Efficient Synthesis of Jolkinolides A and B from Steviol

Article abstract of DOI:10.1055/s-0034-1378317

Jolkinolides, isolated from Euphorbia fischeriana Steud, are naturally occurring tetracyclic ent-abietane diterpenes, some of which exhibit promising antitumor and other biological activity. An efficient strategy for the synthesis of jolkinolides A and B is described starting from readily available steviol in 10 and 11 steps with total yields of over 10%, respectively.

Full text of DOI:10.1055/s-0034-1378317

2574▌
PAPER
paper
Efficient Synthesis of Jolkinolides A and B from Steviol
Jolkinolides A and B from Steviol
Chang-Zhen Zhu,a Ke Wang,a Meng-han Zhang,a Da-Yong Zhang,*a Yang-Chang Wu,b Xiao-Ming Wu,a Wei-Yi Huaa
a
Center of Drug Discovery, College of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, P. R. of China
Fax +86(25)83271307; E-mail: zhangdayong@cpu.edu.cn
b
Graduate Institute of Pharmaceutical Chemistry, College of Pharmacy, China Medical University, 91 Hsueh-Shih Road, Taichung 40402,
Taiwan
Received: 25.04.2014; Accepted after revision: 23.05.2014
of jolkinolides A and B from an easily available material,
Abstract: Jolkinolides, isolated from Euphorbia fischeriana Steud,
steviol (6).
are naturally occurring tetracyclic ent-abietane diterpenes, some of
which exhibit promising antitumor and other biological activity. An
efficient strategy for the synthesis of jolkinolides A and B is de-
scribed starting from readily available steviol in 10 and 11 steps
with total yields of over 10%, respectively.
Our retrosynthetic analysis is shown in Scheme 1, the con-
struction of γ-ylidenebutenolide moiety was anticipated
from diosphenol 3 through the intramolecular Wittig–
Horner reaction developed by Katsumura et al.5 We envi-
sioned that diosphenol 3 would be available in a single
maneuver via the direct oxygenation of 4, which would be
prepared from 5 through stereoselective epoxidation. In
the structure of steviol (6), the A/B ring is trans fused, at
C4 there are β-methyl and α-carboxy groups, at C10 there
is an α-methyl group, and at C5 and C9 there are β-H,
which almost exactly matches those of our target com-
pounds in the structural framework. Therefore, it is rea-
sonable to assume that the key intermediate tricyclic
enone 5 could be derived from steviol (6), which could be
obtained from commercially available stevioside by a lit-
erature method.6
Key words: ent-abietane diterpenes, jolkinolides, steviol, Wittig–
Horner reaction, antitumor activity
The specific structural features and intriguing biological
activity of natural products have attracted the attention of
researchers. Jolkinolides, isolated from Euphorbia fische-
riana Steud,1 are tetracyclic ent-abietane diterpenes char-
acterized by the γ-ylidenebutenolide functionality in ring
D, some of which exhibit significant antitumor activity
with IC50 values ranging from 7.1 nM to 0.5 μM.2 Jolkin-
olides A (1) and B (2) (Figure 1) are representative com-
pounds of the tetracyclic abietane lactones and exhibit
significant antitumor activity against several tumor cell
lines such as Sarcoma 180 and Ehrlich ascites carcinoma
in mice.3 In human leukemic U937 cells, jolkinolide B
was found to reduce cell viability and induce apoptosis in
a dose- and time-dependent manner through PI3K/Akt
and XIAP pathways.4
O
O
OH
O
O
O
O
H
H
H
H
H
H
O
H
H
O
H
O
H
2
1
3
O
O
16
O
12
O
D
O
OH
11
15
O
H
H
17
O
20
13
14
C
1
9
H
H
2
3
8
A
4
10 B
O
H
H
O
H
H
H
H
O
H
H
7
6
H
19
18
COOH
steviol (6)
5
jolkinolide A (1)
jolkinolide B (2)
4
Figure 1 The structure of jolkinolides A and B
Scheme 1 Retrosynthetic analysis of jolkinolides A and B
Katsumura et al.5 firstly accomplished the total synthesis
of (±)-jolkinolides A, B, and E starting from 10-(meth-
oxycarbonyl)-β-ionone through almost twenty steps,
which gave a low yield of the target products. Herein, we
describe a concise and scalable approach to the synthesis
On the basis of the steviol structure skeleton, we anticipat-
ed a functional group transformation by converting the
C19 carboxy functional group into a methyl group and de-
composition of the D ring to get the key intermediate tri-
cyclic enone 5. Accordingly, the synthetic sequence
commenced with reduction of steviol (6) with lithium alu-
minum hydride to afford the diol 7 in a good yield (90%).
Barton–McCombie radical deoxygenation7 was per-
formed on diol 7 to afford 9 in 74% yield (in 2 steps). Al-
lylic oxidation with tert-butyl hydroperoxide and
selenium dioxide8 gave 10 in 80% yield. Ozone oxidation
SYNTHESIS 2014, 46, 2574–2578
Advanced online publication: 09.07.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378317; Art ID: ss-2014-f0269-op
© Georg Thieme Verlag Stuttgart · New York

PAPER
Jolkinolides A and B from Steviol
2575
of 10 at –78 °C in a Criegee rearrangement9 gave com-
pound 11 directly. Decarboxylation of 11 with lead
tetraacetate in refluxing benzene provided the key inter-
mediate enone 5 in 68% yield10 (Scheme 2).
O
H
O
a
b
H
O
O
H
H
H
4
O
5
OH
OH
OCCH(Me)P(OEt)2
O
OH
O
H
a
b
H
H
H
H
H
d
c
H
O
CH2OH
H
COOH
H
O
H
7
6
12
3
O
OH
O
OH
O
O
O
H
c
d
H
H
H
H
H
H
e
H
O
H
O
CH2OCSSMe
H
H
9
8
2
1
OH
O
O
O
(EtO)2P
f
e
OH
H
H
COOH
H
H
H
13
OH
O
11
Scheme 3 Reagents and conditions: (a) 30% H2O2, 4 M NaOH,
MeOH, r.t., 81%; (b) t-BuOK, O2, t-BuOH, 40 °C, 82%; (c) acid 13,
DCC, DMAP, CH2Cl2, r.t., 88%; (d) 60% NaH, THF, r.t., 84%; (e)
MCPBA, CH2Cl2, r.t., 83%.
10
H
5
H20 [δ = 0.82 (s)], while the proton at δ = 2.28 (s, H9) did
not correlate to H14 (δ = 4.03, s), which revealed that both
the C8–C14 and C11–C12 epoxides are β-orientation,
which is in accordance with literature reports.11
Scheme 2 Reagents and conditions: (a) LiAlH4, THF, reflux, 90%;
(b) NaH, CS2, MeI, THF, 89%; (c) Bu3SnH, AIBN, toluene, reflux,
83%; (d) SeO2, t-BuOOH, THF, r.t., 80%; (e) O3, MeOH, –78 °C,
69%; (f) Pb(OAc)4, Cu(OAc)2, pyridine, benzene, reflux, 68%.
O
H
9
H
9
H
11
H
With a sufficient supply of the key intermediate 5, we pro-
ceeded to prepare the advanced intermediate epoxy ke-
tone 4 with hydrogen peroxide in good yield (81%).
Alternatively, treatment of epoxy ketone 4 with a large ex-
cess of potassium tert-butoxide under air at room tem-
perature directly gave diosphenol 3 in 82% yield.
Esterification of diosphenol 3 with 2-(diethoxyphosphor-
yl)propanoic acid (13) in the presence of 4-(dimethylami-
no)pyridine and N,N′-dicyclohexylcarbodiimide provided
12; treatment of 12 with 60% sodium hydride in anhy-
drous tetrahydrofuran provided jolkinolide A (1). The
synthesis of jolkinolide B (2) was completed by treatment
of jolkinolide A (1) with 3-chloroperoxybenzoic acid in
dichloromethane in 83% yield5 (Scheme 3).
H
H
H
H
11 O
O
O
O
3
3
14
14
5
5
H3C
O
H3C
18
O
CH3
CH3
20
H
H
20
CH3
CH3
19
jolkinolide A (1)
jolkinolide B (2)
Figure 2 Key NOESY correlations of jolkinolides A and B
The cytotoxic activities12 of the synthetic jolkinolides A
and B were tested in vitro against five human cancer lines,
which contained human breast cancer cell line (MDA-
MB-231), human breast cancer cell line (MCF-7), human
bladder cancer cell line (T24), human bladder cancer cell
line (J82), and human bladder cancer cell line (NTUB1).
The results showed that jolkinolide B had medium anti-
proliferative activity with IC50 values ranging from 10.1
μM to 81.0 μM and its cytotoxicity against five kinds of
cell lines was better than that of jolkinolide A (Table 1).
In the identification of jolkinolide A by its NOESY spec-
trum (Figure 2), the β-orientation of H9 [δ = 2.64 (d, J =
5.2 Hz)] was supported by the NOESY spectrum, in
which H9 did not correlate with H20 [δ = 0.73 (s)], but
correlated with H5 [δ = 1.19 (m)]. Since H14 did not cor-
relate with H9 [δ = 2.64 (d, J = 5.2 Hz)], this confirmed
that the epoxy ring of jolkinolide A is β-orientation. The
relative configuration of jolkinolide B was also estab-
lished on the basis of a NOESY experiment. The protons
at δ = 4.03 (s, H14) and at δ = 3.67 (s, H11) correlated to
In summary, a concise and scalable approach for the syn-
thesis of jolkinolides A and B has been developed starting
from an easily available material in 10 and 11 steps with
total yields over 10%, respectively. This will give a versa-
tile access to various jolkinolides derivatives and related
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2574–2578

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C.-Z. Zhu et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 4.98 (s, 1 H), 4.82 (s, 1 H), 4.76–
4.76 (d, J = 11.1 Hz, 1 H), 4.41–4.38 (d, J = 10.9 Hz, 1 H), 2.56 (s,
3 H), 2.18–2.10 (m, 3 H), 1.88–1.81 (m, 5 H), 1.77–1.73 (m, 3 H),
1.63–1.42 (m, 9 H), 1.26–1.22 (d, J = 9.5 Hz, 1 H), 1.01 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 216.0, 155.9, 103.0, 80.2, 77.4,
56.8, 54.7, 47.4, 46.9, 41.6, 41.5, 40.1, 39.2, 38.9, 37.7, 36.4, 27.8,
20.4, 20.2, 18.8, 18.2, 17.8.
Table 1 In Vitroa Cytotoxicity Data of Jolkinolides A and B
Antitumor activity in 48 h (IC50 μM)b
MDA-MB-231 MCF-7 T24 J82
Compound
NTUB1
jolkinolide A 90.96
jolkinolide B 12.00
43.02
70.50
37.75 78.81 88.43
10.11 81.02 23.00
MS (ESI): m/z = 417 [M + Na]+.
a Inhibition of cell growth by the listed compounds was determined
using MTT assay.
HRMS: m/z [M + Na]+ calcd for C22H34O2S2Na: 417.1898; found:
417.1907.
b Data represents the mean value of three independent determinations.
ent-13-Hydroxykaur-16-ene (9)
To a solution of 8 (2.30 g, 5.83 mmol) in toluene (50 mL) was added
a catalytic amount of AIBN (0.30 g, 1.81 mmol). The mixture was
purged with N2 for 15 min, then Bu3SnH (3.70 mL, 13.35 mmol)
was added over 3 h via syringe pump with stirring at 90–110 °C.
The mixture was cooled to r.t., sat. NaF solution was added and the
mixture was stirred overnight and then extracted with EtOAc. The
combined organic layers were washed with brine, dried (anhyd
Na2SO4), filtered, and evaporated to dryness to give a residue that
was purified by flash chromatography (silica gel, PE–EtOAc, 15:1)
to give 9 (1.40 g, 4.85 mmol, 83%) as a white amorphous solid; mp
117–119 °C.
diterpenoids that are biologically active with pharmaceu-
tical potential as antitumor and anti-inflammatory agents.
Further structural modification and biological evaluation
are ongoing, and the results will be reported in due course.
1H and 13C NMR spectra were recorded at 300 MHz and 75 MHz,
respectively, relative to internal TMS standard. LRMS and HRMS
were recorded in ESI mode. IR spectra were recorded either on neat
samples (KBr disks) or as thin films. The melting points of the com-
pounds were measured on a Kofler-type Reichert Thermovar micro
hot stage microscope and were uncorrected. Petroleum ether (PE)
used was the fraction boiling in the 30–60 °C range.
IR (KBr): 3111, 2994, 2946, 2992, 2846, 2842, 2360, 2354, 1400,
1367, 1112, 1088, 877 cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.98 (s, 1 H), 4.82 (s, 1 H), 2.19–
2.11 (m, 3 H), 1.85–1.76 (m, 3 H), 1.66–1.65 (m, 2 H), 1.62–1.59
(m, 2 H), 1.58–1.49 (m, 6 H), 1.45–1.42 (m, 2 H), 1.39–1.30 (m, 2
H), 1.28–1.13 (m, 7 H), 1.03 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 156.3, 102.7, 80.4, 56.2, 54.7, 47.6,
47.1, 42.0, 41.7, 41.3, 40.3, 39.4, 39.1, 33.6, 33.3, 23.4, 21.2, 20.2,
18.6, 17.5.
ent-Kaur-16-en-13,19-diol (7)
To a suspension of LiAlH4 (6.70 g, 176.64 mmol) in anhyd THF
was added dropwise a solution of steviol (6, 22.50 g, 70.65 mmol)
in anhyd THF at 0 °C. The mixture was heated to reflux for 6 h, then
quenched with sat. NH4Cl solution, and extracted with EtOAc. The
combined organic layers were washed with brine, dried (anhyd
Na2SO4), filtered, and evaporated to dryness to give a residue that
was purified by flash chromatography (silica gel, PE–EtOAc, 2:1)
to give 7 (19.40 g, 63.72 mmol, 90%) as a white amorphous solid;
mp 231–233 °C.
MS (ESI): m/z = 311 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C20H32ONa: 311.2351; found:
311.2358.
IR (KBr): 3418, 3110, 3002, 1661, 1400, 1275, 1071, 764, 750, 570
cm–1.
ent-Kaur-16-ene-13,15-diol (10)
To a solution of 9 (2.60 g, 9.01 mmol) in THF (30 mL) were added
SeO2 (0.60 g, 5.41 mmol) and t-BuOOH (1 mL) and the mixture
was stirred at r.t. for 12 h. The mixture was diluted with water and
extracted with EtOAc. The combined organic layers were washed
with brine, dried (anhyd Na2SO4), filtered, and evaporated to dry-
ness to give a residue that was purified by flash chromatography
(silica gel, PE–EtOAc, 2:1) to give 10 (2.20 g, 7.23 mmol, 80%) as
a white amorphous solid; mp 244–246 °C.
1H NMR (300 MHz, DMSO-d6): δ = 4.86 (s, 1 H), 4.66 (s, 1 H), 3.50
(m, 1 H), 3.31 (m, 1 H), 2.48 (s, 2 H), 2.01 (s, 2 H), 1.89–1.85 (d,
J = 10.74 Hz, 1 H), 1.75–1.62 (m, 4 H), 1.57–1.21 (m, 7 H), 1.14–
1.10 (d, J = 10.83 Hz, 1 H), 0.92 (s, 3 H), 0.89–0.85 (m, 5 H), 0.82
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 156.7, 102.8, 79.1, 63.1, 56.8, 54.8,
47.8, 46.6, 43.0, 42.0, 41.5, 40.8, 39.7, 35.7, 28.0, 20.4, 20.2, 18.3,
18.2, 13.4.
IR (KBr): 3551, 3474, 3227, 3115, 2932, 1370, 1363, 1004, 562 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.30 (s, 1 H), 5.26 (s, 1 H), 3.82
(s, 1 H), 2.10–2.06 (d, J = 11.1 Hz, 1 H), 1.88–1.76 (m, 4 H), 1.75–
1.49 (m, 5 H), 1.44–1.37 (m, 4 H), 1.31–1.25 (m, 3 H), 1.18–1.11
(m, 2 H), 1.02 (s, 3 H), 0.95–0.92 (m, 1 H), 0.87 (s, 3 H), 0.82 (s, 3
H).
13C NMR (75 MHz, CDCl3): δ = 161.6, 107.1, 80.8, 78.1, 56.2, 53.5,
45.6, 43.4, 42.0, 40.8, 40.5, 39.1, 35.5, 33.9, 33.3, 21.9, 19.9, 19.5,
18.6, 17.8.
MS (ESI): m/z = 327 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C20H32O2Na: 327.2300; found:
327.2309.
(ent-13-Hydroxykaur-16-en-19-oxy)methyl Xanthate (8)
To a solution of 7 (2.00 g, 6.57 mmol) in THF (10 mL) was added
60% NaH (0.47 g, 19.71 mmol) with stirring at 0 °C. The mixture
was heated to reflux for 2 h, then cooled to r.t., CS2 (0.44 mL, 7.23
mmol) was added and the mixture was heated to reflux for 1 h. After
cooling to r.t., MeI (0.44 mL, 7.23 mmol) was added, the mixture
was stirred at r.t. for 1 h, quenched with sat. NH4Cl solution, and ex-
tracted with EtOAc. The combined organic layers were washed
with brine, dried (anhyd Na2SO4), concentrated, and then purified
by chromatography (silica gel, PE–EtOAc, 10:1) to give 8 (2.30 g,
5.83 mmol, 89%) as a white amorphous solid; mp 103–105 °C.
MS (ESI): m/z = 327 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C20H32O2Na: 327.2300; found:
327.2308.
ent-8-Carboxy-13-oxopodocarpane (11)
A solution of 10 (1.50 g, 4.96 mmol) in MeOH (20 mL) was sub-
jected to O3 for 2 h and then Et3N (1.35 mL) was added at –78 °C.
The mixture was stirred and allowed to warm to r.t. over 3 h and
then neutralized with 10% HCl and extracted with EtOAc. The
combined organic layers were washed with brine, dried (anhyd
Na2SO4), filtered, and evaporated to dryness to give a residue that
IR (KBr): 3470, 3302, 2982, 2925, 2849, 2359, 1708, 1695, 1444,
1230, 1070, 1057, 960, 874, 749 cm–1.
Synthesis 2014, 46, 2574–2578
© Georg Thieme Verlag Stuttgart · New York

PAPER
Jolkinolides A and B from Steviol
2577
was purified by flash chromatography (silica gel, PE–EtOAc, 2:1)
to give 11 (1.00 g, 3.42 mmol, 69%) as a white amorphous solid; mp
145–147 °C.
IR (KBr): 3553, 3110, 2967, 1734, 1616, 1399, 1071, 986, 623 cm–1.
to give 3 (0.26 g, 0.94 mmol, 82%) as a white amorphous solid;
mp185–187 °C.
IR (KBr): 3563, 3006, 2920, 2849, 1767, 1698, 1275, 1260, 1204,
1122, 756, 749 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.63–2.59 (d, J = 11.3 Hz, 1 H),
2.04–1.95 (m, 1 H), 1.90–1.58 (m, 5 H), 1.47–1.39 (m, 3 H), 1.36–
1.25 (m, 6 H), 1.16–0.92 (m, 5 H), 0.87 (s, 3 H), 0.82 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 200.3, 165.5, 125.2, 54.0, 51.6,
41.9, 39.5, 39.0, 36.5, 35.4, 33.8, 33.4, 22.4, 22.0, 20.1, 18.7, 15.4.
MS (ESI): m/z = 315 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C18H28O3Na: 315.1936; found:
1H NMR (300 MHz, CDCl3): δ = 5.76 (s, 1 H), 3.37 (s, 1 H), 2.63
(d, J = 5.0 Hz, 1 H), 2.11–2.07 (m, 1 H), 1.87–1.80 (m, 1 H), 1.73–
1.68 (m, 1 H), 1.57–1.45 (m, 6 H), 1.32–1.15 (m, 3 H), 0.94 (s, 3 H),
0.87 (s, 3 H), 0.73 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 189.4, 145.1, 110.2, 63.2, 53.6,
52.7, 41.5, 41.3, 39.7, 33.5, 32.8, 29.7, 21.8, 20.8, 20.3, 18.3, 14.5.
MS (ESI): m/z = 277 [M + H]+.
HRMS: m/z [M – H]+ calcd for C17H23O3: 275.1647; found:
315.1941.
275.1655.
ent-Podocarp-8(14)-en-13-one (5)
To a solution of 11 (0.70 g, 2.39 mmol) in benzene (10 mL) were
added Cu(OAc)2 (0.14 g, 0.72 mmol), pyridine (1.44 mL, 18.81
mmol), and Pb(OAc)4 (1.27 g, 2.87 mmol). The mixture was purged
with N2 for 15 min, it was stirred in the dark for 1 h and then heated
to reflux for 6 h, 10% HCl was added, and the mixture was extracted
with EtOAc. The combined organic layers were washed with brine,
dried (anhyd Na2SO4), and evaporated to dryness to give a residue
that was purified by flash chromatography (silica gel, PE–EtOAc,
10:1) to give 5 (0.40 g, 1.62 mmol, 68%) as a colorless oil liquid.
Jolkinolide A (1)
To a solution of 3 (0.20 g, 0.72 mmol) and acid 13 (0.30 g, 1.59
mmol) in CH2Cl2 (10 mL) were added DCC (0.74 g, 3.62 mmol)
and DMAP (0.09 g, 0.71 mmol) and the mixture was stirred at r.t.
for 10 h. The majority of the solvent was evaporated from the mix-
ture was evaporated, the residue was dissolved with EtOAc, fil-
tered, washed with 1 M HCl and NaHCO3, and evaporated to
dryness to give a residue that was purified by flash chromatography
(silica gel, PE–EtOAc, 3:1) to give 12 (0.30 g, 0.64 mmol, 88%) as
an oil liquid.
IR (KBr): 3320, 2923, 1678, 1596, 1463, 1384, 1283, 924, 893, 731
cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.88 (s, 1 H), 2.51 (d, J = 15.3 Hz,
1 H), 2.41 (d, J = 15.2 Hz, 1 H), 2.31–2.10 (m, 2 H), 2.04–1.92 (m,
3 H), 1.76–1.70 (m, 2 H), 1.62–1.39 (m, 4 H), 1.28–1.06 (m, 3 H),
0.93 (s, 3 H), 0.88 (s, 3 H), 0.82 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 200.3, 165.5, 125.2, 54.0, 51.6,
41.9, 39.5, 39.0, 36.5, 35.4, 33.7, 33.4, 22.4, 22.0, 20.1, 18.7, 15.4.
MS (ESI): m/z = 269 [M + Na]+.
To a stirred solution of 12 (0.23 g, 0.49 mmol) in anhyd THF at 0
°C was added 60% NaH (0.20 g, 4.91 mmol). When the addition
was complete, the mixture was warmed to r.t. for 3 h, then quenched
with sat. NH4Cl solution, and extracted with EtOAc. The combined
organic layers were washed with brine, dried (anhyd Na2SO4), fil-
tered, and evaporated to dryness to give a residue that was purified
by flash chromatography (silica gel, PE–EtOAc, 15:1) to give
jolkinolide A (1) (0.13 g, 0.41 mmol, 84%) as a white amorphous
solid; mp 218–219 °C [Lit.5 mp 202–203 °C; Lit.11c mp ~220 °C
20
25
(dec.)]; [α]D +78 (c 0.05, CHCl3) {Lit.11c [α]D +130 (c 0.7,
HRMS: m/z [M]+ calcd for C17H26O: 246.1984; found: 246.1987.
CHCl3)}.
ent-8β,14β-Epoxy-13-podocarpanone (4)
IR (KBr): 3353, 2922, 2851, 1764, 1289, 1248, 781, 748 cm–1.
To a solution of 5 (1.50 g, 6.09 mmol) in MeOH (20 mL) were add-
ed dropwise 4 M NaOH (4.50 mL) and 30% H2O2 (4.50 mL) with
stirring at 0 °C. The mixture was stirred at r.t. for 8 h, the majority
of the solvent was evaporated, and then 10% HCl (10 mL) was add-
ed and the mixture was extracted with EtOAc. The combined organ-
ic layers were washed with sat. Na2SO3 solution and brine, dried
(anhyd Na2SO4), filtered, and evaporated to dryness to give a resi-
due that was purified by flash chromatography (silica gel, PE–
EtOAc, 20:1) to give 4 (1.30 g, 4.95 mmol, 81%) as a white amor-
phous solid; mp 98–101 °C.
1H NMR (300 MHz, CDCl3): δ = 5.47 (d, J = 5.3 Hz, 1 H), 3.70 (s,
1 H), 2.64 (d, J = 5.2 Hz, 1 H), 2.13 (m, 1 H), 2.08 (s, 3 H), 1.82–
1.76 (m, 1 H), 1.72–1.66 (m, 1 H), 1.65–1.19 (m, 8 H), 0.97 (s, 3 H),
0.87 (s, 3 H), 0.73 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.5, 147.5, 144.9, 125.2, 103.9,
61.1, 54.4, 53.5, 51.8, 41.5, 41.3, 39.8, 34.1, 33.5, 33.4, 21.8, 20.8,
18.4, 14.4, 8.5.
MS (ESI): m/z = 315 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C20H26O3Na: 337.1780; found:
IR (KBr): 3383, 2948, 2923, 1699, 1673, 1595, 1384, 1258, 763,
750 cm–1.
337.1788.
1H NMR (300 MHz, CDCl3): δ = 3.17 (s, 1 H), 2.41–2.37 (m, 1 H),
2.27–2.15 (m, 3 H), 2.08–1.87 (m, 4 H), 1.87–1.76 (m, 3 H), 1.73–
1.51 (m, 5 H), 0.90 (s, 3 H), 0.83 (s, 3 H), 0.81 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 208.9, 67.2, 63.7, 54.4, 48.3, 41.8,
39.8, 39.7, 35.1, 33.8, 33.7, 33.2, 21.7, 21.4, 18.5, 16.7, 16.1.
MS (ESI): m/z = 263 [M + H]+.
HRMS: m/z [M + Na]+ calcd for C17H26O2Na: 285.1831; found:
Jolkinolide B (2)
To a solution of jolkinolide A (1) (23mg, 73 μmol) in CH2Cl2 (3
mL) was added MCPBA (50 mg, 292 μmol). The mixture was
stirred at r.t. for 30 h, then ice water was added and the mixture was
extracted with EtOAc. The combined organic layers were washed
with brine, dried (anhyd Na2SO4), filtered, and evaporated to dry-
ness to give a residue that was purified by flash chromatography
(silica gel, PE–EtOAc, 5:1) to give jolkinolide B (2) (20 mg, 61
μmol, 83%) as a white amorphous solid; mp 216–217 °C [Lit.5 mp
221–222 °C; Lit.11c mp ~215 °C (dec.)]; [α]D25 +240 (c 0.03, CHCl3)
{Lit.11c [α]D25 +220 (c 0.4, CHCl3)}.
285.1837.
ent-8β,14β-Epoxy-12-hydroxypodocarp-11(12)-en-13-one (3)
O2 was bubbled into a mixture of 4 (0.30 g, 1.14 mmol) and t-BuOK
(0.46 g, 4.18 mmol) in anhyd t-BuOH (10 mL). The mixture was
stirred at 40 °C for 40 min, then the majority of the solvent was
evaporated, 10% HCl was added and the mixture was extracted with
EtOAc. The combined organic layers were washed with brine, dried
(anhyd Na2SO4), and evaporated to dryness to give a residue that
was purified by flash chromatography (silica gel, PE–EtOAc, 15:1)
IR (KBr): 3359, 2967, 2924, 1777, 1595, 1275, 1260, 764, 747, 750
cm–1.
1H NMR (300 MHz, CDCl3): δ = 4.03 (s, 1 H), 3.67 (s, 1 H), 2.28
(s, 1 H), 2.08 (s, 3 H), 2.01–1.92 (m, 3 H), 1.83–1.10 (m, 8 H), 0.92
(s, 3 H), 0.88 (s, 3 H), 0.82 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 2574–2578

2578
C.-Z. Zhu et al.
PAPER
13C NMR (75 MHz, CDCl3): δ = 169.5, 148.6, 130.2, 85.2, 66.0,
60.9, 55.3, 53.5, 48.0, 41.3, 39.1, 35.6, 34.6, 33.5, 33.1, 21.9, 20.9,
18.4, 15.4, 8.7.
MS (ESI): m/z = 353 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C20H26O4Na: 353.1729; found:
(6) Ogawa, T.; Nozaki, M.; Matsui, M. Tetrahedron 1980, 36,
2641.
(7) Barton, D. H. R.; Motherwell, W. B.; Stange, A. Synthesis
1981, 743.
(8) Coxon, J. M.; Dansted, E.; Hartshorn, M. P. Org. Synth.
1988, 6, 946.
(9) Bailey, P. S. Chem. Rev. 1958, 58, 925.
353.1737.
(10) (a) McMurry, J. E.; Blaszczak, L. C. J. Org. Chem. 1974, 39,
2217. (b) Schultz, A. G.; Wang, A. J. Org. Chem. 1996, 61,
4857.
Acknowledgment
(11) (a) Hoet, P.; Landa, M.; Rivera, M.; Meerssche, V.;
Germain, G.; Declercq, J. P. Bull. Soc. Chim. Belg. 1980, 89,
385. (b) Pan, Q.; Shi, M. F.; Min, Z. D. J. China Pharm.
Univ. 2004, 35, 16. (c) Uemura, D.; Hirata, Y. Tetrahedron
Lett. 1972, 13, 1387.
We thank the National Natural Science Foundation of China (No.
30973607 and No. 81172934).
References
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provided by Prof. Yangchang Wu research group (China
Medical University) and maintained in a humidified
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MTT solution (0.5 mg/mL) was added and incubated for 1 h.
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Synthesis 2014, 46, 2574–2578
© Georg Thieme Verlag Stuttgart · New York