Synthesis of all the four stereoisomers of (1′S)-1-ethyl-2-methylpropyl 3,13-dimethylpentadecanoate, the major component of the sex pheromone of Paulownia bagworm, Clania variegata

Article abstract of DOI:10.1016/j.tetlet.2009.02.046

All the four stereoisomers of (1′S)-1-ethyl-2-methylpropyl 3,13-dimethylpentadecanoate, the major component of the sex pheromone of Clania variegata, were synthesized by starting from (R)- or (S)-2-methylbutan-1-ol, (R)- or (S)-citronellal, and (S)-2-methylpentan-3-ol. Olefin cross metathesis was employed as the key reaction.

Full text of DOI:10.1016/j.tetlet.2009.02.046

Tetrahedron Letters 50 (2009) 3266–3269
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Tetrahedron Letters
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Synthesis of all the four stereoisomers of (10S)-1-ethyl-2-methylpropyl
3,13-dimethylpentadecanoate, the major component of the sex
pheromone of Paulownia bagworm, Clania variegata
b
Kenji Mori a,b, , Takuya Tashiro
*
a Photosensitive Materials Research Center, Toyo Gosei Co., Ltd, Wakahagi 4-2-1, Inba-mura, Inba-gun, Chiba 270-1609, Japan
b Glycosphingolipid Synthesis Group, Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
All the four stereoisomers of (10S)-1-ethyl-2-methylpropyl 3,13-dimethylpentadecanoate, the major
component of the sex pheromone of Clania variegata, were synthesized by starting from (R)- or (S)-2-
methylbutan-1-ol, (R)- or (S)-citronellal, and (S)-2-methylpentan-3-ol. Olefin cross metathesis was
employed as the key reaction.
Article history:
Received 13 January 2009
Revised 3 February 2009
Accepted 6 February 2009
Available online 11 February 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Clania variegata
Cross metathesis
3,13-Dimethylpentadecanoic acid
2-Methylpentan-3-ol
Pheromone
O
1. Introduction
13 (CH2)9
3
O
1'
The Paulownia bagworm, Clania variegata Snell (Lepidoptera:
Psychidae), is a forest defoliator in managed forests in China. The
major component of its sex pheromone was reported to be (10S)-
1-ethyl-2-methylpropyl 3,13-dimethylpentadecanoate (1, Fig. 1)
by Gries et al.1 As to the absolute configuration of this ester 1, they
assigned S configuration to the alcohol part by synthesis of both
(10R)- and (10S)-1 and their field trapping experiments in China.1
The absolute configuration of the two remaining stereogenic cen-
ters of the carboxylic acid part of 1, however, has remained
unknown.
In continuation of our long-term studies on the absolute config-
uration of pheromones,2 we became interested in clarifying the
stereochemistry of the naturally occurring 1. The standard method
to achieve the goal is to synthesize all the possible stereoisomers of
1 and then to evaluate their pheromone activity. Usually the bio-
logically active stereoisomer of 1 can be regarded as the naturally
occurring 1.2 The ester 1 possesses four stereoisomers. We decided
to employ olefin cross metathesis reaction as the key step to syn-
thesize all the stereoisomers of 1 quickly without complication.3
Scheme 1 shows our retrosynthetic analysis of (3R,13R,10S)-1.
The ester 1 can be dissected to 3,13-dimethylpentadecane moiety
1
Figure 1. Structure 1 of the major component of the sex pheromone of Clania
variegata.
A and the alcohol moiety B. The olefinic acetate A might be synthe-
sized by cross metathesis of C with D, the two metathesis partners.
The optically active olefin C would be prepared from (R)-2-meth-
ylbutanoic acid (E) and 5-hexen-1-ol (F). Another metathesis part-
ner D would be obtainable from (R)-citronellal (G), and the alcohol
part B must be available via asymmetric synthesis. This synthetic
plan was put into practice as reported below.
2. Results and discussion
Synthesis of the metathesis partners, (R)-8 (=C) and (R)-12 (=D),
is summarized in Scheme 2. The starting material for (R)-8 was (R)-
2-methylbutanoic acid (2, T. Hasegawa Co., >99.0% ee), which was
obtained by treatment of ( )-2 with Pseudomonas sp. TH-252-1.4
Reduction of (R)-2 with lithium aluminum hydride gave alcohol
(R)-3, whose tosylate (R)-4 was treated with lithium bromide in
DMF to furnish (R)-2-methylbutyl bromide (5). The Grignard re-
agent prepared from (R)-5 and magnesium in THF was coupled with
* Corresponding author. Tel.: +81 3 3816 6889; fax: +81 3 3813 1516.
E-mail address: kjk-mori@arion.ocn.ne.jp (K. Mori).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.046

K. Mori, T. Tashiro / Tetrahedron Letters 50 (2009) 3266–3269
3267
der the Schlosser conditions5 to give (R)-8, bp 94–96 °C/48 Torr,
O
½
a 2D7
ꢁ
ꢀ 11:0 (c 3.40, pentane), in 42% yield based on (R)-5. Its GC–
(CH2)9
O
MS analysis revealed it to be a 91.2:8.8 mixture of (R)-8 and
(3R,6R)-9. The latter must have been generated in the course of
the preparation of the Grignard reagent. Similarly, commercially
available (S)-3 (Tokyo Kasei) afforded (S)-8, bp 110–115 °C/65 Torr,
(3R,13R,1'S)-1
½
a 2D6
ꢁ
þ 10:6 (c 3.50, pentane), as a 93:7 mixture of (S)-8 and (3S,6S)-
9. The enantiomeric purity of (R)-8 was >98.0% ee, while that of (S)-
8 was 99.0% ee as determined by their GC analysis.6 The overall
yield of (R)-8 was 26% based on (R)-2 (4 steps), while that of (S)-8
was 22% based on (S)-3 (3 steps).
HO
OAc
A
B
PCy3
Ru
PCy3
The other partners of metathesis, (R)- and (S)-12, were prepared
by acetylation of (R)- and (S)-11. These alcohols (R)- and (S)-11,
respectively, were synthesized from the enantiomers of citronellal
(10, Takasago International Corporation, both 97% ee), and em-
ployed as intermediates in the synthesis of the pheromone of an
Okinawan moth, Lyclene dharma dharma.8 Their enantiomeric puri-
Cl
Cl
Ph
Grubbs I
ties were 97.2% ee for both (R)-12, bp 130–134 °C/80 Torr, ½a D26
ꢁ
+1.53 (c 3.41, Et2O) and (S)-12, bp 122–125 °C/60 Torr, ½a D25
ꢁ
OAc
ꢀ1.36 (c 3.12, Et2O).9 The overall yield of (R)-12 was 46% based
on (R)-10 (7 steps), and that of (S)-12 was 45% based on (S)-10 (7
steps).
C
D
G
Scheme 3 shows the synthesis of the key acid (3R,13R)-17 via
the crucial step of olefin cross metathesis.10–13 Because (R)-8 could
be prepared in shorter four steps than (R)-12 (7 steps), 10 equiv of
(R)-8 was mixed with 1 equiv of (R)-12 in dichloromethane. In the
presence of 5 mol % [based on (R)-12] of Grubbs’ first generation
catalyst, the mixture was stirred and heated under reflux for 6 h
under argon. Chromatographic purification of the product first
gave (3R,16R)-14 [50% yield based on (R)-8] and then (3R,13R)-13
contaminated with (3R,10R)-15 in 88% yield based on (R)-12. Since
complete removal of 15 from crude 13 was difficult, the crude
(3R,13R)-13 was subjected to alkaline hydrolysis and hydrogena-
tion over 10% palladium–charcoal. Subsequent chromatographic
CHO
HO
CO2H
E
F
Scheme 1. Retrosynthetic analysis of (3R,13R,10S)-1.
tosylate 7 (obtained by tosylation of commercially available 6) in
the presence of dilithium tetrachlorocuprate at ꢀ65 to ꢀ50 °C un-
a
c
OR
purification gave (3R,13R)-16, ½a D25
ꢁ
ꢀ 2:12 (c 7.64, hexane), in 53%
CO2H
(R)-2
yield based on the crude (3R,13R)-13 (2 steps). Oxidation of
(3R,13R)-16 with Jones chromic acid afforded the desired acid
(R)-3 R = H
(R)-4 R = Ts
b
(3R,13R)-17, ½a D24
ꢁ
ꢀ 0:34 (c 1.39, CHCl3), in 75% yield. The overall
d
+
Br
RO
6 R = H
7 R = Ts
(R)-5
b
a
+
OAc
(R)-8
(R)-12
+
(R)-8 (= C)
Similarly
(3R,6R)-9
b, c
OAc
(3R,13R)-13
OH
+
+
(S)-3
(S)-8
(3R,16R)-14
(3R,10R)-15
ref. 8
AcO
CHO
CHO
OAc
OR
(R)-10
(S)-10
(R)-11 R = H
(R)-12 R = Ac (= D)
e
Similarly
d
CO2H
(CH2)9
OH
(CH2)9
(3R,13R)-17
OAc
(3R,13R)-16
(S)-12
Scheme 2. Synthesis of the metathesis partners 8 and 12. Reagents: (a) LiAlH4,
Et2O; (b) TsCl, C5H5N (51% for 7); (c) LiBr, DMF [63% based on (R)-2, 3 steps]; (d) (i)
(R)-5, Mg, THF ; (ii) 7, THF, Li2CuCl4 [42% based on (R)-5 or 66% based on 7]; (e)
Ac2O, DMAP, C5H5N (82%).
Scheme 3. Synthesis of the acid (3R,13R)-17. Reagents: (a) Grubbs I [ca. 5 mol %
based on (R)-12], (R)-8/(R)-12 = ca. 10:1 in CH2Cl2, reflux, 6 h [88% based on (R)-12];
(b) NaOH, MeOH, aq THF, reflux, 1 h (92%); (c) H2, 10% Pd–C, EtOH, then SiO2
chromatog. (58%); (d) Jones CrO3, acetone (75%).

3268
K. Mori, T. Tashiro / Tetrahedron Letters 50 (2009) 3266–3269
The final step as depicted in Scheme 5 was the esterification of
a
c
b
the four stereoisomers of the acid 17 with (S)-20. 1-Ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride (EDC, 1.6
equiv) was added to a solution of (3R,13R)-17 (1 equiv), (S)-20
(2 equiv), and 4-(N,N-dimethylamino)pyridine (DMAP, 1.9 equiv)
OH
O
( )-18
19
in dichloromethane to give (3R,13R,10S)-1 as an oil, ½a 2D3
ꢀ5.38 (c
ꢁ
1.30, CHCl3), in 83% yield. Its 1H and 13C NMR data18 are in good ac-
cord with those published for (3RS,13RS,10S)-1.1 The MS of
(3R,13R,10S)-118 was also in accord with that of the naturally occur-
ring pheromone component 1.1 Similarly, we synthesized (3R,
+
OH
OH
O
(R)-18
(S)-20
21
(96% ee)
(94% ee)
13S,10S)-1, ½a 2D3
ꢁ
+1.63 (c 1.32, CHCl3), (3S,13R,10S)-1, ½a D23
ꢀ10.8 (c
ꢁ
1.31, CHCl3), and (3S,13S,10S)-1, ½a D23
ꢀ3.42 (c l.20, CHCl3). The
ꢁ
e
d
B
spectral data of these four isomers of 1 were virtually indistin-
guishable.18 The overall yield of (3R,13R,10S)-1 was 13% based on
(R)-10 (12 steps).
(R)-Alpine-Borane®
OBz
O(R)-MTPA
O
C
OMe
C
(R)-22
(S)-23
3. Conclusion
CF3
We synthesized all of the four stereoisomers of (10S)-1-ethyl-2-
methylpropyl 3,13-dimethylpentadecanoate (1), the major compo-
nent of the sex pheromone of C. variegata. Future bioassay of these
four stereoisomers of 1 will hopefully clarify the absolute configu-
ration of the naturally occurring and bioactive component 1. Olefin
cross metathesis has been shown to be a useful reaction in phero-
mone synthesis, especially when a set of stereoisomers has to be
prepared quickly and efficiently.
MTPA
Scheme 4. Synthesis of the alcohol (S)-20. Reagents: (a) Jones CrO3, acetone (73%);
(b) (R)-Alpine-BoraneÒ (47%); (c) H2, 10% Pd–C, pentane (83%); (d) BzCl, DMAP,
C5H5N; (e) (S)-MTPACl, C5H5N.
O
a
CO2H
(CH2)9
(CH2)9
O
Acknowledgments
(3R,13R)-17
(3R,13R,1'S)-1
K.M. thanks Mr. M. Kimura (president, Toyo Gosei Co., Ltd) for
his support. Our thanks are due to Mr. Y. Shikichi (Toyo Gosei
Co., Ltd) for GC–MS and NMR measurements, Dr. S. Tamogami
(T. Hasegawa Co.) for enantioselective GC analysis, Professor T.
Nakata (Tokyo University of Science) for his help in MS, and Dr.
K. Manabe (RIKEN) for his permission to use his GC apparatus. Both
(R)- and (S)-citronellal were supplied by Takasago International
Corporation, and (R)-2-methylbutanoic acid was supplied by T.
Hasegawa Co.
Similarly
+
+
+
(3R,13S,1'S)-1
(3S,13R,1'S)-1
(3S,13S,1'S)-1
OAc
OAc
OAc
(S)-8
(R)-8
(S)-8
(R)-12
(S)-12
(S)-12
References and notes
1. Gries, R.; Khaskin, G.; Tan, Z.-X.; Zhao, B.-G.; King, G. G. S.; Miroshnychenko, A.;
Lin, G.-Q.; Rhainds, M.; Gries, G. J. Chem. Ecol. 2006, 32, 1673–1685.
2. Mori, K. Bioorg. Med. Chem. 2007, 15, 7505–7523.
3. A totally different synthesis of the four isomers of 1 is recorded by Lin and his
co-workers in a patent literature without any spectral and chiroptical data of
the intermediates and final products: Wei, B.; Liu, R.; Zhang, C.; Sun, X.; Lin, G.-
q. Chinese Patent (Faming Zhuanli Shenqing Gongkai Shuomingshu) 2008, CN
101157613(A).
Scheme 5. Synthesis of the target esters 1. Reagents: (a) (S)-20, EDC, DMAP, CH2Cl2
[83% based on (3R,13R)-17].
yield of (3R,13R)-17 was 35% based on (R)-12 (4 steps). Other ster-
eoisomers of the acid 17 could be synthesized in the same manner.
The next task was the synthesis of (S)-2-methylpentan-3-ol
(20). Gries et al. previously prepared (S)-20 by kinetic resolution
of ( )-4-methyl-1-penten-3-ol by Sharpless asymmetric epoxida-
tion.1 As shown in Scheme 4, we synthesized (S)-20 by asymmetric
reduction of 4-methyl-1-pentyn-3-one (19) to (R)-18 with Brown’s
(R)-Alpine-BoraneÒ14 as the key step. Commercially available ( )-
4-methyl-1-pentyn-3-ol (18) was oxidized with Jones chromic acid
to give ketone 19. This was reduced with (R)-Alpine-BoraneÒ to
4. Hashimoto, H.; Tatehara, T.; Komai, T. Jpn. Kokai Tokkyo Koho P 2005-348727A.
5. Fouquet, C.; Schlosser, M. Angew. Chem., Int. Ed. 1974, 13, 82–83.
7
6. (a) GC analysis of (R)-8 [instrument: Agilent 7890; column: CHIRAMIX,Ò
30 m ꢂ 0.25 mm i.d.; column temp.: 40–180 °C (+0.7 °C/min); carrier gas: He,
0.7 mL/min]: tR 42 min (>99.9%, (R)-8], 47 min [<1.0%, (S)-8].; (b) GC analysis of
(S)-8 [same conditions as for (R)-8]: tR 42 min [0.5%, (R)-8], 47 min [99.5%, (S)-8].
7. Tamogami, S.; Awano, K.; Amaike, M.; Takagi, Y.; Kitahara, T. Flavour Frag. J.
2001, 16, 349–352.
8. Mori, K. Tetrahedron, in press, doi:10.1016/j.tet.01.092.
9. (a) GC analysis of (R)-12 [instrument: Agilent 7890; column: 50% octakis-(2,3-
di-O-methoxymethyl-6-O-t-butyldimethylsilyl)-c-cyclodextrin,
30 m ꢂ 0.25 mm i.d.; column temp.: 40–180 °C (+0.7 °C/min); carrier gas: He,
0.7 mL/min]: tR 77 min [98.6%, (R)-12], 78 min [1.4%, (S)-12].; (b) GC analysis of
(S)-12 [same conditions as for (R)-12]: tR 77 min [1.4%, (R)-12], 78 min [98.6%,
(S)-12].
give highly volatile (R)-18, bp 119–121 °C, ½a D25
ꢀ 0:96 (c 1.37,
ꢁ
CHCl3), in 47% yield. The enantiomeric purity of (R)-18 was esti-
mated as 96% ee by HPLC analysis of the corresponding benzoate
(R)-22.15 Hydrogenation of (R)-18 over 10% palladium–charcoal
in pentane afforded a 2:1 mixture of (S)-20 and 21. After chromato-
graphic purification, highly volatile and pure (S)-20, bp 104–
10. Pederson, R. The Efficient Application of Olefin Metathesis in Pharmaceutical
and Fine Chemicals. Sigma–Aldrich CheminarÒ 4.1 (2008). (Sigma–
aldrich.com/cheminars).
11. Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R. A.; Bussmann,
D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58–71.
12. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003,
125, 11360–11370.
13. Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900–1923.
14. Brown, H. C.; Pai, G. G. J. Org. Chem. 1985, 50, 1384–1394.
106 °C, ½a 2D5
ꢁ
ꢀ 14:0 (c 1.10, CHCl3), ½a D25
ꢀ 20:1 (c 1.16, EtOH), Ref.
ꢁ
16 ½a 2D3
ꢀ 16:9 (c 0.39, EtOH), could be secured in 16% yield. Its
ꢁ
enantiomeric purity was estimated as 94.2% ee by GC analysis of
the corresponding (R)-MTPA ester 23.17

K. Mori, T. Tashiro / Tetrahedron Letters 50 (2009) 3266–3269
3269
15. HPLC analysis of (R)-22 [column: ChiralcelÒ OJ-H, 25 cm ꢂ 4.6 mm i.d.; eluent:
hexane/i-PrOH = 9:1; flow rate: 0.5 mL/min; column temp.: 10 °C; detection at
254 nm]: tR 10.96 min [98.0%, (R)-22], 11.91 [2.0%, (S)-22].
16. Mori, K.; Nomi, H.; Chuman, T.; Kohno, M.; Kato, K.; Noguchi, M. Tetrahedron
1982, 38, 3705–3711.
17. GC analysis of (S)-23 [(S)-23 was prepared from (S)-20 employing (S)-MTPACl
(Aldrich, P99% ee). Instrument: Shimadzu GC-2014; column: DB-WAX,Ò
30 m ꢂ 0.25 mm i.d.; column temp.: 130 °C (1 min)–150 °C (+0.25 °C/min);
carrier gas: He; press: 100 kPa]: tR 29.92 min (97.1%), 30.12 min (2.9%).
Diastereomeric purity of (S)-23: 94.2% de.
19.2, 19.7, 24.0, 26.9, 27.1, 29.5, 29.64, 29.65, 29.7, 29.8, 30.0, 30.4, 30.9, 34.4,
36.6, 36.8, 42.3, 79.4, 173.3 ppm; GC–MS [Instrument: Agilent 19091S-433;
column: HP-5MS, 5% phenylmethylsiloxane, 30 m ꢂ 0.25 mm i.d.; carrier gas:
He; press: 60.7 kPa; temp.: 70–230 °C (+10 °C/min)]: tR 17.513 min (1.63%),
19.608 (2.69%), 21.026 [93.4%; (3R,13R,10S)-1]; MS (70 eV, EI): m/z 353 (very
small, M+ꢀ1), 339 (0.5, M+ꢀCH3), 296 (2), 270 (37), 253 (63), 244 (4), 235 (5),
213 (3), 181 (4), 165 (1), 151 (1), 139 (3), 125 (5), 111 (6), 97 (10), 84 (100), 69
(35), 57 (36), 43 (38); HRMS calcd for C17H33O [MꢀC6H13O]+: 253.2531, found:
253.2529. Spectral data of other three isomers of 1 were identical to those of
(3R,13R,10S)-1 within experimental errors. The diastereomers with remote
stereogenic centers such as the isomers of 1 showed virtually identical spectral
data, although they showed different specific rotations. GC retention times of
all the isomers were also identical to that of (3R,13R,10S)-1 within
experimental errors under the same conditions for the analysis of
(3R,13R,10S)-1: tR 21.046 min [88.2%, (3R,13S,10S)-1]; 21.039 [92.2%,
(3S,13R,10S)-1]; 21.058 [93.0%, (3S,13S,10S)-1].
18. Spectral data of (3R,13R,10S)-1: mmax (film): 1735 (s, C@O), 1180 (m), 975 (m)
cmꢀ1; dH (500 MHz, CDCl3): 0.84 (3H, d, J 7.0, CH3), 0.85 (3H, d, J 7.0, CH3), 0.87
(3H, t, J 7.0, CH3), 0.89 (6H, d, J 7.0, CH3 ꢂ 2), 0.94 (3H, d, J 7.0, CH3), 1.05–1.37
(21H, m), 1.48–1.62 (2H, m, 100-H2), 1.83 (1H, d-sept, J 5.0, 7.0, 20-H), 1.91–2.01
(1H, m, 3-H), 2.11 (1H, dd, J 8.0, 15, 2-Ha), 2.31 (1H, dd, J 6.0, 15, 2-Hb), 4.68
(1H, ddd, J 5.0, 5.0, 8.0, 10-H) ppm; dc (126 MHz, CDCl3): 9.9, 11.4, 17.6, 18.6,