First total synthesis of (±)-celaphanol A

Article abstract of DOI:10.1002/jccs.200200089

The first total synthesis of (±)-Celaphanol A was accomplished starting from α-cyclocitral and 3,4-dimethoxy benzyl chloride in six steps. The intramolecular cyclization with BF₃·Et₂O and enolization in t-BuOK/t-BuOH were the key steps. The process of intramolecular cyclization afforded an all-cis isomer intermediate for synthesis of aromatic tricyclic diterpenes.

Full text of DOI:10.1002/jccs.200200089

Journal of the Chinese Chemical Society, 2002, 49, 581-583
581
First Total Synthesis of (±)-Celaphanol A
Pingyan Bie (
Xuanjia Peng (
), Chenglu Zhang (
), Tongxing Wu (
), Anpai Li (
) and Xinfu Pan* (
),
)
Department of Chemistry, National Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, P. R. China
The first total synthesis of (±)-Celaphanol A was accomplished starting from -cyclocitral and 3,4-
dimethoxy benzyl chloride in six steps. The intramolecular cyclization with BF3·Et2O and enolization in
t-BuOK/t-BuOH were the key steps. The process of intramolecular cyclization afforded an all-cis isomer in-
termediate for synthesis of aromatic tricyclic diterpenes.
Scheme I
INTRODUCTION
Celaphanol A (Fig. 1) is a diterpene isolated from the
OMe
OMe
ii
i
OMe
OMe
stems of Celastrus stephanotifolius,1 which has been the sub-
ject of continued and growing interest, due to the range of bi-
ological activities shown by many members of this family.2
Some have been used in traditional medicine3 or as a stimu-
lant4 from ancient times. In order to study further relation-
ships between the structure and biological activity of the
diterpene compound and as an extension of diterpenoid syn-
thesis in our laboratory,5,6 the synthesis of the title compound
was achieved through the AC-ABC ring construction syn-
thetic strategy. We present here the first total synthesis of
(±)-Celaphanol A by a simple convergent route.
+
CHO
OH
CH2Cl
2
1
3
OMe
OMe
OMe
OMe
OMe
OMe
iv
iii
O
4
O
H
H
O
O
(all-cis)
(all-cis)
6
5
OH
OMe
OH
OMe
vi
v
O
O
OH
RESULTS AND DISCUSSION
OH
(±)-Celaphanol A
7
As shown in Scheme I, -cyclocitral (1) and 3,4-
dimethoxy benzyl chloride (2) were used as the starting mate-
rials. The latter was prepared from readily available vanillin
in three steps. The condensation of 1 and the Grignard re-
agent of 2 in dry diethyl ether in a stream of argon afforded
the desired alcohol (3), which was then oxidized with pyr-
idinium chlorochromate in CH2Cl2 to yield ketone (4). The
Reagents and conditions: (i) Mg, Et2O, reflux, 2 h; (ii) PCC,
CH2Cl2, r.t., 2.5 h; (iii) BF3·Et2O, CH2Cl2, r.t.; (iv) CrO3/HOAc,
r.t., 0.5 h; (v) t-BuOK/t-BuOH, r.t., 2 h; (vi) BBr3, CH2Cl2, 0 C,
0.5 h.
intramolecular cyclization of 4 with BF3·Et2O in CH2Cl2 at
room temperature afforded all-cis isomer (5) in over 93%
1
OH
OH
yield and no trans-isomer was detected from its H NMR
spectrum. The cis-configuration of A/B ring junction in 5 was
characterized specifically by an upfield signal of the C4
methyl group at 0.37 ppm. According to the literature,7 when
A/B ring is a cis junction, the C4 methyl group remains
within the sphere of magnetic influence of aromatic ring C,
the chemical shift of the C4 methyl group appears at about
0.40 ppm. When A/B ring is a trans junction, the C4 methyl
group is deshielded by aromatic ring C, the chemical shift of
O
OH
Celaphanol A
Fig. 1.

582 J. Chin. Chem. Soc., Vol. 49, No. 4, 2002
Bie et al.
C4 methyl group will appear at about 1.00 ppm.
Oxidation of compound 5 with CrO3/HOAc afforded
diketone (6) in good yield. Treatment of 6 with t-BuOK/t-
BuOH afforded compound (7) in 80% yield. Finally, demeth-
ylation of 7 with BBr3 in CH2Cl2 furnished the target mole-
cule (±)-Celaphanol A in 85% yield.
with ether. After the addition of water, the mixture was ex-
tracted with ether and washed with brine and dried over
Na2SO4 and then evaporated in vacuo. The residue was puri-
fied by column chromatography using hexane-ethyl acetate
(15:1) as the eluent, to afford 4 (2.57 g: 85%) as an oil. IR:
1688, 2956 cm-1. 1H NMR (200 MHz, CDCl3): ppm 0.95 (s,
6H), 1.38 (s, 3H), 2.92 (s, 1H), 3.70 (d, 2H), 3.84 (s, 3H), 3.86
(s, 3H), 5.57 (s, 1H), 6.73-6.85 (m, 3H). MS (EI): 302, 151,
123, 81.
In conclusion, in the present work, a simple convergent
synthetic route has been developed for the newly discovered
diterpenoid.
(Cis)-4b,6,7,8,8a,10-Hexahydro-2,3-dimethoxy-4b,8,8-
trimethyl-9(5H)-phenanthrenone (5)
EXPERIMENTAL SECTION
To a solution of ketone 4 (302 mg, 1 mmol) in CH2Cl2
(20 mL) was added BF3·Et2O (0.6 mL) dropwise at room tem-
perature. The mixture was allowed to stand for 24 h at this
temperature and then quenched with aqueous sodium bicar-
bonate. After the usual work-up, the product was purified by
column chromatography on silica gel using hexane-ethyl ace-
tate (12:1) as the eluent, to give 5 (282 mg: 93%) as white
needles. Mp: 128-130 C. IR: 1690, 2924 cm-1. 1H NMR (200
MHz, CDCl3): ppm 0.37 (s, 3H), 0.95 (s, 3H), 1.06 (s, 3H),
1.26-2.49 (m, 6H), 2.09 (s, 1H), 3.55 (dd, 2H), 3.86 (s, 3H),
3.91 (s, 3H), 6.57 (s, 1H), 6.85 (s, 1H). MS (EI): 302, 287,
217, 69.
Melting points were measured on a Kofler apparatus
and are not corrected. IR spectra were recorded on a Nicolet
NEXUS 670 FT-IR spectrometer. Mass spectra were re-
corded on a ZAB-HS spectrometer. Elemental analyses were
1
performed on a Carlo-Erba 1106 instrument. The H NMR
and 13C NMR data were recorded in CDCl3 with Bruker
AM-200 and AM-400 MHz spectrometers. The chemical
shifts are reported in ppm and refer CHCl3 and with TMS as
internal standard. Diethyl ether was freshly distilled over
Na/benzophenone and CH2Cl2 was distilled over CaH2 before
use. Standard flash chromatography was employed to purify
the crude reaction mixture using 200-300 mesh silica gel.
(Cis)-1,2,3,4,4a,10a-Hexahydro-6,7-dimethoxy-1,1,4a-
trimethyl-9,10-phenanthrenedione (6)
3,4-Dimethoxy- -(2,4,4-trimethyl-1-cyclohexen-3-yl)-
benzeneethanol (3)
To a solution of 5 (302 mg, 1 mmol) in acetic acid (5
mL) was added CrO3 (100 mg, 1 mmol) in acetic acid (5 mL).
The mixture was stirred at room temperature for 0.5 h, and
then was quenched with water. After extraction with ether,
the combined organic layer was washed with 10% aqueous
NaHCO3 and brine, dried over Na2SO4 and then evaporated in
vacuo. The crude product was purified by column chroma-
tography using hexane-ethyl acetate (6:1) as the eluent, to
give 6 (285 mg: 90%) as yellow solid. Mp: 199-202 C. IR:
1655, 1711 cm-1. 1H NMR (200 MHz, CDCl3): ppm 0.45 (s,
3H), 0.98 (s, 3H), 1.25 (s, 3H), 1.44-2.55 (m, 6H), 2.68 (s,
1H), 3.96 (s, 3H), 4.03 (s, 3H), 6.87 (s, 1H), 7.60 (s, 1H). MS
(EI): 316, 273, 206, 57.
To the Grignard reagent prepared from compound 2
(9.3 g, 50 mmol) and magnesium powder (1.32 g, 55 mmol)
in dry ether (30 mL) under an argon atmosphere, -cyclo-
citral 1 (7.0 g, 46 mmol) in ether (20 mL) was added. After
refluxing for 2 h, the reaction mixture was stirred at room
temperature for 4 h and then quenched with saturated NH4Cl
aqueous solution. The mixture was extracted with ether and
washed with brine and dried over Na2SO4 and then evapo-
rated in vacuo. The residue was purified by column chroma-
tography using hexane-ethyl acetate (6:1) as the eluent, to af-
ford 3 (11.1 g: 79%) as an oil. IR: 2930, 3579 cm-1. 1H NMR
(200 MHz, CDCl3): ppm 0.79 (s, 3H), 0.85 (s, 3H), 1.83 (s,
3H), 3.78 (s, 3H), 3.82 (s, 3H), 4.05 (m, 1H), 5.65 (s, 1H),
6.70-6.79 (m, 3H). MS (EI): 304, 180, 151, 41.
(±)-2,3,4,4a-Tetrahydro-10-hydroxy-6,7-dimethoxy-1,1,4a-
trimethyl-9(1H)-phenanthrenone (7) (Celaphanol A
Dimethyl Ether)
2-(3,4-Dimethoxyphenyl)-1-(2,4,4-trimethyl-1-cyclohexen-
3-yl)ethanone (4)
To a solution of t-BuOK (4.2 g) in t-BuOH (30 mL), di-
ketone 6 (190 mg, 0.6 mmol) was added slowly. The mixture
was stirred at room temperature for 2 h and poured into 10%
aqueous HCl, then extracted with ether. The combined or-
ganic layer was washed with 10% aqueous NaHCO3 and
Pyridinium chlorochromate (3.23 g, 15 mmol) was
added at 0-5 C to a stirred solution of compound 3 (3.04 g,
10 mmol) in CH2Cl2 (20 mL). The mixture was stirred at
room temperature for an additional 2.5 h and then diluted

First Total Synthesis of (±)-Celaphanol A
J. Chin. Chem. Soc., Vol. 49, No. 4, 2002 583
brine, dried over Na2SO4 and then evaporated to dryness. The
residue was purified by flash column chromatography using
hexane-ethyl acetate (10:1) as the eluent, to afford 7 (153 mg:
80%) as white needles. Mp: 119-121 C. IR: 1596, 1622,
3339 cm-1. 1H NMR (200 MHz, CDCl3): ppm 1.43 (s, 3H),
1.44 (s, 3H), 1.52 (s, 3H), 1.75-2.35 (m, 6H), 3.94 (s, 3H),
3.96 (s, 3H), 6.90 (s, 1H), 7.12 (s, 1H), 7.56 (s, 1H). 13C NMR
(400 MHz, CDCl3): 17.52, 27.57, 28.02, 33.62, 34.69, 35.95,
37.63, 40.54, 56.06, 107.23, 107.28, 120.75, 141.29, 143.67,
147.99, 149.81, 153.56, 179.43. MS (EI): 316, 273, 247, 43.
(Found: C, 72.21; H, 7.59. C19H24O4 requires C, 72.13; H,
7.65%).
38.3, 40.8, 111.8, 112.4, 120.8, 140.6, 143.4, 144.9, 149.8,
151.8, 179.9. MS (EI): 288, 273, 245, 232, 218, 190. (Found:
C, 70.92, H, 6.93. C17H20O4 requires C, 70.81; H, 6.99%).
The above data were consistent with the literature.1
Received December 11, 2001.
Key Words
(±)-Celaphanol A; Diterpene; Total synthesis.
REFERENCES
(±)-Celaphanol A
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in CH2Cl2 (2 mL) was stirred at 0 C for 0.5 h, diluted with
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1.54 (s, 3H), 1.60 (s, 3H), 1.59 (m, 1H), 1.75 (m, 2H), 1.89
(m, 1H), 2.39 (m, 1H), 7.05 (s, 1H), 8.24 (s, 1H). 13C NMR
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