Stereoselective synthesis of sex pheromone (R)-4-Methyl-1-nonanol: Non-cross-linked polystyrene supported oxazolidinone as a chiral auxiliary

Article abstract of DOI:10.1002/ejoc.200800758

(R)-4-Methyl-1-nonanol, the sex pheromone of the yellow mealworm (Tenebrio Molitor L.), was synthesized by using non-cross-linked polystyrene supported oxazolidinone as a chiral auxiliary. The stereoselective synthesis was achieved by asymmetric Michael a

Full text of DOI:10.1002/ejoc.200800758

FULL PAPER
DOI: 10.1002/ejoc.200800758
Stereoselective Synthesis of Sex Pheromone (R)-4-Methyl-1-Nonanol: Non-
Cross-Linked Polystyrene Supported Oxazolidinone as a Chiral Auxiliary
Cuifen Lu,[a] Donglai Li,[a] Qiuyan Wang,[a] Guichun Yang,[a] and Zuxing Chen*[a]
Keywords: Chiral auxiliaries / Heterocycles / Michael addition / Pheromones
(R)-4-Methyl-1-nonanol, the sex pheromone of the yellow
mealworm (Tenebrio Molitor L.), was synthesized by using
non-cross-linked polystyrene supported oxazolidinone as a
chiral auxiliary. The stereoselective synthesis was achieved
by asymmetric Michael addition of an organocopper reagent
to non-cross-linked polystyrene supported N-crotonoyoxazo-
lidinone, and the target product was obtained in an overall
yield of 41.8% over seven steps with a high enantiomeric
excess of 98%.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Tanaka et al. as 4-methyl-nonan-1-ol (1; Figure 1) in
1984.[7] Bioassays of the two possible stereoisomers of 1 re-
vealed the (R) enantiomer was the active form of the phero-
mone and that the (S) enantiomer had minimum activity.[8]
Because 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.[7–9] In this paper, we describe a
new synthetic route by applying our previously prepared
non-cross-linked polystyrene supported oxazolidinone[6a] as
a chiral auxiliary to stereoselectively synthesize (R)-1
through a reaction sequence in which the key step is
Michael addition (Scheme 1).
Introduction
Since their first report by Evans in 1981,[1] oxazolidinone
chiral auxiliaries have been widely utilized in, for example,
alkylation, aldol, Diels–Alder, and Michael addition reac-
tions.[2] However, in most cases, the chiral auxiliaries could
not be recovered after the asymmetric reaction. In order
to recycle the expensive material, oxazolidinones have been
supported onto insoluble polymer supports.[3]
Insoluble polymer supports such as Merrifield resin and
Wang resin were applied previously to simplify the pro-
cedure of separation and purification, but there were several
disadvantages, including nonlinear kinetic behavior, un-
equal distribution or access to the chemical reaction, syn-
thetic difficulties in transferring standard organic reactions
to the solid phase, and the use of the recovered support
does not always allow the results obtained in the first run to
be reproduced. Then, chemists started to search for soluble
polymers as supports.[4] This methodology has been demon-
strated to be a very successful process that combines the
superiorities of insoluble polymer supports with the advan-
tages of classic liquid synthesis. In previous reports, our
group has described some liquid-phase methods for the syn-
thesis of small molecule libraries by using poly(ethylene
glycol) (PEG) and non-cross-linked polystyrene (NCPS) as
supports,[5] and grafting of the chiral auxiliary to a soluble
polymer support has already been achieved by us[6] and
other groups.[3e]
Figure 1. Sex pheromone of the yellow mealworm.
Results and Discussion
NCPS-supported oxazolidinone chiral auxiliary 2 was
prepared previously by copolymerizing (4S)-[4Ј-(4ЈЈ-vinyl-
benzyloxy)benzyl]oxazolidinone and styrene with a ratio of
1:1. The loading of the chiral auxiliary was analyzed by
nitrogen elemental analysis.[6a] NCPS-supported N-croton-
yloxazolidinone 3 was obtained smoothly by treating cro-
tonoyl chloride with 2 in the presence of NaH.
The stereoselective Michael addition of an organocopper
reagent to NCPS-supported N-crotonyloxazolidinone was
the key step in the total synthesis of (R)-4-methyl-1-non-
anol. Compound 4 was obtained by Michael addition of an
organocopper reagent to NCPS-supported N-crotonyloxa-
zolidinone 3. Nondestructive removal of the auxiliary group
The yellow mealworm (Tenebrio molitor L) is known to
cause serious losses of stored cereal grains throughout the
world. Its common sex pheromone was first identified by
[a] 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: +86-027-88663043
E-mail: chzux@hubu.edu.cn
1078
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1078–1081

Stereoselective Synthesis of Sex Pheromone (R)-4-Methyl-1-Nonanol
in an overall yield of 41.8% over seven steps in 98%ee.
The method was efficient and the chiral auxiliary can be
recovered by simple filtration.
Experimental Section
General: 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 per-
formed on silica gel H (Yantai, China). Optical rotations were de-
termined with a Perkin–Elmer Model 241 MC polarimeter. IR
spectra were recorded with an IR-spectrum one (PE) spectrometer.
1H NMR (600 MHz) and 13C NMR (150 MHz) spectra were re-
corded with a Varian Unity INOVA 600 spectrometer in CDCl3 by
using TMS as an internal standard. Mass spectra were recorded
with a Finnigan LCQ DUO MS system. Elemental analysis was
determined with a Vario EL III (Germany) analyzer. Optical purity
was estimated by HPLC (Chiracel OD-H; hexane/2-propanol,
70:30; flow rate 1.0 mLmin–1; ELSD PL-ELS2100).
3: To a solution of NCPS-supported oxazolidinone 2 (5.10 g,
12.29 mmol functional group) in dry THF (100 mL) was added
NaH (0.32 g, 13.52 mmol) portionwise, and the mixture was stirred
for 30 min at room temperature. Crotonyl chloride (1.4 mL,
14.96 mmol) was added dropwise to the mixture, and the solution
was stirred for 5 h. The reaction mixture was quenched by the ad-
dition of H2O (50 mL), and THF in the resulting mixture was then
removed under reduced pressure. The aqueous layer was extracted
Scheme 1.
of 4 gave (R)-3-methyloctan-1-ol (5) in high optical purity
(98%ee), which was analyzed by HPLC, and NCPS-sup-
ported chiral auxiliary 2 was recovered by simple filtration. with CH2Cl2 (3ϫ50 mL), and the combined organic layer was
washed with dilute HCl, aqueous saturated NaHCO3, and brine
and dried with MgSO4. After filtration, most of the solvent was
removed under reduced pressure. The viscous solution was dropped
into cold ethanol (200 mL), and the precipitated solid was filtered,
washed with cold ethanol, and dried to afford polymer 3 (5.54 g,
Recovered 2 was reused, and the result obtained by running
a second Michael addition on newly functionalized 3 start-
ing from recovered 2 was similar to the first run (in terms of
both reactions yields and induced stereoselectivities). The
reactions on the polymer support were monitored by nitro-
gen elemental analysis, and all these three reactions were
confirmed to go to completion. A higher yield in the
Michael addition step was observed by using soluble poly-
mer 3 instead of Merrifield resin,[3a] whereas the observed
93.3%). IR (NaCl): ν = 1769, 1677, 1630, 1511, 1403, 820, 760,
˜
700 cm–1. 1H NMR (600 MHz, CDCl3): δ = 7.65–6.25 (m, broad
signal due to the polymer resonance), 4.98 (s, 2 H, OCH2Ar), 4.75
(s, 1 H, CHN), 4.16 (s, 2 H, CH2-OCO), 3.12 (s, 1 H, CH2Ar), 2.78
(s, 1 H, CH2Ar), 1.92 (s, 3 H, CH3), 1.90–1.25 (m, broad signal
stereoselectivity was more similar to those reported for due to the polymer resonance) ppm. 13C NMR (150 MHz, CDCl3):
model substrate 5 under classical solution conditions.[9b]
δ = 164.9, 158.2, 153.5, 146.9, 145.1, 130.4, 127.9–127.6, 125.6,
121.8, 115.1, 66.1, 60.3, 55.3, 53.4, 50.8, 42.7, 40.3, 36.9, 18.5,
Substrate (R)-5 was then subjected to further manipulation
over four reaction steps to obtain the sex pheromone of the
yellow mealworm, (R)-1. In these reactions, the stereocenter
14.1 ppm. C31H31NO4 (481.58): C 77.31, H 6.49, N 2.91; found C
77.35, H 6.46, N 2.89.
4: A three-necked flask was charged with a slurry of CuBr (2.24 g,
15.67 mmol) in THF (30 mL). Methyl sulfide (3.8 mL, 15.67 mmol)
was then added to the flask under an atmosphere of argon. After
being cooled to –78 °C, n-amylmagnesium bromide (15.67 mmol)
in THF was added dropwise, followed by stirring for 10 min. Then,
the solution of polymer 3 (5.0 g, 10.39 mmol functional group) in
THF (10 mL) was slowly added, and the mixture was stirred at
–78 °C for 1 h. The mixture was warmed up to –20 °C and kept at
this temperature for 18 h. The reaction was quenched by the addition
of saturated aqueous NH4Cl (20 mL). After evaporation of the sol-
vent, the aqueous layer was extracted with ethyl acetate, and the
organic layer was washed with saturated aqueous NH4Cl and brine
and dried with MgSO4. After filtration, the filtrate was concen-
trated. The obtained viscous solution was dropped into cold etha-
nol (100 mL), and the precipitated solid was filtered, washed with
of the compound was not touched and the optical yield of
(R)-1 remained as 98%ee.
The use of non-cross-linked polystyrene as a polymer
support instead of cross-linked ones (Merrifield resin) al-
lowed higher loading, easier characterization of the inter-
mediates, and easier interaction between the metal cations
and the coordinating substrates. Thus, some of the intrinsic
disadvantages of solid-phase chemistry were avoided.
Conclusions
In summary, a new method for the synthesis of (R)-4-
methyl-1-nonanol was developed, in which the key step was
a stereoselective Michael addition reaction performed with
the use of non-cross-linked polystyrene supported oxazolid-
cold ethanol, and dried to afford polymer 4 (5.17 g, 90.0%). IR
1
(NaCl): ν = 1784, 1698, 1631, 1512, 1402, 821, 758, 699 cm–1. H
˜
NMR (600 MHz, CDCl3): δ = 7.65–6.25 (m, broad signal due to
inone as a chiral auxiliary. The final product was obtained the polymer resonance), 4.98 (s, 2 H, OCH2Ar), 4.75 (s, 1 H,
Eur. J. Org. Chem. 2009, 1078–1081
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1079

C. Lu, D. Li, Q. Wang, G. Yang, Z. Chen
FULL PAPER
CHN), 4.16 (s, 2 H, CH2-OCO), 3.12 (s, 1 H, CH2Ar), 2.81 (s, 1 NMR (600 MHz, CDCl3): δ = 2.27–2.45 (m, 2 H, CH2-COO),
H, CH2Ar), 2.15 (s, 2 H, COCH2), 1.90–1.25 (m, broad signal due 0.90–1.74 (m, 11 H, CH2, CH), 0.81–0.90 (m, 6 H,CH3) ppm. 13C
to the polymer resonance), 0.98 (s, 6 H, 2CH3) ppm. 13C NMR
NMR (150 MHz, CDCl3): δ = 179.2, 37.2, 34.5, 32.2, 31.6, 30.9,
(150 MHz, CDCl3): δ = 164.9, 158.2, 153.5, 146.9, 145.1, 130.5, 26.6, 22.5, 20.1, 14.2 ppm. MS: m/z = 173.18 [M + H]+.
127.9, 127.6, 115.1, 70.0, 67.9, 66.1, 55.3, 42.7, 40.3, 36.9, 25.6,
1: To a solution of 8 (0.24 g, 1.39 mmol) in dry THF (10 mL) was
23.1, 18.6, 14.0 ppm. C36H43NO4 (553.71): C 78.09, H 7.83, N 2.53,
added a suspension of LiAlH4 (0.064 g, 1.67 mmol) in dry THF
found C 78.12, H 7.79, N 2.51.
(2 mL) over a period of 5 min at 0 °C. The ice bath was removed
and the mixture was stirred at room temperature for 3 h. The mix-
ture was then recooled to 0 °C and dilute HCl was added carefully
to quench the excess amount of LiAlH4. After evaporation of the
solvent, the aqueous layer was extracted with CH2Cl2 (3ϫ10 mL),
and the organic layer was washed with brine and dried with
MgSO4. After filtration, the filtrate was concentrated. Purification
of the crude product by silica gel column chromatography (n-hex-
ane/EtOAc, 8:1) gave (R)-1 as a colorless oil (0.19 g, 88.0%).
[α]2D0 = +1.58 (c = 0.72, CHCl3), ref.[9b] [α]1D8.5= +1.55 (c = 0.72,
5: To a solution of polymer 4 (4.8 g, 8.67 mmol functional group)
in THF (70 mL) was added dropwise a solution of NaBH4 (0.50 g,
13.00 mmol) in ethanol (5 mL) at 0 °C. The ice bath was removed,
and the mixture was stirred at room temperature for 2 h. The mix-
ture was then recooled to 0 °C and dilute HCl was added carefully
to quench the excess amount of NaBH4. After evaporation of the
solvent, the aqueous layer was extracted with ethyl ether, and the
organic layer was washed with brine and dried with MgSO4. After
filtration, the filtrate was concentrated. The obtained viscous solu-
tion was dropped into cold ethanol (100 mL), and the precipitated
solid was filtered and washed with cold ethanol to recover sup-
ported chiral auxiliary 2 (3.3 g, 91.6%). The combined filtrate was
evaporated and purified by silica gel column chromatography (n-
hexane/EtOAc, 6:1) to give 5 as a colorless oil (0.94 g, 75.2%).
[α]2D0 = +4.68 (c = 0.60, hexane), ref.[9b] [α]1D9.5 = +4.78 (c = 0.62,
CHCl ). IR (NaCl): ν = 3337, 2926, 1382, 1050 cm–1. 1H NMR
˜
3
(600 MHz, CDCl3): δ = 3.63 (m, 2 H, OCH2), 2.18 (s, 1 H, OH),
1.24–1.62 (m, 12 H, CH2, CH), 1.11–1.14 (d, 3 H, CH3), 0.87 (m,
3 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 63.4, 36.9, 32.9,
32.6, 32.1, 30.3, 26.7, 22.7, 20.3, 14.2 ppm. MS: m/z = 159.12 [M
+ H]+.
hexane). IR (NaCl): ν = 3337, 2926, 1455, 1382, 1065 cm–1. 1H
˜
NMR (600 MHz, CDCl3): δ = 3.64–3.72 (t, 2 H, OCH2), 1.12–1.62
(m, 11 H, CH2, CH), 0.87–0.91 (m, 6 H, 2CH3) ppm. 13C NMR
(150 MHz, CDCl3): δ = 63.4, 36.9, 32.9, 32.6, 32.2, 30.3, 26.7, 22.7,
14.1 ppm. MS: m/z = 145.22 [M + H]+.
Acknowledgments
We gratefully acknowledge the National Natural Sciences Founda-
tion of China (No. 20772026 and 20372019) and the 2007 excellent
mid-youth innovative team project of the Education Department
of Hubei Province (No. T200701) for financial support.
6: To a solution of 5 (0.6 g, 4.16 mmol) in CH2Cl2 (20 mL) was
added p-toluenesulfonyl chloride (0.95 g, 5.0 mmol) and Et3N
(0.68 mL, 5.0 mmol) at room temperature. After stirring at room
temperature for 3.5 h, the mixture was poured into cold 1  HCl.
The resulting mixture was extracted with diethyl ether. The organic
phase was washed with saturated aqueous NaHCO3 and brine and
dried with MgSO4. After filtration, the filtrate was concentrated.
Purification of the crude product by silica gel column chromatog-
[1] D. A. Evans, J. Bartroli, T. L. Shih, J. Am. Chem. Soc. 1981,
103, 2127–2129.
[2] a) G. A. Reichard, J. Spitler, I. Mergelsberg, A. Miller, G.
Wong, R. Raghavan, J. Jenkins, T. Gan, A. T. McPhail, Tetra-
hedron: Asymmetry 2002, 13, 939–942; b) G. S. Coumbarides,
M. Dingjan, J. Eames, A. Flinn, J. Northen, Y. Yohannes, Tet-
rahedron Lett. 2005, 46, 2897–2902; c) W. Zhang, R. G. Carter,
A. F. Yokochi, J. Org. Chem. 2004, 69, 2569–2572; d) J.-C.
Jung, J.-C. Kim, H.-I. Moon, O.-S. Park, Tetrahedron Lett.
2006, 47, 6433–6437.
[3] a) C. W. Phoon, C. Abell, Tetrahedron Lett. 1998, 39, 2655–
2658; b) T. Kotake, S. Rajesh, Y. Hayashi, Y. Mukai, M. Ueda,
T. Kimura, Y. Kiso, Tetrahedron Lett. 2004, 45, 3651–3654; c)
G. Faita, A. Paio, F. Rancati, P. Seneci, Tetrahedron Lett. 2000,
41, 1265–1269; d) G. Faita, A. Paio, P. Quadrelli, F. Rancati,
P. Seneci, Tetrahedron 2001, 57, 8313–8322; e) D. Desimoni, G.
Faita, A. Galbiati, D. Pasini, P. Quadrelli, F. Rancati, Tetrahe-
dron: Asymmetry 2002, 13, 333–337.
[4] a) S. Doherty, E. G. Robins, I. Pál, C. R. Newman, C. Hard-
acre, D. Rooney, D. A. Mooney, Tetrahedron: Asymmetry 2003,
14, 1517–1527; b) A. K. Gosh, P. Mathivanan, J. Capiello, Tet-
rahedron: Asymmetry 1998, 9, 1–45; c) B. Thierry, C. Audou-
ard, J.-C. Plaquevent, D. Cahard, Synlett 2004, 5, 856–860; d)
G. Giffels, J. Beliczey, M. Felder, U. Kragl, Tetrahedron: Asym-
metry 1998, 9, 691–696.
[5] a) Z. X. Chen, G. Y. Xu, G. C. Yang, W. Wang, React. Funct.
Polym. 2004, 61, 139–146; b) Z. X. Chen, G. Z. Yue, C. F. Lu,
G. C. Yang, Synlett 2004, 7, 1231–1234; c) G. Z. Yue, Y. D.
Wan, S. J. Song, G. C. Yang, Z. X. Chen, Bioorg. Med. Chem.
Lett. 2005, 15, 453; d) C. F. Lu, C. Xie, Z. X. Chen, G. C. Yang,
React. Funct. Polym. 2006, 66, 952–956.
raphy (n-hexane/EtOAc, 8:1) gave colorless oil 6 (1.20 g, 96.5%).
1
IR (NaCl): ν = 2985, 2865, 1601, 1350, 1175, 801 cm–1. H NMR
˜
(600 MHz, CDCl3): δ = 7.30–7.89 (m, Ar), 3.98–4.14 (m, 2 H, CH2-
Ar), 2.45 (s, 3 H, CH2, CH), 0.93–1.56 (m, 11 H, CH2), 0.77–0.93
(m, 6 H, CH3) ppm. 13C NMR (150 MHz, CDCl3): δ = 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 ppm. MS: m/z = 299.28 [M + H]+.
7: To a solution of 6 (1.0 g, 3.35 mmol) in dry dimethyl sulfoxide
(20 mL) was added sodium cyanide (0.17 g, 3.69 mmol), and the
mixture was stirred at 90 °C for 5 h. After evaporation of the sol-
vent under reduced pressure, the residue was dissolved in CH2Cl2
(20 mL), and the resulting mixture was washed with dilute HCl,
aqueous saturated NaHCO3, and brine and then dried with
MgSO4. After filtration, the filtrate was concentrated to give crude
1
7 (0.43 g, 83.7%). IR (NaCl): ν = 2911, 2247, 1215, 796 cm–1. H
˜
NMR (600 MHz, CDCl3): δ = 2.26–2.42 (m, 2 H, CH2-CN), 0.96–
1.66 (m, 11 H, CH2, CH), 0.70–0.94 (d, 6 H, CH3) ppm. 13C NMR
(150 MHz, CDCl3): δ = 119.2, 37.6, 35.2, 32.8, 32.2, 30.5, 26.6,
24.5, 23.1, 15.3, 14.2 ppm. MS: m/z = 154.12 [M + H]+.
8: To a stirred solution of NaOH (1.0 g, 25 mmol) in water (20 mL)
and ethanol (5 mL) was added 7 (0.35 g, 2.29 mmol), and the mix-
ture was stirred at 50 °C for 12 h. After evaporation of ethanol, the
aqueous layer was acidified with concentrated HCl to pH 2 and
extracted with CH2Cl2 (3ϫ20 mL). The combined organic layer
was washed with water and brine and dried with MgSO4. After
[6] a) C. F. Lu, L. M. Lu, Z. X. Chen, G. C. Yang, Hubei Daxue
Xuebao, Ziran Kexueban 2007, 29, 167–169; b) Y. D. Wan, C. F.
Lu, J. Q. Nie, G. C. Yang, Z. X. Chen, J. Chem. Res. 2007, 84–
85; c) J. N. Chen, J. Q. Nie, Y. L. Huang, Z. X. Chen, G. C.
Yang, J. Chem. Res. 2006, 696–697.
filtration, the filtrate was concentrated to give crude 8 (0.33 g,
1
83.9%). IR (NaCl): ν = 3520, 2911, 1711, 1420, 950, 720 cm–1. H
˜
1080
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 1078–1081

Stereoselective Synthesis of Sex Pheromone (R)-4-Methyl-1-Nonanol
[7] Y. Tanaka, H. Honda, K. Ohsawa, I. Yamamoto, Nippon
Noyaku Gakkaishi 1986, 11, 49–55.
[8] Y. Tanaka, H. Honda, K. Ohsawa, I. Yamamoto, Nippon
Noyaku Gakkaishi 1989, 14, 197–202.
[9] a) V. N. Odinokov, G. Y. Ishmurator, M. P. Yakovleva, R. R.
Musiukhov, R. L. Safiullin, A. N. Volgarev, V. D. Komissarov,
G. A. Tolstikov, Dokl. Akad. Nauk. 1992, 326, 842–846;
b) T. Kitahara, S. H. Kang, Proc. Japan. Acad. Ser. B 1994, 70,
181–184; c) Y. Li, J. X. Huang, Z. X. Chen, J. Ren, Yingyong
Huaxue 2001, 18, 828–830; d) G. Y. Ismuratov, M. P. Yakov-
leva, A. V. Galyautdinova, G. A. Tolstikov, Chem. Nat. Compd.
2003, 39, 31–33; e) A. Baeza, C. Nájera, J. M. Sansano, Eur. J.
Org. Chem. 2007, 1101–1112.
Received: July 31, 2008
Published Online: January 13, 2009
Eur. J. Org. Chem. 2009, 1078–1081
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1081