Total synthesis of (+)-cyperolone

Article abstract of DOI:10.1021/ol300058t

The total synthesis of (+)-cyperolone, an eudesmane-derived sesquiterpenoid from Cyperus rotundus, is described. The de novo synthesis was accomplished via a 15 step sequence starting from (R)-(-)-carvone. The synthetic route features a platinum-catalyzed

Full text of DOI:10.1021/ol300058t

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1250–1253
Total Synthesis of (þ)-Cyperolone
‡
‡
,†,‡
Philipp Klahn,†,‡ Alexander Duschek, Clemence Liebert, and Stefan F. Kirsch*
ꢀ
ꢀ
€
Organic Chemistry, Bergische Universitat Wuppertal, Gaussstr. 20, 42119 Wuppertal,
Germany, and Department Chemie, Technische Universitat Munchen, Lichtenbergstr. 4,
€
€
85747 Garching, Germany
sfkirsch@uni-wuppertal.de
Received January 11, 2012
ABSTRACT
The total synthesis of (þ)-cyperolone, an eudesmane-derived sesquiterpenoid from Cyperus rotundus, is described. The de novo synthesis was
accomplished via a 15 step sequence starting from (R)-(ꢀ)-carvone. The synthetic route features a platinum-catalyzed cycloisomerization to
rapidly construct the bicyclic core from a 3-silyloxy-1,5-enyne intermediate.
Cyperolone (1) was isolated first in 1966 by Hikino et al.
from Cyperus rotundus LINNE (Japanese nutgrass).1 The
eudesmane-derived natural product belongs to the rather
small class of cyperane-type sesquiterpenoids, all members
of which were isolated from cognate plants.2 Although the
rhizomes of Japanese nutgrass have found widespread use
in traditional oriental medicine to treat, for example,
menstrual disorders and gynecological diseases,3 the bio-
logical activity of cyperolone has not been fully evaluated.4
We planned to synthesize cyperolone, not only because a
chemical synthesis entry would allow the further explora-
tion of the pharmacology but also because a flexible de
novo approach would provide a general entry into the
entire class of cyperane-type natural products.5 The struc-
ture of cyperolone (1) is characterized by a sterically
congested bicyclic system where all substituents are di-
rected to the same face and two quaternary all-carbon
stereogenic centers are adjacent to each other (Figure 1).
The total synthesis of cyperolone was successfully achieved
in 1966 by Hikino et al. in a semisynthetic approach
starting from R-cyperone, thus, supporting the early struc-
tural assignments.6 Further synthetic entries into cyper-
ane-class natural products are scarce.7,8 In this letter, we
describe the total synthesis of (þ)-cyperolone starting from
(R)-(ꢀ)-carvone.
†
€
Bergische Universitat Wuppertal.
‡
€
Technische Universitat M€unchen.
(1) (a) Hikino, H.; Aota, K.; Maebayashi, Y.; Takemoto, T. Chem.
Pharm. Bull. 1966, 14, 1439–1441. (b) Hikino, H.; Aota, K.; Maebayashi,
Y.; Takemoto, T. Chem. Pharm. Bull. 1967, 15, 1349–1355. (c) Kapadia,
V. H.; Naik, V. G.; Wadia, M. S.; Dev, S. Tetrahedron Lett. 1967, 8,
4661–4667.
(2) Ahmed, A. A.; Jakupovic, J. Phytochemistry 1990, 29, 3658–3661.
(b) El-Ghazouly, M. G.; El-Sebakhy, N. A.; El-Din, A. A. S.; Zdero, C.;
Bohlmann, F. Phytochemistry 1987, 26, 439–443. (c) Todorova, M. N.;
Tsankova, E. T. Phytochemistry 1999, 52, 1515–1518. (d) Ohira, S.;
Hasegawa, T.; Hayashi, K.-I.; Hoshino, T.; Takaoka, D.; Nozaki, H.
Phytochemistry 1998, 47, 1577–1581. (e) Ceccherelli, P.; Curini, M.;
Marcotullio, M. C. J. Nat. Prod. 1988, 51, 1006–1009. (f) Rustaiyan, A.;
Jakupovic, J.; Chau-Thi, T. V.; Bohlmann, F.; Sadjadi, A. Phytochem-
€
istry 1987, 26, 2603–2606. (g) Sonwa, M. M.; Konig, W. A. Phytochem-
istry 2001, 58, 799–810.
Figure 1. Structures of cyperolone (1).
(3) Shi, Y.; Yang, W.; Zhang, J.-S.; Leung, T. C. H.; Yung, K. K. L.
Neuroembryol. Aging 2004, 3, 123–127. (b) Kilani, S.; Sghaier, M. B.;
Limem, I.; Bouhlel, I.; Boubaker, J.; Bhouri, W.; Skandrani, I.; Neffatti,
A.; Ammar, R. B.; Dijoux-Franca, M. G.; Ghedira, K.; Chekir-Ghedira,
L. Bioresour. Technol. 2008, 99, 9004–9008.
(4) Plant growth inhibition was reported: Komai, K.; Seto, N.;
Matsubayashi, K.; Hamada, M. Zasso Kenkyu (Weed Res. Jp.) 1990,
35, 164–168.
(5) Based on 1H NMR data, structural assignments of several
cyperanes appear to be inconsistent, e.g.: ref 2a vs ref 2e. Ceccherelli,
P.; Curini, M.; Marcotullio, M. C.; Rosati, O. Tetrahedron 1989, 45,
3809–3818.
r
10.1021/ol300058t
Published on Web 02/10/2012
2012 American Chemical Society

Cyperolone (1) is a cis-fused bicyclo[4.3]nonane. As
outlined in Figure 2, we planned to construct this bicyclic
core by use of a domino reaction9 previously developed
in our group: In the presence of noble-metal catalysts,
3-silyloxy-1,5-enynes undergo a 6-endo cyclization followed
by a pinacol shift to give five-membered carbocycles.10,11
According to this strategy, we considered bicycle 2 as a key
intermediate that contains the two quaternary stereogenic
centers and that can be easily accessed from 3. Further
elaboration to the target compound 1 would involve the
removal of the carbonyl group. Additionally, the endo-
cyclic alkene moiety would have to be converted into its
epoxide. Powerful hydride nucleophiles are then required
to create the hydroxy group at C3 through epoxide open-
ing. To avoid the risk of competing attack at the acetyl
moiety, we decided to postpone the installation of this
functionality to a late stage of the synthesis. To this end,
bicycle 2 (and its direct precursor 3) were equipped with
a stable silyloxy methylene group (R = CH2OSii-Pr3)
rather than with an acetyl group.12 We further envi-
sioned that 3-silyloxy-1,5-enyne 3 can be prepared from
(R)-(ꢀ)-carvone incorporating the isopropenyl-bearing
stereogenic center at C5.
Our synthesis began with the conversion of (R)-
(ꢀ)-carvone into chlorohydrine 4 followed by hydrolysis
under basic conditions (Scheme 1). Even though only
moderate yields were obtained for the hydrolysis step,
we found this two-step sequence to diol 5 advantageous
over alternative sequences13 since it proved scalable and
highly reliable in terms of yield. Upon selective protec-
tion of the primary hydroxy as triisopropylsilyl ether,
oxidative rearrangement14 to the cyclic enone 6 was
achieved by use of pyridinium chlorochromate (PCC).
Addition of the Grignard reagent derived from propargyl
bromide15 and subsequent silylation of the tertiary hydro-
xy smoothly resulted in the formation of key 3-siloxy-1,
5-enyne 3.
Table 1. Optimization of the Conversion 2f3a
catalyst
(mol %)
additive
(mol %)
temp
yield
(%)b
entry
solvent
(°C)
c
1
2
3
4
5
6
ClAuPPh3 (5)
PtCl2 (10)
PtCl2 (20)
PtCl4 (10)
PtCl4 (10)
PtCl4 (20)
AgSbF6 (5)
cod (80)
CH2Cl2
Ph-Me
Ph-Me
Ph-F
23
100
35
50
35
23
ꢀ
44
76
51
69
80
cod (40)
Ph-Me
Ph-Me
cod (80)
a Conditions: 3, catalyst, i-PrOH, temperature, solvent. b Isolated
yield after column chromatography. c No conversion.
(8) For an approach to the cyperane framework, see: Srikrishna, A.;
Dinesh, C. Tetrahedron: Asymmetry 2005, 16, 2203–2207.
(9) For leading reviews on domino reactions, see: (a) Crone, B.;
Kirsch, S. F. Chem.;Eur. J. 2008, 14, 3514–3522. (b) Kirsch, S. F.
Synthesis 2008, 3183–3204. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115–
136. (d) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem.,
Int. Ed. 2006, 45, 7134–7186. (e) Overman, L. E.; Pennington, L. D.
J. Org. Chem. 2003, 68, 7143–7157. (f) Pellisier, H. Tetrahedron 2006, 62,
2143–2173.
Figure 2. Synthetic plan.
Scheme 1. Synthesis of 3-Silyloxy-1,5-enyne 3
(10) Kirsch, S. F.; Binder, J. T.; Crone, B.; Duschek, A.; Haug, T. T.;
ꢀ
Liebert, C.; Menz, H. Angew. Chem., Int. Ed. 2007, 46, 2310–2313. (b)
Menz, H.; Binder, J. T.; Crone, B.; Duschek, A.; Haug, T. T.; Kirsch,
ꢀ
S. F.; Klahn, P.; Liebert, C. Tetrahedron 2009, 65, 1880–1888. (c) Baskar,
B.; Bae, H. J.; An, S. E.; Cheong, J. Y.; Rhee, Y. H.; Duschek, A.;
Kirsch, S. F. Org. Lett. 2008, 10, 2605–2607.
ꢀ
ꢀ~
(11) For related strategies, see inter alia: (a) Jimenez-Nunez, E.;
Claverie, C. K.; Nieto-Oberhuber, C.; Echavarren, A. M. Angew. Chem.,
Int. Ed. 2006, 45, 5452. (b) Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007,
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129, 6398. (c) Korotchenko, V. N.; Gagne, M. R. J. Org. Chem. 2007, 72,
4877. (d) Sethofer, S. G.; Staben, S. T.; Hung, O. Y.; Toste, F. D. Org.
Lett. 2008, 10, 4315. (e) Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc.
2009, 131, 9178. (f) Alcarazo, M.; Stork, T.; Anoop, A.; Thiel, W.;
€
Furstner, A. Angew. Chem., Int. Ed. 2010, 49, 2542. For an application
in total synthesis, see: (g) Canham, S. M.; France, D. J.; Overman, L. E.
J. Am. Chem. Soc. 2010, 132, 7876.
(12) As an alternative approach, we also investigated substrates 3
with R = ;CHdCH2 and R = ;CtCH. However, these substrates
failed to undergo noble-metal-catalyzed cycloisomerization to 3 as will
be detailed elsewhere.
(13) An established protocol that makes use of methylthiomethyl
lithium addition onto carvone did not provide reproducible yields in our
hands: Tanis, S. P.; McMills, M. C.; Herrinton, P. M. J. Org. Chem.
1985, 50, 5887–5889.
(6) Hikino, H.; Suzuki, N.; Takemoto, T. Chem. Pharm. Bull. 1966,
14, 1441–1443. (b) Hikino, H.; Suzuki, N.; Takemoto, T. Chem. Pharm.
Bull. 1967, 15, 1395–1404.
(7) Hikino, H.; Kohama, T.; Takemoto, T. Tetrahedron 1969, 25,
1037–1045. (b) Mehta, G.; Chetty, G. L.; Nayak, U. R.; Dev, S.
Tetrahedron 1968, 24, 3775–3786.
Org. Lett., Vol. 14, No. 5, 2012
1251

We next investigated the key conversion of enyne 3 into
bicycle 2. Unfortunately, when the conditions developed in
our 2007 study were employed (10 mol % ClAuPPh3
activated by 5 mol % AgSbF6, stoichiometric amounts
ofi-PrOH, 23°C, CH2Cl2),10a not eventracesofthedesired
compound 2 were detected (Table 1, entry 1). We attrib-
uted this lack of reactivity to the reduced nucleophilicity
of the tetrasubstituted olefin moiety; all the previously
reacted 3-silyloxy-1,5-enynes contained internal olefin nu-
cleophiles that were either di- or trisubstituted. Conse-
quently, we started to reexamine the potential of various
transition metal catalysts including gold, palladium, and
copper complexes to make the conversion 3f2 possible.16
It was finally found that, only in the presence of platinum
catalysts, formation of the anticipated product 2 was
indeed possible.17 As shown in Table 1, both PtCl2 and
PtCl4 were active precatalysts in the presence of substoi-
chiometric amounts of cyclooctadiene (cod). The best
yields were obtained when employing 20 mol % of PtCl4
and 80 mol % of cod in toluene at 23 °C (entry 6). Since in
all cases lower catalyst loadings resulted in significantly
reduced yields, the conditions shown in entry 6 were also
utilized for gram-scale reactions to continue our approach
to cyperolone.
tetrasubstituted olefins. It should be pointed out that
substituents at the alkyne terminus lead to a marked
decrease in yield, presumably due to the increased steric
hindrance in the CꢀC bond-forming event. Notably, en-
yne 7a having a triethylsilyloxy group provided diene 8
rather than aldehyde 9. When switching from triethylsily-
loxy to triisopropylsilyloxy, cycloisomerization took place
to achieve the formation of 9 in 41% yield.
With conditions for the formation of key intermediate 2
in hand, we finished the total synthesis of (þ)-cyperolone
as shown in Scheme 3. Removal of the carbonyl group was
Scheme 3. Total Synthesis of (þ)-Cyperolone
Scheme 2. Cycloisomerization of 3-Silyloxy-1,5-enynes
achieved by forming the tosylhydrazone 10 followed by
treatment with DIBAL-H.18 Deprotection of the pri-
mary triisopropylsilyl ether yielded alcohol 12. Vanadium-
catalyzed epoxidation was directed through the homoallylic
(16) For selected reviews on π-activation with carbophilic Lewis
As summarized in Scheme 2, reaction conditions that
utilize PtCl4 as a precatalyst are also successful in the
cycloisomerization of other 3-silyloxy-1,5-enynes having
€
acids, see: (a) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed.
2007, 46, 3410–3449. (b) Corma, A.; Leyva-Perez, A.; Sabater, M. J.
Chem. Rev. 2011, 111, 1657–1721. (c) Gorin, D. J.; Sherry, B. D.; Toste,
F. D. Chem. Rev. 2008, 108, 3351–3378.
(17) For the use of platinum catalysts in π-activation cascades, see
inter alia: (a) Umland, K.-D.; Palisse, A.; Haug, T. T.; Kirsch, S. F.
Angew. Chem., Int. Ed. 2011, 50, 9965–9968. (b) Kirsch, S. F.; Binder,
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Lett. 2000, 41, 3177–3180. (b) Dominguez, M.; Alvarez, R.; Martras, S.;
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1982, 245–258.
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Org. Lett., Vol. 14, No. 5, 2012

alcohol moiety in 12 and, thus, proceeded with complete
diastereocontrol;19 the isopropenyl group remained un-
reacted under these conditions.20 Subsequent oxidation21
of the hydroxy group followed by homologation with the
SeyferthꢀGilbert reagent22 furnished alkyne 15. Nucleo-
philic epoxide opening with LiAlH4 gave the secondary
alcohol 16 in 91% yield. As expected the hydride reagent
opened the epoxide regioselectively from the sterically less
hindered side. Finally, terminal alkyne 15 was successfully
converted into (þ)-cyperolone (1) in 30% yield using HgO
in aqueous H2SO4 and acetone.23 The spectroscopic data
of the synthetic samples were in excellent agreement with
those reported in the literature for the natural product.1
Despite the poor ending step (16f1), the overall end game
strategy (12f1) proved highly useful due to the fact that (i)
it is reasonably short regarding the number of steps and (ii)
it does not require additional protecting group operations.24
It should be mentioned that the major product of the Hg-
mediated hydration was the tricyclic lactone 17 resulting in
44% yield from a ready 5-endo cyclization and subsequent
oxidation. This result demonstrated how steric crowding
hampers the straightforward installation of the acetyl
group. A multitude of hydration conditions led to de-
composition, no reaction, or predominant five-membered
ring formation; in no case, a better yield for the desired
cyperolone target was accomplished.25 Our attempts to
react olefin 18 under Wacker conditions26 most likely
failed for the same reasons.
In summary, we have described an expedient, stereo-
controlled synthesis of (þ)-cyperolone (15 steps, 4.3%
overall yield from carvone). The two quaternary stereo-
genic centers were formed in a novel platinum-catalyzed
cycloisomerization stepthatcombinesanenynecyclization
with a pinacol-type shift. Furthermore, our approach to
cyperolone should provide a general entry into the whole
class of cyperane-type natural products by further elabora-
tion of the isopropenyl group. Applications of this syn-
thetic strategy to the synthesis of other cyperanes and
studiesofthe biological activityof cyperolonearecurrently
underway.
Acknowledgment. This project was supported by the
Fonds der Chemischen Industrie (FCI) and by Deutsche
Forschungsgemeinschaft (DFG). P.K. thanks TUM-GS
and CGS (BUW) for support. Experimental support by
€
Andreas Haring (TUM) is acknowledged. The authors
thank Prof. Dr. Th. Bach (TUM) for support.
Supporting Information Available. Experimental pro-
1
cedures for all compounds, and copies of H and 13C
NMR. This material is available free of charge via the
Internet at http://pubs.acs.org.
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several hydration conditions, the starting material remained unchanged
in all cases.
€
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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