Total synthesis of 3,7-dimethyl-7-hydroxy-2-octen-1,6-olide and 3,7-dimethyl-2,6-octadien-1,6-olide

Article abstract of DOI:10.1080/10286020.2013.803474

3,7-Dimethyl-7-hydroxy-2-octen-1,6-olide (1) and 3,7-dimethyl-2,6-octadien- 1,6-olide (2), the natural bioactive compounds isolated from the fruit of Litsea cubeba and the liverwort Plagiochila rutilans, were totally synthesized using easily available cis-geraniol as raw material in short, convenient, and low-cost, five-step reactions including three steps of oxidation, cyclization, and dehydration, with an overall yield of 47.5% and 37.3%.

Full text of DOI:10.1080/10286020.2013.803474

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Total synthesis of 3,7-dimethyl-7-
hydroxy-2-octen-1,6-olide and 3,7-
dimethyl-2,6-octadien-1,6-olide
Hong-Bo Dong a , Ming-Yan Yang a , Jia-Zheng Jiang a & Ming-An
Wang a
a Department of Applied Chemistry , China Agricultural
University , Beijing , 100193 , China
Published online: 25 Jun 2013.
To cite this article: Hong-Bo Dong , Ming-Yan Yang , Jia-Zheng Jiang & Ming-An Wang (2013) Total
synthesis of 3,7-dimethyl-7-hydroxy-2-octen-1,6-olide and 3,7-dimethyl-2,6-octadien-1,6-olide,
Journal of Asian Natural Products Research, 15:8, 880-884, DOI: 10.1080/10286020.2013.803474
To link to this article: http://dx.doi.org/10.1080/10286020.2013.803474
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Journal of Asian Natural Products Research, 2013
Vol. 15, No. 8, 880–884, http://dx.doi.org/10.1080/10286020.2013.803474
Total synthesis of 3,7-dimethyl-7-hydroxy-2-octen-1,6-olide and
3,7-dimethyl-2,6-octadien-1,6-olide
Hong-Bo Dong, Ming-Yan Yang, Jia-Zheng Jiang and Ming-An Wang*
Department of Applied Chemistry, China Agricultural University, Beijing 100193, China
(Received 14 January 2013; final version received 5 May 2013)
3,7-Dimethyl-7-hydroxy-2-octen-1,6-olide (1) and 3,7-dimethyl-2,6-octadien-1,6-
olide (2), the natural bioactive compounds isolated from the fruit of Litsea cubeba
and the liverwort Plagiochila rutilans, were totally synthesized using easily available
cis-geraniol as raw material in short, convenient, and low-cost, five-step reactions
including three steps of oxidation, cyclization, and dehydration, with an overall yield of
47.5% and 37.3%.
Keywords: total synthesis; 3,7-dimethyl-7-hydroxy-2-octen-1,6-olide; 6-olide; 3,7-
dimethyl-2,6-octadien-1,6-olide
1. Introduction
side chain [12]. Sesquiterpene lactone (4)
was also isolated from Drypetes molun-
duana (Figure 2) and showed anti-inflam-
matory and analgesic activities [13,14].
Because they all have novel strain seven-
membered lactone ring structure, there are
very practical difficult to synthesis them. So
far, only a few synthetic methods of natural
and nonnatural seven-membered lactones
were reported by oxidative lactonization,
the palladium-catalyzed carbonylative
annulation of internal alkynes, the ring-
closing metathesis synthesis of unsaturated
lactones and enzymatic synthesis [15–18].
The only crystal structure of seven-mem-
bered lactone (S)-6-methyl-1-caprolactone
was also reported [19]. Therefore, there has
been great demand for highly efficient
synthetic methods for natural and nonna-
tural seven-membered lactones.
As all we know, a large number of natural
products have the structures of five- or six-
membered lactone ring as well as medium-
ring lactone including 8-, 9-, 10-, and 11-
membered ring [1–4]. For example, clau-
samines A–C and clausevatines D–G
(Figure 1) were first isolated from dried
branches of Clausena anisata in Thailand
[5]. Some of them may display interesting
biological activities including antimalaria,
anti-TB, cytotoxicity, and stimulating glu-
cose uptake in L6 myotubes [6–8].
However, there are a few natural products
having the structure of seven-membered
lactone rings [9]. (6R)-3,7-Dimethyl-7-
hydroxy-2-octen-6-olide (1) was first iso-
lated from the honey bee fungal entomo-
pathogen Ascosphaera apis [10], as well as
the fruit of plant Litsea cubeba in Tibet [11],
and exhibited good antifungal and antiox-
idant activities. 3,7-Dimethyl-2,6-octadien-
1,6-olide (2) is a natural product, which was
first isolated from the Costa Rican liverwort
Plagiochila rutilans. They have a very
unique structure of a seven-membered
lactone ring with an olefin or isopropanol
Lactonization of epoxy carboxylic acid
was a new synthetic strategy, and we will
report the total synthesis of natural
products
3,7-dimethyl-7-hydroxy-2-
octen-1,6-olide (1) and 3,7-dimethyl-2,6-
octadien-1,6-olide (2) using this protocol
as the key step in this paper. Based on the
*Corresponding author. Email: wangma@cau.edu.cn
q 2013 Taylor & Francis

Journal of Asian Natural Products Research
881
OH
OH
OH
R
O
O
O
O
O
O
O
O
N
H
N
H
N
H
N
H
OR
OR
OH
OR
Clausamine A R = H
Clausamine B R = CH3 Clausamine C R = CH3
Clausevatine D R = H
Clausevatine G
Clausevatine E R = β-OH
Clausevatine F R = α-OH
Figure 1. Structures of clausamines A–C and clausevatines D–G.
O
O
O
O
O
O
O
O
O
OH
OH
1
2
3
4
Figure 2. Structures of some typical natural products with seven-membered lactone ring.
above methodology, a short, convenient,
and low-cost synthesis routes of natural
products 3,7-dimethyl-7-hydroxy-2-octen-
1,6-olide (1) and 3,7-dimethyl-2,6-octa-
dien-1,6-olide (2) including four- or five-
step reactions were established with an
overall yields of 47.5% and 37.3%,
respectively (Scheme 1), and it was
suitable for synthesis of the other seven-
membered lactones. This work was in
progress in our laboratory.
2. Results and discussion
We investigated the synthesis of cis-
geranial using cis-geraniol as the key
starting material. First, pyridinium dichro-
mate or pyridinium chlorochromate was
used to oxidize hydroxyl into aldehyde
group, and all attempts under various
conditions showed that only a mixture of
cis- and trans-geranial was obtained in
the ratio of about 1:3 (from 1H NMR
spectrum). But the cis-isomer was our
desired product. Then, the Dess-Martin
O
AcO2H
NaClO2
Dess-Martin
CH2Cl2,r.t.
H2O-Acetone
CH2Cl2,r.t.
HOH2C
HO2C
HO2C
OHC
cis-geraniol
cis-geranial
cis-geranic acid
5
O
O
O
O
O
CSA
SOCl2
Pyridine
O
+
OH
CH2Cl2,r.t.
1
2
6
Scheme 1. Synthetic route of compounds 1 and 2.

882
H.-B. Dong et al.
oxidant reagent was luckily found to
afford cis-isomer with no cis–trans iso-
merization by repeated experiments using
various oxidant reagents [20]. cis-Geranial
was oxidized to cis-geranic acid with
NaClO2 without cis–trans isomerization
[21]. The selective epoxidation of cis-
geranic acid was achieved successfully in
CH2Cl2–water solvent system with per-
acetic acid. After the key intermediate 5 in
hand, we found that it could automatically
cyclize to afford 3,7-dimethyl-7-hydroxy-
2-octen-1,6-olide 1 in the presence of
catalytic quantity of camphorsulfonic acid
[22]. This new synthetic strategy by
lactonization of epoxy carboxylic acid to
prepare lactones including the seven-
membered as well as the other-membered
ring was seldomly referred in literatures.
Finally, dehydration of compound 1 with
SOCl2 in pyridine gave the final products 2
and the byproduct 6 in 15 min [23]. As
given in Table 1, compound 2 became the
major product along with the isomer 6 as
the minor product when the temperature
dropped. The overall yield of 47.5% for 1
was much better than 3% yield in the
chemical transformation of citral as the
byproduct [24], and compound 6 was also
prepared as fragrance [25].
3. Experimental
3.1 General experimental procedures
Melting points were measured on a
Yanagimoto apparatus (Yanagimoto MFG
Co., Kyoto, Japan) and are uncorrected. 1H
and 13C NMR spectra were recorded on
Bru¨ker DPX 300 NMR Spectrometer
(Bru¨ker Biospin Co., Stuttgart, Germany)
withCDCl3 assolventandtetramethylsilane
as internal standard. HR–MS were obtained
on Bru¨ker Apex II mass spectrometer
(Bru¨ker Co., Bremen, Germany) using
nitrobenzoyl alcohol and sodium chloride
as matrix. The solvents were analytical
grade and newly distilled before usage.
3.2 General procedures for the
synthetic compounds
3.2.1 Synthesis of cis-geranial
To a solution of cis-geraniol (10.8 g,
70.0mmol) in CH2Cl2 (60 ml) was added
the Dess-Martin oxidant reagent (33.9 g,
80.0 mmol). The reaction mixture was
stirred for 1.5 h at room temperature. After
thereactionwasfinishedasdetectedbythin-
layer chromatography (TLC), the mixture
was diluted with saturated Na2S2O3 (50 ml)
and extracted with CH2Cl2 (3 £ 100 ml).
The combined organic phases were washed
with brine (3 £ 30 ml), dried with sodium
sulphate anhydrous, and concentrated
in vacuo. Flash chromatography on silica
gel (10:1, v/v; petroleum ether:EtOAc)
afforded a yellow oil cis-geranial 10.3 g,
In
conclusion,
3,7-dimethyl-7-
hydroxy-2-octen-1,6-olide (1) and 3,7-
dimethyl-2,6-octadien-1,6-olide (2) were
synthesized through four- or five-step
reactions with overall yields of 47.5%
and 37.3%, respectively.
1
yield 96.3%. H NMR (300 MHz, CDCl3)
d: 9.89 (d, J ¼ 8.2 Hz, 1H, CHO), 5.87 (d,
J ¼ 8.2 Hz, 1H, CHv), 5.13–5.07 (m, 1H,
CHv), 2.56 (t, J ¼ 7.4Hz, 2H, CH2),
2.28–2.17 (m, 2H, CH2), 1.99 (s, 3H, CH3),
1.68 (s, 3H, CH3), and 1.59 (s, 3H, CH3).
Table 1. The temperature effect on the
product of compounds 2 and 6.
Reaction
temperature
(8C)
Ratioa
of 2:6
Yieldsb of
2 and 6 (%)
3.2.2 Synthesis of cis-geranic acid
A solution of 27.8 g (0.246 mol) of 80%
sodium chlorite and 44.7 g (0.286 mol) of
NaH2PO4 in 250 ml of distilled water was
added dropwise to a stirred mixture of
5.13 g (33.8 mmol) of cis-geranial and
15
0
–20
2:3
3:2
7:1
38.9 and 58.3
55.6 and 36.1
78.4 and 11.6
a Ratio values were from H NMR.
1
b Isolated yields.

Journal of Asian Natural Products Research
883
55 ml 2-methylbut-2-ene in 210 ml of
acetone over 5 h at ambient temperature.
The mixture was stirred for anther 2 h at
ambient temperature. After the reaction
was finished as detected by TLC, the acidic
products were extracted with 300 ml of
EtOAc three times. The organic phase was
combined and dried over magnesium
sulphate. Evaporation of solvent under
reduced pressure, and then flash chroma-
tography on silica gel (10:1, v/v; petroleum
ether:EtOAc) produced a yellow oil cis-
geranic acid 4.84 g, yield 85.1%. 1H NMR
(300 MHz, CDCl3) d: 11.93 (br, 1H, OH),
5.68 (s, 1H, CHv), 5.17–5.12 (m, 1H,
CHv), 2.64 (t, J ¼ 7.5 Hz, 2H, CH2),
2.20–2.12 (m, 2H, CH2), 1.93 (s, 3H, CH3),
1.68 (s, 3H, CH3), and 1.62 (s, 3H, CH3).
CH2Cl2 and 0.33g camphorsulfonic acid.
The mixture was stirred for 4 h at room
temperature. After the reactionwas finished,
the organic phase was washed with 5%
Na2CO3 solution and brine, dried with
sodium sulphate anhydrous, and concen-
trated in vacuo. Flash chromatography on
silica gel (3:1, v/v; petroleum ether:EtOAc)
afforded a light yellow oil (1 7.8 g, yield
65.0%). 1HNMR (300 MHz, CDCl3) d: 5.86
(brq, J ¼ 1.2 Hz, 1H, CHv), 4.04 (dd,
J ¼ 9.0, 2.2 Hz, 1H, CHO), 2.89 (br, 1H,
OH), 2.53 (dt, J ¼ 17.8, 6.0 Hz, 1H, CH2),
2.38–2.33(m, 1H, CH2), 2.19–2.09(m, 1H,
CH2), 1.97 (s, 3H, CH3), 1.96–1.87 (m, 1H,
CH2), 1.28 (s, 3H, CH3), 1.26 (s, 3H, CH3).
13C NMR (75 MHz, CDCl3) d: 168.1, 154.9,
118.1, 84.3, 71.4, 33.5, 27.1, 26.1, 26.0,
24.8. HR-ESI-MS m/z: 185.11705
[M þ H]þ (cacld for C10H17O3,185.11722).
3.2.3 Synthesis of cis-6,7-epoxygeranic
acid (5)
To a solution of cis-geranic acid (10.7 g,
63.9 mmol) in CH2Cl2 (300 ml) was added
the peracetic acid solution (123 ml ¼
10 £ 12.3 ml) and anhydrous sodium car-
bonate (42.1 g ¼ 10 £ 4.21 g). The reac-
tion mixture was stirred for 1.5 h at room
temperature. After the reaction was
finished as detected by TLC, the mixture
was diluted with saturated Na2S2O3
(50 ml) and extracted with CH2Cl2
(3 £ 100 ml). The combined organic
phases were washed with brine
(3 £ 100 ml), dried with sodium sulphate
anhydrous, and concentrated in vacuo to
give a white solid 5 10.5 g, yield 89.2%.
mp 46–488C. 1H NMR (300 MHz, CDCl3)
d: 11.75 (br, 1H, OH), 5.74 (s, 1H, CHv),
2.89–2.66 (m, 3H, CHO þ CH2), 1.95 (s,
3H, CH3), 1.81–1.66 (m, 2H, CH2), 1.31
(s, 3H, CH3), 1.28 (s, 3H, CH3). 13C NMR
(75 MHz, CDCl3) d: 171.4, 162.3, 116.3,
63.8, 58.6, 30.2, 27.6, 25.5, 24.8, 18.6.
3.2.5 Synthesis of 3,7-dimethyl-2,6-
octadien-1,6-olide (2) and its isomer (6)
SOCl2 (1.60 ml, 22.0 mmol) was added
to solutions of compound 1 (0.405 g,
2.20 mmol) in dry pyridine (20 ml) at
2208C. The reaction mixture was stirred
for 15 min, then poured into ice-water
(100 ml), and extracted with EtOAc
(2 £ 50 ml). The combined organic layer
was sequentially washed with 10% HCl,
5% NaHCO3 solution, and brine, dried
with Na2SO4, and evaporated to produce
the residues, which were purified by
column chromatography on silica gel
(10:1, v/v; petroleum ether:EtOAc) and
produced a colorless solid 2 (0.286 g, yield
78.4%) and a colorless oily liquid 6
(0.0402 g, yield 11.0%). Compound 2,
mp 67–698C. 1H NMR (300 MHz, CDCl3)
d: 5.83 (s, 1H, CHv), 2.61 (t, J ¼ 6.3 Hz,
2H, CH2), 2.39 (t, J ¼ 6.3 Hz, 2H, CH2),
1.92 (s, 3H, CH3), 1.69 (s, 3H, CH3), 1.66
(s, 3H, CH3). 13C NMR (75 MHz, CDCl3)
d: 166.1, 155.5, 141.5, 118.0, 117.0,
34.6, 27.4, 26.1, 18.0, 17.1. HR-ESI-
MS m/z: 167.10654 [M þ H]þ (cacld for
3.2.4 Synthesis of 3,7-dimethyl-7-
hydroxy-2-octen-1,6-olide (1)
To a 1000 ml three-necked flask were added
12.0g (65.1 mmol) compound 5, 560 ml
1
C10H15O2, 167.10665). Compound 6, H

884
H.-B. Dong et al.
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