Stereoselective synthesis of the sex pheromone of the yellow mealworm using (S)-4-benzyloxazolidinone as chiral auxiliary

Article abstract of DOI:10.1007/s10600-010-9636-z

(R)-4-Methyl-1-nonanol, the sex pheromone of the yellow mealworn (Tenebrio molitor L.), was synthesized with high stereoselectivity using (S)-4-benzyloxazolidinone as chiral auxiliary. The stereoselective synthesis was achieved by asymmetric Michael addit

Full text of DOI:10.1007/s10600-010-9636-z

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Chemistry of Natural Compounds, Vol. 46, No. 3, 2010
STEREOSELECTIVE SYNTHESIS OF THE SEX PHEROMONE
OF THE YELLOW MEALWORM USING
(S)-4-BENZYLOXAZOLIDINONE
AS CHIRAL AUXILIARY
D. L. Li, C. F. Lu*, G. C. Yang, and Z. X. Chen
UDC 547.268
(R)-4-Methyl-1-nonanol, the sex pheromone of the yellow mealworn (Tenebrio molitor L.), was synthesized
with high stereoselectivity using (S)-4-benzyloxazolidinone as chiral auxiliary. The stereoselective synthesis
was achieved by asymmetric Michael addition of organocopper reagent to N-crotoyloxazolidinone, and the
target product was obtained in an overall yield of 41.8% over 7 steps.
Keywords: (S)-4-benzyloxazolidinone, chiral auxiliaries, Michael addition, synthesis, sex pheromone.
The yellow mealworm (Tenebrio molitor L.) is known to cause serious losses in stored cereal grains throughout the
world. Effective, cost-efficient grain weevil management can be accomplished by monitoring pest populations with pheromone-
baited insect traps and applying control methods only when pest densities reach economic thresholds. Its common sex pheromone
was firstly identified by Tanaka et al as 4-methyl-nonan-1-ol (1) in 1984 [1]. Bioassays of the two possible stereoisomers of 1
revealed that the (R) isomer was the active form of the pheromone and the (S) isomer had minimum activity [2]. Since effective
and cost-efficient control of the yellow mealworm populations can be foreseen with the aid of the sex pheromone, several total
syntheses of the racemate and (R)-1 have been published [3–6].
The Michael addition reaction of organometallics is an important method for carbon–carbon bond formation in organic
synthesis [7–9]. Organocopper reagents are among the most versatile reagents available for Michael addition reactions
[10–13]. The addition of organocopper reagents to chiral alkenoate derivatives such as Evansꢀ oxazolidinone has provided
high diastereoselectivities [14–16].
Recently, our group has undertaken a research program on the preparation of chiral auxiliaries [17–19] and their
application to the synthesis of insect pheromones [20, 21]. In this paper, we have developed an efficient procedure to prepare
the sex pheromone of the yellow mealworm (R)-1 through a key step of stereoselective Michael addition using (S)-4-benzyl-
oxazolidinone as chiral auxiliary (Scheme 1).
The synthesis of (R)-4-methyl-1-nonanol ((R)-1) was carried out as shown in Scheme 1, and the stereoselective
Michael addition of organocopper reagent to N-crotonyloxazolidinone was the key step. Firstly, crotonoyl chloride reacted
with (S)-4-benzyloxazolidinone 2 to give N-crotonyloxazolidinone 3 in 83.8% yield in the presence of NaH. Then the
diastereoisomeric mixture of (S)-3-(3-methyloctanoyl)-4-benzyloxazolidinone was obtained via Michael addition of
organocopper reagent to N-crotonyloxazolidinone 3 in 98% yield, which was analyzed by HPLC. The diastereoisomeric
mixture was separated by silica gel column chromatography, and the (R) isomer 4, (S)-3-((R)-3-methyloctanoyl)-4-
benzyloxazolidinone, was obtained in 86.5% yield. Nondestructive removal of the auxiliary group of the (R) isomer 4 gave
(R)-3-methyloctan-1-ol 5 in 81.6% yield. The (R)-5 was subjected to further manipulation by four steps of reaction to get the
sex pheromone of yellow mealworm (R)-1. In these reactions, the stereocenter of the compounds was not touched, and spectral
data of (R)-1 were in accord with the literature, as well as the specific rotation value [4].
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules & School
of Chemistry and Chemical Engineering, Hubei University, Wuhan 430062, China, fax: 86 27 88663043, e-mail:
lucf@hubu.edu.cn. Published in Khimiya Prirodnykh Soedinenii, No. 3, pp. 372–374, May–June, 2010. Original article
submitted December 23, 2008.
440
0009-3130/10/4603-0440 02010 Springer Science+Business Media, Inc.

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O
O
O
O
O
O
NH
O
N
O
N
a
c
b
2
3
4
f
d
e
TsO
NC
HO
7
6
5
g
HO
HO
C
O
8
(R)-1
a. NaH/THF, crotonyl chloride; b. Me S/CuBr/THF, n-amylmagnesium bromide; c. NaBH /THF; d. TsCl/CH Cl ;
2
4
2
2
e. NaCN/DMF; f. NaOH/H O; g. LiAlH /THF
2
4
Scheme 1
In summary, an efficient synthesis (seven steps, 40.1% overall yield) of optically pure (R)-1 was developed through
a key step of stereoselective Michael addition using (S)-4-benzyloxazolidinone as chiral auxiliary. The method has the advantage
of short routes, high yield, and high stereoselectivity.
EXPERIMENTAL
All organic solvents were dried by standard methods. TLCs were performed on precoated plates of silica gel HF254
(0.5 mm, Yantai, China). Flash column chromatography was performed on silica gel H (Yantai, China). Melting points were
measured on a WRS-1A digital melting point apparatus and uncorrected. Optical rotations were determined with a Perkin–
1
Elmer Model 241 MC polarimeter. IR spectra were recorded on a PE Spectrum One spectrometer, H NMR (600 MHz) and
13
C NMR (150 MHz) spectra were recorded on a Varian Unity INOVA 600 spectrometer in CDCl using TMS as internal
3
standard. Mass spectra were recorded on a Finnigan LCQ DUO MS system. The diastereoisomeric purity was determined by
means of HPLC (Dionex, Ultimate 3000 pump) using solid-phase extraction in reversed phase mode (C8 phase) (70:30 water–
methanol, 1 mL/min, 254 nm).
(S)-3-((E)-But-2-enoyl)-4-benzyloxazolidinone (3). To a solution of the (S)-4-benzyloxazolidinone (2) (5.0 g,
28.22 mmol) in dry THF (70 mL) was added NaH (0.35 g, 31.04 mmol) portionwise, and the mixture was stirred for 30 min at
room temperature. Crotonyl chloride (1.7 mL, 33.86 mmol) was added dropwise to the mixture, and the solution was stirred
for 5 h. The reaction mixture was quenched with H O (50 mL), and then THF in the resulting mixture was removed under
2
reduced pressure. The aqueous layer was extracted with CH Cl (50 mL ꢁ 3), and the organic layers were combined, washed
2
2
with dilute HCl, aqueous saturated NaHCO , and brine, dried over MgSO , and concentrated. Purification of the crude product
3
4
[ꢂ]20
by silica gel column chromatography (n-hexane–EtOAc, 8:1, v/v) gave a white solid 3 (5.8 g, 83.8%).
+77.9ꢃ (c 2.00, CHCl ), mp 84.8–85.1ꢃC, lit. [22] 85.0–86.0ꢃC. IR (NaCl, ꢄ, cm ): 2953, 2914, 2847,
1769, 1677, 1630. H NMR (CDCl , ꢅ, ppm, J/Hz): 7.22–7.35 (7H, m, Ar-H, CH=CH), 4.7 (1H, m, CH), 4.19 (2H, m, OCH ),
+75.3ꢃ (c 2.00,
D
[ꢂ]20
–1
CHCl ), lit. [22]
D
3
3
1
3
2
3.33 (1H, dd, J = 3, J = 13.2, PhCH ), 2.80 (1H, dd, J = 9.6, J = 13.2, PhCH ), 1.99 (3H, t, J = 0.6, J = 5.4, CH ).
1
2
2
1
2
2
1
2
3
13
+
C NMR (CDCl , ꢅ): 164.9, 153.4, 147.0, 135.3, 129.4, 128.9, 127.2, 121.7, 66.0, 55.2, 37.8, 18.6. MS m/z: 246.12 [M + H] .
3
(S)-3-((R)-3-Methyloctanoyl)-4-benzyloxazolidinone (4). A three-necked flask was charged with a slurry of CuBr
(4.39 g, 30.71 mmol) in ether (10 mL), and methyl sulfide (7.4 mL, 30.71 mmol) was added under argon. After cooling to
–78ꢃC, n-amylmagnesium bromide (30.71 mmol) in ether (10 mL) was added dropwise, followed by stirring for 10 min. Then
a solution of 3 (5.0 g, 20.39 mmol) in ether (50 mL) was slowly added, and the mixture was stirred at –78ꢃC for 1 h. The
mixture was warmed up to –20ꢃC, and stirring was kept at –20ꢃC for 18 h. The reaction was quenched by saturated aqueous
NH Cl (20 mL). After evaporation of the solvent, the aqueous layer was extracted by ethyl acetate, and the organic layer was
4
441

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washed with saturated aqueous NH Cl, brine, dried over MgSO , filtered, and concentrated. Purification of the crude product
4
4
–1
by silica gel column chromatography (n-hexane–EtOAc, 16:1, v/v) gave a colorless oil 4 (5.6 g, 86.5%). IR (NaCl, ꢄ, cm ):
2925, 1784, 1698, 1631. H NMR (CDCl , ꢅ, ppm): 7.21–7.34 (5H, m, ArH), 4.69–4.67 (1H, m, NCH), 3.32–3.05 (1H, m,
1
3
CHAr), 2.99–2.96 (1H, m, CHAr), 2.90–2.70 (2H, d, CH ), 2.09–2.05 (1H, m, CH), 1.19–1.39 (8H, m, 4CH ), 1.01–0.96 (3H,
2
2
13
d, CH ), 0.87–0.90 (3H, t, CH ). C NMR (CDCl , ꢅ): 172.8, 153.4, 135.3, 129.4, 128.9, 127.3, 66.0, 55.2, 42.5, 37.9, 36.4,
29.5, 29.1, 22.8, 19.7, 14.06. MS m/z: 318.25 [M + H] .
3
3
3
+
(R)-3-Methyloctan-1-ol (5). To a solution of 4 (4.1 g, 13.0 mmol) in THF (80 mL) was added dropwise a solution of
NaBH (0.75 g, 19.5 mmol) in ethanol (10 mL) at 0ꢃC. The ice bath was removed and the mixture was stirred at room
4
temperature for 2 h. The mixture was then recooled to 0ꢃC, and dilute HCl was added carefully to quench the excess hydride
reagent. After evaporation of the solvent, the aqueous layer was extracted with ethyl ether, and the organic layer was washed
with brine, dried over MgSO , filtered, and concentrated. Purification of the crude product by silica gel column chromatography
4
20
19.5
(n-hexane–EtOAc, 6:1, v/v) gave 5 as a colorless oil (1.52 g, 81.6%).
(c 0.62, hexene). IR (NaCl, ꢄ, cm ): 3337, 2926, 1455, 1382, 1065. H NMR (CDCl , ꢅ, ppm): 3.64–3.72 (2H, t, OCH ),
1.12–1.62 (11H, m, CH , CH), 0.87–0.91 (6H, m, 2CH ). C NMR (CDCl , ꢅ): 63.4, 36.9, 32.9, 32.6, 32.2, 30.3, 26.7, 22.7,
14.1. MS m/z: 145.22 [M + H] .
(R)-3-Methyloctyl-4-methylbenzenesulfonate (6). To a solution of 5 (1.2 g, 8.32 mmol) in CH Cl (30 mL) was
+4.68ꢃ (c 0.60, hexene), lit. [4]
+4.78ꢃ
[ꢂ]D
[ꢂ]D
–1
1
3
2
13
2
3
3
+
2
2
added p-toluenesulfonate (1.9 g, 10.0 mmol) and Et N (1.36 mL, 10.0 mmol). After stirring at room temperature for 3.5 h, the
3
mixture was poured into cold 1 M HCl. The resulting mixture was extracted with diethyl ether. The organic phase was washed
with saturated aqueous NaHCO and brine, dried with MgSO , and concentrated. Purification of the crude product by silica
3
4
20
gel column chromatography (n-hexane–EtOAc, 8:1, v/v) gave a colorless oil 6 (2.4 g, 96.5%).
+3.95ꢃ (c 0.72, MeOH).
[ꢂ]D
[ꢂ]1D9.5
–1
1
lit. [23]
+4.00ꢃ (c 0.72, MeOH). IR (NaCl, ꢄ, cm ): 2985, 2865, 1601, 1350, 1175, 801. H NMR (CDCl , ꢅ, ppm):
3
7.30–7.89 (m, Ar), 3.98–4.14 (2H, m, CH -Ar), 2.45 (3H, s, CH , CH), 0.93–1.56 (11H, m, CH ), 0.77–0.93 (6H, m, CH ).
2
2
2
3
13
C NMR (CDCl , ꢅ): 145.6, 139.8, 131.5, 130.8, 68.6, 37.2, 34.9, 33.2, 32.1, 30.4, 26.7, 24.5, 22.9, 14.3. MS m/z: 299.28
3
+
[M + H] .
(R)-4-Methylnonanenitrile (7). To a solution of 6 (2.0 g, 6.70 mmol) in dry dimethyl sulfoxide (40 mL) was added
sodium cyanide (0.34 g, 7.38 mmol), and the mixture was stirred at 90ꢃC for 5 h. After evaporation of the solvent under
reduced pressure, the residue was dissolved in CH Cl (50 mL), and the resulting mixture was washed with dilute HCl,
2
2
aqueous saturated NaHCO , and brine, dried over MgSO , filtered, and concentrated to give a colorless oil 7 (0.86 g, 83.7%).
3
4
[ꢂ]2D0
[ꢂ]1D9.5
–1
1
+5.65ꢃ (c 0.93, Et O). lit. [23]
+5.76ꢃ (c 0.93, Et O). IR (NaCl, ꢄ, cm ): 2911, 2247, 1215, 796. H NMR
2
2
(CDCl , ꢅ, ppm, J/Hz): 2.26–2.42 (2H, m, CH -CN), 0.96–1.66 (11H, m, CH , CH), 0.70–0.94 (6H, d, J = 3.6, CH ).
C NMR (CDCl , ꢅ): 119.2, 37.6, 35.2, 32.8, 32.2, 30.5, 26.6, 24.5, 23.1, 15.3, 14.2. MS m/z: 154.12 [M + H] .
3
2
2
3
13
+
3
(R)-4-Methylnonanoic Acid (8). To a stirred solution of NaOH (2.0 g, 50 mmol) in water (40 mL) and ethanol
(10 mL) was added 7 (0.70 g, 4.58 mmol), and the mixture was stirred at 50ꢃC for 12 h. After evaporation of ethanol, the
aqueous layer was acidified with conc. HCl to pH 2 and extracted with CH Cl (50 mL ꢁ 3). The combined organic layer was
2
2
washed with water and brine, dried over MgSO , filtered, and concentrated to give a colorless oil 8 (0.66 g, 83.9%).
4
[ꢂ]2D0
[ꢂ]1D9.5
–1
+0.92ꢃ (c 0.79, Et O). lit. [23]
+0.96ꢃ (c 0.79, Et O). IR (NaCl, ꢄ, cm ): 3520, 2911, 1711, 1420, 950, 720.
H NMR (CDCl , ꢅ, ppm): 2.27–2.45 (2H, m, CH -COO), 0.90–1.74 (11H, m, CH , CH), 0.81–0.90 (6H, m, CH ). C NMR
(CDCl , ꢅ): 179.2, 37.2, 34.5, 32.2, 31.6, 30.9, 26.6, 22.5, 20.1, 14.2. MS m/z: 173.18 [M + H] .
2
2
1
13
3
2
2
3
+
3
(R)-4-Methylnonan-1-ol (1). To a solution of 8 (0.48 g, 2.78 mmol) in dry THF (20 mL) was added a suspension of
LiAlH (0.13 g, 3.34 mmol) in dry THF (5 mL) over a period of 5 min at 0ꢃC. The ice bath was removed, and the mixture was
4
stirred at room temperature for 3 h. The mixture was then recooled to 0ꢃC, and dilute HCl was added carefully to quench the
excess hydride reagent. After evaporation of the solvent, the aqueous layer was extracted with CH Cl (20 mL ꢁ 3), and the
2
2
organic layer was washed with brine, dried over MgSO , filtered, and concentrated. Purification of the crude product by silica
4
gel column chromatography (n-hexane–EtOAc, 8:1, v/v) gave the compound (R)-1 as a colorless oil (0.38 g, 88.0%).
[ꢂ]2D0
18.5
–1
1
+1.58ꢃ (c 0.72, CHCl ), lit. [4]
+1.55ꢃ (c 0.72, CHCl ). IR (NaCl, ꢄ, cm ): 3337, 2926, 1382, 1050. H NMR
[ꢂ]D
(CDCl , ꢅ, ppm, J/Hz): 3.63 (2H, m, OCH ), 2.18 (1H, s, OH), 1.24–1.62 (12H, m, CH , CH), 1.11–1.14 (3H, d, J = 5.7, CH ),
3
3
3
2
2
3
13
+
0.87 (3H, m, CH ). C NMR (CDCl , ꢅ): 63.4, 36.9, 32.9, 32.6, 32.1, 30.3, 26.7, 22.7, 20.3, 14.2. MS m/z: 159.12 [M + H] .
3
3
442

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