Stereoselective synthesis of (R)-10-methyltridecan-2-one, the sex pheromone of the southern corn rootworm, using (4S)-benzylthiazolidinethione as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetasy.2009.09.014

The stereoselective synthesis of (R)-10-methyltridecan-2-one, the sex pheromone of the southern corn rootworm, was carried out in 20.7% overall yield based on (4S)-benzylthiazolidinethione (five steps). In the crucial step, the stereogenic center was gene

Full text of DOI:10.1016/j.tetasy.2009.09.014

Tetrahedron: Asymmetry 20 (2009) 2267–2269
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (R)-10-methyltridecan-2-one, the sex pheromone
of the southern corn rootworm, using (4S)-benzylthiazolidinethione
as a chiral auxiliary
*
Cui-Fen Lu, Shou-Bo Zhang, Yan Li, Gui-Chun Yang, Zu-Xing Chen
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules and School of Chemistry and Chemical Engineering, Hubei University,
Wuhan 430062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2009
Accepted 9 September 2009
Available online 14 October 2009
The stereoselective synthesis of (R)-10-methyltridecan-2-one, the sex pheromone of the southern corn
rootworm, was carried out in 20.7% overall yield based on (4S)-benzylthiazolidinethione (five steps). In
the crucial step, the stereogenic center was generated by an asymmetric Michael addition using enanti-
omerically pure (4S)-benzylthiazolidinethione as a chiral auxiliary.
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
1. Introduction
enantiomerically pure (4S)-benzylthiazolidinethione as a chiral
auxiliary.
Chiral auxiliary-mediated asymmetric Michael addition reac-
tions have been studied extensively and are now an important
and general method for asymmetric carbon–carbon bond forma-
tion.1 Organocopper reagents are amongst the most versatile re-
agents available for Michael addition reactions.2 The addition of
organocopper reagents to chiral alkenoate derivatives such as
Evans’ oxazolidinone has provided high diastereoselectivities.3
Using thiazolidinethiones would be advantageous as they are more
easily cleavable auxiliaries when compared to oxazolidinones or
oxazolidinethiones.4 Compared with the very popular oxazolidi-
nones, thiazolidinethiones appear to be more efficient in aldol-type
reactions. The aldol adducts of acylthiazolidinethiones are easily
removed and can be directly converted to aldehydes as well as to
other functional groups. In our previous research, we investigated
the asymmetric Michael addition of organocopper reagents to acy-
loxazolidinones;5 herein, we report Michael additions mediated by
an acylthiazolidinethione.
2. Results and discussion
Our synthetic strategy is shown by the retrosynthetic analysis
as outlined in Scheme 1. The target molecule can be divided into
two fragments, the C1–C7 fragment, containing a ketone unit,
and the C8–C13 fragment, containing a stereogenic center. The
C1–C7 fragment can be prepared from 1-methylcyclohexanol
according to the literature procedures.9,7d,7f For the synthesis of
the C8–C13 fragment, we describe an efficient, scalable, and eco-
nomical second-generation synthesis, utilizing a thiazolidinethi-
one chiral auxiliary to control the stereochemistry at C10 by
means of a key stereoselective Michael addition reaction.
The stereoselective synthesis of the C8–C13 fragment was car-
ried out as shown in Scheme 2. The starting (4S)-benzylthiazolidin-
ethione 3 was treated with crotonoyl chloride to give N-crotonyl
(4S)-benzylthiazolidinethione 4 in 95.6% yield in the presence of
Et3N with DMAP as a catalyst. The Michael addition of the organo-
copper reagent to 4 afforded the product 5 in 91.3% yield after puri-
fication (de = 92% for the crude product). Non-destructive removal
of the auxiliary group of 5 via the selective reduction with (i-
Bu)2AlH gave (R)-3-methylhexanal 6 in 82.2% yield along with
the recovery of 3 (92.6% yield).
(R)-10-Methyltridecan-2-one has been identified as the sex
pheromone secreted by virgin females of the southern corn root
worm.6 Since effective and cost-efficient control of the insect pop-
ulations can be foreseen with the aid of the sex pheromone, several
total syntheses of the racemate and the (R)-enantiomer have been
published.7
Recently, our group has undertaken a research program on the
investigation of chiral auxiliaries and their application to synthesize
the insect pheromones.5,8 Herein, we have developed an efficient
procedure to synthesize stereoselectively (R)-10-methyltridecan-
2-one 1 through the key step of a Michael addition reaction using
As illustrated in Scheme 2, (R)-3-methylhexanal 6 was subjected
to a Wittig reaction with the phosphonium bromide 2 to yield olefin
7. Catalytic hydrogenation of 7 with palladium on charcoal in meth-
anol under hydrogen followed by hydrolysis under acidic conditions
afforded (R)-10-methyltridecan-2-one 1 in 68.4% yield. Over the
course of the synthesis, the stereocenter of the compounds was
not touched and the spectroscopic data of 1 as well as its specific
rotation values were in accordance with the literature.7
* Corresponding author. Tel.: +86 27 50865322; fax: +86 27 88663043.
E-mail address: chzux@hubu.edu.cn (Z.-X. Chen).
0957-4166/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.09.014

2268
C.-F. Lu et al. / Tetrahedron: Asymmetry 20 (2009) 2267–2269
O
O
O
O
-
+
PPh3Br
+
H
C1-C7 fragment
C8-C13 fragment
O
S
H3C
OH
S
N
Bn
O
S
S
+
BrMg
N
Bn
Scheme 1.
S
O
S
O
O
S
BrMg
CuBr-Me2S/THF
Cl
Et3N/DMAP
S
NH
Bn
S
N
S
N
Bn
Bn
5
4
3
O
O
O
n-BuLi/ THF
(i-Bu)2AlH
H
THF
-
O
O
+
6
7
PPh3Br
2
O
1) H2/Pd-C
2) H2SO4/H2O
1
Scheme 2.
apparatus and are uncorrected. Optical rotations were measured
using a sodium D line on WZZ-2B Automatic Polarimeter. HPLC
analyses were carried out on a Dionex chromatograph (Ulti-
mate3000 pump, C8 reversed-phase chromatographic column)
equipped with a diode-array UV detector. Mass spectra were re-
corded on Finnigan LCQ DUO MS system. IR spectra were recorded
on an IR-spectrum one (PE) spectrometer. NMR spectra were re-
corded on Varian Unity Inova 600 spectrometer in CDCl3 (1H at
600 MHz and 13C at 150 MHz) using TMS as the internal standard.
3. Conclusion
In conclusion, we have reported an effective procedure for the
stereoselective synthesis of the sex pheromone (R)-10-methyltrid-
ecan-2-one 1 of the southern corn rootworm using enantiomeri-
cally pure (4S)-benzylthiazolidinethione as a chiral auxiliary. The
key step in our approach was the regio- and stereocontrolled Mi-
chael addition reaction of an organocopper reagent to N-crotonyl
(4S)-benzylthiazolidinethione 4. All of the steps proceeded with
excellent yields and full preservation of chirality, with 1 being ob-
tained in 20.7% overall yield based on 3. Further application of this
methodology to the syntheses of other biologically active com-
pounds is currently underway in our laboratory.
4.2. (S)-3-((E)-But-2-enoyl)-4-benzylthiazolidinethione 4
To
a solution of (4S)-benzylthiazolidinethione 3 (5.0 g,
23.9 mmol), DMAP (0.58 g, 4.7 mmol), and Et3N (3.8 mL, 27.2 mmol)
in dry CH2Cl2 (100 mL) was added crotonyl chloride (2.8 mL,
29.2 mmol) dropwise and the solution was allowed to stir at rt for
2 h. The reaction was quenched with saturated aqueous NH4Cl
(10 mL), and the organic layer was separated. The aqueous layer
was extracted with CH2Cl2 (25 mL ꢀ 3) and the organic layers were
combined, washed with saturated aqueous NaHCO3 and brine, dried
over MgSO4, and concentrated. The crude product was recrystallized
from petroleum ether to give a yellow solid 4 (6.3 g, 95.6%). Mp 76.7–
4. Experimental
4.1. General
All solvents were obtained from commercial sources and dried
or purified by standard procedures before use. Separations by flash
chromatography were performed on 300–400 mesh silica gel.
Melting points were measured on a WRS-1A digital melting point

C.-F. Lu et al. / Tetrahedron: Asymmetry 20 (2009) 2267–2269
2269
77.5 °C; ½a 2D5
ꢁ
¼ þ97:8 (c 0.9, CHCl3); IR (NaCl, cmꢂ1): mmax 3026,
with saturated aqueous NH4Cl, brine, dried over MgSO4, filtered,
and concentrated. Purification of the crude product by silica gel
column chromatography (n-hexane/EtOAc, 16/1, V/V) gave a color-
less oil 7 (1.1 g, 72.6%). IR (NaCl, cmꢂ1): mmax 3350, 3052; 1H NMR
(600 MHz, CDCl3): d 0.89–0.99 (m, 6H), 1.25 (s, 3H), 1.29–1.41 (m,
10H), 1.65 (m, 1H), 2.02–2.18 (m, 4H), 3.81–3.90 (m, 4H), 5.3 (s,
2H); 13C NMR (150 MHz, CDCl3): d 131.24, 111.56, 65.68, 42.45,
40.18, 39.22, 37.52, 35.29, 32.11, 25.44, 22.75, 21.03, 15.15. MS:
m/z = 255.25 (M+H+).
1679, 1634; 1H NMR (600 MHz, CDCl3): d 1.96 (dd, J = 1.5, 7.2 Hz,
3H), 2.92 (d, J = 11.4 Hz, 1H), 3.06 (dd, J = 10.8, 13.2 Hz, 1H), 3.34
(dd, J = 3.6, 13.2 Hz, 1H), 3.40 (dd, J = 9.6, 11.4 Hz, 1H), 5.18–5.21
(m, 1H), 7.05 (dq, J = 7.2, 15.0 Hz, 1H), 7.25–7.35 (m, 6H); 13C NMR
(150 MHz, CDCl3):
d 201.08, 166.34, 145.11, 136.62, 129.47,
128.91, 127.18, 124.55, 68.93, 36.68, 31.47, 18.52. MS: m/
z = 278.10 (M+H+).
4.3. (S)-3-((R)-3-Methylpropyl)-4-benzylthiazolidinethione 5
4.6. (R)-10-Methyltridecan-2-one 1
A three-necked flask was charged with a slurry of CuBr (8.2 g,
56.7 mmol) in ether (10 mL) and dimethyl sulfide (4.1 mL,
17.0 mmol) was added under argon. After cooling to ꢂ78 °C, n-pro-
pylmagnesium bromide (43.2 mmol) in ether (10 mL) was added
dropwise to the mixture, followed by stirring for 10 min. Then a
solution of 4 (6.0 g, 21.6 mmol) in THF (50 mL) was slowly added,
and the mixture was stirred at ꢂ78 °C for 3 h. The mixture was
warmed up to ꢂ20 °C and was kept stirring at ꢂ20 °C for 18 h.
The reaction was quenched with saturated aqueous NH4Cl
(20 mL). After evaporation of the solvent, the aqueous layer was
extracted with ethyl acetate. The organic layer was washed with
saturated aqueous NH4Cl, brine, dried over MgSO4, and the solvent
was removed in vacuo to afford a crude product as a mixture of
diastereomers (92:8). Purification of the crude product by silica
gel column chromatography (n-hexane/EtOAc, 16:1, V/V) gave a
To a solution of 7 (1.0 g, 3.9 mmol) in MeOH (15 mL) was added
a catalytic amount of 10% Pd/C. The reaction mixture was stirred at
rt under hydrogen for 2 h, then filtered through Celite, and the fil-
trate was concentrated under reduced pressure. The residue was
dissolved in acetone (10 mL), after which 10% aqueous H2SO4
(2 mL) was added, and the mixture was stirred at rt for 1.5 h. After
evaporation of the solvent, the residue was extracted with ether,
and the organic layer was washed with saturated aqueous NaHCO3,
brine, dried over MgSO4, filtered, and concentrated. Purification of
the crude product by silica gel column chromatography (n-hexane/
EtOAc, 14:1, V/V) gave a colorless oil 1 (0.5 g, 68.4%). ½a D22
¼ ꢂ1:6 (c
ꢁ
0.9, CHCl3); {lit.7d
½
a 2D4
ꢁ
¼ ꢂ1:6 (c 4.1, CHCl3)} IR (NaCl, cmꢂ1): mmax
1718; 1H NMR (600 MHz, CDCl3): d 0.86–0.94 (m, 3H), 1.24–1.30
(m, 9H), 1.48–1.93 (m, 11H), 2.18 (s, 3H), 2.56 (t, J = 7.5 Hz, 2H);
13C NMR (150 MHz, CDCl3): d 208.97, 43.56, 39.46, 37.35, 32.51,
29.86, 29.65, 29.33, 29.17, 27.21, 23.52, 20.62, 19.64, 14.96.
colorless oil 5 (6.3 g, 91.3%). ½a D25
¼ þ116:3 (c 1.1, CHCl3); IR (NaCl,
ꢁ
cmꢂ1): mmax 3021, 1692, 701; 1H NMR (600 MHz, CDCl3): d 0.84–
0.98 (m, 6H), 1.22–1.61 (m, 4H), 2.12 (s, 1H), 2.88 (dd, J = 4.2,
11.4 Hz, 2H), 3.02–3.07 (m, 2H), 3.22–3.39 (m, 2H), 5.34–5.38 (m,
1H), 7.26–7.35 (m, 5H); 13C NMR (150 MHz, CDCl3): d 201.04,
173.57, 136.56, 129.41, 128.84, 127.14, 68.65, 45.48, 39.01, 36.74,
31.89, 29.63, 20.02, 19.72, 14.23. MS: m/z = 322.15 (M+H+).
Acknowledgments
We gratefully acknowledge the National Natural Sciences Foun-
dation of China (No. 20772026) and the Natural Sciences Founda-
tion of Hubei province in China (No. 2008CDA078) for financial
support.
4.4. (R)-3-Methylhexanal 6
To a solution of 5 (6.0 g, 18.7 mmol) in CH2Cl2 (15 mL) was
added dropwise a solution of DIBALH (37.4 mL, 1 M in hexane) at
ꢂ78 °C under argon and the mixture was stirred for 20 min. Then
to the mixture was added saturated aqueous NH4Cl (10 mL) and
the mixture was warmed up to rt. After stirring for 20 min, the pre-
cipitated solid was filtered, and the filtrate was extracted with
CH2Cl2 (15 mL ꢀ 3). The combined organic layer was washed with
brine, dried over MgSO4, filtered, and concentrated. Purification of
the crude product by silica gel column chromatography (n-hexane/
EtOAc, 8/1, V/V) gave 6 as a colorless oil (1.7 g, 82.2%). IR (NaCl,
cmꢂ1): mmax 3151, 1710; 1H NMR (600 MHz, CDCl3): d 0.78–0.97
(m, 6H), 1.10–1.57 (m, 5H), 2.12–2.23 (m, 2H), 9.76 (d, J = 1.8 Hz,
1H); 13C NMR (150 MHz, CDCl3): d 203.29, 51.01, 39.07, 27.83,
19.98, 19.93, 14.07. MS: m/z = 115.12 (M+H+).
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To a solution of 2 (3.0 g, 6.0 mmol) in dry THF (15 mL) was
added n-BuLi in hexane (32 mL, 2.5 M) dropwise at 0 °C under ar-
gon and the mixture was stirred at 0 °C for 2 h. After cooling to
ꢂ78 °C, a solution of 6 (0.7 g, 6.0 mmol) in dry THF (10 mL) was
added dropwise, and the mixture was stirred at ꢂ78 °C for 1 h
and then warmed up to rt. The stirring was continued for 2 h.
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