Asymmetric synthesis of all stereoisomers of 7,11-dimethylheptadecane and 7-methylheptadecane, the female pheromone components of the spring hemlock looper and the pitch pine looper

Article abstract of DOI:10.1016/S0040-4039(02)00595-6

The asymmetric synthesis of the stereoisomers of 7,11-dimethylheptadecane (1) and 7-methylheptadecane (2) via α-alkylation employing the SAMP/RAMP hydrazone method with high asymmetric induction and good overall yields is described. A mixture of (7S,11R)-1 and (S)-2 is the female-produced sex pheromone of the spring hemlock looper moth (Lambdina athasaria) and the pitch pine looper moth (Lambdina pellucidaria). They are both forest pests in northeastern North America.

Full text of DOI:10.1016/S0040-4039(02)00595-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3467–3470
Asymmetric synthesis of all stereoisomers of
7,11-dimethylheptadecane and 7-methylheptadecane, the female
pheromone components of the spring hemlock looper and the
pitch pine looper
Dieter Enders* and Thomas Schu¨ßeler
Institut fu¨r Organische Chemie, Rheinisch-Westfa¨lische Technische Hochschule, Professor-Pirlet-Str. 1, 52074 Aachen, Germany
Accepted 25 March 2002
Abstract—The asymmetric synthesis of the stereoisomers of 7,11-dimethylheptadecane (1) and 7-methylheptadecane (2) via
a-alkylation employing the SAMP/RAMP hydrazone method with high asymmetric induction and good overall yields is
described. A mixture of (7S,11R)-1 and (S)-2 is the female-produced sex pheromone of the spring hemlock looper moth
(Lambdina athasaria) and the pitch pine looper moth (Lambdina pellucidaria). They are both forest pests in northeastern North
America. © 2002 Elsevier Science Ltd. All rights reserved.
Compounds with stereochemically defined alkyl-
branched hydrocarbon chains are widespread in nature
and especially in the field of pheromones, for instance
as components of the pheromone of different Lambdina
species.1 In 1994 Gries et al. isolated the two methyl-
substituted hydrocarbons, 7,11-dimethylheptadecane
(1) and 7-methylheptadecane (2) as components of the
female sex pheromone of the spring hemlock looper
(SHL), Lambdina athasaria.2 The spring hemlock
looper feeds primarily on hemlock (Tsuga canadensis)
and is a forest pest in northeastern North America (Fig.
1).
female pitch pine looper (PPL), Lambdina pellucidaria,
whose larvae damage pitch pines, Pinus rigida, in north-
eastern North America during sporadic outbreaks.3
Synthetic samples of the racemates of ( )-1, meso-1 and
( )-2 were found to be bioactive.2
The absolute configuration could be determined by an
ex chiral pool approach starting from the enantiomers
of citronellol and methyl 3-hydroxy-2-methyl-
propanoate by Mori et al. in 1999.4 The overall yield of
the pheromones (ee=97%) was 57–74% over five steps
for (R)- and (S)-2; for (R,R)-, (S,S)- and meso-1 the
yield (de >99.9%) was ca. 15–16% over 11 steps. In
coupled gas chromatographic-electroantennographic
detection analyses, Gries et al. have recently established
that the bioactive pheromone compounds are (7R,11S)-
1 (meso-1) and the (S)-configured alkane 2.5
In 1998, the same two methyl-branched alkanes 1 and 2
were identified as the sex pheromone components of the
A further synthesis of the stereoisomers of 1 and 2
starting from both enantiomers of 2,3-epoxy-1-
hydroxy-undecane delivered the alkanes meso-1 in 14%
yield over 24 steps [(S,S)- and (R,R)-1 9% over 27
steps] and (S)- and (R)-2 in 32% yield over 13 steps.6
Figure 1. Pheromones of the spring hemlock looper and the
pitch pine looper.
Because metallated hydrazones are the reagents of
choice for the regio- and stereoselective synthesis of
a-substituted aldehydes and ketones, we decided to
attempt the asymmetric synthesis of all the stereoiso-
mers of the title pheromones employing the SAMP/
RAMP hydrazone methodology.7,8
Keywords: asymmetric synthesis; pheromones; hydrazones; a-alkyla-
tion; hydrocarbon; dithians.
* Corresponding author. Tel.: +49(241)8094676; fax: +49(241)
8092127; e-mail: enders@rwth-aachen.de
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00595-6

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D. Enders, T. Schu¨ßeler / Tetrahedron Letters 43 (2002) 3467–3470
Alkylation of the lithiated 1,3-dithiane (10) with (S)-9
yielded (S)-11, which was again alkylated with (S)-9
using t-butyllithium for the deprotonation to furnish
the double alkylated dithiane (S,S)-12. Subsequent
reductive desulfurization using Raney nickel gave the
target molecule (S,S)-1, [h]2D5=+1.74 (hexane).10 The
yield from n-propanal (3) of (S,S)-1 over nine steps was
46% (Scheme 2). Since there was no step to cause
racemization at the stereogenic centers, (S,S)-1 was
assumed to be of high diastereo- and enantiomeric
purity (de, ee ]98%). Similarly, the enantiomer (R,R)-
1 was synthesized via double alkylation with the iodide
(R)-9 with diastereo- and enantiomeric excess of
]98%, starting from propanal (3) and using RAMP as
the chiral auxiliary via (R)-4, [h]2D6=−1.48 (CHCl3).10
The meso-alkane (R,S)-1 was prepared from (S)-11 by
alkylation with the iodide (R)-9 and subsequent reduc-
tive desulfurization.
As depicted in Scheme 1 the hydrazone (S)-4 was
formed in virtually quantitative yield by treating n-
propanal (3) with (S)-1-amino-2-(methoxymethyl)-
pyrrolidine (SAMP). Deprotonation of (S)-4 was
achieved with lithium tetramethylpiperidide (LiTMP) at
0°C. Alkylation of the azaenolate with 1-iodohexane at
−100°C gave the a-alkylated SAMP-hydrazone (S,S)-5
in excellent yield and a diastereomeric excess de ]96%
(13C NMR). Under the usual alkylation conditions at
−78°C the de was only 90%.
Usually the oxidative cleavage of SAMP hydrazones
with ozone is a clean and quantitative method.9 Never-
theless we chose 4 M HCl for the cleavage of the
hydrazone 5, because the sensibility of the liberated
aldehyde 6 to further oxidation required the use of
alternative conditions.8
Reduction of the aldehyde (S)-6 without isolation was
conveniently carried out using borane dimethyl sulfide
complex. Gas chromatography on a chiral stationary
phase showed that the cleavage of the hydrazone and
the reduction of the aldehyde proceeded with no
detectable racemization, [(S)-7, ee ]99% (GCCSP)]. The
crude alcohol (S)-7 was directly converted to the tosy-
late (S)-8. Former attempts to generate the more reac-
tive nosylate gave only low yields (40%). The tosylate
(S)-8 gave the corresponding iodide (S)-9 upon Finkel-
stein displacement in excellent yield.
Next we turned our attention to the other component
of the female sex pheromone 7-methylheptadecane (2)
(Scheme 3). Hydrazone (S)-14 was formed in virtually
quantitative yield by the treatment of n-octanal (13)
with SAMP. Metallation of (S)-14 with LiTMP at 0°C
and alkylation of the resulting azaenolate with 1-iodo-
decane at −100°C gave the a-alkylated SAMP-hydra-
zone (S,S)-15. After warming to room temperature
over 2 h it was necessary to reflux the mixture for 30
min to increase the yield. Nevertheless, the hydrazone
(S,S)-15 was formed in good yield (68%) and a de of
Scheme 1. Reagents and conditions: (a) rt, 16 h; (b) (i) LiTMP (1.1 equiv.), THF, 0°C, 1 h; (ii) n-HexI (1.1 equiv.), −100°C, 16
h; (c) 4 M HCl, pentane, rt, 15 min; (d) BH3·SMe2 (5.0 equiv.), Et2O, rt, 45 min; (e) TsCl (1.5 equiv.), pyridine, 0°C, 20 h; (f)
NaI (1.4 equiv.), acetone, reflux, 16 h.

D. Enders, T. Schu¨ßeler / Tetrahedron Letters 43 (2002) 3467–3470
3469
Scheme 2. Reagents and conditions: (a) (i) t-BuLi (1.1 equiv.),
THF/HMPA (10:1), −78°C, 5 min; (ii) (S)-9 (1.1 equiv.),
−78°C, 20 min; (iii) rt, 20 min; (b) t-BuLi (1.5 equiv.),
THF/HMPA (10:1), −78°C, 20 min; (ii) (S)-9 (1.6 equiv.),
−78°C, 60 min; (iii) reflux, 30 min; (c) Raney-Ni, H2, i-PrOH,
reflux, 16 h.
]96% (13C NMR). The cleavage of the hydrazone
promoted by BF3·OEt2 and direct dithioketalization
with 1,3-propanedithiol gave the dithiane (S)-16 in
excellent yield and without racemization.11 Desulfuriza-
tion was carried out by using Raney nickel and hydro-
gen at room temperature.12 In this way, the pheromone
(S)-2 was obtained in high purity, enantiomeric excess
and in 58% overall yield (four steps) after chromatogra-
phy, [h]2D4=+0.27 (hexane).10 Similarly, the enantiomer
(R)-2 was synthesized starting from n-octanal (13) and
RAMP as the chiral auxiliary via (R)-14, [h]2D5=–0.26
(CHCl3).10
Scheme 3. Reagents and conditions: (a) rt, 16 h; (b) (i) LiTMP
(1.2 equiv.), THF, 0°C, 2 h; (ii) n-DecI (1.1 equiv.), −100°C,
2
h; (iii) reflux, 30 min; (c) BF3·OEt2 (6.0 equiv.),
HS(CH2)3SH (1.3 equiv.), CH2Cl2, reflux, 72 h; (d) Raney-Ni,
H2, i-PrOH, rt, 48 h.
meso-1 over nine steps was 46% and that of (S)-2
reached 58% over four steps.
Because it was impossible to obtain separation of the
enantiomers of 2 either by GC or HPLC on chiral
stationary phases, the ee could only be determined by
comparison of the optical rotation with the literature,
which was consistent with the data given.10
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft and the Fonds der Chemischen Industrie.
We thank Degussa AG, BASF AG and Bayer AG for
the donation of chemicals. The experimental work of
Raymond Hodiamont is gratefully acknowledged.
Desulfurization in refluxing i-propanol with Raney
nickel caused no epimerization at the stereocenter in the
b-position of 12 even though it is well known that
a-stereogenic centers such as in 16 can suffer from
partial racemization via an elimination–addition pro-
cess. Therefore, the desulfurization of 16 was performed
at room temperature under an atmosphere of hydrogen
for 48 h without detectable racemization.12
References
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Conclusion
In summary, an efficient asymmetric synthesis of all
possible stereoisomers of 7,11-dimethylheptadecane (1)
and 7-methylheptadecane (2) was achieved employing
the SAMP/RAMP-hydrazone method. The yield of
2. Gries, R.; Gries, G.; Li, J.; Maier, C. T.; Lemmon, C. R.;
Slessor, K. N. J. Chem. Ecol. 1994, 20, 2501–2511.
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rotation values: (S,S)-1, [h]2D5=+1.74 (c=10.0, hexane),
(lit.: [h]2D1=+1.77 (c=1.4, hexane)); (R,R)-1 [h]2D6=−1.48
(c=5.5, CHCl3), (lit.: [h]2D2=−1.26 (c=1.38, hexane));
(S)-2 [h]2D4=+0.27 (c=5.0, hexane), (lit.: [h]2D6=+0.275
(c=5.0, hexane)); (R)-2 [h]2D5=−0.26 (c=5.0, CHCl3),
(lit.: [h]2D6=−0.266 (c=5.0, hexane)).
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