Stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate and propionate, the sex pheromones of pine sawflies

Article abstract of DOI:10.1016/j.tetlet.2007.06.123

The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate (2) and propionate (3) was accomplished by utilizing the cheap and easily available chiron (R)-4-methyl-δ-valerolactone (4). The key steps were chelation-controlled addition of Gilmann reagent to chiral β-alkoxy aldehyde 12 and the Cu(I)-catalyzed coupling of Grignard reagent with bromoester 5 in the presence of NMP.

Full text of DOI:10.1016/j.tetlet.2007.06.123

Tetrahedron Letters 48 (2007) 7549–7551
Stereoselective synthesis
of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate
and propionate, the sex pheromones of pine sawflies
a
b
b,
a,
*
*
Zikun Wang, Qihai Xu, Weisheng Tian and Xinfu Pan
a
Department of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
b
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, PR China
Received 17 April 2007; revised 19 June 2007; accepted 22 June 2007
Available online 24 June 2007
Abstract—The stereoselective synthesis of (2S,3S,7S)-3,7-dimethylpentadec-2-yl acetate (2) and propionate (3) was accomplished by
utilizing the cheap and easily available chiron (R)-4-methyl-d-valerolactone (4). The key steps were chelation-controlled addition of
Gilmann reagent to chiral b-alkoxy aldehyde 12 and the Cu(I)-catalyzed coupling of Grignard reagent with bromoester 5 in the pres-
ence of NMP.
Ó 2007 Published by Elsevier Ltd.
Pine sawflies (Hymenoptera: Diprionidae) are widely dis-
tributed in the coniferous forests of Northern Europe,
Asia and North America. Considering they are severe
pests on conifers, the identification and synthesis of
the pheromones of this and related species are essential
for the development of selective monitoring and control
of the populations of these insects. Because of the pio-
O
OH
OH
O
O
ref 8
O
+
HO
HO
Tigogenin
4
Scheme 1.
1
,2
neering work of Coppel, Jewett and co-workers, the
major pheromone components of several species of pine
sawflies were found to be esters of 3,7-dimethyl-2-penta-
decanol 1. Acetate 2 is the most active in the Neodiprion
species, whereas propionate 3 is preferred by the Diprion
8
a green method (Scheme 1). In connection with our
work in using the cheap and easily available lactone 4
as a chiron for the asymmetric syntheses of natural
products, we report here a new route to the esters of
2S,3S,7S)-alcohol 1.
9
2
,3
species. Further researches showed that the esters of
2S,3S,7S)-alcohol 1 were the most active for all Neodi-
(
(
4
5–7
prion species. Up to date, a number of methods have
been developed for the syntheses of stereoisomers of
compound 1. Compared with the existing syntheses of
those pheromones, the present route seems more practi-
cal and economical.
Our retrosynthetic analysis is shown in Scheme 2. The
chelation-controlled addition to aldehyde and the cou-
pling of Grignard reagent with bromide were the key
steps in this synthesis.
The asymmetric synthesis started with lactone 4. On the
As a result of our group’s efforts in resource chemistry
1
0
treatment of HBr gas in MeOH, lactone 4 was con-
verted to bromoester 5. In the presence of NMP,
(
the organic synthetic chemistry based on the rational
utilization of resource compounds), we can produce
R)-4-methyl-d-valerolactone (4) in kilograms scales via
1
1
Cu(I)-catalyzed coupling of Grignard reagent with
bromoester was achieved in high chemoselectivity and
(
yield. After reduction with LiAlH , the alcohol was oxi-
4
1
2
dized by Swern protocol to provide aldehyde 7. By a
TiCl -mediated aldol condensation of the known N-
Keywords: Sex pheromones; Pine sawflies; Chiron; Resource chemistry;
Chelation-controlled.
1
3
4
1
4
*
Corresponding authors. Tel.: +86 931 8912407 (X.P.); e-mail:
panxf@lzu.edu.cn
propionyl-oxazolidinone
with the aldehyde, the
desired compound 9 was achieved. Protection of the
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.06.123

7550
Z. Wang et al. / Tetrahedron Letters 48 (2007) 7549–7551
1
9
Cu(I)-catalyzed coulpling
chelation-controlled addition
TBDMS followed by Mitsunobu reaction afforded
sex pheromones 2 and 3 (see Scheme 3).
2
0
21
Me2CuLi
OR
OBOM
O
O
In conclusion, starting from (R)-4-methyl-d-valerolac-
tone (4), which was regarded as industrial waste in the
past, an efficient synthesis of the active enantiomers of
the pheromones of pine sawflies has been achieved.
The key steps of this synthesis include the highly diaste-
reoselective addition to chiral b-alkoxy aldehyde, and
the Cu(I)-catalyzed coupling of Grignard reagent with
bromoester.
1
2
3
R=H
R=Ac
R=COCH2CH3
aldol condensation
O
O
O
n-C7H15MgBr
n-C8H17
O
Br
O
+
N
Bn
O
O
4
References and notes
Scheme 2. Retrosynthetic analysis of 1.
1
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2
1
976, 192, 51.
1
5
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4
2
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6
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1
7
1
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e
11
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BOMO
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h
j
n-C8H17
n-C8H17
n-C8H17
O
1
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R2=TBDMS
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k
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n-C8H17
m
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2
O
O
R4=H
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o
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OCOCH2CH3
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n-C8H17
1
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3
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Scheme 3. Reagents and conditions: (a) dry HBr, MeOH, rt, 56%; (b)
equiv NMP, 3% Li CuCl , CH (CH CH MgBr, THF, rt, 92%; (c)
1) LiAlH , Et , CH Cl , ꢀ78 °C
O, ꢀ78 °C , 90%; (2) DMSO, (COCl)
to 0 °C, 85%; (d) 8, TiCl , iPr NEt, NMP, CH Cl , 0 °C, 82%; (e)
BOMCl, iPr NEt, TBAI, CH Cl , 0 °C to rt, 80%; (f) NaBH , THF/
O (v/v,1:2.5), 0 °C to rt, 87%; (g) IBX, DMSO, rt 88%; (h)
Me CuLi, Et
O, ꢀ78 °C, 76%; (i) TBDMSCl, imidazole, DMF, rt
5%; (j) H , 10% Pd–C, EtOAc/MeOH (v/v,3:1), rt 90%; (k) MsCl,
Et N, CH Cl , 0 °C to rt, 96%; (l) NaBH , HMPA, 80 °C, 78%; (m)
HF (40%), CH CN, rt, 94%; (n) DEAD, Ph P, pyridine, AcOH, THF,
45 °C to 0 °C, 80%; (o) DEAD, Ph P, pyridine, CH CH COOH,
THF, ꢀ45 °C to 0 °C, 77%.
4
(
2
4
3
2
)
5
2
4
2
2
2
2
4
2
2
2
2
2
2
4
H
2
2
2
9
2
3
2
2
4
3
3
ꢀ
3
3
2
8. Tian, W. S. CN1061985C.

Z. Wang et al. / Tetrahedron Letters 48 (2007) 7549–7551
. Tian, W. S.; Ding, K.; Huang, Y. CN 200410093260.4.
7551
2
D
5
9
20. (2S,3S,7S)-3,7-Dimethylpentadec-2-yl acetate (2): ½aꢁ
1
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ꢀ5.6 (c 0.18, hexane); IR(film): 2963, 2928, 2857, 1741,
ꢀ
1 1
1465, 1374, 1261 1246, 1098, 1020, 803 cm ; H NMR
(CDCl , 300 MHz) d: 4.70–4.83 (m, 1H), 2.03 (s, 3H),
0.95–1.60 (m, 22H), 1.16 (d, J = 6.3 Hz, 3H), 0.76–0.84
1
3
5
6, 2733.
1
3
1
1
1
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3
(m, 9H); C NMR (CDCl , 75 MHz) d: 170.8, 74.137.6,
37.3, 37.0, 32.8, 32.8, 31.9, 30.0, 29.7, 29.4, 27.0, 24.5, 22.7,
+
21.3, 19.7, 17.0, 14.8, 14.1; MS EI m/z (%): 239 (M ꢀ59,
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1
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D
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1
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1464, 1378, 1261 1193, 1084, 1019, 805 cm ; H NMR
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J = 7.5 Hz, 2H), 1.16 (d, J = 6.6 Hz, 3H), 1.14 (t,
J = 7.6 Hz, 3H), 0.99–1.60 (m, 22H), 0.93–0.76 (m, 9H);
1
1
1
8
1
3
1
3
C NMR (CDCl , 75 MHz) d: 174.1, 73.8, 37.7, 37.3,
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+
19.7, 17.0, 14.8, 14.1, 9.3; MS EI m/z (%): 238 (M ꢀ74, 2),
155(1), 139(3), 125(4), 111(3), 101(20), 86(21), 69(15),
57(100).
1