A concise total synthesis of (±)-acutifolone A

Article abstract of DOI:10.1039/b905910e

Starting from 4-methylcyclohexanone (7), a concise total synthesis of the pinguisane-type sesquiterpenoid acutifolone A, in racemic form, has been accomplished in 14 steps with an overall yield of 14.5%. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b905910e

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A concise total synthesis of ( )-acutifolone A†
Ming-Tsang Hsieh,a,c Hsing-Jang Liu,*a Tai Wei Lyb and Kak-Shan Shia*c
Received 24th March 2009, Accepted 21st May 2009
First published as an Advance Article on the web 19th June 2009
DOI: 10.1039/b905910e
Starting from 4-methylcyclohexanone (7), a concise total synthesis of the pinguisane-type
sesquiterpenoid acutifolone A, in racemic form, has been accomplished in 14 steps with an overall yield
of 14.5%.
reaction whereby keto ester 3 successfully furnished keto ester 4
Introduction
(84%) in the presence of palladium acetate (Scheme 1, Eq. 2).
Encouraged by this result, we embarked on the total synthesis of
acutifolone A (1), culminating in the second total synthesis of this
structurally complex natural product.
Pinguisane-type sesquiterpenoids1 possess an intriguing arrange-
ment of several contiguously cis-oriented substituents along the
perhydroindane core. Additionally, their carbon skeleton appears
to be inconsistent with the isoprene rule, while biologically this
family of natural products has been shown to possess a wide
variety of interesting and/or medically relevant activities including
piscicidal, antineoplastic, and microbicidal properties.2,3 These
aforementioned factors make them attractive targets for total
synthesis, of which several have been documented.4,5
Scheme
1
Palladium(II) acetate mediated methylenecyclopentane
annulation process.
Results and discussion
In 1998 and 2000, Asakawa and co-workers reported the
structural elucidation of acutifolones A (1)6 and B (2)7 as members
of the pinguisane family of natural products as isolated from the
ether extracts of the Japanese liverwort Porella acutifolia subsp.
tosana.8 Recently, Nishiyama et al. reported the first total synthesis
of acutifolone A in racemic form via a sequence involving more
than thirty synthetic operations which also served to corroborate
the structural assignments of Asakawa.5
Several years ago, our laboratories developed a novel approach
to bicyclic systems9 containing a cyclopentane ring appended with
a methylene moiety (Scheme 1, Eq. 1). We extrapolated that the
same process, with minor modifications to the starting substrate,
would provide not only an effective route towards the bicyclo[4.3.0]
core present in pinguisane sesquiterpenoids, but also allow for the
establishment of the required cis-ring junction of these natural
products in one step. This supposition was realized by a model
Our retrosynthetic strategy is outlined in Scheme 2. Target
molecule 1 is anticipated to be derived from advanced intermediate
5, the synthesis of which should be achieved from keto ester
6 via the aforementioned cyclopentene annulation followed by
hydrogenation. The required keto ester 6 is projected to be readily
prepared from 4-methylcyclohexanone (7) via a synthetic sequence
of carbomethoxylation followed by two individual Michael addi-
tion reactions. Since the vicinal methyl groups need to be cis-
oriented, the two Michael addition reactions would involve the
addition of the methyl group first, followed by the 1-butenyl group.
We surmised that this particular order of addition would lead to
the desired stereochemical outcome as the methyl group on C-4
would serve to persuade the incoming 1-butenyl anion to attack
from the face opposite to itself.
aDepartment of Chemistry, National Tsing Hua University, Hsinchu, Taiwan
30013, R.O.C
bAxikin Pharmaceuticals, Inc., 10835 Road to the Cure, Suite 250, San
Diego, CA 92121, USA
cDivision of Biotechnology and Pharmaceutical Research, National Health
Research Institutes, Miaoli County 35053, Taiwan, R.O.C. E-mail:
ksshia@nhri.org.tw; Fax: +886-37-586456; Tel: +886-37-246166 ext:35709
Scheme 2 The retrosynthetic analysis of 1.
† Electronic supplementary information (ESI) available: 1H and 13C spectra
for all new compounds and an X-ray crystallographical picture of 5a.13
CCDC reference number 706353. For ESI and crystallographic data in
CIF or other electronic format see DOI: 10.1039/b905910e
The synthesis of the annulation precursor 6 began with the
4-methylcyclohexanone (7) which was carbomethoxylated in the
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Table 1 Palladium(II) mediated annulation process of 6 under various
presence of dimethyl carbonate and sodium hydride to furnish
keto ester 8 (Scheme 3). Intermediate 8 thus obtained was treated
with phenylselenyl chloride in the presence of pyridine followed
by oxidative elimination with hydrogen peroxide at 0 ◦C10 to yield
enone ester 9 which in turn, without purification,11 underwent
the first 1,4-conjugate addition with freshly prepared lithium
dimethylcuprate to afford the desired keto ester 10 in 77% yield
over three steps. Subsequently, compound 10 was transformed
to enone 11 in 91% overall yield using the same process as that
utilized to oxidize ketone 8 to enone 9. Exposure of enone ester 11
to the magnesium organocuprate freshly generated from 4-bromo-
1-butene, magnesium turnings and cuprous iodide, provided keto
ester 6 in 76% yield. Even though all the spectroscopic evidence
for 6 was in agreement with the proposed structure, the critical
issue of relative stereochemistry between all the appendages
could not be unequivocally established due to facile keto–enol
tautomerization. The indicated stereochemistry followed from the
subsequent transformations (vide infra).
reaction conditions
Yield (%)
Entry Conditions
Time 12
13
1
2
3
4
5
6
7
1.0 eq. Pd(OAc)2, THF, rt
3 h 25
5 h 22
8 h 19
10 h 22
16 h 30
32
28
29
43
54
39
41
1.0 eq. Pd(OAc)2, DMSO, rt
1.0 eq. Pd(OAc)2, THF, rt
1.2 eq. Pd(OAc)2, THF, rt
1.4 eq. Pd(OAc)2, THF, rt
1.0 eq. Cu(OAc)2, 0.1 eq. Pd(OAc)2, THF, rt 60 h 11
1.5 eq. Cu(OAc)2, 0.25 eq. Pd(OAc)2, THF, rt 52 h 16
Scheme 4 Reagents and conditions: (i) Pd(OAc)2 (1.4 equiv.), THF, rt,
16 h, 84%, (12/13 = 0.56); (ii) H2, 10% Pd/C, MeOH, rt, 90%.
13, individually, over a catalytic amount of 10% Pd/C furnished
keto ester 5 as a mixture consisting predominantly of the product
with the desired stereochemistry, contaminated with a trace of
the undesired b-isomer.12 Interestingly, it was observed that even
though both olefins 12 and 13 furnished the reduced product 5
in excellent yield, there was a remarkable difference in reaction
rate with ketone 12 being reduced much faster than ketone
13. The relative stereochemistry of the major component of 5
was confirmed by the single crystal X-ray crystallography of its
corresponding 2,4-DNP derivative 5a (Fig. 1).13 This experiment
not only served to confirm the stereochemical outcome of the
hydrogenation reaction, but also validated our design of the
sequence of the double Michael addition reactions (vide supra).
With the desired stereochemistry of keto ester 5 established,
we approached the concluding phase of the total synthesis of
target 1. Although keto ester 5 was an advanced intermediate
in the only previously reported total synthesis of acutifolone A,5b,c
we were of the belief that a more concise sequence of events
could be experimentally realized to convert keto ester 5 into 1.
A key operation in this would be to identify a short process for
installation of an a,b-unsaturated enone system into keto ester 5.
Towards this end, the corresponding trimethylsilyl enol ether of
ketone 5 obtained under standard conditions14 was oxidized by
Pd(OAc)2 in refluxing acetonitrile15 to furnish the desired enone
14 in 67% yield over two steps (Scheme 5). Subsequent treatment
Scheme 3 Reagents and conditions: (i) NaH, CO(OMe)2, THF, reflux, 2 h,
87%; (ii) PhSeCl, pyridine, CH2Cl2, 0 oC, 1 h then 30% H2O2, 0 oC, 8 min;
(iii) MeLi, CuI, THF, -78 oC, 30 min, 77% over three steps; (iv) PhSeCl,
pyridine, CH2Cl2, rt, 3 h then 30% H2O2, 0 ◦C, 10 min, 91% over two steps;
(v) 3-butenylmagnesium bromide, CuI, THF/Me2S (20:1), -78 oC, 30 min,
76%.
With the synthetic sequence towards the annulation precursor
6 mapped out and achieved, we were ready to tackle the key
transformation in our retrosynthetic strategy towards acutifolone
A. Initial attempts at the annulation reaction using previously
established reaction conditions (1.0 equiv. Pd(OAc)2, THF, rt)
yielded unspectacular results. Gratifyingly, after a brief investi-
gation into this reaction during which various parameters such as
reagents, solvents, additives (Cu(OAc)2 or K2CO3), and time were
systematically varied, we arrived at a satisfactory set of reaction
conditions (Table 1, Entry 5) to achieve this key annulation process.
Although the annulation process identified furnished a mixture
of product 12 and its isomer 13, these were readily separated
and both are amenable for our total synthesis of acutifolone
A. As indicated in Scheme 4, hydrogenation of ketones 12 and
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to demonstrate the utility of our previously developed annulation
reaction as an efficient approach to the indanyl systems highly
prevalent in nature.
Experimental
General
All reactions were performed under an atmosphere of argon or
nitrogen unless otherwise stated. All solvents were dried prior to
use and reagents were employed as received. Analytical thin layer
chromatography was performed on SiO2 60 F-254 plates and flash
column chromatography was carried out using SiO2 60 (particle
size 0.040–0.055 mm, 230–400 mesh), both of which are available
from E. Merck. Visualization was performed under UV irradiation
at 254 nm followed by staining with vanillin (60 g of vanillin in 1 L
of 95% ethanol containing 10 mL of conc. H2SO4) and charring by
heat gun. Fourier transform infrared spectra (IR) were recorded on
Bomen MR-100 and expressed in cm-1. 1H and 13C NMR spectra
were recorded on Bruker Avance EX 400 FT NMR or Bruker
DMX-600. Chloroform-d was used as the solvent and TMS (d =
0.00 ppm) as an internal standard. Chemical shifts are reported as
d values in ppm as referenced to TMS. Multiplicities are recorded
as s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet),
sext (sextet), sept (septet), dd (doublet of doublet), dt (doublet of
triplet), br (broadened), m (multiplet). Coupling constants (J) are
expressed in Hz. HRMS were measured by JEOL JMS-HX110
spectrometer and spectral data were recorded as m/z values.
Fig. 1 The X-ray crystal structure of 5a (thermal ellipsoids are shown at
50% probability).
5-Methyl-2-oxocyclohexanecarboxylic acid methyl ester (8). To
a stirred suspension of sodium hydride (60%, 3.42 g, 85.58 mmol)
in dimethyl carbonate (50 mL, 597.36 mmol) at room temperature
was added 4-methylcyclohexanone (6.00 g, 53.49 mmol) in
dimethyl carbonate (5 mL, 59.74 mmol) dropwise. The reaction
mixture was heated to reflux for 2 h and then cooled to 0 ◦C.
2 N HCl (30 mL) was added cautiously to quench the reaction.
The aqueous layer was separated and extracted with diethyl ether
(3 ¥ 50 mL). The combined organic extracts were washed with
brine, dried over MgSO4, filtered and concentrated to give the
crude product, which was purified by flash chromatography on
silica gel with EtOAc/n-hexane (1:10) to afford compound 8
(7.92 g, 87% yield) as a colorless oil: IR (CH2Cl2, cast) nmax 2925,
Scheme 5 Reagents and conditions: (i) LHMDS, THF, -78 oC, 15 min
then Me3SiCl, 3 h; (ii) Pd(OAc)2, CH3CN, reflux, 50 h, 67% over two
steps; (iii) vinylmagnesium bromide, CuI, THF/Me2S (20:1), -78 oC to
oC, 2 h, 87%; (iv) LHMDS, THF, -78 oC, 15 min then Me3SiCl, 3 h;
1
2854, 1734, 1669, 1625 cm-1; H NMR (CDCl3, 400 MHz): d
0
(v) Pd(OAc)2, CH3CN, reflux, 52 h, 66% over two steps.
12.10 (br s, 1H), d 3.71 (s, 3H), 2.36–2.26 (m, 4H), 1.75–1.69 (m,
3H), 1.65–1.61 (m, 2H), 1.28–1.22 (m, 2H), 1.01–0.90 (m, 4H); 13
C
of enone 14 with the magnesium organocuprate reagent, readily
prepared by the addition of vinylmagnesium bromide to a mixt◦ure
of cuprous iodide and dimethyl sulfide (cat.) in THF at -78 C,
gave Michael adduct 15 in good yield (87%). Finally, following
the same protocol for the transformation of ketone 5 to enone 14,
acutofolone A was achieved from enone 15 in 66% yield over two
steps, the spectroscopic results of which were found to be identical
to those reported in the literature.5b,c,6
NMR (CDCl3, 100 MHz): d 172.9 (C), 171.9 (C), 97.0 (C), 51.3
(CH2), 30.7 (CH2), 29.8 (CH2), 28.9 (CH2), 28.5 (CH2), 21.3 (CH3);
HRMS (EI) calcd. for C9H14N3: 170.1943; found: 170.1945.
2,3-Dimethyl-6-oxocyclohexanecarboxylic acid methyl ester (10).
To a stirred solution of phenylselenyl chloride (0.63 g, 3.27 mmol)
in CH2Cl2 (15 mL) at 0 ◦C was added pyridine (0.4 mL,
5.13 mmol) dropwise. After stirring for 20 min, compound 8
(0.50 g, 2.93 mmol) in CH2Cl2 (8 mL) was added. The resulting
mixture was stirred at room temperature for 1 h and then washed
with 1 N HCl solution (5 mL) to remove pyridine. The organic layer
was separated and H2O2 (30%, 0.9 mL, 9.34 mmol) was introduced
dropwise at 0 ◦C. The resulting mixture was kept stirring for
8 min at the same temperature and saturated NaHCO3 solution
(10 mL) was added to quench the reaction. The aqueous layer was
Conclusions
In conclusion, a total synthesis of the pinguisane-type sesquiter-
penoid acutifolone A, in racemic form, is reported. Not only
is this the most concise (14 steps) and efficient (14.5% overall
yield) total synthesis of acutifolone A, but this work also serves
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separated and extracted with CH2Cl2 (2 ¥ 15 mL). The combined
organic extracts were washed with brine, dried over Na2SO4,
filtered and concentrated to give the crude compound 9, which
was dried under vacuum and used without further purification.
To a stirred suspension of copper(I) iodide (0.62 g, 3.16 mmol)
in anhydrous THF (15 mL) was added methyllithium (4.6 mL,
7.35 mmol) dropwise at 0 ◦C. The resulting colorless solution was
stirred at the same temperature for 40 min and then cooled to
-78 ◦C, at which time a solution of the crude compound 9 in
anhydrous THF (10 mL) was introduced dropwise. After reaction
was complete (ca. 30 min), saturated NH4Cl solution (10 mL) was
added. The aqueous layer was separated and extracted with diethyl
ether (3 ¥ 20 mL). The combined organic extracts were washed
with brine, dried over MgSO4, filtered and concentrated to give
the crude product, which was purified by flash chromatography
on silica gel with EtOAc/n-hexane (1:9) to afford compound 10
(0.42 g, 77% yield over three steps) as a colorless oil: IR (CH2Cl2,
cast) nmax 2954, 2927, 2872, 1748, 1714, 1651, 1614 cm-1; 1H NMR
(CDCl3, 600 MHz) a mixture of enol and keto forms in a ratio
of 2:3 d 12.25 (br s, 0.44H), 3.73 (s, 3H), 3.06 (d, J = 12.0 Hz,
0.56H), 2.43 (ddd, J = 14.1, 4.2, 2.9 Hz, 1H), 2.39–2.33 (m, 1H),
2.31–2.24 (m, 1H), 2.15 (dt, J = 3.3, 18.7 Hz, 1H), 1.99–1.95 (m,
solution of compound 11 (0.25 g, 1.37 mmol) in anhydrous THF
(6 mL) was introduced. The resulting mixture was stirred for
another 1 h at 0 ◦C. Saturated NH4Cl solution (8 mL) was added
to quench the reaction. The aqueous layer was separated and
extracted with diethyl ether (3 ¥ 15 mL). The combined organic
extracts were washed with brine, dried over MgSO4, filtered and
concentrated to give the crude residue, which was purified by
flash chromatography on silica gel with EtOAc/n-hexane (1:9)
to afford compound 6 (0.25 g, 76% yield) as a yellow oil: IR
(CH2Cl2, cast) nmax 3077, 2969, 2950, 2877, 1752, 1715, 1641 cm-1;
1H NMR (CDCl3, 600 MHz): a mixture of enol and keto forms
in a ratio of 1:5 was observed. d 13.05 (s, 0.17H), 5.76–5.71 (m,
1H), 4.99–4.90 (m, 2H), 3.69–3.63 (m, 3H), 3.26 (s, 0.83H), 2.86
(dq, J = 20.0, 7.3 Hz, 1H), 2.41–2.37 (m, 1H), 2.32–2.28 (m,
2H), 2.03–1.99 (m, 1H), 1.95–1.87 (m, 2H), 1.63–1.55 (m, 1H),
1.52–1.49 (m, 1H), 0.99–0.97 (m, 3H), 0.90–0.76 (m, 3H); 13C
NMR (CDCl3, 150 MHz): d 207.0 (C), 169.2 (C), 138.6 (CH),
114.4 (CH2), 65.4 (CH), 52.0 (CH3), 43.6 (C), 38.6 (CH2), 37.4
(CH2), 33.5 (CH), 30.3 (CH2), 27.3 (CH2), 17.7 (CH3), 14.9 (CH3);
HRMS (EI) calcd. for C14H22O3: 238.1569; found: 238.1569.
(3aR*,7R*,7aS*)-Methyl
octahydro-1H-indene-3a-carboxylate (12) and (3aR*,7R*,7aS*)-
methyl 3,7,7a-trimethyl-4-oxo-3a,4,5,6,7,7a-hexahydro-1H-
7,7a-dimethyl-3-methylene-4-oxo-
1H), 1.53–1.37 (m, 1H), 1.05–1.00 (m, 3H), 0.98–0.91 (m, 3H); 13
C
NMR (CDCl3, 150 MHz) d 206.0 (C), 173.5 (C), 171.6 (C), 170.4
(C), 101.3 (C), 64.4 (CH), 51.9 (CH2), 51.2 (CH2), 42.2 (CH), 41.2
(CH2), 36.8 (CH), 34.3 (CH2), 33.8 (CH), 33.2 (CH), 25.4 (CH2),
23.4 (CH2), 22.0 (CH3), 18.9 (CH3 ¥ 2), 18.7 (CH3); HRMS (EI)
calcd. For C10H16O3: 184.1099; found: 184.1096.
indene-3a-carboxylate (13). To a solution of compound 6
(120 mg, 0.50 mmol) in THF (8 mL) was added Pd(OAc)2 (0.16 g,
0.71 mmol) at room temperature. The resulting mixture was
stirred at the same temperature for 16 h. H2O (10 mL) was
added to quench the reaction. The aqueous layer was separated
and extracted with Et2O (3 ¥ 15 mL). The combined organic
extracts were washed with brine, dried over MgSO4, filtered and
concentrated to give the crude product, which was purified by
flash chromatography on silica gel with EtOAc/n-hexane (1:5)
to afford compound 12 (36 mg, 30% yield) as a colorless oil: IR
2,3-Dimethyl-6-oxocyclohex-1-enecarboxylic acid methyl ester
(11). To a stirred solution of phenylselenyl chloride (0.46 g,
2.39 mmol) in CH2Cl2 (15 mL) at 0 ◦C was added pyridine
(0.3 mL, 3.87 mmol) slowly. After stirring for 20 min at the same
temperature, compound 10 (0.40 g, 2.17 mmol) in CH2Cl2 (8 mL)
was added. The resulting mixture was stirred at 0 ◦C for 3 h and
then washed with 1 N HCl solution (5 mL) to remove pyridine. The
organic layer was separated and H2O2 (30%, 0.8 mL, 8.30 mmol)
was added dropwise at 0 ◦C. The resulting mixture was kept
stirring for 10 min at the same temperature and saturated NaHCO3
solution (5 mL) was added to quench the reaction. The aqueous
layer was separated and extracted with CH2Cl2 (2 ¥ 15 mL). The
combined organic extracts were washed with brine, dried over
Na2SO4, filtered and concentrated to give the crude product, which
was purified by flash chromatography on silica gel with EtOAc/n-
hexane (1:4) to afford compound 11 (0.36 g, 91% yield for two
steps) as a yellow oil: IR (CH2Cl2, cast) nmax 2952, 2925, 1748,
1714, 1653, 1614, 1457 cm-1; 1H NMR (CDCl3, 600 MHz) d 3.79
(s, 3 H), 2.51 (ddd, J = 12.0, 10.4, 6.0 Hz, 1H), 2.36 (ddd, J = 17.0,
7.1, 4.9 Hz, 1H), 2.47–2.43(m, 1H), 2.15–2.09(m, 1H), 1.94 (s, 3H),
1.78–1.73 (m, 1H), 1.22 (d, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
150 MHz): d 194.9 (C), 167.6 (C), 163.9 (C), 132.6 (C), 52.1 (CH3),
34.7 (CH), 33.9 (CH2), 29.1 (CH2), 20.4 (CH3), 17.4 (CH3); HRMS
(EI) calcd. for C10H14O3: 182.0943; found: 182.0942.
1
(CH2Cl2, cast) nmax 2956, 2933, 1742, 1715, 1641, 1462 cm-1; H
NMR (CDCl3, 600 MHz): d 5.10 (t, J = 2.2 Hz, 1H), 4.88 (t, J =
2.5 Hz, 1H), 3.68 (s, 3H), 2.66–2.61 (m, 1H), 2.52–2.45 (m, 1H),
2.44–2.36 (m, 2H), 1.87 (ddd, J = 13.1, 8.5, 1.8 Hz, 1H), 1.74–1.67
(m, 3H), 1.50 (dt, J = 13.4, 10.3 Hz, 1H), 0.96 (s, 3H), 0.95 (m,
3H); 13C NMR (CDCl3, 150 MHz): d 206.9 (C), 171.5 (C), 150.2
(C), 111.6 (CH2), 75.5 (C), 52.9 (C), 52.0 (CH3), 38.1 (CH2), 34.6
(CH2), 33.1 (CH), 29.7 (CH2), 28.5 (CH2), 17.4 (CH3), 16.4 (CH3);
HRMS (EI) calcd. for C14H20O3: 236.1412; found: 236.1416.
Further elution gave compound 13 (64 mg, 54% yield) as
a yellow oil: IR (CH2Cl2, cast) nmax 2987, 2911, 1739, 1711,
1
1644 cm-1; H NMR (CDCl3, 600 MHz): d 5.65 (s, 1H), 3.67
(s, 3H), 2.57–2.52 (m, 1H), 2.39–2.35 (m, 1H), 2.22–2.16 (m, 1H),
2.14–2.11 (m, 1H), 1.87–1.77 (m, 2H), 1.69–1.66 (m, 1H), 1.61 (q,
J = 1.8 Hz, 3H), 0.99 (m, 3H), 0.98 (s, 3H); 13C NMR (CDCl3,
150 MHz): d 208.0 (C), 171.4 (C), 137.5 (C), 130.3 (CH), 77.5
(C), 51.8 (C), 51.7 (CH3), 45.6 (CH2), 37.7 (CH), 37.1 (CH2), 26.5
(CH2), 20.4 (CH3), 16.6 (CH3), 15.0 (CH3); HRMS (EI) calcd. for
C14H20O3: 236.1412; found: 236.1412.
2-But-3-enyl-2,3-dimethyl-6-oxocyclohexanecarboxylic
acid
(3R*,3aR*,7R*,7aS*)-Methyl
hydro-1H-indene-3a-carboxylate (5). To
of compound 12 (88 mg, 0.37 mmol) in MeOH (6 mL) was
added Pd/C (0.01 g, 10% w/w) in one portion. The resulting
mixture was hydrogenated under 1 atmosphere of H2 at room
temperature. After reaction was complete (ca. 8 h), the mixture
3,7,7a-trimethyl-4-oxoocta-
stirred solution
methyl ester (6). To a stirred suspension of CuI (0.28 g,
1.49 mmol) in THF (10 mL) were sequentially added Me2S
(0.5 mL) and freshly prepared 3-butenylmagnesium bromide
solution (10.5 mL, 0.36 M in THF, 3.80 mmol) dropwise at
-78 ◦C. After stirring for 30 min at the same temperature, a
a
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was filtered by celite and concentrated to give the crude product,
which was purified by flash chromatography on silica gel with
EtOAc/n-hexane (1:5) to afford the major component (a-CH3)
of compound 5 (80 mg, 90% yield) as a colorless oil: IR (CH2Cl2,
allowed to warm to room temperature and stirred for another
3 h. H2O (6 mL) was added to quench the reaction. The aqueous
layer was separated and extracted with Et2O (3 ¥ 15 mL). The
combined organic extracts were washed brine, dried over MgSO4,
filtered and concentrated. The crude silyl enol ether thus obtained
was further dried under vacuum and used without purification in
the following transformation.
1
cast) nmax 2956, 2933, 2876, 1731, 1712 cm-1; H NMR (CDCl3,
600 MHz): d 3.65 (s, 3H), 2.57 (ddd, J = 16.7, 7.5, 4.4 Hz, 1H),
2.42–2.34 (m, 2H), 1.80–1.71 (m, 4H), 1.66–1.59 (m, 3H), 1.06 (d,
J = 6.8 Hz, 3H), 0.95 (s, 3H), 0.92 (d, J = 6.5 Hz, 3H); 13C NMR
(CDCl3, 150 MHz): d 210.1 (C), 171.0 (C), 72.5 (C), 51.3 (C),
51.0 (CH3), 41.6 (CH), 37.8 (CH2), 37.2 (CH2), 36.0 (CH), 30.8
(CH2), 28.1 (CH2), 18.0 (CH3), 16.4 (CH3), 15.4 (CH3); HRMS
(EI) calcd. for C14H22O3: 238.1569; found: 238.1565.
Alternatively, compound 5 could be achieved using 13 as the
starting material in a longer reaction time: to a stirred solution
of compound 13 (102 mg, 0.43 mmol) in MeOH (6 mL) was
added Pd/C (0.01 g, 10% w/w) in one portion. The resulting
mixture was hydrogenated under 1 atmosphere of H2 at room
temperature. After reaction was complete (ca. 15 h), the mixture
was filtered by celite and concentrated to give the crude product,
which was purified by flash chromatography on silica gel with
EtOAc/n-hexane (1:5) to afford the major component (a-CH3) of
compound 5 (90 mg, 88% yield) as a colorless oil.
To a solution of the crude silyl enol ether in CH3CN (4 mL) was
added Pd(OAc)2 (51 mg, 0.23 mmol) in one portion. The reaction
mixture was heated to reflux for 50 h and then cooled to room
temperature. H2O (5 mL) was added to quench the reaction. The
resulting aqueous solution was separated and extracted with Et2O
(3 ¥ 15 mL). The combined organic extracts were washed brine,
dried over MgSO4, filtered and concentrated to give the crude
residue, which was purified by flash chromatography on silica gel
with EtOAc/n-hexane (1:6) to afford compound 14 (30 mg, 67%
yield over two steps) as a yellow oil: IR (CH2Cl2 cast) nmax 2956,
2932, 2870, 1723, 1683, 1628 cm-1; 1H NMR (CDCl3, 600 MHz):
d 6.52 (dd, J = 10.2, 2.0 Hz, 1H), 6.00 (dd, J = 10.2, 2.9 Hz, 1H),
3.60 (s, 3H), 2.57–2.52 (m, 1H), 2.41–2.34 (m, 1H), 2.01–1.95 (m,
1H), 1.85–1.73 (m, 2H), 1.66–161 (m, 1H), 1.12 (d, J = 6.2 Hz,
3H), 1.10 (d, J = 5.6 Hz, 3H), 0.85 (s, 3H); 13C NMR (CDCl3,
150 MHz): d 195.7 (C), 171.2 (C), 151.9 (CH), 127.5 (CH), 70.4
(C), 53.2 (C), 51.1 (CH3), 39.2 (CH), 35.4 (CH), 34.9 (CH2), 30.8
(CH2), 17.9 (CH3), 15.4 (CH3), 14.5 (CH3); HRMS (EI) calcd. for
C14H20O3: 236.1412; found: 236.1413.
(3R*,3aR*,7R,7aS*)-4-[(2,4-Dinitrophenyl)-hydrazono]-3,7,7a-
trimethyl-octahydroindene-3a-carboxylic acid methyl ester (5a).
A two-neck round bottom flask equipped with a Dean-Stark and
a condenser, was charged with compound 5 (49 mg, 0.25 mmol),
p-TSA (2 mg, 0.01 mmol) and benzene (10 mL). The reaction
mixture was heated to reflux for 5 days with azeotropic removal of
water and then cooled to room temperature. Saturated NaHCO3
solution (5 mL) was added. The resulting aqueous solution
was extracted with Et2O (3 ¥ 15 mL). The combined organic
extracts were washed with brine, dried over Na2SO4, filtered and
concentrated to give the crude product, which was purified by
flash chromatography on silica gel with EtOAc/n-hexane (1:9)
to afford compound 5a (46 mg, 90% yield) as an orange solid,
which was further recrystallized from ethyl acetate and n-hexane
to afford a crystalline compound in bright-orange color.
(3R*,3aR*,7R*,7aS*)-Methyl 3,7,7a-trimethyl-4-oxo-6-vinyl-
octahydro-1H-indene-3a-carboxylate (15). To a suspension of
copper(I) iodide (28 mg, 0.15 mmol) in anhydrous THF (5 mL) was
added vinylmagnesium bromide (0.3 mL, 0.30 mmol) dropwise at
-78 ◦C. The resulting mixture was stirred at the same temperature
for 30 min, at which time a solution of compound 14 (28 mg,
0.12 mmol) in anhydrous THF (5 mL) was introduced dropwise.
The resulting mixture was warmed and kept stirring at 0 ◦C for 2 h.
H2O (5 mL) and saturated NaHCO3 solution (5 mL) was added
to quench the reaction. The aqueous layer was separated and
extracted with Et2O (3 ¥ 15 mL). The combined organic extracts
were washed brine, dried over MgSO4, filtered and concentrated to
give the crude residue, which was purified by flash chromatography
on silica gel with EtOAc/n-hexane (1:9) to afford compound 15
(27 mg, 87% yield) as a colorless oil: IR (CH2Cl2 cast) nmax 2967,
2911, 2881, 1723, 1686, 1641 cm-1; 1H NMR (CDCl3, 600 MHz):
d 5.58–5.54 (m, 1H), 4.99–4.95 (m, 2H), 3.67 (s, 3H), 2.76 (dd,
J = 16.1, 7.7 Hz, 1H), 2.45–2.36 (m, 2H), 2.23 (dd, J = 16.1,
7.6 Hz, 1H), 1.82–1.76 (m, 3 H), 1.66–163 (m, 1H), 1.42–1.37 (m,
1H), 1.08 (d, J = 6.8 Hz, 3H), 1.01 (s, 3H), 0.89 (d, J = 6.7 Hz,
3H); 13C NMR (CDCl3, 150 MHz): d 209.1 (C), 170.9 (C), 141.2
(CH), 114.8 (CH2), 72.6 (C), 52.7 (C), 51.1 (CH3), 43.9 (CH), 43.6
(CH2), 41.4 (CH), 40.4 (CH), 38.2 (CH2), 30.7 (CH2), 18.8 (CH3),
15.1 (CH3), 14.4 (CH3); HRMS (EI) calcd. for C16H24O3: 264.1725;
found: 264.1725.
Mp 139–141 ◦C; IR (CH2Cl2, cast) nmax 3321, 2950, 1729, 1618,
1
1592, 1518 cm-1; H NMR (CDCl3, 600 MHz): d 11.18 (br s,
1H), 9.11 (d, J = 2.6 Hz, 1H), 8.28 (dd, J = 8.8, 2.5 Hz, 1 H),
7.83 (d, J = 9.6 Hz, 1H), 3.67 (s, 3H), 2.56 (ddd, J = 16.8, 7.7,
3.7 Hz, 2 H), 2.56–2.50 (m, 2H), 1.88–1.79 (m, 2H), 1.72–1.63
(m, 4H), 1.25 (d, J = 6.8 Hz, 3H), 0.96–0.94 (m, 6H); 13C NMR
(CDCl3, 150 MHz): d 172.5 (C), 161.0 (C), 145.4 (C), 137.8 (C),
130.1 (CH), 129.2 (C), 123.5 (CH), 116.4 (CH), 67.2 (C), 51.3
(C), 51.0 (CH3), 43.9 (CH), 38.9 (CH2), 37.7 (CH), 31.4 (CH2),
26.4 (CH2), 24.6 (CH2), 18.3 (CH3), 16.5 (CH3), 16.0 (CH3);
HRMS (EI) calcd. For C20H26N4O6: 418.1852; found: 418.1852.
X-ray crystallographic data of compound 5a (CCDC 706353)
are available via www.ccdc.cam.ac.uk/conts/retrieving.html or
mailto:deposit@ccdc.cam.ac.uk.†
(3R*,3aR*,7R*,7aS*)-Methyl 3,7,7a-trimethyl-4-oxo-2,3,3a,4,
7,7a-hexahydro-1H-indene-3a-carboxylate (14). To a solution of
compound 5 (45 mg, 0.19 mmol) in THF (6 mL) was added
LHMDS (0.4 mL, 1 M in THF, 0.40 mmol) dropwise at
-78 ◦C. The resulting mixture was stirred at the same temperature
for 15 min, and then TMSCl (45 mg, 0.42 mmol) in anhydrous
THF (6 mL) was added in one portion. The reaction mixture was
( )-Acutifolone A (1)
To a solution of compound 15 (21 mg, 0.08 mmol) in THF (2.5 mL)
was added LHMDS (0.2 mL, 0.20 mmol) dropwise at -78 ◦C. The
resulting mixture was stirred at the same temperature for 15 min,
and then TMSCl (22 mg, 0.20 mmol) in anhydrous THF (2 mL)
was added in one portion. The reaction mixture was warmed and
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kept stirring at room temperature for 3 h. H2O (6 mL) was added
to quench the reaction. The aqueous layer was extracted with Et2O
(3 ¥ 15 mL). The combined organic extracts were washed brine,
dried over MgSO4, filtered and concentrated to give the crude
silyl enol ether, which was further dried under vacuum and used
without further purification in the following transformation.
To a solution of the crude silyl enol ether in CH3CN (4 mL) was
added Pd(OAc)2 (22 mg, 0.10 mmol). The reaction mixture was
heated to reflux for 52 h and then cooled to room temperature. H2O
(5 mL) was added to quench the reaction. The aqueous layer was
extracted with Et2O (3 ¥ 15 mL). The combined organic extracts
were washed brine, dried over MgSO4, filtered and concentrated to
give the crude residue, which was purified by flash chromatography
on silica gel with EtOAc/n-hexane (1:6) to afford synthetic product
1 (14 mg, 66% yield over two steps) as a yellow oil: IR (CH2Cl2 cast)
2 Y. Asakawa, J. Hattori Bot. Lab., 1998, 84, 91.
3 Y. Asakawa, Bryophytes: Their Chemistry and Chemotaxonomy, Claren-
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Schinzer, K. Ringe, P. G. Jonse and D. Doring, Tetrahedron Lett.,
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Phytochemistry, 2000, 53, 593.
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9 L. R. Kung, C. H. Tu, K. S. Shia and H. J. Liu, Chem. Commun., 2003,
20, 2490.
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J. Org. Chem., 1981, 46, 2920.
1
nmax 2966, 2878, 1728, 1711, 1663, 1460 cm-1; H NMR (CDCl3,
600 MHz): d 6.43 (dd, J = 17.5, 10.8 Hz, 1H), 5.97 (s, 1H), 5.67
(d, J = 17.5 Hz, 1H), 5.43 (d, J = 10.9 Hz, 1H), 3.65 (s, 3H),
2.60 (q, J = 7.1 Hz, 1H), 2.20-2.16 (m, 1H), 1.72–1.57 (m, 3H),
1.48–1.51 (m, 1H), 1.23 (d, J = 6.9 Hz, 3H), 1.16 (d, J = 7.1 Hz,
3H), 1.08 (s, 3 H); 13C NMR (CDCl3, 150 MHz): d 197.2 (C), 171.2
(C), 160.4 (C), 136.8 (CH), 124.4 (C), 120.2 (CH2), 67.3 (C), 51.1
(CH3), 49.8 (C), 45.8 (CH), 40.9 (CH2), 38.4 (CH), 31.4 (CH2), 23.3
(CH3), 18.1 (CH3), 15.6 (CH3); HRMS (EI) calcd. for C16H22O3:
262.1569; found: 262.1575.
11 This compound was found to be rather unstable. Attempted purification
by flash chromatography resulted in substantial loss of material.
12 The ratio of a pair of epimers of 5 (a-CH3:b-CH3 = 18:1) was
determined by GC-MS analysis, wherein two distinct peaks displayed
the same formula weight. The minor component, unavailable by
chromatographic purification, was tentatively assigned as the b isomer
after the major component was unambiguously identified as the a
isomer13.
13 CCDC 706353 (5a) contains the supplementary crystallographic
data for this paper.† These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html or de-
posit@ccdc.cam.ac.uk. Single crystals of 5a were recrystallized from
EtOAc/n-hexane and mounted in the 150 K N2 stream of Siemens
Smart CCD diffractometer equipped with a Mo Ka radiation source
Acknowledgements
We are grateful to the National Science Council and the National
Health Research Institutes of the Republic of China for financial
support.
˚
(l = 0.71073 A). Crystal data: C20H26N4O6, M = 418.45, Monoclinic,
3
˚
˚
a = 10.3756(6), b = 12.6325(7), c = 16.2827(9) A, V = 2058.0(2) A ,
space group P2(1)/n, Z = 4, a total of 15394 reflections were collected
in the range 2.07 < 2q < 25.03. Of these, 3635 were independent; for
the observed data, wR2 = 0.0888, R = 0.0334.
References
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W. Herz, G. W. Kirby, R. E. Moore, W. Steglich and Ch. Tamm, Eds.;
Springer, Wien, New York, 1995; Vol. 65, pp. 1–562.
15 T. Saegusa, Y. Ito and T. Hirao, J. Org. Chem., 1978, 43, 1011.
3290 | Org. Biomol. Chem., 2009, 7, 3285–3290
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The Royal Society of Chemistry 2009
©