Asymmetric synthesis of (2R,5S)-2-methyl-5-hexanolide, the sex pheromone of carpenter bee Xylocopa hirutissima

Article abstract of DOI:10.1016/j.tetasy.2008.08.026

The stereoselective synthesis of the (2R,5S)-2-methyl-5-hexanolide, a sex pheromone of Xylocopa hirutissima, has been achieved in 6 steps and 33% overall yield. The synthesis relies on an asymmetric N-acetyl thiazolidinethione aldol reaction to establish the C5 stereogenic centers. The remaining stereogenic center at C2 was set through a N-propionylprolinol-mediated asymmetric alkylation reaction.

Full text of DOI:10.1016/j.tetasy.2008.08.026

Tetrahedron: Asymmetry 19 (2008) 2164–2166
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of (2R,5S)-2-methyl-5-hexanolide, the sex pheromone
of carpenter bee Xylocopa hirutissima
*
Jian-Hong Yang, Gui-Chun Yang , Cui-Fen Lu, 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:
The stereoselective synthesis of the (2R,5S)-2-methyl-5-hexanolide, a sex pheromone of Xylocopa hirutiss-
ima, has been achieved in 6 steps and 33% overall yield. The synthesis relies on an asymmetric N-acetyl
thiazolidinethione aldol reaction to establish the C5 stereogenic centers. The remaining stereogenic cen-
ter at C2 was set through a N-propionylprolinol-mediated asymmetric alkylation reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 22 July 2008
Accepted 25 August 2008
Available online 1 October 2008
1. Introduction
S
S
S
OH
OTBS
O
O
O
a
c
b
e
S
N
S
N
S
N
(2R,5S)-2-Methyl-5-hexanolide was isolated and identified as a
major component of the sex pheromone from the male Xylocopa
hirutissima in 1976.1 Due to its attractive biological activities, var-
ious methods for the synthesis of (2R,5S)-2-methyl-5-hexanolide
have been described.2 Wu et al.3 reported a synthesis of this phero-
mone with 20% overall yield from (4S)-3-methacryloyl-4-phenyl-
2-oxazolidinone involving an asymmetric conjugate addition as a
key step. Sonoda et al.4 described a one-step synthesis of the sex
pheromone via the transition-metal-mediated carbonylation of
saturated alcohols with CO. Very recently, via the intermolecular
asymmetric alkylation of (4S)-iodobutan-2-ol with 2-ethyl-4,4-di-
methyl-2-oxazoline, the synthesis of the sex pheromone has been
reported.5 However, there are currently only a few syntheses of the
optically active pheromone.6 Furthermore, these methods suffer
from disadvantages such as low overall yields, low enantiometric
purity and the use of expensive starting materials. In connection
with our studies on the chiral auxiliary-mediated asymmetric syn-
thesis of the pheromone of insects,7 we were interested in develop-
ing a simple and feasible route to (2R,5S)-2-methyl-5-hexanolide.
Herein, we report a novel method for the stereoselective synthesis
of (2R,5S)-2-methyl-5-hexanolide employing an asymmetric aldol
condensation and asymmetric alkylation reaction as the key steps
(Scheme 1).
Bn
Bn
Bn
4
3
2
HO
O
OTBS
OTBS
OTBS
d
HO
f
I
N
5
6
7
O
O
1
Scheme 1. Reagents and conditions: (a) TiCl4, DIPEA, CH2Cl2, 0 °C, then acetalde-
hyde (55.8%); (b) TBSCl, 2,6-lutidine, DMF (97.4%); (c) NaBH4, C2H5OH (93.1%); (d)
Ph3P, I2, imidazole (93.2%); (e) (S)-prolinol propionamide, n-BuLi, diisopropylamine,
THF, ꢀ78 °C to 0 °C (83.8%); (f) 1 M HCl, reflux (82.2%).
asymmetric aldol reaction8 of its titanium enolate with acetalde-
hyde at 0 °C afforded the aldol product 3 in 56% yield after purifi-
cation (de = 76% for the crude aldol products). The absolute
configuration of compound 3 was demonstrated by X-ray analysis.9
Protection of its secondary hydroxyl group with TBSCl afforded the
silyl ether 4 in 97% yield. Cleavage of the chiral auxiliary moiety
was accomplished following Wu’s10 procedure to obtain the pro-
tected alcohol 5 in 93% yield along with the recovery of the (S)-
4-benzyl-1,3-thiazolidine-2-thione (95% yield). Conversion of this
alcohol to alkyl iodide 6 by treatment with Ph3P, imidazole and
I2 (93% yield) would serve as the electrophile for a diastereoselec-
tive alkylation reaction to install the C2 stereocenter of the target
molecule. Due to the lower nucleophilicity exhibited by enolates
2. Results and discussion
The stereoselective synthesis of 1 was carried out, as shown in
Scheme 1. Thus, starting with the N-acetyl thiazolidinethione 2, the
* Corresponding author. Tel.: +86 27 50865322; fax: +86 27 88663043.
E-mail address: yangguichun@hubu.edu.cn (G.-C. Yang).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.026

J.-H. Yang et al. / Tetrahedron: Asymmetry 19 (2008) 2164–2166
2165
derived from (S)-4-benzyl-1,3-thiazolidine-2-thione, the more
reactive enolate derived from the prolinol propionamide was em-
ployed in the alkylation reaction.11 Thus, the dianion of N-propio-
nylprolinol was reacted with the alkyl iodide to give 7 in 84% yield
(de = 92% for the crude alkylation products). Subsequent acid
5H); 13C NMR (125 MHz, CDCl3Þ: d 22.3, 32.0, 36.8, 47.3, 64.0,
68.2, 127.3, 128.9, 129.4, 136.3, 173.1, 201.4.
4.3. (3S)-1-[(S)-4-Benzyl-2-thioxothazolidin-3-yl]-3-(tert-
butyldimethylsilyloxy)butan-1-one 4
hydrolysis of 7 gave the desired lactone 1 in 82% yield (98% ee12
)
after column chromatography. The analytical and spectroscopic
data of the pheromone, as well as the specific rotation value were
in agreement with the literature.2
To a solution of 3 (1.06 g, 3.6 mmol) in DMF (15 mL) were added
TBSCl (2.16 g, 14.3 mmol) and 2,6-lutidine (2.1 mL, 17.9 mmol).
The solution was stirred at room temperature for 5 h. Then ice
water (60 mL) was added and the mixture was extracted with
CH2Cl2 (2 ꢂ 40 mL). The organic layer was washed with saturated
aqueous sodium bicarbonate, brine, dried over anhydrous sodium
sulfate, and concentrated in vacuo. Flash chromatography (hex-
ane/EtOAc, 100:1) provided the silyl ether 4 (1.43 g, 97% yield).
3. Conclusion
In conclusion, we have provided an effective procedure for the
stereoselective synthesis of the sex pheromone of X. hirutissima
(33% overall yield) from easily available starting materials. In this
approach, the C2 stereocenter was established by employing an
N-propionylprolinol-mediated asymmetric alkylation reaction,
the C5 stereocenter was set through an asymmetric acyl-thiazo-
lidinethione aldol reaction. Further application of this meth-
odology to the syntheses of other biologically active compounds
is currently underway in our laboratory.
Mp 72.9–73.7 °C;
½
a 2D5
ꢁ
¼ þ120:2 (c 1.220, CHCl3Þ; IR (NaCl,
cmꢀ1Þ: mmax 3027, 1700, 1602, 1168; 1H NMR (600 MHz, CDCl3Þ: d
0.06 (s, 3H), 0.09 (s, 3H), 0.85 (s, 9H), 1.24 (d, J = 5.4 Hz, 3H), 2.88
(d, J = 11.4 Hz, 1H), 3.04 (dd, J = 10.8, 13.2 Hz, 1H), 3.13 (dd,
J = 4.2, 16.2 Hz, 1H), 3.26 (dd, J = 3.6, 13.2 Hz, 1H), 3.45 (dd,
J = 6.6, 11.4 Hz, 1H), 3.57 (dd, J = 8.4, 16.2 Hz, 1H), 4.44–4.47 (m,
1H), 5.24–5.27 (m, 1H), 7.28–7.36 (m, 5H); 13C NMR (125 MHz,
CDCl3Þ: d ꢀ4.8, ꢀ4.4, 17.9, 24.1, 25.8, 32.2, 36.6, 48.0, 65.8, 68.7,
127.2, 128.9, 129.4, 136.6, 172.2, 201.1.
4. Experimental
4.1. General
4.4. (S)-3-(tert-Butyldimethylsilyloxy)-1-butanol 5
NaBH4 (1.78 g, 31.2 mmol) was added to a stirred solution of 4
(3.19 g, 7.79 mmol) in EtOH (45 mL). After stirring at room temper-
ature for 3 h, the excess NaBH4 was carefully destroyed by the
dropwise addition of 1 M HCl. The solution was removed in vacuo,
and the residue was extracted with EtOAc (3 ꢂ 30 mL). The organic
phase was washed with brine, dried over anhydrous sodium sul-
fate, and concentrated in vacuo. Flash chromatography (hexane/
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
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 (PE) spectrometer. NMR spectra were recorded
on Varian Unity Inova 600 spectrometer in CDCl3 (1H at 600 MHz
and 13C at 125 MHz) using TMS as the internal standard.
EtOAc, 20:1) provided
5
as
a
colorless oil (1.48 g, 93%).
¼ þ25 (c 2.00, CHCl3Þ};
½
a 2D5
ꢁ
¼ þ24:6 (c 0.906, CHCl3Þ {lit.13
½ ꢁ
a 2D5
IR (NaCl, cmꢀ1Þ: mmax 3368, 1472, 1376; 1H NMR (600 MHz,
CDCl3Þ: d 0.09 (s, 3H), 0.10 (s, 3H), 0.90 (s, 9H), 1.20 (d, J = 6.0 Hz,
3H), 1.61–1.66 (m, 1H), 1.76–1.81 (m, 1H), 2.56 (s, 1H), 3.70–
3.74 (m, 1H), 3.82–3.86 (m, 1H), 4.09–4.13 (m, 1H); 13C NMR
(125 MHz, CDCl3Þ: d ꢀ5.0, ꢀ4.4, 17.9, 23.4, 25.8, 40.4, 60.4, 68.3.
4.2. (3S)-1-[(S)-4-Benzyl-2-thioxothazolidin-3-yl]-3-
4.5. (S)-3-(tert-Butyldimethylsilyloxy)butyl iodide 6
hydroxybutan-1-one 3
To a solution of 5 (1.07 g, 5.2 mmol) in CH2Cl2 (25 mL) were
added imidazole (1.06 g, 15.6 mmol), Ph3P (2.73 g, 10.4 mmol),
and I2 (2.64 g, 10.4 mmol). The solution was stirred at room tem-
perature for 3 h and then washed with saturated aqueous sodium
thiosulfate, saturated aqueous sodium bicarbonate, and brine. The
organic phase was dried over anhydrous sodium sulfate and con-
centrated in vacuo. Flash chromatography (hexane/EtOAc, 100:1)
A solution of N-acetyl (4S)-benzylthiazolidinethione (1.25 g,
4.98 mmol) in freshly distilled CH2Cl2 (30 mL) at 0 °C was treated
dropwise with a solution of TiCl4 (5.5 mL, 1 M solution in CH2Cl2,
5.48 mmol) under Ar, and the solution was allowed to stir for
20 min. To the yellow mixture was added diisopropylethylamine
(4.98 mmol, 0.83 mL), and the solution was stirred for 40 min at
provided the alkyl iodide 6 (1.52 g, 93%). ½a D25
ꢁ
¼ þ50:2 (c 0.833,
0 °C.
A solution of acetaldehyde (5.5 mL, 1.36 M in CH2Cl2,
CHCl3Þ {lit.14
½
a 2D5
ꢁ
¼ þ45:9 (c 1.66, CHCl3Þ}; IR (NaCl, cmꢀ1Þ: mmax
7.47 mmol) was transferred via cannula to the reaction mixture,
which was then stirred for 1 h at 0 °C. The reaction was quenched
with saturated ammonium chloride (30 mL), and the layers were
separated. The organic layer was dried over anhydrous sodium sul-
fate, and the solvent was removed in vacuum to afford the crude
aldol products as a mixture of diastereomers (88:12). Purification
by flash chromatography (hexane/EtOAc, 5:1) afforded 3 (0.78 g,
56%) as a yellow solid, which was recrystallized from EtOAc–petro-
leum ether to give a yellow needle crystal. Mp 75.7–76.5 °C;
2956, 2929, 2892, 2857, 1472, 1375; 1H NMR (600 MHz, CDCl3Þ: d
0.08 (s, 3H), 0.10 (s, 3H), 0.89 (s, 9H), 1.15(d, J = 6.0 Hz, 3H), 1.86–
1.96 (m, 2H), 3.18–3.26 (m, 2H), 3.86–3.91 (m, 1H); 13C NMR
(125 MHz, CDCl3Þ: d ꢀ4.6, ꢀ4.2, 3.5, 18.0, 23.5, 25.8, 43.2, 68.2.
4.6. (2R,5S)-5-(tert-Butyldimethylsilyloxy)-1-[(S)-2-
(hydroxymethyl)pyrrolidin-1-yl]-2-methylhexan-1-one 7
½
a 2D5
ꢁ
¼ þ167:2 (c 1.143, CHCl3Þ; IR (NaCl, cmꢀ1Þ: mmax 3426, 3026,
A
solution of LDA was prepared from diisopropylamine
1693, 1603, 1496, 1166; 1H NMR (600 MHz, CDCl3Þ: d 1.28 (d, J =
6.6 Hz, 3H), 2.80 (d, J = 3.6 Hz, 1H), 2.91 (d, J = 12.0 Hz, 1H), 3.05
(dd, J = 10.8, 13.2 Hz, 1H), 3.12 (dd, J = 9.3, 17.7 Hz, 1H), 3.22 (dd,
J = 3.6, 13.2 Hz, 1H), 3.41 (dd, J = 7.5, 11.1 Hz, 1H), 3.66 (dd, J = 2.4,
17.4 Hz, 1H), 4.32–4.35 (m, 1H), 5.39–5.42 (m, 1H), 7.29–7.36 (m,
(0.47 mL, 3.31 mmol) and n-BuLi (3.31 mmol) in dry THF under
Ar at 0 °C. The (S)-prolinol propionamide (0.26 g, 1.66 mmol) in
THF (1 mL) was slowly added, and the mixture was stirred at room
temperature for 30 min then cooled to ꢀ78 °C, and the iodide 6
(0.40 g, 1.27 mmol) was added. The resulting solution was slowly

2166
J.-H. Yang et al. / Tetrahedron: Asymmetry 19 (2008) 2164–2166
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warmed to room temperature over 4 h and then quenched with
saturated aqueous ammonium chloride, and extracted with
CH2Cl2 (3 ꢂ 30 mL). The organic phase was dried over anhydrous
sodium sulfate and concentrated in vacuo to afford the crude alkyl-
ation products as a mixture of diastereomers (96:4). Flash chroma-
tography (hexane/EtOAc, 2:1) provided the product 7 (0.37 g, 84%).
½
a 2D5
ꢁ
¼ þ22:5 (c 0.600, CHCl3Þ; IR (NaCl, cmꢀ1Þ: mmax 3401, 1621,
1463, 1373, 1057; 1H NMR (600 MHz, CDCl3Þ: d 0.08 (s, 6H), 0.92
(s, 9H), 1.15 (d, J = 6.0 Hz, 3H), 1.18 (d, J = 7.2 Hz, 3H), 1.36–1.45
(m, 2H), 1.49–1.54 (m, 1H), 1.63–1.71 (m, 2H), 1.88–1.94 (m,
1H), 1.97–2.02 (m, 1H), 2.04–2.08 (m, 1H), 2.57–2.60 (m, 1H),
3.51–3.54 (m, 1H), 3.60–3.66 (m, 2H), 3.79–3.82 (m, 1H), 4.24–
4.27 (m, 1H), 5.20 (s, 1H); 13C NMR (125 MHz, CDCl3Þ: d ꢀ4.8,
ꢀ4.5, 17.7, 18.0, 23.7, 24.3, 25.7, 25.8, 28.0, 29.8, 37.3, 38.1, 47.7,
60.6, 66.9, 68.6, 177.8.
4.7. (2R,5S)-2-Methyl-5-hexanolide 1
3. Wu, M.-J.; Yeh, J.-Y. Org. Prep. Proced. Int. 1994, 26, 671–674.
4. Tsunoi, S.; Ryu, I.; Sonoda, N. J. Am. Chem. Soc. 1994, 116, 5473–5474.
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A mixture of 7 (0.66 g, 0.360 mmol) and 1 N HCl (3 mL) was stir-
red under reflux for 2 h and extracted with CH2Cl2 (3 ꢂ 30 mL). The
organic phase was dried over anhydrous sodium sulfate and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (hexane/EtOAc, 10:1) to give the product 1 (0.20 g, 82%). Mp
49–50 °C. ½a 2D5
ꢁ
¼ ꢀ95:1 (c 0.427, CHCl3Þ [lit.2q
½
a 2D5
ꢁ
¼ ꢀ91:0 (c
0.73, CHCl3Þ]; IR (NaCl, cmꢀ1Þ: mmax 2971, 2939, 2879, 1738; 1H
NMR (600 MHz, CDCl3Þ: d 1.20 (d, J=6.6 Hz, 3H), 1.36 (d, J=6.6 Hz,
3H), 1.52–1.64 (m, 2H), 1.90–1.94 (m, 1H), 2.06–2.10 (m, 1H),
2.58–2.59 (m, 1H), 4.44–4.47 (m, 1H); 13C NMR (125 MHz,
CDCl3): d 16.4, 21.3, 25.8, 28.6, 33.2, 74.6, 176.5; MS (ESI): 129
(M++1, 100).
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3802–3810.
Acknowledgement
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5290–5313.
12. Enantiomeric purity was estimated by HPLC (Chiracel OD-H, hexane/
isopropanol 70:30, flow rate 1.0 mL/min, ELSD PL-ELS2100).
This work was supported financially by Science Foundation of
China (Grant No. 20772026).
13. Lu, J.-P.; Ma, J.-Y.; Xie, X.-G.; Chen, B.; She, X.-G.; Pan, X.-F. Tetrahedron:
Asymmetry 2006, 17, 1066–1073.
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