Asymmetric synthesis of a sex pheromone (3S,5R,6S)-3,5-dimethyl-6-isopropyl-3,4,5,6-tetrahydropyran-2-one

Article abstract of DOI:10.1016/j.tetasy.2009.07.019

An Oppolzer anti-aldol approach for the synthesis of the sex pheromone (3S,5R,6S)-3,5-dimethyl-6-isopropyl-3,4,5,6-tetrahydropyran-2-one is reported.

Full text of DOI:10.1016/j.tetasy.2009.07.019

Tetrahedron: Asymmetry 20 (2009) 1806–1808
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of a sex pheromone
(3S,5R,6S)-3,5-dimethyl-6-isopropyl-3,4,5,6-tetrahydropyran-2-one
*
Peddikotla Prabhakar, Singanaboina Rajaram, Yenamandra Venkateswarlu
Organic Chemistry Division-I, Natural Products Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An Oppolzer anti-aldol approach for the synthesis of the sex pheromone (3S,5R,6S)-3,5-dimethyl-6-iso-
propyl-3,4,5,6-tetrahydropyran-2-one is reported.
Received 4 June 2009
Accepted 15 July 2009
Available online 18 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
aged that compound 5 is a key intermediate, which can be derived
from isobutyraldehyde and N-propionylbornane-10,2-sultam 3.5
The insect sex pheromone (3S,5R,6S)-3,5-dimethyl-6-isopropyl-
3,4,5,6-tetrahydropyran-2-one secreted by Macrocentrus grandii,1
controls the population of the European corn borer Ostrinia nubilal-
is, in an environmentally friendly way to solve agricultural prob-
Oppolzer anti-aldol condensation products such as 4 are valuable
building blocks as illustrated by the total synthesis of (3S,5R,6S)-
3,5-dimethyl-6-isopropyl-3,4,5,6-tetrahydropyran-2-one 1.
lems. Compound
1 is one of the three components of the
2. Results and discussion
pheromone mixture which was first isolated in 1992 from larval
parasitoid M. grandii.2 Lactone rings are an important structural
feature of many natural products and are very important core moi-
ety in many biologically important macrolide molecules such as
methynolide, neomethymycin, methymycin, narbomycin, picro-
mycin and a number of microbial macrolide antibiotics.3 Our par-
ticular interest is to synthesize the pheromone (3S,5R,6S)-3,5-
dimethyl-6-isopropyl-3,4,5,6-tetrahydropyran-2-one 1, which has
a similar structure to Prelog-Djerassi lactone 2. With this in mind,
we explored an Oppolzer anti-aldol reaction for the synthesis of
this molecule as it offers better diastereomeric excess and high
The stereoselective synthesis of 1 was carried out, as shown
in Scheme 2. Thus, the N-propionylbornane-10,2-sultam 3 was
subjected to an asymmetric aldol reaction6 with isobutyralde-
hyde at ꢀ78 °C to afford the anti-aldol product 4 in 75.3% yield
(de = 84%) and confirmed by the 1H NMR and specific rotation.7
Reductive cleavage of anti-aldol product 4 with LAH gave 1,3-
diol 5 in 92% yield.8 The primary hydroxyl group in 5 was
selectively tosylated by using TsCl, Bu2SnO and triethylamine
in dichloromethane to afford tosylated compound 6 in 90%
yield.9 The tosyl group in 6 was replaced by iodine by reaction
with NaI in acetone to yield iodo alcohol 7 in 92% yield.10 Next,
the compound 7 was propionylated with propionyl chloride in
the presence of triethylamine and a catalytic amount of DMAP
in dry dichloromethane to afford ester 8 in 90% yield.11 The
cyclization of ester 8 using LHMDS in the presence of HMPA in
dry THF gave the desired lactone 1 in 76% yield after column
chromatography.12
yield. Although some synthetic methods have been reported,4
a
more convergent and stereoselective synthesis of 1 is desirable.
As a result, we report an efficient synthesis of 1.
O
O
O
O
The analytical and spectroscopic data of pheromone 1, as well
as the specific rotation values were in agreement with the litera-
ture.2 All the compounds were fully characterized by 1H NMR,
13C NMR, mass and IR spectroscopic data.
COOH
2
1
Herein, we report an efficient and practical synthesis of the
pheromone from commercially available isobutyraldehyde. From
the retrosynthetic analysis of compound 1 (Scheme 1), we envis-
3. Conclusion
In conclusion a simple and highly efficient Oppolzer anti-aldol
condensation approach for total synthesis of pheromone 1 was
developed with an overall yield of 39.2%.
* Corresponding author. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail address: luchem@iict.res.in (Y. Venkateswarlu).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.019

P. Prabhakar et al. / Tetrahedron: Asymmetry 20 (2009) 1806–1808
1807
O
O
O
OH OH
O
O
H
I
5
8
1
Scheme 1. Retrosynthesis of pheromone.
O
O
OH
OH OH
b
a
N
N
S
S
O
O
O
O
4
5
3
O
I
OH
OTs
OH
O
d
c
e
I
6
7
8
O
f
O
1
Scheme 2. Reagents and conditions: (a) Isobutyraldehyde, TiCl4, iPr2EtN, dry DCM, 3 h, 75%; (b) LAH, dry ether, 2 h, 92%; (c) TsCl, TEA, Bu2SnO, DMAP, dry DCM, 5 h, 90%; (d)
NaI, dry acetone, reflux, 2 h, 92%; (e) propionyl chloride, TEA, DMAP, dry DCM, 3 h, 90%; (f) LHMDS (1.5 M solution in THF), HMPA, dry THF, 5 h, 76%.
temperature and stirred for another 90 min. After completion of
the reaction, the reaction mixture was quenched with saturated
NH4Cl (10 mL) solution and extracted into dichloromethane
(3 ꢁ 20 mL), and dried over anhydrous Na2SO4. The solvent was re-
moved under vacuum and the residue was purified by column
chromatography (silica gel, 60–120 mesh; hexane/ethyl ace-
tate = 9:1) to afford compound 4 (Rf : 0.6, hexane/EtOAc 80:20)
4. Experimental
4.1. General methods
Solvents were dried over standard drying agents and were
freshly distilled prior to use. Chemicals were purchased and used
without further purification. All column chromatographic separa-
tions were performed using silica gel (Acme’s, 60–120 mesh).
Organic solutions were dried over anhydrous Na2SO4 and concen-
trated below 40 °C in vacuo. 1H NMR (200 MHz and 300 MHz) and
13C NMR (50 MHz and 75 MHz) spectra were measured on a Varian
Gemini FT-200 MHz spectrometer and Bruker Avance 300 MHz
with tetramethylsilane as an internal standard for solutions in
deuteriochloroform. J values are given in hertz. The IR spectra
were recorded on a Perkin-Elmer IR-683 spectrophotometer with
NaCl optics. Optical rotations were measured with JASCO DIP 300
digital polarimeter at 25 °C. Mass spectra were recorded on CEC-
21-11013 or Fannigan Mat 1210 double focusing mass spectrome-
ters operating at a direct inlet system or LC/MSD Trap SL (Agilent
Technologies).
as a white solid (0.95 g, 75.3% yield): ½a D25
ꢂ
¼ ꢀ70:5 (c 1.0, CHCl3);
IR (film): 3541, 2963, 1691, 1326, 1212, 772, 537 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): d 0.93 (d, 3H, J = 6.6 Hz), 0.98 (s, 1H), 1.01 (d,
3H, J = 6.6 Hz), 1.16 (s, 3H), 1.19 (d, 3H, J = 6.7 Hz), 1.29–1.47 (m,
2H), 1.61–1.74 (m, 1H), 1.84–1.97 (m, 3H), 2.06 (td, 2H, J =
6.4 Hz), 2.32 (br s, 1H), 3.29–3.38 (m, 1H), 3.48 (d, 2H, J = 7.5 Hz),
3.49–3.55 (dd, 1H, J = 5, 9 Hz), 3.87–3.93 (t, 1H, J = 6.4 Hz); 13C
NMR (75 MHz, CDCl3): d 14.5, 15.6, 19.8, 19.9, 20.7, 26.2, 31.1,
33.2, 38.7, 42.9, 44.6, 48.1, 48.5, 53.1, 65.6, 80.4, 176.1; ESI-MS:
m/z 344 [M+1]+.
4.1.2. (2R,3S)-2,4-Dimethylpentane-1,3-diol 5
To a cooled (0 °C) stirred suspension of lithium aluminium hy-
dride (166 mg, 4.36 mmol) in dry ether (10 mL) was added com-
pound 4 (1.0 g, 2.91 mmol) over a period of 2 h. After completion
of the reaction as determined by TLC, the reaction mixture was
quenched with saturated Na2SO4 solution, filtered and extracted
into ethyl acetate (5 ꢁ 10 mL), dried over anhydrous Na2SO4 and
concentrated under reduced pressure to give crude compound 5.
The crude 5 was purified by silica gel column chromatography (sil-
4.1.1. (2R)-N-[2S,3S)-2,4-Dimethyl-3-hydroxypentan-1-oyl]bor-
nane-10,2-sultam 4
To a stirred solution of compound 3 (1.0 g, 3.69 mmol) in
dichloromethane (10 mL) was added TiCl4 (1.2 mL), and diisopro-
pylethylamine (2.0 mL) slowly at ꢀ78 °C for 90 min, and then
isobutyraldehyde (0.8 g, 11.08 mmol) was added at the same

1808
P. Prabhakar et al. / Tetrahedron: Asymmetry 20 (2009) 1806–1808
ica gel, 60–120 mesh; hexane/ethyl acetate = 9:1) to obtain pure
propionylated compound 8 (Rf : 0.7, hexane/EtOAc 90:10) (110 mg,
compound 5 (Rf : 0.3, hexane/EtOAc 70:30) in 92 % yield as white
90% yield) as a pale yellow liquid. ½a D25
ꢂ
¼ ꢀ7 (c 1.0, CHCl3); IR
crystalline solid (350 mg). ½a D25
ꢂ
¼ þ8 (c 1.0, CHCl3); IR (KBr):
(neat): 2969, 2936, 2878, 1737, 1462, 1187 and 1076 cmꢀ1 1H
;
3313, 2968, 2928, 2874, 1228, 1038, 989, 693 cmꢀ1
;
1H NMR
NMR (300 MHz, CDCl3): d 0.89 (d, 3H, J = 6.7 Hz), 0.91 (d, 3H,
J = 6.7 Hz), 1.02 (d, 3H, J = 6.7 Hz), 1.17 (d, 3H, J = 7.5 Hz), 1.84–
1.97 (m, 1H), 2.08–2.20 (m, 1H), 2.31–2.41 (q, 2H, J = 7.5,
15.1 Hz), 3.27–3.35 (dd, 1H, J = 6.9, 10.7 Hz), 3.44–3.51 (dd, 1H,
J = 5.6, 10.7 Hz), 4.83–4.89 (dd, 1H, J = 3.9, 7.7 Hz); 13C NMR
(75 MHz, CDCl3): d 9.38, 11.69, 14.97, 17.94, 19.19, 27.69, 29.90,
37.40, 80.00, 174.23; ESI-MS: m/z 299 [M+1]+.
(300 MHz, CDCl3): d 0.85(d, 3H, J = 6.7 Hz), 0.92 (d, 3H, J = 6.9 Hz),
1.00(d, 3H, J = 6.6 Hz), 1.60–1.74 (m, 1H), 1.75–1.87 (m, 1H), 2.82
(br s, 1H), 3.02 (br s, 1H), 3.38 (dd, 1H, J = 1.2, 9.0 Hz), 3.56–3.76
(m, 2H); 13C NMR (75 MHz, CDCl3): d 9.10, 19.21, 19.67, 31.49,
36.23, 67.83, 79.75; ESI-MS: m/z 131[M+1]+.
4.1.3. (2R,3S)-3-Hydroxy-2,4-dimethylpentyl 4-methylbenzene-
sulfonate 6
4.1.6. (3S,5R,6S)-3,5-Dimethyl-6-isopropyl-3,4,5,6-tetrahydropy-
ran-2-one 1
To a stirred solution of diol 5 (100 mg, 0.76 mmol) in dry dichlo-
romethane (5 mL) were added dry triethylamine (3.0 equiv) and
catalytic amounts of DMAP and Bu2SnO at 0 °C for half an hour,
after which tosyl chloride (137 mg, 0.72 mmol) was added to
the reaction mixture and the reaction was stirred for 5 h. After
completion of the reaction as determined by TLC, water was added
to the reaction mixture and it was extracted into dichloromethane,
and dried over anhydrous Na2SO4. The solvent was evaporated
under reduced pressure, and was purified by silica gel column
chromatography (silica gel, 60–120 mesh) using hexane/ethyl
acetate (9:1) to obtain compound 6 (Rf: 0.7, hexane/EtOAc 70:30)
To a solution of compound 8 (90 mg, 0.335 mmol) in dry
tetrahydrofuran (3 ml) were added LHMDS (lithium hexamethyl-
disilazine) (48.62 mg, 0.30 mmol) and HMPA (hexamethyl phos-
phoramide) (108 mg, 0.6 mmol) and reaction mixture was stirred
for 5 h at ꢀ78 °C. After completion of the reaction, the reaction
mixture was quenched with saturated NH4Cl and extracted into
ethyl acetate (3 ꢁ 20 mL). The combined organic layer was dried
over anhydrous Na2SO4. The solvent was removed under reduced
pressure to afford crude compound 1 as a pale yellow liquid. Puri-
fication of the crude product by silica gel column chromatography
using hexane/ethyl acetate (9:1) as eluent gave 1 (Rf : 0.5, hexane/
(195 mg, 90% yield) as a colourless liquid; ½a D25
ꢂ
¼ þ21 (c 1.0,
CHCl3); IR (neat): 3558, 2965, 1354, 1177, 960 and 823 cmꢀ1
;
1H
EtOAc 90:10) (38 mg, 76% yield) as
¼ ꢀ24:5 (c 1.0, CHCl3); IR (neat): 2926, 1728, 1459, 1212,
1058, 772, 537 cmꢀ1 1H NMR (300 MHz, CDCl3): 0.90 (3H, d,
a pale yellow liquid.
NMR (300 MHz, CDCl3): d 0.81 (d, 3H, J = 6.7 Hz), 0.84 (d, 3H,
J = 6.7 Hz), 0.97 (d, 3H, J = 6.7 Hz), 1.26 (t, 1H, J = 7.5 Hz), 1.57–
1.70 (m, 1H), 1.73 (d, 1H, J = 3.7 Hz), 2.46 (s, 3H), 3.18–3.28 (m,
1H), 4.00–4.12 (m, 1H), 7.33 (d, 2H, J = 7.5 Hz), 7.77 (d, 2H,
J = 8.3 Hz); 13C NMR(75 MHz, CDCl3): d 8.97, 18.96, 19.51, 21.73,
31.02, 35.02, 72.88, 75.48, 128.01, 129.79, 133.57, 144.38; ESI-
MS: m/z 287 [M+1].
½ ꢂ
a 2D5
;
J = 6.6 Hz), 0.96 (3H, d, J = 6.9 Hz), 1.09 (3H, d, J = 6.6 Hz), 1.25
(3H, d, J = 6.6 Hz), 1.29 (1H, m), 1.79–1.92 (1H, m), 1.93–2.20
(2H, m), 2.48 (1H, dt, J = 1.1, 6.6 Hz), 3.78 (1H, dd, J = 2.2, 9.8 Hz);
13C NMR (75 MHz, CDCl3): d 14.9, 15.7, 18.0, 20.0, 27.7, 28.8,
32.0, 35.3, 85.3, 176.6; ESI-MS: m/z 170 [M]+ and 127 (MꢀC3H7+).
4.1.4. (2S,3S)-1-Iodo-2,4-dimethylpentan-3-ol 7
Acknowledgements
To a solution of tosylated compound 6 (100 mg, 0.35 mmol) in
dry acetone (5 ml), NaI (105 mg, 0.70 mmol) was added and stirred
at 70 °C for 2 h. After completion of the reaction as determined by
TLC, acetone was removed, and water was added to the reaction
mixture and it was extracted into ethyl acetate (4 ꢁ 20 mL), dried
over anhydrous Na2SO4 and concentrated under reduced pressure
to give crude product 7 which was purified by silica gel column
chromatography (silica gel, 60–120 mesh) using hexane/ethyl ace-
tate (9:1) to obtain pure compound 7 (Rf : 0.6, hexane/EtOAc
The authors are thankful to CSIR, Ministry of Earth Sciences
(MoES), and Department of Biotechnology (DBT) New Delhi, India
respectively, for the financial support and Dr. J. S. Yadav Director, In-
dian Institute of Chemical Technology (IICT), for his encouragement.
References
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¼ ꢀ32:5 (c
ꢂ
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2.0, CHCl3); IR (neat): 3427, 2963, 1461, 1381, 1192 and 977
cmꢀ1 1H NMR (300 MHz, CDCl3): d 0.89 (d, 3H, J = 6.6 Hz), 0.99
;
(d, 3H, J = 6.6 Hz), 1.01 (d, 3H, J = 6.6 Hz), 1.23–1.34 (m, 1H),
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6.0 Hz), 3.23–3.31 (dd, 1H, J = 7.3, 9.6 Hz); 13C NMR (75 MHz,
CDCl3): d 13.42, 13.87, 18.77, 19.17, 31.27, 37.70, 78.71; ESI-MS:
m/z 243 [M+1]+.
4.1.5. (2S,3S)-1-Iodo-2,4-dimethylpentan-3-yl propionate 8
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was quenched with saturated aq. ammonium chloride solution
and extracted into dichloromethane (3 ꢁ 20 mL). The combined
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