First asymmetric synthesis of 6-methyl-3-nonanone, the female-produced sex pheromone of the caddisfly Hesperophylax occidentalis

Article abstract of DOI:10.1039/b006832m

The asymmetric synthesis of the female-produced sex pheromone of the caddisfly Hesperophylax occidentalis, (S)-and (R)-6-methyl-3-nonanone, starting from the simple starting materials propanal, propyl iodide and 2-butanone, in good overall yields is described. The stereogenic centre at the C-6 position of the pheromone was generated via α-alkylation employing the SAMP/RAMP hydrazone method with high asymmetric induction (ee = 94 and 92%).

Full text of DOI:10.1039/b006832m

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First asymmetric synthesis of 6-methyl-3-nonanone, the
female-produced sex pheromone of the caddisÑy Hesperophylax
occidentalis
Dieter Enders* and Thomas Schueler
Institut fur Organische Chemie, Rheinisch-W estfalische T echnische Hochschule, Professor-Pirlet-
Strae 1, 52074 Aachen, Germany. E-mail: Enders=RW T H-aachen.de; Fax ]49 241 8888 127
Received (in Montpellier, France) 16th August 2000, Accepted 27th September 2000
First published as an Advance Article on the web 20th November 2000
The asymmetric synthesis of the female-produced sex pheromone of the caddisÑy Hesperophylax occidentalis, (S)-
and (R)-6-methyl-3-nonanone, starting from the simple starting materials propanal, propyl iodide and 2-butanone,
in good overall yields is described. The stereogenic centre at the C-6 position of the pheromone was generated via
a-alkylation employing the SAMP/RAMP hydrazone method with high asymmetric induction (ee \ 94 and 92%).
The female-produced sex pheromone of the caddisÑy Hes-
perophylax occidentalis was isolated in 1996 by Bjostad et al.1
and identiÐed as 6-methyl-3-nonanone (1). By synthesizing
this racemic ketone and closely related analogues they demon-
strated by an electroantennogram experiment that rac-1
shows the strongest response.1 However, at this stage the
absolute conÐguration of this natural product, an important
question in the pheromone area,2 could not be determined.
dation led us to search for alternative conditions.7 Therefore,
we chose 3 M HCl for the cleavage of the hydrazone.7
Reduction of the aldehyde (S)-5 without isolation was con-
veniently carried out using the borane dimethyl sulÐde
complex. Gas chromatography on a chiral stationary phase
showed that the cleavage of the hydrazone and reduction of
the aldehyde proceeded with no detectable racemization. The
crude alcohol (S)-6 was directly converted to nosylate (S)-7.
Previously the nosylate (S)-7 was obtained in 30% overall
yield from (S)-3 (75% per step) by using the salt method5h7 for
the cleavage of the SAMP hydrazone. By using 3 M HCl for
the cleavage we obtained nosylate (S)-7 in 69% yield over four
steps.
We envisaged the in situ conversion of the sulfonate (S)-7 to
the iodide (S)-8 and subsequent a-alkylation of butanone
dimethylhydrazone, however, all attempts to use the in situ
iodide proceeded without success. Small amounts of free
iodine seem to interfere with the alkylation. It was necessary,
therefore, to isolate and purify iodide (S)-8. The regioselective
alkylation of 2-butanone with (S)-8 was carried out via the
corresponding lithiated dimethylhydrazone and proceeded in
nearly quantitative yield.8,9 The hydrazone was cleaved with
2 M HCl on work up, and the pheromone (S)-1 was obtained
in high purity, enantiomeric excess (ee \ 94%) and yield after
chromatography.
Similarly, the enantiomer (R)-1 was synthesized with an
enantiomeric excess of 92%, starting from propanal (2) and
using RAMP as the chiral auxiliary. In this case the diastereo-
meric excess of the alkylation was excellent, too. (R,R)-4 was
isolated in 93% yield and de P 94%.
In conclusion, the Ðrst asymmetric synthesis of both enan-
tiomers of the sex pheromone of the caddisÑy H. occidentalis
was achieved employing the SAMP/RAMP-hydrazone
method and starting from the simple substrates propanal,
propyl iodide and 2-butanone. The yield from 2 of (S)-1
(ee \ 94%) over seven steps was 55% and that of (R)-1
(ee \ 92%) reached 51%.
In 1997 Mori et al.3 obtained both enantiomers of 1 by an
ex chiral pool approach starting from (S)- or (R)-citronellal,
respectively. The overall yield of the pheromone (ee \ ca.
97%) was 12È18% over six steps. The biological evaluation of
these samples by Bjostad et al.4 showed that the R enantiomer
of 1 is much more active than the S-conÐgurated ketone.
Because metallated hydrazones are the reagents of choice
for the regio- and stereoselective synthesis of substituted
ketones, we decided to attempt the Ðrst asymmetric synthesis
of both enantiomers of the title pheromone employing our
SAMP/RAMP hydrazone methodology.5
Results and discussion
Scheme 1 summarizes the asymmetric synthesis of the enantio-
mers of 1. The synthesis of iodide (S)-8 was previously report-
ed by our laboratory in a total synthesis of (])-pectinatone.6
Meanwhile we could optimize the synthesis of this important
key building block of pheromone (S)-1 with better yields and a
better enantiomeric excess.
Hydrazone (S)-3 was formed in virtually quantitative yield
by treating propanal (2) with (S)-1-amino-2-(methoxymethyl)
pyrrolidine (SAMP). Deprotonation of (S)-3 was achieved
with lithium tetramethylpiperidide (LiTMP) at 0 ¡C. Alkyl-
ation of the azaenolate with 1-iodopropane at [78 ¡C gave
the a-alkylated SAMP-hydrazone (S,S)-4 in excellent yield and
a diastereomeric excess (de) of 95%.
Experimental
All reagents were of commercial quality used from freshly
opened containers. Solvents were dried and puriÐed by con-
ventional methods prior to use. THF was freshly distilled
from sodiumÈlead alloy under Ar. All aqueous solutions were
saturated. All reactions were carried out under an argon
Usually the oxidative cleavage of SAMP hydrazones with
ozone is a clean and quantitative method, however, the sus-
ceptibility of the liberated aldehyde in this case to further oxi-
DOI: 10.1039/b006832m
New J. Chem., 2000, 24, 973È975
973
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2000

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reaction mixture was diluted with CH Cl (50 ml) and Ðltered.
2
2
The Ðltrate was dried (MgSO ) and concentrated in vacuo to
4
give a pale yellow oil. The crude product was distilled under
reduced pressure (bp 67 ¡C at 3 mbar) to yield hydrazone (S)-3
as a colourless oil (3.91 g, 98%). The analytical data were con-
sistent with the data given in the literature.5
(R)-(Ô)-2-Methoxymethyl-1-(1º-propylidenamino)-
pyrrolidine, [(R)-3]. In the same manner as described above 2
(2.60 g, 45.7 mmol) was converted to (R)-3 (6.68 g, 95%) using
RAMP (5.40 g, 41.5 mmol) as the chiral auxiliary.
(2S,2ºS)-2-Methoxymethyl-1-(2º-methyl-1º-pentyliden-
amino)pyrrolidine, [(S,S)-4]. To a cooled solution (0 ¡C) of
2,2,6,6-tetramethylpiperidine (3.24 g, 23 mmol) in dry THF (20
ml) under Ar was slowly added n-BuLi (1.6 M in hexane, 14.4
ml, 23 mmol); the mixture was stirred for 1 h. A solution of
(S)-3 (3.55 g, 21 mmol) in dry THF (5 ml) was added slowly
and stirring maintained at 0 ¡C for 1 h. The resulting orange
solution was cooled to [78 ¡C and 1-iodopropane (3.91 g, 23
mmol) added dropwise. The mixture was allowed to warm to
room temperature over 20 h before being quenched with pH 7
bu†er (20 ml). The aqueous phase was extracted with Et O
2
(2 ] 25 ml), the combined organic extracts washed with
aqueous NH Cl (50 ml) and brine (50 ml), dried (MgSO ) and
4
4
concentrated in vacuo. PuriÐcation by Ñash chromatography
(silica gel; pentaneÈEt O, 4 : 1, containing 1% Et N, R 0.67)
2
3
f
gave (S,S)-4 (3.99 g, 90%, de P 95% by 13C NMR) as an oil.
The analytical data were consistent with the data given in the
literature.5
(2R,2ºR)-2-Methoxymethyl-1-(2ºmethyl-1º-pentyliden-
amino)pyrrolidine, [(R,R)-4]. In the same manner as described
above, (R)-3 (4.47 g, 26.3 mmol) was converted to (R,R)-4 (4.59
g, 93%, de P 94% by 13C NMR), which was obtained as a
pale oil.
(S)-(Ô)-2-Methylpentanal [(S)-5]. A solution of the hydra-
zone (S,S)-4 (705 mg, 3.33 mmol) in pentane (30 ml) was
stirred with aqueous 3 M HCl (20 ml) at room temperature
for 15 min. The two phases were separated, and the aqueous
Scheme
1
Synthesis of (R)- and (S)-6-methyl-3-nonanone (1).
phase was extracted with Et O (3 ] 15 ml). The combined
Reagents and conditions: (a) SAMP, CH Cl , rt; (b) LiTMP, THF,
2
2
2
organic extracts were washed with aqueous NaHCO (20 ml)
0 ¡C, then n-C H I, [78 ¡C to rt, 20 h; (c) 3 M HCl, pentane; (d)
3
7
3
and brine (20 ml), dried (MgSO ) and used in the next step
4
BH É Me S, Et O; (e) p-NO C H SO Cl, pyr, DMAP, CH Cl , rt;
3
2
2
2
6
4
2
2 2
(f) LiI, CH Cl ; (g) 1. C H [C2NÈN(CH ) ]CH , n-BuLi, THF, 0 ¡C;
3 2
(reduction) without isolation. The analytical data (after iso-
2
2
2
5
3
2. 2 M HCl.
lation of a small aliquot) were consistent with the data given
in the literature.5,10
atmosphere using dry solvents unless otherwise stated. n-BuLi
(1.6 M in hexane) was purchased from Merck, Darmstadt.
Preparative column chromatography used Merck silica gel 60,
particle size 0.040È0.063 mm (230È400 mesh, Ñash). Analytical
(R)-(+ )-2-Methylpentanal, [(R)-5]. In the same manner as
described above (R,R)-4 (703 mg, 3.32 mmol) was converted to
(R)-5.
TLC used silica gel 60 F
Optical rotation values were measured on a PerkinÈElmer
plates from Merck, Darmstadt.
254
(S)-(Ô)-2-Methyl-1-pentanol, [(S)-6]. To a cooled solution
P241 polarimeter; solvents used were of Merck UVASOL-
(0 ¡C) of the crude aldehyde (S)-5 in Et OÈpentane (3 : 2, 75
quality. Microanalyses were obtained with
a Heraeus
2
2
ml) under Ar was slowly added BH É Me S (1.27 g,16.7 mmol)
CHN-O-RAPID element analyzer. Mass spectra were
acquired on a Finnigan MAT 212 (CI 100 eV; EI 70 eV)
spectrometer. IR spectra were taken on a PerkinÈElmer
FT/IR 1750. 1H NMR (300 and 400 MHz) and 13C NMR (75
and 100 MHz) spectra were recorded on Gemini 300 or
3
and the mixture stirred for 45 min. The mixture was quenched
with aqueous 3 M HCl (20 ml) and stirred at room tem-
perature for another 90 min. The aqueous phase was extracted
with Et O (3 ] 20 ml). The combined organic extracts were
2
washed with aqueous Na SO (30 ml) and dried (MgSO ).
Varian Inova 400 (CDCl as solvent, TMS as internal
2
3
4
3
Concentration in vacuo gave alcohol (S)-6 [288 mg, 85%,
ee P 94% by GC-CSP (column: Lipodex A)] as a colourless
oil. No further puriÐcation was necessary. The analytical data
were consistent with the data given in the literature.11
standard) spectrometers.
Synthesis and characterization
(S)-(Ô)-2-Methoxymethyl-1-(1º-propylidenamino)-
pyrrolidine, [(S)-3]. To a cooled solution (0 ¡C) of SAMP
(R)-(+ )-2-Methyl-1-pentanol, [(R)-6]. In the same manner
as described above, (R)-5 was converted to (R)-6 [276 mg,
82%, ee P 93% by GC-CSP (column: Lipodex A)] which was
obtained as a colourless oil.
(3.06 g, 23.6 mmol) in CH Cl (10 ml), molecular sieves (4 A, 2
2
2
g) and propanal 2 (1.64 g, 28.3 mmol) were added sequentially.
The mixture was stirred at room temperature for 20 h. The
974
New J. Chem., 2000, 24, 973È975

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(S)-(+ )-2-Methylpentyl p-nitrophenylsulfonate, [(S)-7]. To
a cooled solution (0 ¡C) of (S)-6 (238 mg, 2.3 mmol) in dry
CH Cl (50 ml) under Ar was added pyridine (360 mg, 4.6
(S)-(+ )-6-Methyl-3-nonanone, [(S)-1]. To a cooled solution
(0 ¡C) of 2-butanone dimethylhydrazone (210 mg, 1.76 mmol)
in dry THF (30 ml) under Ar was slowly added n-BuLi (1.6 M
in hexane, 1.17 ml, 1.88 mmol); the mixture was stirred for 1 h.
The resulting yellow solution of the aza-enolate was warmed
up to room temperature and iodide (S)-8 (265 mg, 1.25 mmol)
was added dropwise. The colour changed immediately from
yellow to a greenish brownÈblack. The solution was stirred at
room temperature for 20 h and quenched with 2 M HCl over
a period of 30 min. The aqueous phase was extracted with
CH Cl (2 ] 30 ml), the combined organic extracts washed
2
2
mmol) and DMAP (20 mg, cat.).
A solution of p-
nitrophenylsulfonyl chloride (559 mg, 2.5 mmol) in CH Cl
2
2
(10 ml) was added slowly. The resulting yellow reaction
mixture was stirred for 30 h and quenched with 1 M HCl (20
ml). The aqueous phase was extracted with CH Cl (3 ] 20
2
2
ml); the combined organic extracts were washed with aqueous
NaHCO (20 ml) and brine (20 ml), dried (MgSO ) and con-
3
4
centrated in vacuo to give nosylate (S)-7 (594 mg, 90%) as a
2
2
yellow solid. [a]25: ]2.8 (c \ 1.05, CHCl ), mp 39 ¡C. IR
with brine (50 ml), dried (MgSO ) and concentrated in
D
3
4
(KBr) l: 3113, 2961, 2933, 2874, 1610, 1541, 1469, 1405, 1366,
1353, 1314, 1186, 1110, 1096, 1013, 962, 933, 897, 857, 843,
823, 739, 683, 619, 596, 568, 467 cm~1. EI-MS (70 eV) m/z:
204 (5), 187 (9), 186 (17), 157 (4), 123 (7), 122 (17), 92 (6), 85
(11), 84 (C H `, 100), 77 (4), 76 (12), 75 (13), 71 (56), 70 (14),
vacuo. PuriÐcation by Ñash chromatography (silica gel,
pentaneÈEt O, 4 : 1, containing 1% Et N, R 0.8) gave the title
2
3
f
ketone (S)-1 (195 mg, 100%) as a colourless oil. [a]22: ]2.85
D
(c \ 2.00, CHCl ). Lit. [a]25: ]3.07 (c \ 12.1, CHCl ).3 The
analytical data were consistent with the data given in the liter-
3
D
3
6
12
69 (33), 57 (5), 56 (54), 55 (26), 50 (8%). 1H NMR (300 MHz,
ature.3
CDCl ): d 8.41 (2H, d, J \ 9.06, H ), 8.11 (2H, d, J \ 9.06,
3
9
H ), 4.00 (1H, dd, J \ 5.71, J \ 9.40, H ), 3.92 (1H, dd,
(R)-(Ô)-6-Methyl-3-nonanone, [(R)-1]. In the same manner
as described above, (R)-8 (124 mg, 0.80 mmol) was converted
to (R)-1 (122 mg, 98%), which was obtained as a colourless oil.
[a]22: [2.70 (c \ 2.05, CHCl ). Lit. [a]25: [3.12 (c \ 12.1,
8
1
J \ 6.71, J \ 9.40, H ), 1.83 (1H, oct, J \ 5.71, H ), 1.05È1.35
1
2
(4H, m, H , H ), 0.91 (3H, d, J \ 6.72, H ), 0.86 (3H, t,
4
3
6
J \ 7.05 Hz, H , H ). 13C NMR (75 MHz, CDCl ): d 150.74
2
5
3
D
3
D
(C ), 142.07 (C ), 129.21 (C ), 124.45 (C ), 76.42 (C ), 34.79
10
(C ), 32.66 (C ), 19.72 (C ), 16.35 (C ), 14.06 (C ). Anal. calc.
CHCl ).3
7
9
8
1
3
3
2
4
6
5
for C
H
NO S: C 50.16, H 5.96, N 4.87; found: C 50.32, H
12 17
5
5.96, N 4.62%.
Acknowledgements
(R)-(Ô)-2-Methylpentyl p-nitrophenylsulfonate, [(R)-7]. In
the same manner as described above, (R)-6 (251 mg, 2.46
mmol) was converted to (R)-7 (607 mg, 86%), which was
obtained as a yellow solid. [a]25: [2.7 (c \ 1.25, CHCl ).
We thank Dr L. B. Bjostad for helpful discussions. This work
was supported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie. We thank Degussa AG,
BASF AG and Bayer AG for the donation of chemicals.
D
3
(S)-(+ )-1-Iodo-2-methylpentane, [(S)-8]. Lithium iodide
(300 mg, 2.23 mmol) was heated in vacuo before use. Nosylate
(S)-7 (535 mg, 1.86 mmol) was added in one portion, and the
mixture was dissolved in dry THF (10 ml) and stirred at room
temperature for 5 h. The precipitated lithium sulfonate salt
was dissolved after adding pentane (5 ml) by quenching of
aqueous 1 M HCl (20 ml). The aqueous phase was extracted
with CH Cl (20 ml), the combined organic extracts washed
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2
2
with aqueous Na S O (20 ml) and brine (20 ml) and dried
2 2
3
4
(MgSO ). Concentration in vacuo gave iodide (S)-8 [315 mg,
4
80%, ee P 94% by GC-CSP (column: Lipodex G)] as a
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6
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colourless oil. No further puriÐcation was necessary. The ana-
lytical data were consistent with the data given in the liter-
ature.11
8
9
(R)-(Ô)-1-Iodo-2-methylpentane, [(R)-8]. In the same
manner as described above (R)-7 (571 mg, 1.99 mmol) was
converted to (R)-8 [354 mg, 84%, ee P 92% by GC-CSP
(column: Lipodex G)] obtained as a colourless oil.
10 W. Fenzl, R. Koster and H.-J. Zimmermann, L iebigs Ann. Chem.,
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New J. Chem., 2000, 24, 973È975
975