A new route to eremophilanes: synthesis of (±)-eremophilenolide, (±)-eremophiledinone, and (±)-deoxyeremopetasidione

Article abstract of DOI:10.1016/j.tetlet.2008.08.006

A new and efficient route to the family of eremophilanes is reported. Key steps are the highly stereocontrolled Diels-Alder reaction and aldol condensation to furnish a cis-decalin system with the desired stereochemistry present in the eremophilane family of natural products. This approach is general and was utilized for the synthesis of (±)-eremophilenolide, (±)-eremophiledinone, and (±)-deoxyeremopetasidione.

Full text of DOI:10.1016/j.tetlet.2008.08.006

Tetrahedron Letters 49 (2008) 6084–6086
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A new route to eremophilanes: synthesis of ( )-eremophilenolide,
( )-eremophiledinone, and ( )-deoxyeremopetasidione q
P. Srinivas a,b, D. Srinivasa Reddy a, K. Shiva Kumar a, P. K. Dubey b, Javed Iqbal a, Parthasarathi Das a,
*
a Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
b Department of Chemistry, JNTU College of Engineering, Kukatpally, Hyderabad 500 085, AP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and efficient route to the family of eremophilanes is reported. Key steps are the highly stereocon-
trolled Diels–Alder reaction and aldol condensation to furnish cis-decalin system with the
desired stereochemistry present in the eremophilane family of natural products. This approach
is general and was utilized for the synthesis of ( )-eremophilenolide, ( )-eremophiledinone, and
( )-deoxyeremopetasidione.
Received 7 May 2008
Revised 15 July 2008
Accepted 3 August 2008
Available online 8 August 2008
a
Ó 2008 Elsevier Ltd. All rights reserved.
A large variety of natural products of biological importance pos-
sess the decalin skeleton as an integral part of their structure.
Functionalized decalins with suitable stereochemistry are possible
intermediates for several terpenoids and related natural products.1
The eremophilane group of sesquiterpene natural products is char-
acterized by the cis-fused [4.4.0] decalin architecture with a cis-
1,2-dimethyl substitution pattern.2 The diverse biological proper-
ties of eremophilanes combined with the unique structural and
conformational challenges have attracted considerable synthetic
attention.3 Despite their well known medical values (antioxidant,
O
O
HO
O
O
H
H
3
1
2
( ) eremopetasidione
( ) fukinone
( ) aristolone
O
CO2Me
antiradical, and antifeedant properties), the eremophilenolides,4
a
O
subclass of eremophilane natural products, are believed to be
interconnected biogenetically with furanoeremophilanes, and have
received very little attention.5 Deoxyeremopetasidione 4, a deriva-
tive of (-)-eremopitasidione 3,6 which was isolated recently from
the rhizome of Petasites japonicus MAXIM, a nor sesquiterpenoid
possessing the same cis-fused [4.4.0] decalin architecture, has been
used for the treatment of tonsillitis, contusion, and poisonous
snake bites in Chinese medicine, but has received very little atten-
tion. The combination of novel structural features and promising
biological activity prompted us to explore a general strategy for
the synthesis of ( )-eremophilenolide 6, ( )-eremophiledinone 5,
and ( )-deoxyeremopetasidione 4 (Fig. 1).
We herein report our efforts on the synthesis of these sesquiter-
penes using a highly stereocontrolled Diels–Alder reaction and an
aldol condensation as the key steps.
Retrosynthetically, we envisioned eremophilenolide 6 (Scheme
1) from eremophiledinone 5, which is also a naturally occurring
eremophilane through reduction of the carbonyl group followed
O
O
O
H
H
H
H
4
5
6
( ) deoxy eremo ( ) eremophiledinone
petasidione
( ) eremophilenolide
Figure 1. Selected eremophilanes possesing the cis-decalin system.
by lactonization. The compound 5 could be prepared from the
intermediate 7 using an intramolecular aldol condensation. The
Diels–Alder adduct 9 obtained from diene 11 and tiglic aldehyde
10 would serve as a precursor for the synthesis of 7 through inter-
mediate 8.
Our synthesis began with the Lewis acid (BF3ÁEt2O)-mediated
Diels–Alder reaction between known diene 117 and commercially
available tiglic aldehyde 10 to furnish the adduct 98 with excellent
stereoselectivity.9 Protection of the aldehyde as an acetal followed
by LiOH-mediated hydrolysis resulted in acid 12 in good yield.
Weinreb amide formation with N,O-dimethyl hydroxylamine-
hydrochloride followed by Grignard reaction between the resulting
amide 8 and 1310 gave the desired carbon chain the elongated
product 14. Removal of the unwanted double bond and deprotec-
tion of the benzyl group were achieved in a single step in the
q
DRL Publication No. 667.
* Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304 5438.
E-mail addresses: parthasarathi@drreddys.com, parthads@yahoo.com (P. Das).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.006

P. Srinivas et al. / Tetrahedron Letters 49 (2008) 6084–6086
6085
tral data of both natural products 512 and 613 are compared well
with those of the literature values.4 We have accomplished the to-
tal synthesis of ( ) eremophilenolide 6 in eleven steps and in 15%
overall yield.
Retrosynthetically, ( )-deoxyeremopetasidione 4 (Scheme 3)
can be prepared from an intermediate cis-decalin 18. The com-
pound 18 could be prepared from 17 using an intramolecular aldol
condensation. The common intermediate 8 would serve as a pre-
cursor for the synthesis of 17.
redn.
CO2Me
O
O
O
O
H
H
H
6
5
O
aldol
O
CH2OH
Our synthesis began with the conversion of Weinreb amide 8
into ketone 19 through a Grignard reaction with methyl magne-
sium chloride followed by removal of the double bond with 10%
Pd/C in methanol to give 20. Subsequent deprotection of the alde-
hyde group with 6 N HCl in DCM followed by intramolecular con-
densation with 15% KOH in methanol furnished the desired key
intermediate cis-decalin derivative 1814 in 90% isolated yield
(Scheme 4). Hydrogenation of enone 18 in the presence of 10%
Pd/C in methanol produced decalin 21 in 90% yield. The C-acyla-
tion15 of the enolate derived from 21 with pyruvonitrile, and
subsequent treatment with NaOH produced 22. Finally, dehydro-
genation16 of the enol was performed with DDQ to accomplish
the total synthesis of ( )-deoxyeremopetasidione 417 (Scheme 4).
Here, we have accomplished the total synthesis of ( )-deoxyeremo-
petasidione in eight synthetic steps from intermediate 8 in 44%
overall yield.
O
H
H
O
OMe
N
7
8
CHO
O
10
DA
+
CO2Et
CO2Et
H
9
11
Scheme 1.
presence of the 10% Pd/C, HCOONH4 to give alcohol 15 in 92% yield.
As expected, when we treated 15 with 6 N HCl in DCM in order to
deprotect the aldehyde group, the cis-decalin derivative 16 was
isolated in 80% yield as a result of an in situ acid-mediated aldol
condensation. Oxidation of the primary alcohol in 16 using Jone’s
reagent followed by esterification with diazomethane resulted in
the ( )-eremophiledinone 5. Stereoselective reduction of the car-
bonyl group in 5 using NaBH4 followed by heating the product with
DBU in benzene furnished the natural product ( )-eremophileno-
lide 6 in 70% isolated yield over two steps (Scheme 2).11 The spec-
4
O
H
18
O
O
O
N
O
O
CHO
10
b, c
CO2Et
O
a
O
+
H
H
CO2H
OMe
CO2Et
O
8
17
H
9
H
12
11
Scheme 3.
O
O
O
N
O
d
e
MgBr
O
O
NH.HCl
c, d
a
H
H
O
b
O
OBn
13
O
OMe
OBn
OH
8
O
8
O
14
H
H
O
O
O
19
20
O
g
O
f
e
f, g
O
O
H
H
OH
O
O
15
OH
H
H
21
H
16
18
22
O
O
j
CO2Me
h, i
O
h
O
O
H
5
H
H
6
H
4
Scheme 2. Reagents and conditions: (a) BF3ÁEt2O, DCM, À78 °C to rt, 75%; (b)
(CH2OH)2, cat. PTSA, benzene, 81%, (c) LiOH, MeOH, H2O, 85%; (d) EDC, HOBt, Et3N,
DCM, 90%; (e) 13, THF, 0 °C, 90%; (f) 10% Pd/C, HCO2NH4, MeOH, reflux, 92%; (g) 6N
HCl, DCM, reflux, 80%; (h) Jone’s reagent, acetone, rt, 70%; (i) CH2N2, ether, 68%; and
(j) NaBH4, MeOH, rt, DBU, benzene, reflux, 70% in two steps.
Scheme 4. Reagents and conditions: (a) MeMgCl, THF, 0 °C, 90%; (b) 10% Pd/C,
MeOH, 90%; (c) 6 N HCl, reflux; (d) 15% KOH, MeOH, 85%; (e) 10% Pd/C, MeOH, 90%;
(f) LiHMDS, CH3COCN, THF, À78 °C, 84%; (g) NaOH, THF, 85%; and (h) DDQ, dioxane,
85%.

6086
P. Srinivas et al. / Tetrahedron Letters 49 (2008) 6084–6086
Shougakukun, Tokyo, 1985,
p
2386.; (b) Yaoita, Y.-F.; Kikuchi, M.
In summary, we have developed an efficient, short, and highly
Phytochemistry 1994, 37, 1765; (c) Hsu, D.-S.; Hsu, P.-Y.; Liao, C.-C. Org. Lett.
2001, 3, 263.
stereocontrolled route to the synthesis of ( )-deoxyeremopetasid-
ione 4, ( )-eremophiledinone 5 and ( )-eremophilenolide 6. Novel
application of a Lewis acid mediated Diels-Alder reaction and aldol
condensation strategy to construct the cis-decalin system and fur-
ther synthetic manipulation to the natural products was carried
out in a planned and optimized sequence. This approach is general,
and uses inexpensive and commercially available starting materi-
als to generate various structural analogs of eremophilanes for bio-
logical investigation.
8. Experimental procedure and spectral data for 9: To a solution of diene 11 (7.5 g,
53.57 mmol) and tiglic aldehyde 10 (11.2 g, 134 mmol) in dry DCM (265 ml)
was added BF3ÁEt2O (15.5 g, 107.14 mmol) dropwise at À78 °C. The reaction
was allowed to warm to rt and stirred overnight. The DCM layer was washed
with 10% NaHCO3 followed by water and brine, then dried over Na2SO4, and
evaporated in vacuum. The residue was purified by flash column
chromatography over silica gel (ethyl acetate/hexane, 0.2:99.8) to afford 9 g
(75%) of 9 as a light brown colored oil. IR (neat, cmÀ1) 2978, 1732, 1174; 1H
NMR (400 MHz, CDCl3) d = 9.60 (s, 1H), 5.71–5.66 (m, 1H), 5.64–5.97 (m 1H),
4.13 (q, J = 7.2 Hz, 2H), 2.65–2.59 (m, 1H), 2.45 (dd, J = 5.4 Hz, 15.8 Hz, 1H),
2.37–2.30 (m, 1H), 2.25–2.18 (m, 1H), 2.17–2.05 (m, 1H), 1.79–1.72 (m, 1H),
1.25 (t, J = 7.2 Hz, 3H), 1.08 (s, 3H), 0.93 (d, J = 6.8 Hz, 3H); 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; Mass (ESI): 225 [M+H]+.
Acknowledgments
9. (a) Reddy, D. S. Org. Lett. 2004, 6, 3345; (b) Reddy, D. S.; Palani, K.;
Balasubrahmanyam, D.; Vijju, K. V. B.; Iqbal, J. Tetrahedron Lett. 2005, 46, 5211.
10. (a) Eliel, E. L.; Clawson, L.; Knox, D. E. J. Org. Chem. 1985, 50, 2707; (b) Somers, P.
K.; Wandless, T. J.; Schreiber, S. L. J. Am. Chem. Soc. 1991, 113, 8045; (c) Boons,
G.-J.; Clase, J. A.; Lennon, I. C.; Ley, S. V.; Staunton, J. Tetrahedron 1995, 51, 5417.
11. Naya, L.; Matsumoto, T.; Makiyama, M.; Tsumura, M. Heterocycles 1978, 10, 177.
12. Spectral data of 5: IR (neat, cm-1): 2993, 1737, 1676; 1H NMR (400 MHz; CDCl3):
d = 6.63 (br s, 1H), 3.67–3.62 (m, 1H), 3.65 (s, 3H), 2.68–2.61 (m, 1H), 2.32–2.26
(m, 1H), 2.09–2.04 (m, 1H), 1.82–1.70 (m, 2H), 1.57–1.43 (m, 3H,), 1.39–1.23
(m, 2H), 1.27 (d, J = 7.3 Hz, 3H), 1.12 (s, 3H), 0.92 (d, J = 6.9 Hz, 3H); 13C NMR
(50 MHz; CDCl3) d = 198.4, 175.0, 156.4, 136.6, 51.8, 39.4, 38.9, 38.2, 37.9, 36.1,
We thank Dr. Reddy’s Laboratories Ltd for their support and
encouragement. Help from the analytical department in recording
the spectral data is appreciated.
References and notes
1. (a) Merritt, A. T.; Ley, S. V. Nat. Prod. Rep. 1992, 9, 243; (b) Ley, S. V.; Denholm, A.
A.; Wood, A. Nat. Prod. Rep. 1993, 10, 109; (c) Hanson, J. R. Nat. Prod. Rep. 1999,
16, 209.
2. General reviews on eremophilanes: (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1;
(b) Fraga, B. M. Nat. Prod. Rep. 2002, 19, 650.
3. (a) Synthesis of eremophilanes and related compounds: (a) Fisher, N. H.; Oliver,
E. J.; Fisher, H. D. In Progress in the Chemistry of Organic Natural Products; Herz,
W.; Grisebach, H. K.; Eds., G. W. Spinger: New York, 1979; Vol. 38, Chapter 2.;
(b) Prasad, C. V. C.; Chan, T. H. J. Org. Chem. 1987, 52, 120; (c) Srikrishna, A.;
Nagaraju, S.; Venkateswarlu, S.; Hiremath, U. S.; Reddy, T. J.; Venugopalan, P. J.
Chem. Soc., Perkin Trans. 1 1999, 2069; (d) Srikrishna, A.; Reddy, T. J. Arkivoc
2001, viii, 9; (e) Silva, L. F., Jr. Synthesis 2001, 671; (f) Back, T. G.; Nava-Salgado,
V. O.; Payne, J. E. J. Org. Chem. 2001, 66, 4361; (g) 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; (h) Mehta, G.;
Senthil Kumaran, R. S. Tetrahedron Lett. 2003, 44, 7055; (i) Reddy, D. S.; Kozmin,
S. A. J. Org. Chem. 2004, 69, 4860.
30.2, 27.0, 20.8, 20.4, 16.5, 15.8; HRMS calculated for
265.1804, found 265.1801.
C
16H25O3 [M+H]+
13. Spectral data of 6: IR (neat, cm-1): 2932, 1738; 1H NMR (400 MHz; CDCl3):
d = 4.66–4.61 (m, 1H), 2.89 (d, J = 15 Hz, 1H,), 2.01–2.05 (m, 1H), 1.89–1.64 (m,
4H), 1.80 (s, 3H), 1.48–1.33 (m, 5H), 1.28–1.20 (m, 1H), 1.03 (s, 3H), 0.88 (d,
J = 6.5 Hz, 3H); 13C NMR (50 MHz; CDCl3) d = 174.9, 161.1, 120.5, 80.4, 40.2,
39.8, 36.4, 35.2, 30.6, 30.0, 26.7, 21.6, 20.6, 15.9, 8.2; HRMS calculated for
C
15H23O2[M+H]+ 235.1698, found 235.1700.
14. Spectral data of 18: IR (neat, cmÀ1): 2925, 1680, 1375; 1H NMR (400 MHz;
CDCl3): d = 6.81 (d, J = 10.2 Hz, 1H), 5.91 (d, J = 10.2 Hz, 1H), 2.65 (dd, J = 12.7,
17 Hz, 1H), 2.20 (dd, J = 4.4, 17 Hz, 1H), 2.09–2.03 (m, 1H), 1.84–1.72 (m, 2H),
1.57–1.40 (m, 3H), 1.39–1.24 (m, 2H), 1.21 (s, 3H), 0.92 (d, J = 6.8 Hz, 3H); 13C
NMR (50 MHz; CDCl3) d = 200.6, 161.3, 127.1, 39.8, 39.3, 38.8, 35.65, 30.1, 27.1,
20.4, 20.2, 15.9; mass (ESI): 179 [M+H]+.
4. Isolation of eremophilenolides: (a) Sugama, K. O.; Hayashi, K.; Mitsuhashi, H.
Phytochemistry 1985, 24, 1531; (b) Georges, M.; Jean-Marc, N.; Lousiette, L. M-
O.; Paul, A.; Abdelhamid, B.; Abdessmed, K. Phytochemistry 1990, 29, 2207; (c)
Paul, A.; Abdelhamid, B.; Georges, M.; Lousiette, L. M-O. Phytochemistry 1991,
30, 2083; (d) Wang, W.; Gao, K.; Jia, Z. J. Nat. Prod. 2002, 65, 714.
5. Synthetic approaches for eremophilenolides: (a) Nagakura, I.; Maeda, S.; Ueno,
M.; Funamizu, M.; Kitahara, Y. Chem. Lett. 1975, 1143; (b) Miyashita, T. M.;
Kumazawa, T.; Yishikoshi, A. Chem. Lett. 1979, 163; (c) Acobi, P. A.; Craig, T. A.;
Walker, D. G.; Arrick, B. A.; Frechette, R. F. J. Am. Chem. Soc. 1984, 106, 4450; (d)
Laura, H. M.; Shanmugham, M. S.; White, J. D.; Drew, M. G. B. Org. Biomol. Chem.
2006, 4, 1020.
15. Tang, Q.; Sen, S. E. Tetrahedron Lett. 1998, 39, 2249.
16. Edwards, J. A.; Calzada, M. C.; Ibanez, L. C.; Rivera, M. E. C.; Urquiza, R.; Cardona,
L.; Orr, J. C.; Bowers, A. J. Org. Chem. 1964, 29, 3481.
17. Spectral data of 4: IR (neat, cm-1): 2930, 1691, 1680, 1357, 1250; 1H NMR
(400 MHz; CDCl3): d = 7.49 (s, 1H), 2.73 (dd, J = 12.4, 16.6 Hz, 1H), 2.46 (s, 3H),
2.32 (dd, J = 4.4, 16.6 Hz, 1H), 2.15–2.06 (m, 1H), 1.87–1.82 (m, 1H), 1.78–1.72
(m, 1H), 1.59–1.55 (m, 1H), 1.54–1.40 (m, 2H), 1.39–1.33 (m, 2H), 1.18 (s, 3H),
0.95 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz; CDCl3) d = 198.4, 197.6, 166.5,
136.9, 40.4, 39.6, 39.4, 35.5, 30.7, 30.2, 26.8, 20.2, 20.1, 15.9; HRMS calculated
for C14H21O2 [M+H]+ 221.1547, found 221.1551.
6. Isolation and synthesis of eremopetasidione: (a) Dictionary of chinese Meteria
Medica; Shanghai Scientific Technological Publishers and Shougakukun;