Total synthesis of (±)-petasitolone and (±)-fukinone

Article abstract of DOI:10.1055/s-0029-1218150

An efficient, general, and fully stereocontrolled synthesis of eremophilane-type compounds is disclosed. The approach features a highly diastereoselective Diels-Alder/aldol sequence to give a common intermediate, which is subsequently exploited to produce

Full text of DOI:10.1055/s-0029-1218150

PAPER
3833
Total Synthesis of ( )-Petasitolone and ( )-Fukinone
T
otal
S
ynthesi
r
s
of
(
)-
i
n
(
)
i
-Fukin
v
one as Pasikanti,a,b Dumbala Srinivasa Reddy,a Javed Iqbal,a Pramod Kumar Dubey,b Parthasarathi Das*a
a
Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, AP, India
Fax +91(40)23045438; E-mail: parthads@yahoo.com
Department of Chemistry, JNTU College of Engineering, Kukatpally, Hyderabad 500085, AP, India
b
Received 26 June 2009
Alder adduct 8, obtained from (E)-2-methylbut-2-enal
(tiglic aldehyde, 9) and diene 10, would serve as a precur-
sor for the synthesis of 6 via intermediate 7 (Scheme 1).
Abstract: An efficient, general, and fully stereocontrolled synthe-
sis of eremophilane-type compounds is disclosed. The approach
features a highly diastereoselective Diels–Alder/aldol sequence to
give a common intermediate, which is subsequently exploited to
produce ( )-petasitolone and ( )-fukinone in a short sequence.
OH
Key words: eremophilane, Diels–Alder reactions, aldol reactions,
condensation
O
O
O
H
H
1
2
The decahydronaphthalene (Decalin) skeleton is one of
the most prevalent structural motifs in numerous natural
products.1–3 In particular, terpenoids possessing the
decahydronaphthalene moiety display a wide variety of
biological activities that may have medicinal potential.3
Owing to their importance in nature, the synthesis of
decahydronaphthalenes has become a major focal point of
synthetic chemistry. The structural complexity of the iso-
lated natural products demands the development of new
and efficient strategies to construct stereochemically rich
and multifunctional decahydronaphthalenes. For this rea-
son, there has been a great deal of interest in developing
methods for their synthesis, as reflected by the flurry of
reports in this area from various groups around the globe
over the last decade.4
O
H
H
3
4
Figure 1 Selected eremophilanes possessing a cis-decahydronaph-
thalene-related skeleton
CO2Me
1
or
2
O
H
5
O
O
O
The eremophilane-type sesquiterpenes ( )-petasitolone
(1)5 and ( )-fukinone (2)6 have been isolated from rhi-
zomes of Petasites japonicus Maxim. These natural prod-
ucts possess three stereogenic centers, two methyl groups,
and a hydrogen atom on a cis-decahydronaphthalene-
related skeleton (Figure 1). The diverse biological proper-
ties of these eremophilanes, combined with their unique
structural and conformational challenges, have attracted
considerable synthetic attention.7,8 Recently, we devel-
oped an efficient, short, and highly stereocontrolled route
to the cis-decahydronaphthalene system and applied this
method in the synthesis of ( )-eremophilenolide, ( )-ere-
mophiledinone, and ( )-deoxyeremopetasidione.9 In this
paper, we report the total synthesis of ( )-petasitolone (1)
and ( )-fukinone (2) using this methodology.10
O
O
H
O
7
H
O
6
OMe
CO2Me
N
Me
O
CHO
9
+
CO2Et
H
CO2Et
10
8
Scheme 1 Retrosynthesis of ( )-petasitolone and ( )-fukinone
In accordance with the synthetic plan, our synthesis began
with the Lewis acid (BF3·OEt2) mediated Diels–Alder re-
action between known diene 10 and commercially avail-
able (E)-2-methylbut-2-enal (9). The reaction occurred
with excellent stereoselectivity11 to give adduct 8 contain-
ing the desired stereocenters. Protection of the aldehyde
as acetal 11, followed by the removal of the unwanted
double bond in the presence of 10% palladium on carbon
in methanol, produced saturated ester 12. Lithium hydrox-
ide mediated hydrolysis of the ester resulted in acid 13,
Retrosynthetically, we envisaged that ( )-petasitolone (1)
and ( )-fukinone (2) could be derived from the common
intermediate 5. Compound 5 would be prepared from
acetal 6 by intramolecular aldol condensation. Diels–
SYNTHESIS 2009, No. 22, pp 3833–3837
x
x.
x
x
.
2
0
0
9
Advanced online publication: 07.10.2009
DOI: 10.1055/s-0029-1218150; Art ID: P09109SS
© Georg Thieme Verlag Stuttgart · New York

3834
S. Pasikanti et al.
PAPER
and coupling between the acid and N,O-dimethylhydrox- was followed by subsequent treatment with 6 M hydro-
ylamine hydrochloride yielded Weinreb amide 7. chloric acid in N,N-dimethylformamide to yield ( )-fuki-
Grignard addition to the amide gave methyl ketone 14. none 2 (Scheme 3).
The subsequent treatment of the methyl ketone with me-
thyl chloroformate in the presence of lithium hexamethyl-
OH
disilazide gave the desired carbon-chain-elongated12
CO2Me
a
O
O
product 6. To our expectation, when we exposed com-
pound 6 to 6 M hydrochloric acid in dichloromethane for
the deprotection of the aldehyde moiety, cis-decahy-
dronaphthalene derivative 15 was isolated in 80% yield as
a result of an in-situ acid-mediated aldol condensation.
The protection of the ketone functionality as a ketal pro-
duced the common intermediate 5 (Scheme 2).
H
O
H
16
O
5
c
b
OH
CO2Me
O
O
CHO
9
O
H
H
17
O
a
b
1
+
CO2Et
d, e
H
8
CO2Et
O
10
O
c
d
O
O
O
H
H
H
CO2Et
CO2Et
2
11
12
O
O
O
O
Scheme 3 Reagents and conditions: (a) MeMgCl, THF, 0 °C, 1 h,
92% yield; (b) 6 M HCl, CH2Cl2, reflux, 1 h, 80% yield; (c) 10% Pd/
C, MeOH, 1 h, 85% yield; (d) MeMgCl, THF, 0 °C, 1 h; (e) DMF, 6
M HCl, r.t., 30 min, 64% yield over two steps
e
f
MeONHMe⋅HCl
H
H
O
CO2H
OMe
N
13
7
In conclusion, we have accomplished the total synthesis
of ( )-petasitolone (1) in 11 steps (17% overall yield) and
( )-fukinone (2) in 12 steps (13% overall yield). The ap-
plied Lewis acid mediated Diels–Alder reaction and the
aldol condensation strategy remain the key steps in our
synthesis.
Me
O
O
O
O
h
g
H
O
H
O
CO2Me
14
15
6
Infrared spectra were recorded on a Shimadzu IR Prestige 21 FT-IR
CO2Me
i
CO2Me
O
1
spectrometer. The H NMR (400 MHz) and 13C NMR (50 MHz)
spectra were determined in CDCl3 soln on Varian Mercury Plus
(400 MHz) and Gemini 2000 (200 MHz) spectrometers, respective-
ly. Proton chemical shifts are relative to TMS as the internal stan-
dard and are expressed in ppm. Melting points were determined
using a Buchi Melting Point B-540 melting point apparatus and are
uncorrected. Mass spectrometry was performed on a Perkin-Elmer
API 3000 instrument using ESI. Column chromatography was car-
ried out using silica gel, grade 100–200 mesh. The reactions were
monitored by TLC on silica gel plates (60 F254), visualizing with
UV light, I2 spray, or KMnO4 charing. Unless stated otherwise, the
reactions were performed under argon. The solvents THF, CH2Cl2,
and benzene were obtained from a dry solvent system. All other re-
agents were purchased from Aldrich at the highest commercial
quality and were used without further purification.
O
H
H
5
O
Scheme 2 Reagents and conditions: (a) BF3·OEt2, CH2Cl2, –78 °C
to r.t., 75% yield; (b) (CH2OH)2, PTSA (cat.), benzene, 81% yield; (c)
10% Pd/C, MeOH, 90% yield; (d) aq LiOH, THF, MeOH, 85% yield;
(e) EDC, 1H-benzotriazol-1-ol, Et3N, CH2Cl2, 90% yield; (f)
MeMgCl, THF, 0 °C, 90% yield; (g) LiHMDS, methyl chloroforma-
te, THF, –78 °C, 87% yield; (h) 6 M HCl, CH2Cl2, reflux, 30 min,
80% yield; (i) (CH2OH)2, PTSA (cat.), benzene, 90% yield
A Grignard reaction between resulting ketal 5 and meth-
ylmagnesium chloride, followed by the deprotection of
ketal 16 using 6 M hydrochloric acid, allowed us to ac-
complish the total synthesis of ( )-petasitolone (1)
(Scheme 3).
Ethyl [(1R*,5R*,6S*)-6-Formyl-5,6-dimethylcyclohex-2-
enyl]acetate (8)
To a solution of diene 10 (7.5 g, 53.6 mmol) and (E)-2-methylbut-
2-enal (9) (11.2 g, 134.0 mmol) in dry CH2Cl2 (265 mL) was added
BF3·OEt2 (15.5 g, 107.1 mmol) dropwise at –78 °C. The mixture
was allowed to warm to r.t. and was stirred overnight. The CH2Cl2
layer was washed with 10% NaHCO3 (3 × 100 mL) followed by
H2O (100 mL) and brine (100 mL), and then was dried (MgSO4) and
The synthesis of ( )-fukinone (2) began by the removal of
the double bond in ketal 5 in the presence of 10% palladi-
um on carbon in methanol to yield product 17. Compound
17 was reacted with methylmagnesium chloride, and this
Synthesis 2009, No. 22, 3833–3837 © Thieme Stuttgart · New York

PAPER
Total Synthesis of ( )-Petasitolone and ( )-Fukinone
3835
concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, EtOAc–hexane, 0.2:99.8) to afford ad-
duct 8. Yield: 9.0 g (75%); light-brown oil.
IR (neat): 2978, 1732, 1174 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.60 (s, 1 H), 5.71–5.66 (m, 1 H),
5.64–5.97 (m, 1 H), 4.13 (q, J = 7.2 Hz, 2 H), 2.65–2.59 (m, 1 H),
2.45 (dd, J = 5.4, 15.8 Hz, 1 H), 2.37–2.30 (m, 1 H), 2.25–2.18 (m,
1 H), 2.17–2.05 (m, 1 H), 1.79–1.72 (m, 1 H), 1.25 (t, J = 7.2 Hz, 3
H), 1.08 (s, 3 H), 0.93 (d, J = 6.8 Hz, 3 H).
acidified to pH 2 with 2 M HCl. The aqueous layer was extracted
with EtOAc (3 × 100 mL), and the combined organic layers were
washed with H2O (100 mL) and brine (100 mL), dried (MgSO4),
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography (silica gel, EtOAc–hexane, 10:90) to give
acid 13. Yield: 3.8 g (85%); colorless oil.
IR (neat): 2932, 1704, 1410, 1093 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.83 (s, 1 H), 3.95–3.89 (m, 2 H),
3.83–3.77 (m, 2 H), 2.73 (dd, J = 3.4, 15.6 Hz, 1 H), 2.37 (dd, J =
10.7, 15.6 Hz, 1 H), 2.17–2.13 (m, 1 H), 1.94–1.85 (m, 1 H), 1.69–
1.60 (m, 1 H), 1.59–1.46 (m, 3 H), 1.44–1.38 (m, 1 H), 1.30–1.25
(m, 1 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.91 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 175.2, 102.3, 59.2, 59.0, 36.0, 31.6,
29.2, 27.2, 24.2, 21.3, 14.9, 10.8, 10.2.
13C NMR (50 MHz, CDCl3): d = 206.6, 172.6, 127.4, 126.1, 60.4,
49.6, 37.6, 35.6, 30.65, 29.5, 15.7, 15.6, 13.9.
ESI-MS: m/z = 225 [M + H]+.
Ethyl [(1R*,5R*,6S*)-6-(1,3-Dioxolan-2-yl)-5,6-dimethylcyclo-
hex-2-enyl]acetate (11)
ESI-MS: m/z = 243 [M + H]+.
To a solution of aldehyde 8 (5.8 g, 25.9 mmol) and ethane-1,2-diol
(3.2 g, 51.6 mmol) in benzene (52 mL) was added a catalytic
amount of PTSA (0.24 g, 1.29 mmol), and the mixture was heated
under reflux using Dean–Stark apparatus. After 2 h, the organic lay-
er was washed with sat. NaHCO3 (2 × 25 mL) and brine (25 mL),
dried (MgSO4), and concentrated in vacuo to give an oil, which was
purified by flash column chromatography (silica gel, EtOAc–
hexane, 5:95) to give acetal 11. Yield: 5.6 g (81%); colorless oil.
[(1S*,2S*,3R*)-2-(1,3-Dioxolan-2-yl)-2,3-dimethylcyclohexyl]-
N-methoxy-N-methylacetamide (7)
To a solution of acid 13 (4.00 g, 16.52 mmol) in CH2Cl2 (84 mL)
was added EDC (4.74 g, 24.75 mmol) and 1H-benzotriazol-1-ol
(3.34 g, 24.78 mmol) at 0 °C. To this mixture was then added N,O-
dimethylhydroxylamine hydrochloride (1.61 g, 16.52 mmol) fol-
lowed by Et3N (3.47 mL, 24.78 mmol). The resulting solution was
allowed to stir overnight at r.t., and then the mixture was diluted
with CH2Cl2 (84 mL) and successively washed with 10% citric acid
(2 × 100 mL), sat. aq NaHCO3 (2 × 100 mL), H2O (100 mL), and
brine (100 mL). The organic layer was dried (MgSO4) and concen-
trated under reduced pressure, and the residue was purified by flash
column chromatography (silica gel, EtOAc–hexane, 10:90) to give
amide 7. Yield: 4.24 g (90%); colorless oil.
IR (neat): 2978, 2883, 1732, 1091 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.66–5.63 (m, 1 H), 5.56–5.53 (m,
1 H), 4.71 (s, 1 H), 4.13 (q, J = 7.0 Hz, 2 H), 3.95–3.88 (m, 2 H),
3.82–3.76 (m, 2 H), 2.72 (dd, J = 4.2, 15.2 Hz, 1 H), 2.56–2.52 (m,
1 H), 2.21 (dd, J = 4.2, 15.2 Hz, 1 H), 2.21–2.12 (m, 1 H), 1.97–1.93
(m, 1 H), 1.74–1.69 (m, 1 H), 1.26 (t, J = 7.0 Hz, 3 H), 0.94 (d, J =
6.9 Hz, 3 H), 0.88 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 173.6, 128.5, 126.0, 107.1, 64.6,
64.4, 60.1, 40.6, 38.6, 36.5, 31.5, 30.6, 16.3, 14.4, 14.3.
ESI-MS: m/z = 269 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C15H24O4: 269.1759; found:
IR (neat): 2933, 1660, 1093 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.89 (s, 1 H), 3.93–3.85 (m, 2 H),
3.83–3.78 (m, 2 H), 3.68 (s, 3 H), 3.17 (s, 3 H), 2.65 (dd, J = 3.4,
15.1 Hz, 1 H), 2.56–2.54 (m, 1 H), 2.24–2.21 (m, 1 H), 1.96–1.91
(m, 1 H), 1.64–1.58 (m, 2 H), 1.54–1.47 (m, 2 H), 1.39–1.25 (m, 2
H), 0.94 (d, J = 6.8 Hz, 3 H), 0.91 (s, 3 H).
269.1759.
13C NMR (50 MHz, CDCl3): d = 175.0, 107.6, 76.4, 64.5, 64.3, 61.0,
Ethyl [(1S*,2S*,3R*)-2-(1,3-Dioxolan-2-yl)-2,3-dimethylcyclo-
hexyl]acetate (12)
41.4, 36.5, 32.7, 31.9, 29.6, 26.6, 20.4, 16.2, 15.5.
ESI-MS: m/z = 286 [M + H]+.
A mixture of acetal 11 (2.0 g, 7.5 mmol), 10% Pd/C (0.4 g), and abs
MeOH (23 mL) was stirred under hydrogen at atmospheric pressure
for 1 h at r.t. The mixture was then filtered on a pad of Celite, and
the filtrate was concentrated under reduced pressure. The crude
product was purified by flash column chromatography (silica gel,
EtOAc–hexane, 5:95) to afford saturated ester 12. Yield: 1.8 g
(90%); colorless oil.
1-[(1S*,2S*,3R*)-2-(1,3-Dioxolan-2-yl)-2,3-dimethylcyclohex-
yl]propan-2-one (14)
To a solution of amide 7 (2.0 g, 7.0 mmol) in THF (21 mL) at 0 °C
was added 3 M MeMgCl in THF (3.5 mL, 10.5 mmol) dropwise.
After 1 h at 0 °C, the reaction was quenched with sat. aq NH4Cl
(20 mL). The layers were separated and the aqueous phase was ex-
tracted with EtOAc (2 × 100 mL). The combined organic layers
were washed with H2O (2 × 50 mL) and brine (50 mL), dried (anhyd
MgSO4), and concentrated under reduced pressure. The crude prod-
uct was purified by flash column chromatography (silica gel,
EtOAc–hexane, 5:95) to afford methyl ketone 14. Yield: 1.5 g
(90%); colorless oil.
IR (neat): 2932, 1733, 1160, 1094, 1035 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.83 (s, 1 H), 4.10 (q, J = 7.1 Hz,
2 H), 3.93–3.87 (m, 2 H), 3.80–3.77 (m, 2 H), 2.63 (dd, J = 3.6, 15.2
Hz, 1 H), 2.32 (dd, J = 10.9, 15.2 Hz, 1 H), 2.17–2.11 (m, 1 H),
1.91–1.87 (m, 1 H), 1.63–1.54 (m, 2 H), 1.53–1.45 (m, 2 H), 1.38–
1.27 (m, 2 H), 1.24 (t, J = 7.1 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H),
0.89 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 174.4, 107.6, 64.6, 64.4, 59.9, 41.9,
37.3, 34.9, 32.6, 29.7, 26.7, 20.3, 16.2, 15.5, 14.4.
ESI-MS: m/z = 271 [M + H]+.
IR (neat): 2929, 2877, 1714, 1354, 1091 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.79 (s, 1 H), 3.93–3.81 (m, 2 H),
3.80–3.76 (m, 2 H), 2.76 (dd, J = 3.4, 16.6 Hz, 1 H), 2.41 (dd, J =
9.8, 16.6 Hz, 1 H), 2.25–2.19 (m, 1 H), 2.12 (s, 3 H), 1.90–1.85 (m,
1 H), 1.63–1.39 (m, 4 H), 1.30–1.22 (m, 2 H), 0.92 (d, J = 6.8 Hz, 3
H), 0.89 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 209.7, 107.8, 64.6, 64.3, 44.2, 41.4,
36.0, 32.5, 30.2, 29.7, 26.9, 20.4, 16.4, 15.4.
[(1S*,2S*,3R*)-2-(1,3-Dioxolan-2-yl)-2,3-dimethylcyclohex-
yl]acetic Acid (13)
To a stirred solution of saturated ester 12 (5.0 g, 18.5 mmol) in THF
(32 mL) and MeOH (32 mL) was added aq LiOH (32 mL, 37.0
mmol) at 0 °C. The resulting mixture was stirred for 5 h at r.t. and
then was concentrated under reduced pressure. The residue was
ESI-MS: m/z = 241 [M + H]+.
Synthesis 2009, No. 22, 3833–3837 © Thieme Stuttgart · New York

3836
S. Pasikanti et al.
PAPER
ESI-HRMS: m/z [M + H]+ calcd for C14H24O3: 241.1804; found:
ane, 5:95) to give ketal 5. Yield: 1.60 g (90%); white solid; mp 87–
241.1797.
88 °C.
IR (KBr): 2926, 1728, 1259, 1058 cm–1.
Methyl 4-[(1S*,2S*,3R*)-2-(1,3-Dioxolan-2-yl)-2,3-dimethylcy-
clohexyl]-3-oxobutanoate (6)
1H NMR (400 MHz, CDCl3): d = 7.03 (s, 1 H), 4.26–4.20 (m, 2 H),
4.05–3.94 (m, 2 H), 3.72 (s, 3 H), 2.16 (t, J = 13.7 Hz, 1 H), 1.90–
1.85 (m, 1 H), 1.78–1.72 (m, 2 H), 1.52 (dd, J = 2.4, 12.8 Hz, 2 H),
1.50–1.37 (m, 3 H), 1.25–1.21 (m, 1 H), 1.04 (s, 3 H), 0.89 (d, J =
6.6 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 165.9, 155.4, 128.6, 106.9, 65.8,
65.0, 51.4, 38.6, 38.0, 37.2, 34.1, 30.6, 27.4, 21.2, 19.0, 16.3.
To a solution of methyl ketone 14 (3.0 g, 12.5 mmol) in dry THF
(63 mL) under nitrogen at –78 °C was added 1 M LiHMDS in hex-
ane (31.5 mL, 37.5 mmol) dropwise over a 10-min period, and the
resulting mixture was stirred at the same temperature for 1 h. Meth-
yl chloroformate (1.5 mL, 15.0 mmol) was then added in one por-
tion and the mixture was stirred at the same temperature for a further
1 h. The reaction was quenched with aq NH4Cl (30 mL) and the
mixture was extracted with EtOAc (3 × 40 mL). The combined or-
ganic layers were washed with H2O (40 mL) and brine (40 mL),
dried (anhyd MgSO4), and concentrated under reduced pressure.
The crude mixture was purified by flash column chromatography
(silica gel, EtOAc–hexane, 7:93) to afford ester 6. Yield: 3.2 g
(87%); colorless oil.
ESI-MS: m/z = 281 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C16H24O4: 281.1753; found:
281.1763.
2-{(4a¢S*,5¢R*,8a¢S*)-4a¢,5¢-Dimethyl-4a¢,5¢,6¢,7¢,8¢,8a¢-hexahy-
dro-1H¢-spiro[1,3-dioxolane-2,2¢-naphthalene]-3¢-yl}propan-2-
ol (16)
IR (neat): 2931, 1749, 1716, 1091 cm–1.
To a solution of ketal 5 (570 mg, 2.03 mmol) in THF (10 mL) at 0
°C was added 3 M MeMgCl in THF (72.7 mL, 8.12 mmol) drop-
wise. After 1 h at 0 °C, the reaction was quenched with sat. aq
NH4Cl (10 mL). The layers were separated and the aqueous phase
was extracted with EtOAc (3 × 20 mL). The combined organic lay-
ers were washed with H2O (2 × 10 mL) and brine (10 mL), dried
(anhyd MgSO4), and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (silica
gel, EtOAc–hexane, 12:88) to afford alcohol 16. Yield: 520 mg
(92%); white solid; mp 121–122 °C.
1H NMR (400 MHz, CDCl3): d = 4.77 (s, 1 H), 3.93–3.82 (m, 2 H),
3.80–3.75 (m, 2 H), 3.73 (s, 3 H), 3.45 (s, 2 H), 2.90 (dd, J = 3.9,
16.9 Hz, 1 H), 2.49 (dd, J = 9.3, 16.9 Hz, 1 H), 2.26–2.23 (m, 1 H),
1.88–1.86 (m, 1 H), 1.62–1.40 (m, 4 H), 1.30–1.25 (m, 2 H), 0.91
(d, J = 7.0 Hz, 3 H), 0.89 (s, 3 H).
13C NMR (50 MHz, CDCl3): d = 203.0, 167.73, 107.7, 64.5, 64.2,
52.1, 49.1, 43.8, 41.3, 35.64, 32.4, 29.6, 26.9, 20.4, 16.3, 15.4.
ESI-MS: m/z = 299 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C16H26O5: 299.1858; found:
IR (KBr): 3491, 2922, 1369, 1165 cm–1.
299.1849.
1H NMR (400 MHz, CDCl3): d = 5.60 (s, 1 H), 4.20–3.96 (m, 4 H),
2.03 (t, J = 13.2 Hz, 1 H), 1.86–1.75 (m, 2 H), 1.71–1.62 (m, 2 H),
1.48 (dd, J = 2.4, 12.8 Hz, 2 H), 1.41 (s, 3 H), 1.40 (s, 3 H), 1.37–
1.31 (m, 2 H), 1.24–1.16 (m, 1 H), 0.98 (s, 3 H), 0.85 (d, J = 6.8 Hz,
3 H).
13C NMR (50 MHz, CDCl3): d = 140.6, 136.9, 110.9, 72.8, 63.9,
62.8, 37.9, 37.2, 35.4, 34.9, 31.2, 30.9, 30.0, 27.9, 21.6, 19.6, 16.2.
Methyl (4aS*,8R*,8aS*)-8,8a-Dimethyl-3-oxo-3,4,4a,5,6,7,8,8a-
octahydronaphthalene-2-carboxylate (15)
To a solution of ester 6 (1.50 g, 5.03 mmol) in CH2Cl2 (25.16 mL)
was added 6 M HCl (25.16 mL), and the mixture was heated under
reflux for 30 min. The mixture was then cooled to r.t. and extracted
with CH2Cl2 (3 × 50 mL). The combined extracts were washed with
H2O (50 mL) and brine (50 mL), dried (MgSO4), and concentrated
under reduced pressure. The crude compound was purified by flash
column chromatography (silica gel, EtOAc–hexane, 10:90) to af-
ford bicyclic compound 15. Yield: 0.95 g (80%); colorless oil.
ESI-MS: m/z = 281 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C17H28O3: 281.2117; found:
281.2129.
IR (neat): 1749, 1716, 1091 cm–1.
(4aS*,5R*,8aS*)-3-(2-Hydroxypropan-2-yl)-4a,5-dimethyl-
4a,5,6,7,8,8a-hexahydronaphthalen-2(1H)-one [( )-Petasito-
lone, 1]
1H NMR (400 MHz, CDCl3): d = 7.53 (s, 1 H), 3.81 (s, 3 H), 2.73
(dd, J = 12.5, 16.8 Hz, 1 H), 2.32 (dd, J = 4.4, 16.8 Hz, 1 H), 2.12–
2.08 (m, 1 H), 1.89–1.84 (m, 1 H), 1.78–1.70 (m, 1 H), 1.59–1.42
(m, 2 H), 1.40–1.25 (m, 3 H), 1.19 (s, 3 H), 0.96 (d, J = 6.8 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 195.1, 166.3, 165.2, 130.1, 52.0,
40.1, 39.5, 39.2, 35.4, 35.0, 29.6, 26.8, 20.1, 15.8.
ESI-MS: m/z = 237 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C14H20O3: 237.1491; found:
To a solution of ketal 16 (120 mg, 0.43 mmol) in CH2Cl2 (2.2 mL)
was added 6 M HCl (2.2 mL), and the mixture was heated under re-
flux for 1 h. The mixture was then cooled to r.t. and extracted with
CH2Cl2 (3 × 10 mL). The combined extracts were washed with H2O
(2 × 10 mL) and brine (10 mL), dried (MgSO4), and concentrated
under reduced pressure. The crude compound was purified by flash
column chromatography (silica gel, EtOAc–hexane, 10:90) to af-
ford ( )-petasitolone (1). Yield: 101 mg (80%); colorless oil.
237.1484.
IR (neat): 3446, 2964, 2926, 1654, 1355 cm–1.
Methyl (4a¢S*,5¢R*,8a¢S*)-4a¢,5¢-Dimethyl-4a¢,5¢,6¢,7¢,8¢,8a¢-
hexahydro-1¢H-spiro[1,3-dioxolane-2,2¢-naphthalene]-3¢-car-
boxylate (5)
To a mixture of oxo ester 15 (1.50 g, 6.35 mmol) and ethane-1,2-
diol (0.87 g, 12.70 mmol) in benzene (32 mL) was added a catalytic
amount of PTSA (0.12 g, 0.63 mmol), and the mixture was heated
under reflux using Dean–Stark apparatus. After 2 h, the organic lay-
er was washed with sat. NaHCO3 (2 × 15 mL) and brine (15 mL),
dried (MgSO4), and concentrated in vacuo to give an oil, which was
purified by flash column chromatography (silica gel, EtOAc–hex-
1H NMR (400 MHz, CDCl3): d = 6.70 (s, 1 H), 4.53 (br s, 1 H), 2.70
(dd, J = 12.5, 17.3 Hz, 1 H), 2.26 (dd, J = 4.6, 17.3 Hz, 1 H), 2.08–
2.01 (m, 1 H), 1.82–1.69 (m, 2 H), 1.57–1.54 (m, 1 H), 1.53–1.28
(m, 10 H), 1.22 (s, 3 H), 0.92 (d, J = 6.8 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 202.6, 154.9, 141.0, 71.7, 40.6,
39.4, 38.5, 35.6, 30.1, 29.3, 29.1, 26.8, 20.6, 20.4, 15.9.
ESI-MS: m/z = 219 [M – OH]+.
ESI-HRMS: m/z [M – OH]+ calcd for C15H23O: 219.1749; found:
219.1750.
Synthesis 2009, No. 22, 3833–3837 © Thieme Stuttgart · New York

PAPER
Total Synthesis of ( )-Petasitolone and ( )-Fukinone
3837
Methyl (4a¢S*,5¢R*,8a¢S*)-4a¢,5¢-Dimethyloctahydro-1¢H-
spiro[1,3-dioxolane-2,2¢-naphthalene]-3¢-carboxylate (17)
A mixture of unsaturated ketal 5 (500 mg, 1.78 mmol), 10% Pd/C
(100 mg), and abs MeOH (9 mL) was stirred under hydrogen at at-
mospheric pressure for 1 h at r.t. The mixture was then filtered on a
pad of Celite, and the filtrate was concentrated under reduced pres-
sure. The crude product was purified by flash column chromatogra-
phy (silica gel, EtOAc–hexane, 15:85) to afford saturated ketal 17.
Acknowledgment
We thank Dr. Reddy’s Laboratories Ltd. for financial support and
encouragement. Help from the analytical department in recording
spectral data is appreciated.
References
(1) (a) Devon, T. K.; Scott, A. I. Handbook of Naturally
Occurring Compounds, Vols. I and II; Academic: New
York, 1972. (b) Terpenoids and Steroids, Vols. 1-12; The
Chemical Society: London, 1971-1983. (c) Ho, T. L.
Carbocyclic Construction in Terpene Synthesis; VCH: New
York, 1988.
Yield: 430 mg (85%); colorless oil.
IR (neat): 3435, 2926, 2870, 1701 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.99 (dd, J = 3.6, 8.4 Hz, 2 H),
3.73 (dd, J = 4.4, 8.8 Hz, 2 H), 3.72 (s, 3 H), 2.65 (d, J = 17.6 Hz, 1
H), 2.38 (dd, J = 6.8, 18.0 Hz, 1 H), 2.12–2.07 (m, 1 H), 1.85 (d, J
= 17.2 Hz, 1 H), 1.72–1.69 (m, 2 H), 1.56–1.49 (m, 4 H), 1.33–1.21
(m, 3 H), 0.90 (d, J = 6.4 Hz, 3 H), 0.89 (s, 3 H).
(2) For a review on cis-decahydronaphthalene, see: Singh, V.;
Iyer, S. R.; Pal, S. Tetrahedron 2005, 61, 9197.
(3) (a) Glasby, J. S. Encyclopedia of the Terpenoids; Wiley:
13C NMR (50 MHz, CDCl3): d = 168.2, 161.2, 107.7, 69.9, 60.9,
Chichester, 1982. For more recent reports on
51.4, 35.8, 34.5, 34.0, 33.9, 29.7, 29.4, 28.1, 23.5, 20.5, 15.0.
sesquiterpenoids, see: (b) Fragan, B. M. Nat. Prod. Rep.
2003, 20, 392. For diterpenoids, see: (c) Hanson, J. R. Nat.
Prod. Rep. 2004, 21, 312. For triterpenoids, see:
(d) Connolly, J. D.; Hill, R. A. Nat. Prod. Rep. 2003, 20,
640.
ESI-MS: m/z = 283 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C16H26O4: 283.1909; found:
283.1896.
(4) (a) Fisher, N. H.; Oliver, E. J.; Fisher, H. D. In Progress in
the Chemistry of Organic Natural Products, Vol. 38; Herz,
W.; Grisebach, H. K., Eds.; Springer: New York, 1979,
Chap. 2. (b) Srikrishna, A.; Nagaraju, S.; Venkateswarlu, S.;
Hiremath, U. S.; Reddy, T. J.; Venugopalan, P. J. Chem.
Soc., Perkin Trans. 1 1999, 2069. (c) Fleming, F. F.; Shook,
B. C.; Jiang, T.; Steward, O. W. Org. Lett. 1999, 1, 1547.
(d) Silva, L. F. Jr. Synthesis 2001, 671. (e) Back, T. G.;
Nava-Salgado, V. O.; Payne, J. E. J. Org. Chem. 2001, 66,
4361. (f) Brocksom, T. J.; Coelho, F.; Depres, J. P.; Green,
A. E.; Freire de Lima, M. E.; Hamelin, O.; Hartmann, B.;
Kanazawa, A. M.; Wang, Y. J. Am. Chem. Soc. 2002, 124,
15313. (g) Mehta, G.; Senthil Kumaran, R. Tetrahedron
Lett. 2003, 44, 7055. (h) Hsu, D.-S.; Hsu, P.-Y.; Lee, Y.-C.;
Liao, C.-C. J. Org. Chem. 2008, 73, 2554.
(4aS*,5R*,8aS*)-3-Isopropylidene-4a,5-dimethyl-
1,4,4a,5,6,7,8,8a-octahydronaphthalen-2-one [( )-Fukinone, 2]
To a solution of ketal 17 (90 mg, 0.32 mmol) in THF (3 mL) at 0 °C
was added 3 M MeMgCl in THF (0.43 mL, 1.28 mmol) dropwise.
After 1 h at 0 °C, the reaction was quenched with sat. aq NH4Cl
(5 mL). The layers were separated and the aqueous phase was ex-
tracted with EtOAc (3 × 10 mL). The combined organic layers were
washed with H2O (2 × 5 mL) and brine (5 mL), dried (anhyd
MgSO4), and concentrated under reduced pressure. The crude alco-
hol was dissolved in DMF (2 mL), and to this solution was added 6
M HCl (2 mL) and the mixture was stirred at r.t. for 30 min. Then,
H2O (5 mL) was added and the mixture was extracted with EtOAc
(3 × 10 mL). The combined organic layers were washed with H2O
(2 × 10 mL) and brine (10 mL), dried (anhyd MgSO4), and concen-
trated under reduced pressure. The crude product was purified by
flash column chromatography (silica gel, EtOAc–hexane, 5:95) to
afford ( )-fukinone (2). Yield: 45 mg (64%); colorless oil.
(5) Naya, K.; Yoshimura, F.; Takagi, I. Bull. Chem. Soc. Jpn.
1971, 44, 3165.
(6) Naya, K.; Takagi, I.; Kawaguchi, Y.; Asada, Y.; Hirose, Y.;
IR (neat): 2927, 2865, 1686, 1448 cm–1.
Shinoda, N. Tetrahedron 1968, 24, 5871.
1H NMR (400 MHz, CDCl3): d = 2.74 (d, J = 14.5 Hz, 1 H), 2.55
(dd, J = 10.7, 16.3 Hz, 1 H), 2.26 (dd, J = 5.6, 16.3 Hz, 1 H), 2.00–
1.88 (m, 1 H), 1.94 (s, 3 H), 1.79 (s, 3 H), 1.77–1.66 (m, 4 H), 1.55–
1.23 (m, 4 H), 0.96 (s, 3 H), 0.85 (d, J = 6.9 Hz, 3 H).
13C NMR (50 MHz, CDCl3): d = 206.0, 139.9, 131.2, 44.0, 41.3,
40.6, 36.7, 32.3, 30.1, 29.6, 27.2, 22.5, 21.5, 20.9, 16.0.
ESI-MS: m/z = 221 [M + H]+.
ESI-HRMS: m/z [M + H]+ calcd for C15H24O: 221.1905; found:
(7) Liu, H.-J.; Ngooi, T. K. Can. J. Chem. 1984, 62, 2676.
(8) (a) Piers, E.; Smillie, R. D. J. Org. Chem. 1970, 35, 3997.
(b) Marshall, J. A.; Cohen, G. M. Tetrahedron Lett. 1970,
11, 3865. (c) Torrence, A. K.; Pinder, A. R. Tetrahedron
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Chem. 1987, 52, 120. (e) Reddy, D. S.; Kozmin, S. A.
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(9) Srinivas, P.; Reddy, D. S.; Shiva Kumar, K.; Dubey, P. K.;
Iqbal, J.; Das, P. Tetrahedron Lett. 2008, 49, 6084.
(10) DRL Publication No. 667-A.
221.1898.
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Palani, K.; Balasubrahmanyam, D.; Vijju, K. V. B.; Iqbal, J.
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Synthesis 2009, No. 22, 3833–3837 © Thieme Stuttgart · New York