakanishi, K. Mori),
Elsevier, Oxford 1999, pp. 197Ϫ261.
R. G. Riley, R. M. Silverstein, J. C. Moser, Science 1974, 183,
760Ϫ762.
[12]
(S)-1-Bromo-2-methylpentane [(S)-9c]: The synthesis was essentially
the same as for rac-9b. Bromine (0.53 mL, 10 mmol), triphenylpho-
sphane (2.63 g, 10 mmol), and 8c (815 mg, 8.0 mmol) yielded 1.04 g
[13]
[14]
J. Meinwald, A. F. Kluge, J. E. Carrel, T. Eisner, Proc. Natl.
(78 %) of (S)-9c. Same NMR and MS data as for rac-9c, [α]D
ϭ
Acad. Sci. USA 1971, 68, 1467Ϫ1468.
Ϫ1.5 (c ϭ 7.97, CHCl3) {ref.:[22] Ϫ0.9 (c ϭ 50, diethyl ether)}.
[15]
D. Enders, U. Baus, Liebigs Ann. Chem. 1983, 1439Ϫ1445.
[16]
H. M. Fales, T. M. Jaouni, J. O. Schmidt, M. S. Blum, J. Chem.
(4S,6S)-4,6-Dimethyl-3-nonanone [(4S,6S)-4c]: In a reaction carried
out analogously to the synthesis of (4S,6S)-4b, 670 mg (3.4 mmol)
of 5 and 730 mg (4.4 mmol) of (S)-9c yielded 332 mg (57 %) of
(4S,6S)-4c. Same NMR and MS data as for rac-4c. Ϫ [α]D ϭ ϩ11.6
(c ϭ 0.85, CH2Cl2), ee (chiral GC) ϭ 97%. Ϫ HR-MS: calcd.
170.1670; found 170.1705.
Ecol. 1980, 6, 895Ϫ903.
H. M. Fales, M. S. Blum, R. W. Crewe, J. M. Brand, J. Insect
Physiol. 1972, 18, 1077Ϫ1088.
H. J. Bestmann, A. B. Attygalle, J. Glasbrenner, R. Riemer, O.
[17]
[18]
Vostrowsky, M. G. Constantino, G. Malikian, E. D. Morgan,
Liebigs Ann. Chem. 1988, 55Ϫ60.
[19]
R. Bartelt, D. Weisleder, Bioorg. Med. Chem. 1996, 4, 429Ϫ438.
[20]
W. O. Haag, E. I. Heiba, Tetrahedron Lett. 1965, 3679Ϫ3682.
[21]
L. R. Terrell, J. S. Ward, R. E. Maleczka, Tetrahedron Lett.
Acknowledgments
C. L. would like to thank the Knut and Alice Wallenberg Founda-
tion, the Swedish Natural Science Research Council, and the Royal
Swedish Academy of Science for funding. W. F. thanks the Fonds
1999, 40, 3097Ϫ3100.
P. A. Levene, L. A. Mikeska, J. Biol. Chem. 1929, 84, 571Ϫ599.
[22]
Received February 6, 2001
[O01053]
Eur. J. Org. Chem. 2001, 3175Ϫ3179
3179