First asymmetric total syntheses and determination of absolute configurations of (+)-eudesmadiene-12,6-olide and (+)-frullanolide

Article abstract of DOI:10.1021/ol4003724

The first asymmetric total syntheses of sesquiterpene lactones (+)-eudesmadiene-12,6-olide (1) and (+)-frullanolide (2) have been accomplished from 4-bromo-2-methoxyphenol (5) in 12 and 13 synthetic steps, respectively, and the absolute configurations of

Full text of DOI:10.1021/ol4003724

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1584–1587
First Asymmetric Total Syntheses and
Determination of Absolute Configurations
of (þ)-Eudesmadiene-12,6-olide and
(þ)-Frullanolide
Yu-Yu Chou and Chun-Chen Liao*
Department of Chemistry, National TsingHua University, Hsinchu 30013, Taiwan, and
Department of Chemistry, Chung Yuan Christian University, Chungli 32023, Taiwan
ccliao@cycu.edu.tw
Received February 6, 2013
ABSTRACT
The first asymmetric total syntheses of sesquiterpene lactones (þ)-eudesmadiene-12,6-olide (1) and (þ)-frullanolide (2) have been accomplished from
4-bromo-2-methoxyphenol (5) in 12 and 13 synthetic steps, respectively, and the absolute configurations of these two natural products were determined.
(þ)-Eudesmadiene-12,6-olide (1) was isolated from the
plant of the Frullania muscicol in 1994 by Sim-Sim and co-
workers.1a Recently, it has been found to have in vivo
antitrypanosomal activity against Trypanosoma brucei
brucei GUTat 3.1, with an EC50 value of 0.18 g/mL, and
cytotoxicity against the MRC-5 cell in a concentration of
6.5 g/mL (EC50).1b (þ)-Frullanolide (2) is an allergy-
producing substance that occurs in certain plant material
of the Frullania tamarisci (L.).2 Compounds 1 and 2
are densely oxygenated members of the eudesmanolide
family of sesquiterpene lactones, which also include their
stereoisomers arbusculin B (3) and critonilide (4, Figure 1).3
R-Methylene-γ-butyrolactones, which are a very often
encountered skeleton, have biological activity such as
allergenic activity,2a,c exhibiting growth-inhibitory activity
in vivo against animal tumor systems and in vivo against
cells derived from human carcinoma of the nasopharynx
(KB),4 or effecting regulation of plant growth and anti-
mitotic activity.5
Several methods have been reported for the synthesis of
(()-frullanolide (2).6 A convergent route to R-substituted
acrylic esters and application to the total synthesis of
(()-frullanolide was developed by Still and co-workers
in 1977.6a Later, Petragnani et al. reported a synthesis of
(()-frullanolide from 2-phenylselenopropanoic acid.6d,e
Subsequently, Clive and co-worker developed an ele-
gant synthesis of (()-frullanolide from hydronapthalene
derivatives.6g However, syntheses of eudesmadiene-12,6-
olide and chiral (þ)-frullanolide are still lacking. We are
(1) (a) Kraut, L.; Mues, R.; Sim-Sim, M. Phytochemistry 1994, 37,
1337–1346. (b) Otoguro, K.; Iwatsuki, M.; Ishiyama, A.; Namatame,
M.; Nishihara-Tukashima, A.; Kiyohara, H.; Hashimoto, T.; Asakawa,
Y.; Omura, A.; Yamada, H. Phytochemistry 2011, 72, 2024–2030.
(2) (a) Knocke, H.; Ourisson, G.; Perold, G. W.; Foussereau, J.;
Maleville, J. Science 1969, 166, 239–240. (b) Perold, G. W.; Muller, J.-C.;
Ourisson, G. Tetrahedron 1972, 28, 5797–5803. (c) Mitchell, J. C.;
Dupuis, G.; Gessman, T. A. Brit. J. Dermatol. 1972, 87, 235–240 and
references cited therein.
Figure 1. Various types of eudesmanolide family of sesquiter-
pene lactones.
(4) Kupchan, S. M.; Eakin, M. A.; Thomas, M. A. J. Med. Chem.
1971, 14, 1147–1152.
(5) Shibaoka, H.; Shimokariyama, M.; Iriuchijima, S.; Tamura, S.
(3) (a) Fraga, B. M. Nat. Prod. Rep. 2002, 19, 650–672. (b) Merten, J.;
Hennig, A.; Schwab, P.; Frohlich, R.; Tokalov, S. V.; Gutzeit, H. O.;
Metz, P. Eur. J. Org. Chem. 2006, 1144–1161. (c) Wu, Q.-X.; Shi, Y. P.;
Jia, Z.-J. Nat. Prod. Rep. 2006, 23, 699–734.
Plant Cell Physiol. 1967, 8, 297–305.
r
10.1021/ol4003724
Published on Web 03/13/2013
2013 American Chemical Society

interested in the molecules (þ)-eudesmadiene-12,6-olide
(1) and (þ)-frullanolide (2) because of their significant
biological activities and structural characteristics, their
substituents possessing all cis-configurations, and their
absolute configurations which, to our knowledge, are not
yet known, and we wish to develop a more general and
highly stereocontrolled total synthetic method.
Scheme 1. Retrosynthetic Analysis of 1 and 2
Masked o-benzoquinones (MOBs),7 a highly reactive
class of cyclohexa-2,4-dienones with extensive utility, can
be easily generated in situ by oxidation of the correspond-
ing 2-methoxyphenols with hypervalent iodine reagents8
such as diacetoxyiodobenzene (DAIB) in the presence of
an appropriate alcohol. In the course of our investigations on
the DielsꢀAlder reactions of MOBs, we developed a flurry
of synthetic strategies to synthesize natural and unnatural
products.9 Recently, we published intriguing results from a
highly diastereoselective and asymmetric DielsꢀAlder pro-
tocol of MOBs leading to highly functionalized and novel
tricyclic ring systems with multiple stereogenic centers10
and disclosed the results of photooxygenation reactions of
MOBs affording a variety of functionalized cyclopenteno-
nes.11 We have also developed a three-step synthesis of
optically pure bicyclo[2.2.2]oct-5-en-2-ones via carbohy-
drate-templated asymmetric intramolecular DielsꢀAlder
reactions of MOBs12 and reported the syntheses of opti-
cally pure conduramines via a hetero-DielsꢀAlder reac-
tion of MOBs with homochiral nitroso dienophiles.13
We herein report the first asymmetric total synthesis of
sesquiterpene lactones (þ)-eudesmadiene-12,6-olide (1)
and (þ)-frullanolide (2) using an MOB strategy and the
determination of their absolute configurations.
Retrosynthetically, the tricyclic compound 13 constitu-
tes the key building block for the syntheses of 1 and 2.
Logically, the intermediate 13 could be conceived by a
protocol involving the anionic oxy-Cope rearrangement
from bicyclo[2.2.2]octenone 12a which could be formally
envisioned by the asymmetric intermolecular DielsꢀAlder
reaction of the corresponding MOB derived from 4-sub-
stituted 2-methoxyphenol (5) with homochiral furan (R)-7.
Here the furan behaves as a dienophile rather than a diene,
as well as a precursor of the γ-butyrolactone moieties in 1
and 2, followed by coupling and Grignard reactions
(Scheme 1). The chemoselective addition of the homodiene
of the MOB onto the less substituted double bond of
furan (R)-7 will control the proper regiochemistry of the
γ-butyrolactone ring; the endoaddition will dictate all
cis-configurations of substituents in 1 and 2 after the anionic
oxy-Cope rearrangement. The facially selective addition
from the less hindered side of furan (R)-7 will ensure the
high diastereoselectivity in 13 and eventually result in the
high enantioselective formation of 1 and 2. Thus the design
will be a short and efficient entry to 1 and 2 with anticipated
high chemo-, regio-, stereo-, and diastereoselectivities.14
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Org. Lett., Vol. 15, No. 7, 2013
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Table 1. Optimization of Reaction Conditions for the Anionic
Oxy-Cope Rearrangement of 12
Scheme 2. Synthesis of Key Intermediate 13
base/
equiv
products/
yields (%)b
entry
solvent t (h) T (°C)a
c
c
1
2
3
4
5
KH/5
THF
24
24
24
24
20
rt
ꢀ
ꢀ
KH/5
THF
80
KHMDS/5
KHMDS/5
KHMDS/5
THF
80
12a /70 þ 14 /15
12a /30 þ 13 /50
13 /87
PhMe
PhMe
100
130
a Oil bath temperature. b Isolated yields after silica gel column
chromatography. c Recovered starting material.
chloride reagent system to generate syn-12a and anti-12b
(20:1) in 80% and 5% isolated yields, respectively.18
With compound 12a in hand, we screened with KH
and KHMDS under various conditions; the best results
were obtained when 12a was treated with KHMDS and
18-crown-6 in refluxing toluene to give cis-decalin 13 in
87% yield via anionic oxy-Cope rearrangement (Table 1,
Scheme 2).19 The relative configuration was confirmed
with nuclear Overhauser enhancement experiments
(NOE, Figure 2) and X-ray diffraction studies (Figure 3
for ORTEP diagram and CCDC 900657). The absolute
stereochemistry with four stereogenic centers (5S,6S,7R,
10R) of 13 was thus determined accordingly as the chiral
center C-13 derived from the corresponding part of homo-
chiralfuran(R)-7maintaining the sameconfigurations. All
the products were well characterized with their spectral
data (see Supporting Information).
The key intermediate 13 under the Huang-Minlon re-
duction conditions20 provided enol ether 15, which was
further transformed into 16 in 75% yield via tandem
reactions including hydrolysis of the enol ether, hydroge-
nation of the double bond and the hydrogenolysis of the
benzyl group, and sodium periodate mediated oxidativeꢀ
elimination reactions. After having compound 16 in hand,
we tried with several reagents to convert its carbonyl group
into the methylene group of 17; the best results were
obtained when compound 16 was treated with the Takai
reagent21 in THF/CH2Cl2 at 0 °C (Table 2, Scheme 3).
To achieve the synthesis of our target molecule (þ)-
eudesmadiene-12,6-olide 1, compound 17 was treated with
paraformaldehyde3b,22 in the presence of sodium hydride
Initially we planned to use 4-methyl-2-methoxyphenol
as a starting material to address the possibility of an
efficient construction of functionalized bicyclic compound
12a; however, the corresponding MOB did not add to
homochiral furan (R)-715 but proceeded mainly with
dimerization.16 Thus we tried a detour strategy17 and
started with the intermolecular DielsꢀAlder reactions of
MOB 6 prepared in situ from commercially accessible
4-bromo-2-methoxyphenol (5) in the presence of DAIB
and homochiral furan (R)-7 to obtain DielsꢀAlder adduct
8 in 73% yield with97% de; the chemical yield of 8 is due to
the formation of dimer 9 (Scheme 2).10 Compound 8 was
treated with benzyl bromide, in the presence of tetrabutyl-
ammonium iodide, and sodium hydride at 80 °C for 4 h to
give the benzylated product 10 in 92% yield which, upon
simple recrystallization, was obtained in high de (>99%).
The homochiral 10 is a viable substrate for the cross-
coupling reaction to afford 11, in excellent yield, which
was treated with a vinylmagnesium bromideꢀcerium(III)
(19) For a selection of similar anionic oxy-cope rearragements, see:
(a) Devaux, J.-F; Hanna, I.; Lallemand, J.-Y. J. Org. Chem. 1993,
58, 2349–2350. (b) Martin, S. F.; Assercq, J.-M.; Austin, R. E.;
Dantanarayana, A. P.; Fishpaugh, J. R.; Gluchowski, C.; Guinn,
D. E.; Martmann, M.; Tanaka, T.; Wagner, R.; White, J. B. Tetrahedron
1995, 51, 3455–3482. (c) Njardarson, J. T.; Wood, J. L. Org. Lett. 2001,
3, 2431–2434.
(15) Kusakabe, M.; Kitano, Y.; Kobayashi, Y.; Sato, F. J. Org.
Chem. 1989, 54, 2085–2091.
(16) Drutu, I.; Njardarson, J. T.; Wood, J. L. Org. Lett. 2002, 4, 493–
496.
(17) Chittimalla, S. K.; Hsiao, H.-Y.; Liao, C.-C. Org. Biomol. Chem.
2006, 4, 2267–2277.
(18) Juo, W.-J.; Lee, T.-H.; Liu, W.-C.; Ko, S.; Chittimalla, S. K.;
(20) Huang-Minlon J. Am. Chem. Soc. 1946, 68, 2487–2488.
(21) Li, G.; Padwa, A. Org. Lett. 2011, 13, 3767–3769.
Rao, C. P.; Liao, C.-C. J. Org. Chem. 2007, 72, 7992–8004.
1586
Org. Lett., Vol. 15, No. 7, 2013

Scheme 3. Syntheses of (þ)-Eudesmadiene-12,6-olide (1) and
(þ)-Frullanolide (2)
Figure 2. 1H NMR studies of NOE (%) for 13.
Figure 3. ORTEP diagram of key intermediate 13.
In conclusion, we have successfully accomplished the
first asymmetric total syntheses of (þ)-eudesmadiene-12,6-
olide 1 and (þ)-frullanolide 2 in 14.4% and 9.5% overall
yields and 12 and 13 synthetic steps, respectively; an
asymmetric intermolecular DielsꢀAlder reaction of
MOB 6 with homochiral furan (R)-7, in high chemo-,
regio-, stereo-, and diastereoselectivities, and an anionic
oxy-Cope rearrangement with 12a are the key steps. The
absolute stereochemistry with four stereogenic centers
(5S,6S,7R,10R) of 13, and accordingly those of 1 and 2,
was determined from the X-ray diffraction studies of 13
and its chiral center C-13 derived from the chiral carbon
atom of homochiral furan (R)-7.
Table 2. Survey of Reaction Conditions to Transform 16 into 1
entry
reagents
solvent
T (°C)a
t (h) yield (%)b
1
2
3
4
5
CH3PPh3Br, NaH
THF 0 °C to rt
5
40
35
42
44
53
CH3PPh3Br, KOtBu THF 0 °C to rt
CH3PPh3Br, nBuLi THF 0 °C to rt
CH3PPh3Br, nBuLi THF ꢀ78 °C to rt
7
8
8
Zn, CH2I2, TiCl4
THF/ rt
CH2Cl2
15
Acknowledgment. The financial support from the
CYCU distinctive research area project as Grant CYCU-
99-CR-CH and National Science Council (NSC) of Taiwan
(Grant Nos.: NSC 99-2113-M-033-002, 100-2113-M-033-
005) is gratefully aknowledged. We thank Dr. S.-Y. Gao
for some preliminary studies and are grateful to Professor
Gary J. Chuang and Dr. B. Devendar for their helpful
discussions. Y.-Y.C. thanks NSC of Taiwan (Grant No.:
NSC 100-2811-M-033-007) for a postdoctoral fellowship.
6
7
Zn, PbCl4,
THF/ ꢀ78 °C to rt 20
71
78
CH2I2, TiCl4
Zn, PbCl4,
CH2Cl2
THF/ 0 °C to rt
24
CH2I2, TiCl4
CH2Cl2
a Oil bath temperature. b Isolated yields after silica gel column
chromatography.
to produce the desired compound 1 in 68% yield. Finally, 1
was converted into another important sesquiterpene lac-
tone (þ)-frullanolide 2 in the presence of p-toluenesulfonic
acid (Scheme 3).23 The spectral data and the specific
rotations of the presently synthesized compounds 1 and 2
are in good agreement with those reported.1a
Supporting Information Available. Experimental de-
tails; 1H, 13C NMR and DEPT spectra for compounds 1,
1
2, 10ꢀ17; 1Hꢀ H COSY spectrum for compound 13; and
HPLC chromatogram for compound 10. This material
is available free of charge via the Internet at http://
pubs.acs.org.
(22) Noya, B.; Paredes, M. D.; Ozores, L.; Alonso, R. J. Org. Chem.
2000, 65, 5960–5968.
(23) Piers, E.; Breau, M. L.; Han, Y.; Plourde, G. L.; Yeh, W. L.
J. Chem. Soc., Perkin Trans. 1 1995, 963–965.
The authors declare no competing financial interest.
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