Synthesis of the ABC skeleton of the aglycon of Echinoside A

Article abstract of DOI:10.1016/j.cclet.2015.08.010

Echinoside A is a triterpene saponin isolated from the sea cucumber Actinopyga echinites (JAEGER), which displays potent antitumor activities in vitro and in vivo. Here, we report the synthesis of the ABC-fused ring skeleton of the aglycon of Echinoside A, with the enantiomerically pure (+)-Wieland-Miescher ketone being used as starting material and a Robinson annulation as the key reaction.

Full text of DOI:10.1016/j.cclet.2015.08.010

Chinese Chemical Letters 26 (2015) 1331–1335
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis of the ABC skeleton of the aglycon of Echinoside A
b,
Jun Yu a, , Biao Yu
*
*
a Department of Chemistry, University of Science and Technology of China, Anhui 230026, China
b State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Echinoside A is a triterpene saponin isolated from the sea cucumber Actinopyga echinites (JAEGER), which
displays potent antitumor activities in vitro and in vivo. Here, we report the synthesis of the ABC-fused
ring skeleton of the aglycon of Echinoside A, with the enantiomerically pure (+)-Wieland–Miescher
ketone being used as starting material and a Robinson annulation as the key reaction.
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 7 July 2015
Received in revised form 22 July 2015
Accepted 3 August 2015
Available online 20 August 2015
Keywords:
Echinoside A
Wieland–Miescher ketone
Robinson annulation
Saponin
1. Introduction
2. Experimental
Sea cucumber saponins are common secondary metabolites
produced by holothurian species, which play an important role in
the chemical defense of the slow-moving animals while show a
wide spectrum of pharmacological activities. Echinoside A, a
lanostane-type triterpene oligosaccharide, was isolated from the
sea cucumber Actinopyga echinites (JAEGER) by Kitagawa et al. [1]
(Fig. 1). This compound demonstrated potent activities in vitro and
in vivo against a broad-spectrum of antitumor cells, especially it
could directly kill P-gp-mediated multidrug-resistant tumor cells
[2].
Echinoside A consists of a linear tetrasaccharide attached to a
pentacyclic triterpene aglycon. The construction of the pentacyclic
triterpene aglycon constitutes the most challenging part of the
synthesis; in fact, the synthesis of Echinoside A has never been
reported so far [3]. As shown in Scheme 1, we envisaged to
construct the pentacyclic aglycon (1) by introduction of the double
Commercial reagents were used without further purification
unless specialized. Solvents were dried and redistilled prior to use
in the usual way. Thin layer chromatography (TLC) was performed
on precoated plates of Silica Gel HF254 (0.2 mm, Yantai, China).
Flash column chromatography was performed on Silica Gel H
(10–40
m, Yantai, China). Optical rotations were determined with a
Perkin–Elmer Model 241 MC polarimeter. 1H NMR and 13C NMR
spectra were recorded on a Bruker AM 400 spectrometer with
Me4Si as the internal standard. Chemical shifts were recorded in
d
values and J values were given in Hz. Mass spectra were obtained
on a HP5989A or a VG Quatro mass spectrometer.
Wieland–Miescher ketone 9: A suspension of ketone 6 (25.0 g,
198.18 mmol) in water (60 mL) was treated with HOAc (0.6 mL),
hydroquinone (225 mg, 2.043 mmol), and fresh distilled methyl
vinyl ketone (32 mL, 387.10 mmol). Refluxed at 80 8C overnight,
returned to the room temperature, NaCl (20.0 g) was added, then
the mixture was diluted with EtOAc. The solution was washed with
brine, dried with Na2SO4, and then concentrated to afford the crude
product 8 (30.15 g, 78%).
In a standard glass vial with stirrer bar was added triketone 8
(6.14 g, 31.29 mmol) followed by the catalyst 10 (335 mg,
0.625 mmol) and benzoic acid (20 mg, 0.164 mmol). The resulting
mixture darkened and was stirred for 7 days. The mixture was
absorbed onto silica gel and purified by column chromatography
(petroleum ether/EtOAc 3:1–1:1) to give the Wieland–Miescher
ketone 9 (5.19 g, 93%, 90% ee) as a clear oil. Recrystallization from
Et2O gives a white crystalline solid (99.5% ee) [4]. 1H NMR
bond at the
a position of the ketone in skeleton 2, followed by
reduction of the ketone. Compound 2 could be constructed via an
intramolecular Aldol reaction from compound 3, which would be
synthesized through a Michael addition between the terminal
alkyl iodide 5 and the ABC skeleton 4. Herein, we report the
synthesis of the key ABC skeleton intermediate (4).
*
Corresponding authors.
E-mail addresses: yujun10@mail.ustc.edu.cn (J. Yu), byu@mail.sioc.ac.cn (B. Yu).
http://dx.doi.org/10.1016/j.cclet.2015.08.010
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

1332
J. Yu, B. Yu / Chinese Chemical Letters 26 (2015) 1331–1335
addition of CH3I (17.1 mL, 274.335 mmol). The mixture was
allowed to stir for 30 min after which the ammonia was allowed
to evaporate. The mixture was concentrated and the residue was
diluted with CH2Cl2 and washed with water, brine, dried over
Na2SO4, and concentrated. The residue was purified by silica gel
column chromatography (petroleum ether/EtOAc = 25:1) to afford
13 (2.86 g, 81%) as colorless oil [7]. 1H NMR (500 MHz, chloroform-
d):
d 3.98–3.83 (m, 4H), 2.62 (ddd, 1H, J = 15.1, 13.6, 6.3 Hz), 2.33
(ddd, 1H, J = 15.2, 5.3, 3.5 Hz), 1.99–1.90 (m, 1H), 1.89–1.83 (m,
1H), 1.77–1.64 (m, 3H), 1.55–1.43 (m, 4H), 1.24 (s, 3H), 1.08 (s, 3H),
1.04 (s, 3H).
Fig. 1. The structure of Echinoside A.
(400 MHz, chloroform-d):
2H), 2.57–2.43 (m, 4H), 2.22–2.09 (m, 3H), 1.72 (tdt, 1H, J = 13.3,
9.0, 4.4 Hz), 1.46 (s, 3H).
d 5.86 (d, 1H, J = 1.9 Hz), 2.80–2.68 (m,
Compound 14: A solution of 13 (1.23 g, 4.86 mmol) in EtOH
(15 mL) was treated with NaBH4 (184 mg, 4.86 mmol) at À40 8C for
2 h. Diluted with Et2O and washed with water and brine, the
organic layer was dried over Na2SO4 and concentrated. The residue
was purified by silica gel column chromatography (petroleum
ether/EtOAc 10:1) to afford 14 (1.10 g, 89%) as colorless crystal [7].
d 3.98–3.88 (m, 3H), 3.83 (dd,
1H, J = 7.5, 3.6 Hz), 3.30–3.20 (m, 1H), 1.74–1.24 (m, 12H), 1.05 (s,
3H), 0.99 (s, 3H), 0.80 (s, 3H).
Compound 15: A solution of 14 (500 mg, 1.97 mmol) in EtOH/
H2O (18 mL/2 mL), was treated with PPTS (64 mg, 0.26 mmol) and
refluxed for 2 h. The solvent was concentrated and diluted with
CH2Cl2. The mixture was washed with water and brine, dried over
Na2SO4, and concentrated, affording the crude product.
.
˚
Compound 11: 4 A molecular sieves (2.5 g) and p-TsOH H2O
(2.20 g, 11.566 mmol) were added to a solution of 9 (2.10 g,
11.783 mmol) in ethylene glycol (40 mL). After being stirred at
room temperature for 30 min, the reaction mixture was poured
slowly into a 2:1 mixture of ice-water/sat. aqueous NaHCO3. The
mixture was extracted with EtOAc four times, and the combined
organic layers were washed with brine, dried over Na2SO4.
Concentration and purification by silica gel column chromatog-
raphy (petroleum ether/EtOAc = 6:1) afforded 11 (2.28 g, 87%)
as a yellow oil [5]. 1H NMR (400 MHz, chloroform-d):
1H, J = 1.9 Hz), 4.07–3.85 (m, 4H), 2.41 (ddd, 2H, J = 10.9, 4.8,
3.0 Hz), 2.35–2.24 (m, 2H), 1.96–1.85 (m, 1H), 1.85–1.59
(m, 5H), 1.36 (s, 3H).
1H NMR (400 MHz, chloroform-d):
d 5.82 (d,
The crude product was dissolved in CH2Cl2 (10 mL), and was
then treated with DIPEA (1.72 mL, 9.83 mmol), MOMCl (0.74 mL,
9.83 mmol) at room temperature for 2 h. Quenched with saturated
NH4Cl, diluted with CH2Cl2, and washed with water and brine, the
resulting organic layer was dried over Na2SO4 and concentrated.
The residue was purified by silica gel column chromatography
(petroleum ether/EtOAc 15:1) to afford 15 (490 mg, 98%) as
Compound 12: A solution of 11 (2.28 g, 10.257 mmol) in n-
propanol (20 mL), was treated with PhSH (1.6 mL, 15.521 mmol),
37% HCHO (1.26 mL, 16.555 mmol), Et3N (1.4 mL, 15.521 mmol),
and HCOOK (1.044 g, 12.416 mmol) at 100 8C for 24 h. Then the
mixture was diluted with CH2Cl2, and the solution was washed
with saturated aqueous NaHCO3 and brine, dried with Na2SO4.
Concentration and purification by silica gel column chromatogra-
phy (petroleum ether/EtOAc 8:1) afforded 12 (2.86 g, 81%) as
colorless oil. 1H NMR (400 MHz, chloroform-d):
d 4.74 (d, 1H,
J = 6.8 Hz), 4.60 (d, 1H, J = 6.8 Hz), 3.39 (s, 3H), 3.10–3.02 (m, 1H),
2.57 (td, 1H, J = 13.9, 7.0 Hz), 2.20 (dddd, 1H, J = 14.1, 5.0, 2.2,
1.3 Hz), 2.13–2.03 (m, 1H), 1.91–1.83 (m, 1H), 1.76 (dt, 1H, J = 6.7,
2.6 Hz), 1.74–1.68 (m, 1H), 1.68–1.53 (m, 4H), 1.16 (s, 3H), 1.13
(d, 1H, J = 3.3 Hz), 1.00 (s, 3H), 0.92 (s, 3H). ESI-MS (m/z): 277.1
[M+Na]+. HRMS (m/z): [M+H]+ calcd. for C15H27O3 255.1955, found
255.1952.
Compound 16: A solution of 15 (1.5 g, 5.897 mmol) in dry
toluene/THF (15 mL/5 mL), was treated with 60% NaH (472 mg,
11.8 mmol) at 0 8C for 30 min. HCOOEt (5 mL) was added and
stirring continued at room temperature for 4 h. Quenched with
saturated NH4Cl, diluted with EtOAc and washed with water and
brine, the resulting organic layer was dried over Na2SO4 and
concentrated to afford a crude product.
yellow crystals [6]. 1H NMR (400 MHz, chloroform-d):
d 7.43–7.36
(m, 2H), 7.30–7.17 (m, 3H), 4.02–3.89 (m, 5H), 3.76 (d, 1H,
J = 11.5 Hz), 2.66 (ddt, 1H, J = 15.5, 4.2, 2.0 Hz), 2.49 (dt, 1H, J = 16.0,
4.4 Hz), 2.37 (ddd, 1H, J = 16.0, 13.9, 4.9 Hz), 2.24 (td, 1H, J = 13.5,
4.9 Hz), 2.03 (td, 1H, J = 14.6, 5.6 Hz), 1.85 (td, 1H, J = 13.5, 4.5 Hz),
1.75 (ddt, 1H, J = 10.2, 4.5, 2.5 Hz), 1.70–1.62 (m, 2H), 1.57–1.50 (m,
1H), 1.32 (s, 3H).
Compound 13: A solution of 12 (6.30 g, 18.79 mmol) in
THF/tBuOH (100 mL/3.5 mL), was added to a stirred solution of
3 equiv. of lithium in liquid ammonia (500 mL) over a 20–30 min
period. The solution was allowed to stir at À72 8C for another
45 min, whereupon 100 mL of THF was added followed by rapid
Scheme 1. Retrosynthetic analysis of the aglycon 1.

J. Yu, B. Yu / Chinese Chemical Letters 26 (2015) 1331–1335
1333
The crude product was dissolved in CH2Cl2 (10 mL) and then
treated with MVK (2.0 mL, 23.56 mmol) and Et3N (2.5 mL,
17.69 mmol). After stirring at room temperature for 4 h, the
mixture was concentrated to afford a crude product.
concentrated. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc 15:1) to afford 19
25
D
(38 mg, 67%) as colorless oil. [
a]
23.0 (c 0.70, CHCl3); 1H
NMR (400 MHz, chloroform-d):
d
12.05 (s, 1H), 4.73 (t, 1H,
The crude product was dissolved in HOBut (25 mL) and then
treated with KOBut (990 mg, 8.85 mmol). After stirring at room
temperature overnight, the mixture was quenched with water
and concentrated. The residue was diluted with EtOAc and washed
with water and brine. The organic layer was dried over Na2SO4 and
concentrated. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc 6:1) to afford 16 (1.52 g,
J = 5.1 Hz), 4.60 (dd, 1H, J = 6.9, 2.6 Hz), 3.73 (s, 3H), 3.38 (s, 3H),
3.09 (dd, 1H, J = 11.7, 4.2 Hz), 2.39 (dd, 1H, J = 15.7, 5.2 Hz),
2.25–2.05 (m, 2H), 1.99–1.88 (m, 1H), 1.80–1.49 (m, 6H), 1.38 (ddd,
2H, J = 16.4, 9.5, 3.5 Hz), 1.04 (td, 2H, J = 12.6, 5.2 Hz), 0.97 (s, 3H),
0.91–0.88 (m, 1H), 0.86 (s, 3H), 0.84 (s, 3H). 13C NMR (101 MHz,
chloroform-d):
d 172.61, 171.77, 96.50, 95.99, 84.97, 55.57, 54.45,
51.37, 50.02, 38.62, 37.18, 36.14, 34.56, 31.87, 30.90, 28.59, 28.35,
24.05, 21.00, 16.66, 13.80. ESI-MS (m/z): 389.4 [M+Na]+. HRMS
(m/z): [M+Na]+ calcd. for C21H34NaO5 389.2298, found 389.2300.
Compound 20: A solution of 19 (47 mg, 0.13 mmol) in dry
84%) as colorless oil. 1H NMR (400 MHz, chloroform-d):
d 5.78 (d,
1H, J = 1.5 Hz), 4.73 (d, 1H, J = 6.8 Hz), 4.59 (d, 1H, J = 6.8 Hz), 3.36
(s, 3H), 3.06 (dd, 1H, J = 11.5, 4.2 Hz), 2.52 (dddt, 1H, J = 14.2, 7.4,
5.3, 2.1 Hz), 2.35 (dt, 1H, J = 16.2, 4.9 Hz), 2.22 (ddd, 1H, J = 16.2,
12.7, 5.0 Hz), 2.10–1.97 (m, 2H), 1.92–1.84 (m, 1H), 1.76–1.43 (m,
6H), 1.25–1.15 (m, 1H), 1.10 (s, 3H), 1.04 (dd, 1H, J = 12.2, 2.8 Hz),
0.96 (s, 3H), 0.86 (s, 3H). 13C NMR (101 MHz, chloroform-d):
CH2Cl2 (2 mL) was treated with pyridine (50
mL) and PhSeCl
(50 mg, 0.256 mmol) at 0 8C. The mixture was then stirred at room
temperature overnight. Diluted with CH2Cl2 and washed with
1 mol/L HCl and water. The organic layer was added 30% H2O2
(1.5 mL), stirred at room temperature for 10 min until the yellow
solution turned to colorless. The organic layer was washed with aq.
NaHCO3 and brine, respectively, and was then dried over Na2SO4,
and concentrated. The residue was purified by silica gel column
d
201.23, 175.58, 119.84, 96.04, 84.34, 55.56, 52.45, 40.53, 39.30,
35.92, 35.02, 34.63, 34.19, 29.28, 28.11, 24.20, 21.33, 21.09, 16.49.
ESI-MS (m/z): 329.4 [M+Na]+; HRMS (m/z): [M+Na]+ calcd. for
C
19H30O3Na 329.2087, found 329.2091.
Compound 17: solution of 16 (38 mg, 0.12 mmol) in
dimethoxyethane (2 mL) was treated with 60% NaH (10 mg,
0.25 mmol) and dimethyl carbonate (21 L, 0.25 mmol). The
A
chromatography (petroleum ether/EtOAc = 6:1) to afford 20
25
(34 mg, 73%) as colorless oil. [
a
]
D
16.9 (c 1.0, CHCl3); 1H NMR
m
(500 MHz, chloroform-d): d 7.40 (d, 1H, J = 1.8 Hz), 4.73 (d, 1H,
mixture was refluxed under nitrogen for 2 h, and then quenched
with saturated NH4Cl and diluted with EtOAc. The mixture was
washed with water and brine, dried over Na2SO4, and concentrat-
ed. The residue was purified by preparative thin-layer chromatog-
raphy (petroleum ether/EtOAc 4:1) to afford 17 (5 mg) as colorless
J = 6.8 Hz), 4.59 (d, 1H, J = 6.8 Hz), 3.78 (s, 3H), 3.37 (s, 3H), 3.07 (dd,
1H, J = 11.7, 4.3 Hz), 2.50 (dd, 1H, J = 15.8, 3.3 Hz), 2.44 (tdd, 1H,
J = 10.6, 4.1, 1.8 Hz), 2.17 (dd, 1H, J = 15.7, 14.3 Hz), 2.09 (dd, 1H,
J = 13.0, 3.5 Hz), 1.84–1.72 (m, 2H), 1.64 (dt, 1H, J = 13.0, 3.5 Hz),
1.60–1.40 (m, 3H), 1.30–1.21 (m, 1H), 1.02 (dd, 1H, J = 13.3, 3.9 Hz),
0.96 (s, 3H), 0.90 (s, 3H), 0.88 (d, 1H, J = 2.5 Hz), 0.82 (s, 3H). 13C
oil. 1H NMR (400 MHz, chloroform-d):
d 6.83 (d, 1H, J = 8.1 Hz),
6.63 (d, 1H, J = 2.6 Hz), 6.50 (dd, 1H, J = 8.2, 2.6 Hz), 4.72 (d, 1H,
J = 6.9), 4.60–4.56 (d, 1H, J = 6.9), 3.35 (s, 3H), 3.09 (dd, 1H, J = 11.7,
4.4 Hz), 2.81 (ddd, 1H, J = 16.7, 6.7, 1.8 Hz), 2.76–2.64 (m, 1H),
2.20–2.10 (m, 1H), 1.90–1.74 (m, 2H), 1.74–1.58 (m, 2H), 1.48–1.34
(m, 1H), 1.28–1.16 (m, 1H), 1.12 (s, 3H), 0.98 (s, 3H), 0.84 (s, 3H).
ESI-MS (m/z): 327.4 [M+Na]+.
Compound 18: A solution of 16 (60 mg, 0.196 mmol) in THF/
EtOH (3 mL/0.03 mL) was added dropwise to a stirred liquid
ammonia (10 mL) at À72 8C, and then lithium (60 mg) was added
to the solution. The solution was allowed to stir for 4 h at À72 8C.
Quenched with saturated NH4Cl after which the ammonia was
allowed to evaporate. The mixture was diluted with EtOAc and
washed with water and brine. The organic layer was dried over
Na2SO4 and concentrated. The residue was purified by silica gel
NMR (126 MHz, chloroform-d): d 195.54, 165.07, 161.25, 131.26,
96.04, 84.61, 55.58, 53.97, 52.90, 52.21, 38.79, 38.65, 37.15, 36.21,
36.05, 32.14, 28.06, 24.04, 21.42, 16.35, 14.27. ESI-MS (m/z): 387.3
[M+Na]+; HRMS (m/z): [M+H]+ calcd. for C21H33O5: 365.2323,
found 365.2326.
Compound 21: To a solution of 20 (30 mg, 0.082 mmol) in dry
THF (1 mL) was added a freshly prepared solution of Me2CuLi
(0.38 mL, 0.09 mmol) in THF. After being stirred at À78 8C for 1 h,
the mixture was quenched with saturated NH4Cl. The resulting
mixture was diluted with EtOAc and washed with water and brine,
respectively. The organic layer was dried over Na2SO4 and
concentrated. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc 5:1) to afford 21 (28 mg,
25
89%) as yellow oil. [
a
]
D
14.0 (c 1.2, CHCl3); 1H NMR (500 MHz,
column chromatography (petroleum ether/EtOAc 6:1) to afford 18
chloroform-d): d 12.13 (s, 0.13H), 4.73 (d, 1H, J = 6.7 Hz), 4.60 (d,
21.4 (c 0.50, CHCl3); 1H NMR
1H, J = 6.8 Hz), 3.75 (s, 3H), 3.38 (s, 3H), 3.08 (ddd, 2H, J = 11.6, 4.9,
2.5 Hz), 2.42 (dd, 1H, J = 13.2, 3.6 Hz), 2.16 (dq, 1H, J = 13.2, 3.9 Hz),
2.13–2.03 (m, 1H), 1.75 (dt, 1H, J = 11.6, 4.0 Hz), 1.69 (ddd, 2H,
J = 10.8, 4.6, 2.3 Hz), 1.61–1.47 (m, 3H), 1.43–1.29 (m, 2H), 1.27–
1.15 (m, 2H), 1.11–1.04 (m, 1H), 0.99 (d, 3H, J = 6.4 Hz), 0.97 (s, 3H),
0.95–0.90 (m, 1H), 0.88 (s, 3H), 0.83 (s, 3H). HRMS (m/z): [M+H]+
calcd. for C22H37O5 381.2636, found 381.2638.
25
(1.52 g, 84%) as colorless oil. [
a
]
D
(400 MHz, chloroform-d):
d
4.72 (dd, 1H, J = 6.8, 1.4 Hz), 4.59 (dd,
1H, J = 6.8, 1.5 Hz), 3.37 (s, 3H), 3.11–3.00 (m, 1H), 2.29 (dq, 3H,
J = 11.6, 6.6, 5.1 Hz), 2.03 (t, 1H, J = 13.4 Hz), 1.99–1.92 (m, 1H),
1.88 (dt, 1H, J = 12.2, 3.6 Hz), 1.74 (m, 1H), 1.67–1.46 (m, 4H),
1.46–1.32 (m, 1H), 1.32–1.17 (m, 1H), 1.13–1.04 (m, 1H), 1.02–0.98
(m, 1H), 0.98–0.94 (m, 1H), 0.95 (s, 3H), 0.88 (s, 3H), 0.85 (d, 1H,
J = 2.0 Hz), 0.82 (s, 3H). 13C NMR (101 MHz, chloroform-d):
Compound 4: A solution of 21 (822 mg, 2.160 mmol) in dry
CH2Cl2 (20 mL) was treated with pyridine (0.5 mL) and PhSeCl
(827 mg, 4.320 mmol) at 0 8C. After stirring at room temperature
overnight, the mixture was diluted with CH2Cl2 and washed with
1 mol/L HCl and water. The organic layer was added 30% H2O2
(2.0 mL), stirred at room temperature for 10 min until the yellow
solution turned to colorless. The mixture was washed with aq.
NaHCO3 and brine, respectively, and was then dried over Na2SO4
and concentrated. The residue was purified by silica gel column
chromatography (petroleum ether/EtOAc 6:1–4:1) to afford 4
(406 mg, 49%) as white solid together with 20 (335 mg, 41%). 4:
d
213.12, 96.01, 84.85, 55.77, 55.55, 54.25, 41.13, 40.95, 38.63,
36.81, 36.59, 35.31, 34.10, 34.01, 28.29, 24.09, 21.05, 16.53, 13.82.
ESI-MS (m/z): 331.3 [M+Na]+. HRMS (m/z): [M+Na]+ calcd. for
C19H32NaO3:331.2244, found 331.2244.
Compound 19: To a mixture of 60% NaH (28 mg, 0.93 mmol)
and 30% KH (15 mg, 0.11 mmol) in dry THF (0.5 mL) was added 18
(48 mg, 0.16 mmol) in dry THF (2 mL) and dimethyl carbonate
(33
mL, 0.40 mmol) at 0 8C. The temperature was raised to 70 8C
and the mixture refluxed for 4 h. After cooling down to 0 8C, the
mixture was acidized with 50% HOAc, and diluted with EtOAc. The
mixture was washed with water, aq. NaHCO3, and brine,
respectively. The organic layer was dried over Na2SO4 and
[a
]
D
25 7.56 (c 1.1, CHCl3); 1H NMR (400 MHz, chloroform-d):
d
4.74
(d, 1H, J = 6.8 Hz), 4.60 (d, 1H, J = 6.8 Hz), 3.81 (s, 3H), 3.38 (s, 3H),

1334
J. Yu, B. Yu / Chinese Chemical Letters 26 (2015) 1331–1335
Scheme 2. Preparation of (+)-Wieland–Miescher ketone 9.
3.09 (dd, 1H, J = 11.6, 4.3 Hz), 2.47 (dd, 1H, J = 15.8, 3.3 Hz),
2.39–2.23 (m, 2H), 2.14 (dd, 1H, J = 15.8, 14.4 Hz), 1.91 (s, 3H), 1.79
(dt, 2H, J = 13.1, 3.8 Hz), 1.70–1.42 (m, 5H), 1.15 (dd, 1H, J = 12.8,
4.3 Hz), 1.02 (dd, 1H, J = 13.3, 3.8 Hz), 0.97 (s, 3H), 0.90 (s, 3H), 0.83
protected ketone 15 in 98% over two steps. Then, the annulation of
15 in order to give the tricyclic enone 16 was achieved under the
standard conditions exemplified in Spencer’s work [12]. More
precisely, the annulation was accomplished by formylation of the
ketone 15, followed by a Robinson annulation employing MVK 7,
with concomitant removal of the formyl group under basic
conditions. Enone 16 was finally isolated in 84% yield over three
steps. The stereochemistry of the C8-H was determined by NOE
analysis which exhibits a strong correlation with the C15-H. Other
attempts employing 3-penten-2-one and 4-methyl-3-penten-2-
one instead of MVK failed to construct the corresponding triketone
intermediate via the Robinson annulation.
(s, 3H). 13C NMR (101 MHz, chloroform-d):
d 195.99, 167.69,
162.39, 133.01, 96.04, 84.58, 77.24, 55.61, 53.90, 52.25, 51.92,
39.96, 38.57, 37.33, 36.27, 30.09, 28.04, 24.13, 21.38, 19.31, 16.35,
14.34. ESI-MS (m/z): 401.3 [M+Na]+. HRMS (m/z): [M+H]+ calcd. for
C
22H35O5: 379.2479, found: 379.2480.
3. Results and discussion
Our synthesis started with the preparation of (+)-Wieland–
Miescher ketone (9) through a Robinson annulation reaction
(Scheme 2). The Michael addition between 2-methyl-1,3-cyclohex-
anedione 6 and methyl vinyl ketone (MVK) 7 provided the triketone
8. Then, the L-proline-promoted aldolization of triketone 8 yielded
the Wieland–Miescher ketone 9, albeit in poor enantioselectivity
(50–70% ee) [8]. Following the procedure reported by Bonjoch [9],
With the annulation product 16 in hand, we focused our efforts
on the installation of the methoxycarbonyl group at the C-13
position (Scheme 4). Treatment of 16 with lithium diisopropyla-
mide (LDA) in À78 8C, followed by addition of methyl chlorofor-
mate led to no product, whereas treatment of 16 with NaH and
dimethyl carbonate in dimethoxyethane afforded the aromatiza-
tion product 17. Consequently, we decided to reduce the C9–C11
double bond at an earlier stage. At first, hydrogenation of 16 was
adopted in the presence of catalytic Pd/C, but the desired saturated
treatment of triketone
8 with N-tosyl-(S)-binam-prolinamide
(catalyst 10) through a solvent-free Robinson annulation procedure
afforded 9 in high enantioselectivity (90% ee). In addition, the (+)-
Wieland–Miescher ketone 9 could be enantiomerically enriched by
recrystallization from Et2O (99.5% ee).
The (+)-Wieland–Miescher ketone 9 was selectively protected
as ketal 11, which was subsequently subjected to Kirk–Petrow
conditions (Scheme 3) [10]. Indeed, ketal 11 was treated with
PhSH, HCHO, Et3N and HCOOK in n-propanol at 100 8C for 24 h to
furnish the thiol 12 in 81% yield. Reductive alkylation of the enone
under Birch conditions provided the 4,4-dimethyl-trans-decalone
derivative 13 (87%), which was reduced into the corresponding
alcohol 14 by NaBH4 (89%) [11]. Deacetalization followed by
protection of the hydroxyl group of 14 with MOMCl afforded the
ketone was isolated in
a mixture of the two C9-isomers.
Gratifyingly, reduction under Birch conditions yielded the
saturated ketone 18 as a single isomer (82%) [13]. Carbomethox-
ylation was then achieved by heating at 70 8C a mixture of 18 and
dimethyl carbonate in the presence of NaH and KH in THF.
Subsequent phenylselenation and dehydroselenation of 19 pro-
vided the desired
Methylation of 20 with Me2CuLi in THF afforded ketone 21 in 89%
yield, which was subjected to similar phenylselenation/
a,b-unsaturated ketone 20 in 73% yield [14].
a
dehydroselenation protocol, thus providing the desired key
intermediate 4 in 49% yield (83% yield based on recovered starting
materials).
O
O
O
O
O
O
O
Li, NH3(l), CH3I, THF, tBuOH,
-40 oC to r.t., 87%
PhSH, HCHO, Et3N, HCOOK,
n-propanol, 100 oC, 24 h, 81%
ethylene glycol, 4Å MS
p-TsOH-H2O, r.t., 87%
O
O
O
O
H
12
11
13
9
SPh
O
H
nOe
15
O
1) NaH, HCOOEt, toluene, THF, 0oC to r.t.
2) methyl vinyl ketone, NEt3, DCM, r.t.
O
O
1) PPTS, 90% EtOH
NaBH4, EtOH,
-40 oC, 89%
2) MOMCl, DIPEA, DCM
2 steps, 98%
8
MOMO
3) KOBut, HOBut, r.t., overnight
3 steps, 84%
H
HO
MOMO
H
H
16
14
15
Scheme 3. Construction of the ABC ring framework.

J. Yu, B. Yu / Chinese Chemical Letters 26 (2015) 1331–1335
1335
Scheme 4. Synthesis of the key ABC skeleton intermediate 4.
(b) B. Yu, J. Sun, Current synthesis of triterpene saponins, Chem. Asian J. 4 (2009)
642–654.
4. Conclusion
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binam-prolinamides as organocatalysts for the enantioselective solvent-free
intra- and inter-molecular aldol reaction, Tetrahedron 69 (2013) 1307–1315.
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ligands for the glucocorticoid receptor: receptor binding and in vivo activity,
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a common eastern tricyclic lactone for construction of the nodulisporic acids, Org.
Process Res. Dev. 11 (2007) 19–24.
[7] H. Hisahiro, U. Hisashi, Optically pure (4aS)-(+)- or (4aR)-(À)-1,4a-dimethyl-4,4a,
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In conclusion, we have achieved the synthesis of the key
ABC-fused ring skeleton of the aglycon of Echinoside A (i.e., 4). The
synthesis starts from the (+)-Wieland–Miescher ketone and
requires 16 steps and in 13% overall yield with Robinson
annulation as a key reaction. The availability of this advanced
intermediate would facilitate the synthesis of Echinoside A and the
related saponins from sea cucumbers.
Acknowledgment
This work was financially supported by the Ministry of Science
and Technology of China (No. 2013AA092903).
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