Total synthesis of (3Z,9Z,6S,7R) and (3Z,9Z,6R,7S)-6,7-epoxy-3,9-octadecadienes

Article abstract of DOI:10.1080/00397911.2017.1342842

(3Z,9Z,6S,7R)-6,7-epoxy-3,9-octadecadiene (1) and (3Z,9Z,6R,7S)-6,7-epoxy-3,9-octadecadiene (2) have been stereoselectively synthesized in eight steps from 2-pentyn-1-ol with an overall yield of 8%. The key steps involved the Sharpless asymmetric dihydrox

Full text of DOI:10.1080/00397911.2017.1342842

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Total synthesis of (3Z,9Z,6S,7R) and
(3Z,9Z,6R,7S)-6,7-epoxy-3,9-octadecadienes
Kai Xu, Shuai Zhao, Jia-Kuan Xu, Ming-Wei Shan, Jia-Li Yu, Yu-Bo Wang,
Cheng-Fang Zhang & Xin Chen
To cite this article: Kai Xu, Shuai Zhao, Jia-Kuan Xu, Ming-Wei Shan, Jia-Li Yu, Yu-Bo Wang,
Cheng-Fang Zhang & Xin Chen (2017): Total synthesis of (3Z,9Z,6S,7R) and (3Z,9Z,6R,7S)-6,7-
epoxy-3,9-octadecadienes, Synthetic Communications, DOI: 10.1080/00397911.2017.1342842
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1342842
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Date: 12 September 2017, At: 01:40

SYNTHETIC COMMUNICATIONS®
https://doi.org/10.1080/00397911.2017.1342842
Total synthesis of (3Z,9Z,6S,7R) and (3Z,9Z,6R,7S)-6,7-epoxy-
3
,9-octadecadienes
a
a
b
a
a
c
Kai Xu , Shuai Zhao , Jia-Kuan Xu , Ming-Wei Shan , Jia-Li Yu , Yu-Bo Wang ,
Cheng-Fang Zhang , and Xin Chen
c
a
a
School of Pharmaceutical and Life Sciences, Changzhou University, Changzhou, Jiangsu, P. R. China;
b
c
Changzhou Municipal Agricultural Commission, Changzhou, Jiangsu, P. R. China; Changzhou Nimrod
Biotech Inc., Changzhou, Jiangsu, P. R. China
ABSTRACT
ARTICLE HISTORY
(
3Z,9Z,6S,7R)-6,7-epoxy-3,9-octadecadiene (1) and (3Z,9Z,6R,7S)-6,7-
Received 9 March 2017
epoxy-3,9-octadecadiene (2) have been stereoselectively synthesized
in eight steps from 2-pentyn-1-ol with an overall yield of 8%. The key
steps involved the Sharpless asymmetric dihydroxylation of (2E)-oct-2-
en-5-yn-1-ol (6). The new synthetic method is suitable for multigram-
scale preparation of 1 and 2 and might be used for producing sufficient
quantities of the sex pheromone components for management of the
pest of tea plantations.
KEYWORDS
(3Z,9Z,6R,7S)-6,7-epoxy-
3,9-octadecadiene; sex
pheromone; sharpless
asymmetric dihydroxylation;
synthesis
GRAPHICAL ABSTRACT
Introduction
Tea geometrid Ectropis oblique Prout is one of the most destructive defoliator pests of tea
[1]
plantations in China. Tea farmers usually use chemical insecticides to control the pest,
but the practice has resulted in pesticide residues on the tea and environmental pollution
[
2]
concerns. As an environmentally friendly and pest-targeting method, sex pheromone
technology has been widely used for monitoring and controlling the insect pests for organic
[
3–7]
[1]
tea plantations, fruits, and vegetable.
Recently, Yang et al. identified (3Z,9Z)-6,
7
-epoxy-3,9-octadecadiene [(3Z,9Z)-6,7-epo-18:Hy] as the major sex pheromone
component of E. Oblique. Wen et al. reported (3Z,9Z)-6,7-epo-18:Hy as the major
component of Ectropis grisescens Warren, another destructive pest for tea in China.
[
8]
CONTACT Jia-Kuan Xu
13001, P. R. China; Xin Chen
University, Changzhou, Jiangsu 213164, P. R. China.
Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/lsyc.
13861033648@139.com
Changzhou Municipal Agricultural Commission, Changzhou, Jiangsu
2
xinchen@cczu.edu.cn
School of Pharmaceutical and Life Sciences, Changzhou
1
13
Supplemental data (full experimental detail, H and C NMR spectra) for this article can be accessed on the publisher’s
website.
2017 Taylor & Francis
©

2
K. XU ET AL.
Scheme 1. Chemical structures of 1 and 2.
In fact, (3Z,9Z)-6,7-epo-18:Hy is composed of a pair of enantiomers: (3Z,9Z,6R,7S)-6,7-
epo-18:Hy (1) and (3Z,9Z,6S,7R)-6,7-epo-18:Hy (2) (Scheme 1), although neither Yang
[
1]
[8]
et al. nor Wen et al. specified the stereochemistry of the epoxide in the sex pheromone
components. Few reports were found in the literature regarding the synthesis of 1 and 2.
[
1]
Yang et al. prepared an inseparable racemic mixture of 1 and 2 by epoxidation of
(
3Z,6Z,9Z)-3,6,9-octadetriene with m-chloroperoxybenzoic acid. By using the Sharpless
[
9]
asymmetric epoxidation as the key step, Millar and Underhill synthesized optical pure
1
and 2 despite of less satisfactory stereoselectivity (with 88% ee).
Our objective was to develop an efficient preparative-scale method for synthesizing
both 1 and 2 in gram quantities and with higher stereoselectivity, so that a field trial could
be performed for management of E. Oblique using sex pheromone technology in
Jiangsu Province, China. Here we report a convenient synthesis of 1 and 2 from relatively
inexpensive materials.
Results and discussion
2
-Pentyn-1-ol (3) was chosen as the starting material for synthesis of 1 and 2 (Scheme 2).
[
10]
3
was converted into the corresponding tosylate (4) by treating with tosyl chloride.
The
coupling of 4 with propargyl alcohol in the presence of CuI afforded octa-2,5-diyn-1-ol (5),
and then 5 was partially reduced with LiAlH in diethyl ether to give (2E)-oct-2-
4
[
11]
en-5-yn-1-ol (6).
Under the standard Sharpless asymmetric dihydroxylation conditions
[
12–16]
(
AD-mix-alpha, MeSO NH , t-BuOH/H O ¼ 1:1, 0 °C),
6 was transformed into
2
2
2
(
2R,3R)-oct-5-yne-1,2,3-triol (7) with 80% ee. After one recrystallization in dichloro-
methane, the ee value was enriched to 95.7%. The ee values of 7 were determined by chiral
HPLC analysis of its monobenzoyl ester
[
17]
of 7.
The triol 7 was selectively tosylated to give the monotosylate 8 by treating with tosyl
chloride under basic condition (Scheme 3). Subsequently, 8 was treated with K CO in
2
3
MeOH to give epoxy alkyne 9. Unfortunately, treatment of 9 with tosyl chloride in the
presence of sodium hydride resulted in a complicated product mixture. When 7 was
[
18,19]
reacted with tosylimidazole (Ts-Im),
tosylated epoxide 10 and its regioisomer 11 were
resulted with a ratio of 2:1, but their separation was tedious. After tosylimidazole was
replaced with bulky 2,4,6-triisopropyl-benzene-sulfonylimidazole[20] (TPS-Im), epoxide
Scheme 2. Reagents and conditions: (a) TsCl, KOH, Et O, rt, 3 h, 98%, (b) propargyl alcohol, K CO , CuI,
2
2
3
TBAI, DMF, rt, 8 h, 90%, (c) LiAlH , Et O, 0 °C-rt, 18 h, 80%, and (d) AD-mix-alpha, MeSO NH , t-BuOH:
4
2
2
2
H2O ¼ 1:1, 0 °C, 72 h, 70%.

SYNTHETIC COMMUNICATIONS®
3
Scheme 3. Reagents and conditions: (a) TsCl, pyridine, rt, 12 h, 35%, (b) K CO , MeOH, rt, 3 h, 63%,
2
3
(
3
c) TsCl, NaH, THF, 0 °C-rt, 3 h, (d) NaH, Ts-Im, THF, rt, 3 h, 35% (for 10), and (e) NaH, TPS-Im, THF, rt,
h, 41% (for 12).
1
2 and its regioisomer 13 were obtained with improved regioselectivity (with a ratio of 3:1
for 12 and 13) (Scheme 3). More importantly, the desired product is much easier to be
separated from the mixture. 12 was obtained in 41% yield and with 94.6% ee.
With the key chiral epoxide 12 in hand, we turned our attention to the remaining steps
in the synthetic sequence. Ring opening of epoxide 12 with excess lithiated 1-decyne in the
[17]
presence of boron trifluoride etherate
gave diyne alcohol 14 in 51% yield (Scheme 4).
Upon treatment with solid K CO in MeOH, 14 was cyclized to afford diyne epoxide
2
3
1
5 in 80% yield. In the final step, catalytic hydrogenation of 15 in the presence of Lindlar
[
20,21]
catalyst
resulted in the target compound (3Z,9Z,6R,7S)-6,7-epo-18:Hy (1) with
satisfactory yield (95%).
By following the same synthetic sequence for 1, 2 was obtained smoothly starting from
(
E)-oct-2-en-5-yn-1-ol (6) (Scheme 5). By replacing AD-mix-alpha with AD-mix-beta,
6
was proceeded Sharpless asymmetric dihydroxylation to give (2S,3S)-oct-5-yne-1,2,3-triol
(
16) with 82% ee. After one recrystallization in dichloromethane, the ee value was enriched
to 95.1%. 16 was treated with NaH/TPS-Im to afford epoxide 17 in 42% yield and with 96%
ee. Ring opening of epoxide 17 with excess lithiated 1-decyne in the presence of boron
trifluoride etherate gave diyne alcohol 18 in 52% yield. The subsequent cyclization of 18
with K CO in MeOH resulted in the formation of diyne epoxide 19 in 80% yield. Finally,
2
3
(
3Z,9Z,6S,7R)-6,7-epo-18:Hy (2) was obtained through catalytic hydrogenation of 19 in the
presence of Lindlar catalyst.
Scheme 4. Reagent and conditions: (a) 1-decyne, n-BuLi, BF ·Et O, THF, À 78 °C, 40 min, 51%, (b) K CO ,
3
2
2
3
MeOH, rt, 3 h, 80%, and (c) H , Lindlar catalyst, MeOH, rt, 1 h, 95%.
2

4
K. XU ET AL.
Scheme 5. Regent and conditions: (a) AD-mix-beta, MeSO NH , t-BuOH:H O ¼ 1:1, 0 °C, 72 h, 72%,
2
2
2
(
b) NaH, TPS-Im, THF, 0 °C, 3 h, 42%, (c) 1-decyne, n-BuLi, BF ·Et O, THF, À 78 °C, 1 h, 52%, (d) K CO ,
3
2
2
3
MeOH, rt, 3 h, 80%, and (e) Lindlar catalyst, MeOH, rt, 1 h, 93%.
In conclusion, a concise and efficient synthetic route has been developed for synthesizing
3Z,9Z,6R,7S)-6,7-epo-18:Hy (1) and (3Z,9Z,6S,7R)-6,7-epo-18:Hy (2). The overall yield for
(
the eight-step procedure is about 8% starting from 2-pentyn-1-ol. The simplicity and
scalability of the preparation and its low cost suggest that the method might have
practical potential for producing sufficient quantities of the sex pheromone components
for monitoring and controlling of the insect pest.
Experimental
(
2S,3S)-Oct-5-yne-1,2,3-triol (7)
To a stirred solution of 6 (1.8 g, 14.5 mmol) in t-BuOH (70 mL) and H O (70 mL) at 0 °C
2
was added AD-mix-alpha (40 g), followed by benzenesulfonamide (1.4 g, 14.5 mmol), and
the mixture was stirred at 0 °C for 72 h. The reaction was quenched by adding solid sodium
sulfite (21 g; vigorous CO evolution!), and the resulting mixture was extracted with EtOAc
2
(
3 � 100 mL). The combined extracts were washed with brine (80 mL), dried (anhydrous
Na SO ), and concentrated. The crude product was purified by column chromatography
2
4
on silica gel (CH Cl /MeOH, 20:1) to afford a solid which was recrystallized from
2
2
2
0
dichloromethane to give 7 (1.6 g, 70% yield) as white solid. mp 67–70 °C; ½aꢀ þ1.4
D
1
(
c ¼ 1.00, CH Cl ); 95.7% ee; H NMR (400 MHz, CDCl ): δ 1.12 (t, J ¼ 7.5 Hz, 3H),
2
2
3
2
.17 (q, J ¼ 7.5 Hz, 2H), 2.47 (t, J ¼ 16.8 Hz, 2H), 3.75-0-3.80 (m, 4H), 4.01 (s, 1H);
1
3
C NMR (100 MHz, CDCl ): δ 12.5, 14.2, 24.1, 64.6, 71.2, 72.9, 75.2, 84.6; HRMS (ESI):
3
þ
m/z [MþNa] calcd for C H O Na: 181.0835; found: 181.0825.
8
14 3
The enantiomeric excess of the triol 7 was determined by chiral HPLC analysis of its
monobenzoyl ester in comparison to the corresponding racemic mixture. Analysis con-
ditions: column Chiralpak AD-H, 4.6 � 250 mm, n-hexane/i-PrOH ¼ 60:40, 0.5 mL/min,
flow rate 0.5 mL/min, λ ¼ 250 nm. The retention times corresponding to the monobenzoyl
ester of 7 and its enantiomer are 12 and 10 min, respectively.
(
S)-1-((S)-Oxiran-2-yl)hex-3-yn-1-yl 2,4,6-triisopropylbenzene-sulfonate (12)
To a stirred suspension of NaH (60% in oil dispersion) (2.9 g, 72 mmol) in dry THF (240 mL)
at 0 °C was added in portion 7 (3.8 g, 24 mmol), followed by TPS-Im (20 g, 60 mmol), and

SYNTHETIC COMMUNICATIONS®
5
the whole mixture was then stirred for 3 h. Cold H O (100 mL) was added, and the
2
resulting mixture was extracted with EtOAc (3 � 40 mL). The combined extracts were
washed with brine (50 mL) and then dried (anhydrous Na SO ). Evaporation of the
2
4
solvent gave the crude product, which contains 12 and its regioisomer 13 with a ratio
of 3:1. The mixture was purified by flash chromatography on silica gel (hexane/EtOAc,
2
0
5
0:1) to afford 12 and 13. For 12 (4.1g, 41% yield; colorless oil): ½aꢀ þ2.0 (c ¼ 1.00,
D
1
CH Cl ); 94.6% ee; H NMR (300 MHz, CDCl ): δ 1.04 (t, J ¼ 7.5 Hz, 3H), 1.22–1.29
2
2
3
(
m, 18H), 2.01–2.08 (m, 2H), 2.60–2.70 (m, 2H), 2.81 (dd, J ¼ 2.55, 4.81 Hz, 1H),
2
.90–2.93 (m, 2H), 3.20–3.28 (m, 1H), 4.12–4.16 (m, 2H), 4.50–4.54 (m, 1H), 7.18
1
3
(
s, 2H); C NMR (75 MHz, CDCl ): δ 12.3, 14.0, 23.0, 23.6, 24.7, 24.8, 29.8, 34.3, 45.5,
3
þ
5
2.4, 72.8, 79.4, 85.2, 123.8, 130.7, 150.6, 153.7; HRMS (ESI): m/z [MþNa] calcd for
C H O SNa: 429.2070; found: 429.2073. For 13 (1.3 g, 14% yield; colorless oil):
2
3
34 4
1
H NMR (400 MHz, CDCl ): δ 1.08 (t, J ¼ 7.5 Hz, 3H), 1.25–1.28 (m, 18H), 2.07–2.26
3
(
m, 3H), 2.52–2.61 (m, 1H), 2.85–2.99 (m, 1H), 3.18–3.28 (m, 2H), 4.03–4.22 (m, 3H),
13
4
1
1
.39 (dd, J ¼ 3.81, 11.42 Hz, 1H), 7.20 (s, 2H); C NMR (100 MHz, CDCl ): δ 12.4,
3
4.0, 19.1, 23.7, 24.8, 24.8, 29.8, 34.4, 53.5, 54.7, 67.1, 73.1, 84.9, 124.0, 129.1, 151.0,
þ
54.1; HRMS (ESI): m/z [MþNa] calcd for C H O SNa: 429.2070; found: 429.2073.
2
3
34 4
The enantiomeric excess of 12 was determined by chiral HPLC analysis (column,
Chiralpak AD-H, 4.6 � 250 mm, n-hexane/i-PrOH ¼ 97:3; flow rate: 0.5 mL/min,
λ ¼ 230 nm). The retention times corresponding to 12 and its enantiomer are 12.8 and
1
0.2 min, respectively.
(
3Z,9Z,6R,7S)-6,7-epoxy-3,9-octadecadiene (1)
To a solution of 15 (1 g, 3.8 mmol) in MeOH (40 mL) was added the Lindlar catalyst
90 mg), and the mixture was stirred under hydrogen atmosphere (with a balloon filled
(
with hydrogen) at rt for 1 h. After the removal of the catalyst through a celite pad, the
filtrate was concentrated, and the residue was purified by flash chromatography on silica
2
0
gel (hexane/EtOAc, 100:1) to afford 1 (950 mg, 95% yield) as light yellow oil. ½aꢀ þ2.2
D
9
20
1
(
c ¼ 1.00, CH Cl ) [Lit. ½aꢀ
þ1.1 (c ¼ 6.47, CH Cl )]; H NMR (300 MHz, CDCl ):
2
2
365
2
2
3
δ 0.88 (t, J ¼ 6.7 Hz, 3H), 0.98 (t, J ¼ 7.5 Hz, 3H), 1.26–1.35 (m, 15H), 2.01–2.12
(
5
2
m, 4H), 2.16–2.26 (m, 2H), 2.37–2.46 (m, 2H), 2.92–2.98 (m, 2H), 5.35–5.46 (m, 2H),
1
3
.49–5.58 (m, 2H); C NMR (75 MHz, CDCl ): δ 14.4, 14.5, 21.0, 22.9, 26.3, 26.4, 27.7,
3
þ
9.5, 29.7, 29.8, 32.1, 56.8, 123.4, 123.9, 133.1, 134.6; HRMS (ESI): m/z [MþH] calcd
for C H O: 265.2526, found: 265.2524.
18
33
Acknowledgments
We gratefully acknowledge the financial support from the Tri-Innovation Agricultural Program of
Jiangsu Province (SXGC[2016]070) and Changzhou Science and Technology Program (CJ20160056).
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