Stereo- and regioselective construction of vicinal stereogenic quaternary carbon atoms: Enantiospecific approach to cyperanes

Article abstract of DOI:10.1016/j.tetasy.2005.05.021

An enantiospecific approach to a functionalised carbon framework of the sesquiterpenes, cyperanes, starting from the monoterpene (R)-carvone has been accomplished. A combination of a Claisen rearrangement, intramolecular diazo ketone cyclopropanation and

Full text of DOI:10.1016/j.tetasy.2005.05.021

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2203–2207
Stereo- and regioselective construction of vicinal stereogenic
quaternary carbon atoms: enantiospecific approach to cyperanes
Adusumilli Srikrishna* and Chikkana Dinesh
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 3 May 2005; accepted 17 May 2005
Abstract—An enantiospecific approach to a functionalised carbon framework of the sesquiterpenes, cyperanes, starting from the
monoterpene (R)-carvone has been accomplished. A combination of a Claisen rearrangement, intramolecular diazo ketone cyclo-
propanation and regiospecific cyclopropane ring cleavage has been exploited for the stereo and regiospecific generation of the vicinal
stereogenic quaternary carbon atoms.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
dus LINNE have been subjected tonumerous studies
resulting in the isolation of many terpenoids.1 Hikino
et al.2 have reported the isolation of sesquiterpene
cyperolone 1, containing the 1-ethyl-3-isopropyl-6-
methylbi- cyclo[4.3.0]nonane 2 (cyperane) carbon frame-
work, from the tuber of nutgrass C. rotundus LINNE of
Japanese origin. Dev et al.4 have reported the isolation
of cyperolone 1 from the same oil of Indian origin.
Results obtained from chemical studies on cyperus
plants showed that cyperolone 1 and other chemical
constituents of C. rotundus LINNE are responsible for
plant growth inhibitory activities, antimicrobial activi-
ties and insect repellent activities.5 Subsequently, the iso-
lation of sesquiterpenes 3–8, which have the cyperane
carbon framework, were reported (Chart 1).6
The dried tuberous roots or rhizome of Cyperus rotun-
dus LINNE, an officially listed traditional medicine in
Chinese pharmacopoeia, are used in the treatment of ill-
nesses connected with child birth or menstrual disorder.
In Vietnam and Japan, it is often used for treating stom-
ach ache, irregular menstruation, dysentery, nausea and
gynecological diseases. In Malaysia, it is used to cure
pain in the nose by inhaling smoke from the burning
drug, while in Indonesia, it is used as a stimulant and
stomachic. In India, it is used as diuretic and for irregu-
lar menstruation, fever, disorder in digestive tract and
various haematological diseases. The essential oil, as
well as the solvent extracts of the rhizomes of C. rotun-
5
7
9
1
3
HO2C
OH
OH
OH
XylO
O
O
O
15
3 (cyperane xyloside)
4 (cyperanic acid)
1 (cyperolone)
2 (cyperane)
HO2C
OH
OH
OH
OH
OH
HO
HO
O
O
O
O
O
5 (epi cyperanic acid)
7
8
6
Chart 1.
*
Corresponding author. Tel.: +91 80 22932215; fax: +91 80 23600683; e-mail: ask@orgchem.iisc.ernet.in
0957-4166/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.021

2204
A. Srikrishna, C. Dinesh / Tetrahedron: Asymmetry 16 (2005) 2203–2207
The presence of a bicyclo[4.3.0]nonane carbon frame-
work incorporating two stereogenic quaternary carbon
atoms at the ring junction positions and three to four
stereogenic centres make cyperanes attractive synthetic
targets. Despite the known biological properties, very
little effort has been directed towards the synthesis of
anation of diazo ketone 10 derived from acid 11 would
generate tricyclic ketone 12, which could be transformed
into3- epi-cyperane 13 via reductive cyclopropane ring
cleavage (Scheme 1). Acid 11, being a c,d-unsaturated
carbonyl system, could be obtained via a stereoselective
Claisen rearrangement of allyl alcohol 14, which could
be obtained from carvone 9 via 3-ethylcarvone 15.
3
cyperanes. Hikinoet al. reported the first synthesis of
cyperolone 1 by employing a pinacol–pinacolone rear-
rangement as the key step. Subsequently, research
groups of Dev7 and Hikino8 reported the rearrangement
of epoxy-eudesmanes to generate cyperane and epi-
cyperanes. Ceccherelli et al.9 reported the synthesis of
an analogue of cyperanic acid. Herein, we report an
enantioselective approach to the functionalised carbon
framework of cyperanes starting from the readily and
abundantly available monoterpene (R)-carvone 9,
employing a combination of Claisen rearrangement–
intramolecular diazo ketone cyclopropanation–regio-
selective cyclopropane ring cleavage for the construction
of the vicinal stereogenic quaternary carbon atoms.
The sequence was started with the conversion of (R)-
carvone 9 into( S)-3-ethylcarvone 15, employing a 1,3-
alkylative enone transposition strategy (Scheme 2).10
Thus, a sonochemically accelerated Barbier reaction of
carvone 9 with ethyl bromide and lithium in THF fur-
nished the tertiary alcohol 16, which on oxidation with
PCC and silica gel, generated (S)-3-ethylcarvone 15 in
70% yield. Reduction of 3-ethylcarvone 15 with LAH
in ether at ꢀ70 °C gave allyl alcohol 14 in a highly regio-
and stereoselective manner.11 The orthoester Claisen
rearrangement12 of the allyl alcohol 14 with triethyl ortho-
acetate and a catalytic amount of propionic acid in a
sealed tube at 180 °C generated ester 17, which on
hydrolysis with sodium hydroxide in refluxing aqueous
methanol furnished acid 11. Reaction of acid 11 with
oxalyl chloride, followed by treatment of the resultant
acid chloride with an excess of ethereal diazomethane
2. Results and discussion
Initially the synthesis of a 3-epi-cyperane was investi-
gated. It was anticipated that intramolecular cycloprop-
generated diazoketnoe
10. Copper and anhydrous
N2
O
O
O
10
13
12
OH
CO2H
O
9
14
11
Scheme 1.
O
b
a
OH
O
9
16
15
c
OH
e
O
O
d
OH
OEt
11
14
17
f
g
h
O
O
O
N2
13
12
10
Scheme 2. Reagents, conditions and yields: (a) EtBr, Li, ))), THF, 40 min, rt; (b) PCC, silica gel, CH2Cl2, 6 h; 70% for two steps; (c) LAH, Et2O,
ꢀ70 °C, 95%; (d) MeC(OEt)3, EtCOOH, 180 °C, 96 h, 61%; (e) 5% NaOH, H2O–MeOH, reflux, 7 h, 95%; (f) (COCl)2, C6H6, rt, 2 h; CH2N2, Et2O,
rt, 2 h; (g) Cu, CuSO4, c-C6H12, W-lamp, 5 h, 57% from acid 11; (h) Li, liq. NH3, THF, 76%.

A. Srikrishna, C. Dinesh / Tetrahedron: Asymmetry 16 (2005) 2203–2207
2205
copper sulfate catalysed decomposition of diazo ketone
10 in refluxing cyclohexane, irradiated by a tungsten
lamp, led to the intramolecular insertion of the inter-
mediate keto-carbenoid into the olefin ring in a regio-
and stereoselective manner,13 resulting in the formation
of tricyclic ketone 12, whose structure was established
from its spectral data. It was readily identified that
regioselective cleavage of the C2–C9 cyclopropane bond
in 12 transforms it into an epi-cyperane. Accordingly,
treatment of tricyclic ketone 12 with lithium in liquid
ammonia furnished bicylic ketone17 13 via regiospecific
cyclopropane ring cleavage.14
of the intermediate keto-carbenoid into the ring olefin,
resulting in the formation of the tricyclic ketone 24.
Regioselective cyclopropane ring cleavage of tricyclic
ketone 24 using lithium in liquid ammonia furnished
bicyclic ketone 25. Attention was then turned towards
the oxidative degradation15 of the phenyl group. Hydro-
genation of the isopropenyl moiety in 25 using 10% pal-
ladium on carbon as the catalyst under 1 atm of
hydrogen in ethanol furnished the bicyclic ketone 26.
Reaction of the bicyclic ketone 26 with a catalytic
amount of ruthenium chloride and sodium periodate
in a 1:1:1 mixture of acetonitrile, water and carbon tet-
rachloride furnished the keto acid 27, which on esterifi-
cation with an excess of diazomethane in ether,
generated the ketoester 28.18
Next, attention was turned towards the synthesis of an
epi-cyperane having functionality at C-15 position. Phe-
nyl group was considered as a masked carboxylic acid
group. It was envisaged that substitution of a benzyl
group in the place of the ethyl group would be a suitable
choice, and the sequence was carried out via 3-benzyl-
carvone 18 (Scheme 3). Thus, sonochemically acceler-
ated Barbier reaction of carvone 9 with benzyl
bromide and lithium in THF at 0 °C, followed by oxida-
tion of the resultant tertiary alcohol 19 with a mixture of
PCC and silica gel in methylene chloride at room tem-
perature furnished enone 18 in 63% yield. Regio- and
stereoselective reduction of enone 18 with LAH in ether
at low temperature (ꢀ70 °C) furnished allyl alcohol 20.
The orthoester Claisen rearrangement of allyl alcohol
20 with triethyl orthoacetate and a catalytic amount of
propionic acid in a sealed tube at 180 °C, generated ester
21 in a stereoselective manner, which on hydrolysis with
sodium hydroxide in refluxing aqueous methanol, fur-
nished acid 22. Acid 22 was converted into the diazo ke-
tone 23 via the corresponding acid chloride. Copper and
anhydrous copper sulfate catalysed decomposition of
the diazoketone 23 in refluxing cyclohexane, irradiated
by a tungsten lamp, led to the intramolecular insertion
After successfully accomplishing the synthesis of 13 and
28, attention was focussed on the synthesis of a cype-
rane. For the synthesis of a cyperane, it was obvious
that the isopropyl group needed to be syn tothe ring
junction substituents. Since the stereochemistry of the
ring junction positions were derived from the stereo-
chemistry of the hydroxy group in the allyl alcohol 20,
inversion of the stereochemistry of the hydroxy group
in allyl alcohol 20 would change the stereochemistry
of the ring junction substituents syn to the isopro-
penyl group; hence a Mitsunobu reaction16 was chosen
(Scheme 4). Consequently, the reaction of allyl alcohol
20 with triphenylphosphine and diethyl azo-dicarboxy-
late (DEAD) in the presence of benzoic acid in THF,
generated benzoate 29 in 63% yield. Hydrolysis of the
benzoate group in 29 using potassium carbonate in
methanol, furnished the anti-alcohol 30. The structure
of alcohol 30 was deduced from its spectral data in com-
parison with that of the syn-alcohol 20. The orthoester
Claisen rearrangement of the allyl alcohol 30 with tri-
ethyl orthoacetate and a catalytic amount of propionic
OH
O
c
a
b
OH
O
Ph
Ph
f
9
Ph
19
18
20
d
N2
O
g
O
O
CO2R
e
Ph
Ph
Ph
Ph
24
23
21 R = Et
22 R = H
h
j
i
O
O
CO2R
27 R = H
28 R = Me
Ph
25
26
k
Scheme 3. Reagents, conditions and yields: (a) PhCH2Br, Li, ))), THF, 0 °C ! rt, 1 h; (b) PCC, silica gel, CH2Cl2, 8 h; 63% for two steps; (c) LAH,
Et2O, ꢀ70 °C, 90%; (d) MeC(OEt)3, EtCOOH, 180 °C, 96 h, 58%; (e) 5% NaOH, H2O–MeOH, reflux, 7 h, 98%; (f) (COCl)2, C6H6, rt, 2 h; CH2N2,
Et2O, rt, 2 h; (g) Cu, CuSO4, c-C6H12, W-lamp, 5 h, 63% from acid 22; (h) Li, liq. NH3, THF, 83%; (i) 10% Pd/C, EtOH, H2, 6 h, 99%; (j)
RuCl3ÆxH2O, CCl4, H2O, MeCN, rt, 8 h, 57%; (k) CH2N2, Et2O, 0 °C, 2 h, 90%.

2206
A. Srikrishna, C. Dinesh / Tetrahedron: Asymmetry 16 (2005) 2203–2207
OH
OCOPh
OH
a
b
Ph
Ph
Ph
20
29
30
c
N2
O
e
O
f
CO2R
d
Ph
Ph
31 R = Et
32 R = H
Ph
34
g
33
i
O
O
O
h
Ph
Ph
COOMe
37
35
36
Scheme 4. Reagents, conditions and yields: (a) PPh3, DEAD, PhCOOH, THF, rt, 24 h, 63%; (b) K2CO3, MeOH, rt, 10 h, 84%; (c) MeC(OEt)3,
EtCOOH, 180 °C, 72 h, 61%; (d) 5% NaOH, H2O–MeOH, reflux, 7 h, 92%; (e) (COCl)2, C6H6, rt, 2 h, CH2N2, Et2O, rt, 2 h; (f) Cu, CuSO4, c-C6H12
,
W-lamp, 6 h, 55% from acid 32; (g) Li, liq. NH3, THF, 80%; (h) 10% Pd/C, EtOH, H2, 6 h, 99%; (i) RuCl3ÆxH2O, CCl4, H2O, MeCN, rt, 8 h; CH2N2,
Et2O, 0 °C, 2 h, 55%.
acid in a sealed tube at 180 °C, followed by hydrolysis of
the resultant ester 31 with sodium hydroxide in refluxing
aqueous methanol, furnished acid 32. Acid 32 was then
transformed into diazo ketone 33, which on treatment
with copper and anhydrous copper sulfate in refluxing
cyclohexane, irradiated by a tungsten lamp, led to the
formation of tricyclic ketone 34. Regioselective cyclo-
propane ring cleavage of tricyclic ketone 34 using
lithium under liquid ammonia conditions furnished
bicyclic ketone 35, which on hydrogenation using 10%
palladium on carbon as the catalyst in ethanol at
1 atm of hydrogen furnished bicyclic ketone 36. Oxida-
tive degradation of the phenyl group in the bicyclic
ketone 36 with a catalytic amount of ruthenium chloride
and sodium periodate in a 1:1:1 mixture of acetonitrile,
water and carbon tetrachloride followed by esterifica-
tion with diazomethane in ether furnished ester 37.19
References
1. Sonwa, M. M.; Konig, W. A. Phytochemistry 2001, 58,
799.
2. Hikino, H.; Aota, K.; Maebayashi, Y.; Takemoto, T.
Chem. Pharm. Bull. 1966, 14, 1439.
3. Hikino, H.; Aota, K.; Norio, S.; Takemoto, T. Chem.
Pharm. Bull. 1966, 14, 1441.
4. Kapadia, V. H.; Naik, V. G.; Wadia, M. S.; Dev, S.
Tetrahedron Lett. 1967, 4661.
5. Komai, K.; Seto, N.; Matsubayashi, K.; Hamada, M.
Zasso Kenkyu 1990, 35, 64.
6. El-Ghazouly, M. G.; El-Sebakhy, N. A.; El-Din, A. A. S.;
Zdero, C.; Bohlmann, F. Phytochemistry 1987, 26, 439;
Ceccherelli, P.; Curini, M.; Marcotullio, M. C. J. Nat. Prod.
1988, 51, 1006; Ceccherelli, P.; Curini, M.; Marcotulio, M.
C.; Menghini, A. Phytochemistry 1985, 2987; Ahmed, A.
A.; Jakupovic, J. Phytochemistry 1990, 29, 3658; Todorova,
M. N.; Tsankova, E. T. Phytochemistry 1999, 52, 1515;
Ohira, S.; Hasegawa, T.; Hayashi, K.-i.; Hoshino, T.;
Takaoka, D.; Nozaki, H. Phytochemistry 1998, 48, 1577.
7. Mehta, G.; Chetty, G. L.; Nayak, U. R.; Dev, S.
Tetrahedron 1968, 24, 3775.
3. Conclusion
In conclusion, we have developed a convenient short
enantioselective approach for the construction of the
complete carbon framework of cyperane sesquiterpenes.
A sequence comprising of a Claisen rearrangement,
intramolecular diazo ketone cyclopropanation and regio-
selective cyclopropane ring cleavage reaction has been
exploited for the construction of the two vicinal stereo-
genic quaternary carbon atoms. The strategy herein is
general and suitable for the synthesis of several ana-
logues of cyperanes to assess their biological potential,
which is currently under investigation.
8. Hikino, H.; Kohama, T.; Takemoto, T. Tetrahedron 1969,
25, 1037.
9. Ceccherelli, P.; Curini, M.; Marcotullio, M. C.; Rosati, O.
Tetrahedron 1989, 45, 3809.
10. (a) Buchi, G.; Egger, B. J. Org. Chem. 1971, 36, 2021; (b)
Srikrishna, A.; Hemamalini, P. Indian J. Chem. 1990, 29B,
479.
11. Garver, L.; van Eikeren, P.; Byrd, J. E. J. Org. Chem.
1976, 41, 2773.
12. Johnson, W. S.; Werthemann, L.; Bartlett, W. R.; Brock-
som, T. J.; Li, T. T.; Faulkner, D. J.; Petersen, M. R. J.
Am. Chem. Soc. 1970, 92, 741.
13. (a) Stork, G.; Ficini, J. J. Am. Chem. Soc. 1961, 83, 4678;
(b) Burke, S. D.; Grieco, P. A. Org. React. 1979, 26, 361;
(c) Mander, L. N. Synlett 1991, 134.
14. (a) Norin, T. Acta Chem. Scand. 1963, 17, 738; (b) Dauben,
W. G.; Deviny, E. J. J. Org. Chem. 1966, 31, 3794; (c)
Dauben, W. G.; Wolf, R. E. J. Org. Chem. 1970, 35, 374;
(d) Dauben, W. G.; Wolf, R. E. J. Org. Chem. 1970, 35,
2361; (e) Norin, T. Acta Chem. Scand. 1965, 19, 1289.
Acknowledgements
We thank the Council of Scientific and Industrial Re-
search, New Delhi for the award of a research fellowship
toC.D.

A. Srikrishna, C. Dinesh / Tetrahedron: Asymmetry 16 (2005) 2203–2207
2207
15. Nunez, M. T.; Martin, V. S. J. Org. Chem. 1990, 55, 1928.
16. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Hughes, D. L.
Org. React. 1992, 42, 335.
d, J 19.2 Hz), 2.33 (1H, d, J 13.5 Hz), 2.20 (1H, d, J
18.9 Hz), 1.75 (1H, d, J 19.2 Hz), 1.70–1.00 (7H, m), 1.05–
1.00 (1H, m), 0.98 (3H, s), 0.86 (3H, d, J 6.6 Hz), 0.84 (3H,
d, J 6.6 Hz). 13C NMR (75 MHz, CDCl3 + CCl4): d 217.1
(C), 172.5 (C), 51.4 (CH3), 51.3 (CH2), 47.6 (CH2), 42.6
(C), 41.0 (C), 39.0 (CH), 38.0 (CH2), 35.6 (CH2), 32.6
(CH2), 32.5 (CH), 25.6 (CH3), 25.2 (CH2), 19.9 (CH3),
17. All the compounds exhibited spectral data (IR, 1H and 13
C
NMR and mass) consistent with their structures. Selected
28
D
spectral data for 13: ½aŠ ¼ ꢀ47.5 (c 1.2, CHCl3). IR
(neat):
m
max/cmꢀ11742, 887. 1H NMR (300 MHz,
CDCl3 + CCl4): d 4.67 (2H, s), 2.69 (1H, d, J 18.6 Hz),
2.20 (1H, d, J 18.3 Hz), 1.98 (1H, d, J 18.3 Hz), 1.75–1.20
(10H, m), 1.72 (3H, s), 0.98 (3H, s), 0.85 (3H, t, J 7.5 Hz).
13C NMR (75 MHz, CDCl3 + CCl4): d 217.6 (C), 149.3
(C), 109.0 (CH2), 50.4 (CH2), 48.5 (CH2), 43.8 (C), 40.8
(C), 40.0 (CH), 35.3 (CH2), 32.7 (CH2), 27.0 (CH2), 25.4
19.6 (CH3).
23
19. For 37: ½aŠ ¼ ꢀ57.0 (c 1.0, CHCl3). IR (neat): mmax/cmꢀ1
D
1739. 1H NMR (300 MHz, CDCl3 + CCl4): d 3.65 (3H, s),
2.40–2.00 (3H, m), 1.90 (1H, d, J 18.0 Hz), 1.75–1.00
(10H, m), 1.11 (3H, s), 0.90 (3H, d, J 6.6 Hz), 0.89 (3H, d,
J 6.6 Hz). 13C NMR (75 MHz, CDCl3 + CCl4): d 215.9
(C), 171.8 (C), 52.5 (CH2), 51.2 (CH3), 44.4 (CH2), 43.9
(C), 41.9 (CH2), 40.2 (C), 38.6 (CH), 37.4 (CH2),
33.4 (CH2), 32.5 (CH), 24.7 (CH2), 20.1 (CH3), 19.5 (2C,
CH3).
(CH3), 24.3 (CH2), 21.1 (CH3), 9.6 (CH3).
23
D
18. For 28: ½aŠ ¼ ꢀ40.0 (c 0.5, CHCl3). IR (neat): mmax/cmꢀ1
1739. 1H NMR (300 MHz, CDCl3 + CCl4): d 3.65 (3H, s),
2.67 (1H, d, J 13.5 Hz), 2.60 (1H, d, J 18.9 Hz), 2.52 (1H,