Synthesis of β-Keto Lactone with Basic Skeleton of Przewalskin B

Article abstract of DOI:10.1002/jhet.2239

The synthesis of β-keto lactone was completed using cyclohexanone as starting material. The α,β-unsaturated lactone was obtained through Reformatsky reaction and iodolactonization. The aforementioned lactone was converted into target compound 1 (β-keto lactone) by Nef oxidation and Claisen condensation in six steps with 17.9% overall yield.

Full text of DOI:10.1002/jhet.2239

1412
Synthesis of β-Keto Lactone with Basic Skeleton of Przewalskin B
Vol 53
a
b
b
b
a
a
c
*
*
Jing-Ping Liu, Li-Qin Wang, Yong Zhao, Yan Zhao, Ying-Hui He, Zi-Rong Wang, and Hong-Bin Zhang
aTechnical and Vocational Education College, Yunnan Normal University, Kunming 650092, People’s Republic of China
bDepartment of Chemistry, Yunnan Normal University, Kunming 650092, People’s Republic of China
cSchool of Chemical Science and Technology, Yunnan University, Kunming 650091, People’s Republic of China
*
E-mail: liujp72@163.com; zhanghb@ynu.edu.cn
Received December 5, 2013
DOI 10.1002/jhet.2239
Published online 15 August 2016 in Wiley Online Library (wileyonlinelibrary.com).
The synthesis of β-keto lactone was completed using cyclohexanone as starting material. The α,β-
unsaturated lactone was obtained through Reformatsky reaction and iodolactonization. The aforementioned
lactone was converted into target compound 1 (β-keto lactone) by Nef oxidation and Claisen condensation in
six steps with 17.9% overall yield.
J. Heterocyclic Chem., 53, 1412 (2016).
INTRODUCTION
(Fig. 2). Compound 1 contains the important active
structural domains of the natural product Przewalskin B.
The synthetic route of compound 1 is more simple and
convenient than Przewalskin B. The synthesis study of
compound 1 lays a foundation for the development of
small-molecule drugs.
β-ketonic esters are important metabolites in plants and
animals and are also important intermediates for the
biosynthesis of a variety of useful organic compounds such
as fats, ribose, β-amino acid, and β-hydroxyl acid [1,2].
They have found applications in treating tumors and
hypertension as well as in the manufacture of protease
inhibitors [3,4]. Most β-ketonic esters are nontoxic,
aromatic, and are often used as food additives [5–7].
Przewalskin B isolated from Salvia przewalskii in
Shangri-La, Yunnan Province, shows significant anti-HIV-1
activity and other physiological activities [8]. One salient
feature of Przewalskin B is that it is a tetracyclic diterpene with
the structure of β-ketonic esters (Fig. 1).
RESULTS AND DISCUSSION
By means of Reformatsky reaction, compound 2 can be
easily synthesized using cyclohexanone. At the temperature
of 0°C, compound 3 can be synthesized using SOCl2/py./
CH2Cl2 after 1 h of reaction. Compound 3 is hydrolyzed
in 10% aqueous solution of KOH, and the resulting acids
can be directly used in iodolactonization without purifica-
tion. Using I2/KI/sat. NaHCO3 system and ethyl acetate as
solvent, the reaction proceeded at room temperature for
On the basis of the physiological activities of β-ketonic
esters and relevant reports on the synthesis of Przewalskin
B [9,10], we proposed a synthetic scheme of compound 1
© 2016 Wiley Periodicals, Inc.

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Synthesis of β-Keto Lactone
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EXPERIMENTAL
All regents were used as
General experimental.
purchased from Acros, Aldrich, and Fluka without further
purification. Anhydrous CH2Cl2 was freshly distilled from
CaH2, and THF was dried by Na. For reactions carried out
under Ar, the mixtures were degassed at high vacuum and
purged with Ar at least three times. The course of reaction
was monitored by TLC. 1H-NMR and 13C-NMR spectra
were recorded at ambient temperature with a Bruker
Avance 300 (300MHz for 1H and 75.5 MHz for 13°C;
Bruker, Germany) instrument in which TMS was used as
internal standard for all measurements. MS data were
recorded by using a VG Auto spec-3000 spectrometer or a
Finnigan MAT 90 instrument. IR spectra were measured
as KBr pellets by using a Bio-Rad FTS-135 spectrometer.
CC was performed by using silica gel (200–300 mesh;
Qingdao Marine Chemical, China).
Figure 1. The structure of Przewalskin B.
Figure 2. The structure of compound 1.
Preparation of Zn–Cu couple.
Zinc dust (392 mg,
6 mmol) was added to a hot (80°C), well stirred solution
of Cu(OAc)2 · H2O (22.4 mg, 0.1 mmol) in glacial acetic
acid (1 mL). After about 30 s, the solution became
colorless due to the deposition of the copper on the zinc.
The silt-like couple was allowed to settle for about 1 min,
followed by careful decantation of as much of the acetic
acid as possible without loss of the deposits. The dark
red-gray couple was then washed with a 1-mL portion of
acetic acid and thrice with 1 mL of diethyl ether, followed
by drying in a stream of nitrogen and subsequent
suspension in dry THF (5 mL). The Zn/Cu couple
resulting from this procedure was used for Reformatsky
18h. Then, the saturated aqueous solution of Na2S2O3 was
added. The extraction solution was dried and concentrated.
Later, Et3N was added for reaction at room temperature
for 2 h. Finally, compound 4 was obtained by column
chromatography (CC) (Scheme 1).
Because 1,4-addition is impossible between vinyl
grignard reagent and compound 4, fluorine anion was used
as alkaline to facilitate the 1,4-addition of nitromethane to
compound 5. The oxidation of nitro group in compound 5
by KMnO4 results in compound 6 (Scheme 2).
The condensation between compound 6 and methyl
isovalerate leads to the target product, compound 1
(Scheme 3).
reaction. The procedure can readily be scaled up 10-fold.
Preparation of ethyl 2-(1-hydroxycyclohexyl)acetate (2).
The Zn–Cu pair was suspended in dry THF (10 mL). A
solution of ethyl 2-bromoacetate (1 g, 6 mmol ) was
added dropwise at 70°C and stirred for 1 h. Then, the
solution of cyclohexanone (0.2 g, 2 mmol ) in THF
(1 mL) was added dropwise. The reaction mixture was
stirred for 3 h at 70°C and cooled to room temperature,
and then aqueous solution of NH4Cl (10 mL) was added.
The resulting mixture was extracted with ethyl acetate
(3 × 5 mL), dried by Na2SO4, removed of the solvent in
vacuo. The crude product was purified by flash
chromatography giving compound 2 (87%). 1H-NMR
(300 MHz, CDCl3): δ = 3.97 (q, J = 7.10 Hz, 2H), 3.35
Compound 1 was tested for cytotoxicity against BEL-
7402, A-549, HT-29, HL-60, MOLT-4 tumor cell lines,
and anti-HIV-1 activity was evaluated by the inhibition
for the cytopathic effects of HIV-1 (EC50). Compound 1
exerted minimal cytotoxicity against the five cell lines
(IC50 > 200 μg/mL) and showed anti-HIV activity with
EC50 = 28.45 μg/mL and selectivity index = 3.51.
In summary, the synthesis of compound 1 has been achieved
in six steps with 17.9% overall yield starting from the commer-
cially available cyclohexenone, involving Reformatsky
reaction, iodolactonization, Nef oxidation, and Claisen con-
densation as key steps to furnish the target compound.
Scheme 1. Synthesis and reaction of 5,6,7,7a-tetrahydrobenzofuran-2(4H)-one (4). Reagents and conditions: (a) BrCH2CO2Et, Zn-Cu, THF, reflux, 87%.
(b) SOCl2, pyridine, CH2Cl2, 0°C, 88%. (c) i: 10%KOH, MeOH; ii: I2, KI, NaHCO3; iii: Et3N, three steps, 55%.
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J.-P. Liu, L.-Q. Wang, Y. Zhao, Y. Zhao, Y.-H. He, Z.-R. Wang, and H.-B. Zhang
Vol 53
was extracted into ethyl acetate using three 15–mL portions.
The organic phases were combined, dried over MgSO4, and
concentrated on a rotary evaporator without further purification.
A solution of KI (2.02 g, 12.15 mmol) and I2 (0.93 g,
3.64 mmol) in 5 mL of water was added to a solution of
crude carboxylic acid (0.34 g, 2.43 mmol) in ethyl acetate
(5 mL) and sat. NaHCO3 (1.02 g, 12.15 mmol), and the
resulting mixture was allowed to stand for 18 h in the dark.
Enough Na2S2O3 was then added to decolorize the mix-
ture, followed by 10 mL of ethyl acetate. The two layers
were separated, and the aqueous phase was extracted with
ethyl acetate. The combined organic layers were dried over
MgSO4 and concentrated on a rotary evaporator. Et3N
(2.45 g, 24.3 mmol) was added to a solution of the crude
iodolactone in 1 mL of dry benzene under N2 at room temper-
ature. After 24 h, the reaction mixture was concentrated to a
brown residue, which was purified by CC to provide com-
Scheme 2. Synthesis and reaction of octahydro-2-oxobenzofuran-3a-
carbaldehyde (6). Reagents and conditions: (a) CH3NO2, TBAF, THF,
70°C, 85%. (b) KMnO4, MgSO4, KOH, CH3OH, rt, 78%.
Scheme 3. Synthesis and reaction of target compound (1). Reagents and
conditions: LDA, THF, À78°C, 64%.
1
pound 4 (55%). H-NMR (300 MHz, CDCl3): δ = 5.71 (s,
1H), 4.71 (dd, J = 6.41 Hz, 1H), 2.85–2.90 (br.d, 1H), 2.53
(br.s, 1H), 2.21–2.38 (m, 1H), 1.88–2.04 (m, 2H), 1.20–
1.53 (m, 3H) ppm; 13C-NMR (75 MHz, CDCl3): δ = 173.35,
172.49, 111.93, 81.33, 34.33, 27.97, 26.49, 22.31 ppm; IR
(KBr): υmax = 2949, 1778, 1448 cmÀ1; MS (EI): m/z: 138;
HRMS: m/z: calcd for C8H10O2: 138.0681; found: 138.0683.
Preparation of hexahydro-3a-(nitromethyl)benzofuran-2(3H)-
one (5). Compound 4 (2.2 g, 16 mmol)was dissolved in
THF (10 mL) and stirred at 70°C with nitromethane (1.95 g,
32 mmol) and tetrabutylammonium fluoride (1 M in
tetrahydrofuran, 24 mL, 24.0 mmol). After 18 h, the mixture
was cooled to room temperature, diluted with ethyl acetate
(40 mL), and washed with 2 N HCl (20 mL) and then brine
(2 × 30 mL). The organic phase was collected and dried
(MgSO4) and the solvent removed in vacuo. The residue
was purified by flash chromatography (silica, ethyl acetate/
heptane, 1 : 9) to give compound 5 (85%). 1H-NMR
(300 MHz, CDCl3): δ = 4.58 (d, J = 11.78 Hz, 1H), 4.44 (d,
J = 11.78 Hz, 1H), 2.76 (d, J = 17.10 Hz, 1H), 2.41 (d,
J = 17.10 Hz, 1H), 1.37–1.63 (m, 8H) ppm; 13C-NMR
(75 MHz, CDCl3): δ = 174.73, 79.32, 78.44, 41.78, 28.87,
25.56, 20.23, 19.11 ppm; IR (KBr): υmax = 1771,
1549 cmÀ1; MS (EI): m/z: 200 [M + H]+.
(br.s, 1H), 2.23–2.28 (br.d, 2H), 1.21–1.48 (overlap, 10H),
1.10 (t, J = 7.10 Hz, 3H) ppm; 13C-NMR (75 MHz,
CDCl3): δ = 172.46, 69.63, 60.18, 45.33, 37.22, 25.47,
22.22, 14.01 ppm; IR (KBr): υmax = 3516, 1718 cmÀ1
MS (EI): m/z: 186.
;
Preparation of ethyl 2-cyclohexenylacetate (3). To an ice-
water-cooled solution of compound 2 (3 g, 16.13 mmol) in
dry pyridine (2.55 g, 32.26 mmol) and CH2Cl2 (10 mL)
was added thionyl chloride (2.09 g, 17.74 mmol)
dropwise under stirring over a 5-min period. After 1 h of
stirring, the reaction mixture was poured into ice-water
and extracted with ether. The ether layer was washed
with water and dried over Na2SO4. Removal of solvent
followed by CC gave compound 3 (88%). 1H-NMR
(300 MHz, CDCl3): δ = 5.56 (t, J = 7.88 Hz, 1H), 4.10 (q,
J = 7.11 Hz, 2H), 2.76–2.92 (br.d, 2H), 1.96–2.08 (br.s,
3H), 1.51–1.62 (br.s, 5H), 1.24 (t, J = 7.11 Hz, 3H) ppm;
13C-NMR (75 MHz, CDCl3): δ = 171.96, 131.17, 125.49,
60.35, 43.64, 28.35, 25.25, 22.70, 21.97, 14.21 ppm; IR
(KBr): υmax = 3413, 2938, 1738, 1459 cmÀ1; MS (EI):
Preparation of octahydro-2-oxobenzofuran-3a-carbaldehyde
(6). A solution of compound 5 (0.3 g, 1.51 mmol) in MeOH
(5 mL) at 0°C was mixed with a solution of KOH (85%)
(0.09 g, 1.66 mmol) in MeOH (2 mL). The mixture was stirred
at 0°C for 20 min and a freshly prepared solution of KMnO4
(0.18 g, 1.13 mmol) and MgSO4 (0.14g, 1.15mmol) in H2O
(10 mL) was added dropwise, over 40 min, to the
aforementioned mixture. After the mixture was stirred at
0°C for an additional hour, the mixture was diluted with
EtOAc (50 mL) and filtered through a pad of Celite. The
Celite pad was washed with EtOAc (3 × 50 mL). The
combined filtrates were washed with brine (1 × 20 mL)
and H2O (1 × 10 mL), dried (MgSO4), filtered, and the
m/z: 168.
Preparation of 5,6,7,7a-tetrahydrobenzofuran-2(4H)-one (4).
To a solution of 10% aqueous KOH (1.12 g, 20 mmol) was
added compound 3 (1.68 g, 10 mmol) in CH3OH (15 mL).
After 24 h at room temperature, CH3OH was removed on a
rotary evaporator, and the aqueous mixture was diluted
with 15 mL of water. The aqueous layer was acidified to
pH 6 by the dropwise addition of concentrated HCl, which
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Synthesis of β-Keto Lactone
1415
filtrate evaporated in vacuo. The residue was purified by
flash chromatography (silica, ethyl acetate/heptane, 1 : 5)
to give compound
1707 cmÀ1; MS (EI): m/z: 234; MS (HR-ESI): m/z: calcd for
C14H18NaO+3[M + Na]+: 257.1148; found: 257.1149.
6
(78%). 1H-NMR (300 MHz,
CDCl3): δ = 9.37 (s, 1H), 4.53 (t, J = 3.46 Hz, 1H), 2.47
(d, J = 17.12 Hz, 1H), 2.36 (d, J = 17.12 Hz, 1H), 1.18–
1.63 (m, 8H) ppm; 13C-NMR (75 MHz, CDCl3):
δ = 198.88, 175.11, 72.83, 56.10, 38.77, 28.53, 25.96, 22.05,
21.28 ppm; IR (KBr): υmax=1772, 1715cmÀ1; MS (EI): m/z:
168; MS (HR-ESI): m/z: calcd for C9H12NaO+3[M + Na]+:
Acknowledgment. This work was supported by a grant from the
Science Foundation of Science and Technology Department of
Yunnan Province (no. 2010CD048).
191.0679; found: 191.0681.
Preparation of compound 1. To a solution of methyl
REFERENCES AND NOTES
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under N2 atmosphere was added LDA (1 M, 2.62 mmol,
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compound 6 (0.4 g, 2.38 mmol) in THF (1 mL) was added
dropwise. After 2 h of stirring, this mixture was added
another LDA (1 M, 5.24 mmol, 5.24 mL) at the same
temperature. After the addition was complete, the mixture
was stirred for 18 h. Then, aqueous solution of NH4Cl
(10 mL) was added. The resulting mixture was extracted
with ethyl acetate (3 × 5 mL), dried by Na2SO4, and
removed of the solvent in vacuo. The crude product was
purified by flash chromatography giving compound 1
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(t, J = 3.45 Hz, 1H), 3.30 (s, 1H), 2.57–2.61 (m, 1H), 2.21–
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13C-NMR (75 MHz, CDCl3): δ = 197.87, 170.22, 158.71,
150.49, 80.11, 57.27, 50.31, 30.84, 29.66, 24.86, 22.34,
21.59, 21.00, 20.79 ppm; IR (KBr): υmax = 2954, 1771,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet