Synthetic study of yonarolide: Stereoselective construction of the tricyclic core

Article abstract of DOI:10.1016/j.tetlet.2011.04.092

Stereoselective construction of the tricyclic core of yonarolide (1), a marine norditerpenoid, was achieved. This synthetic route includes a Diels-Alder reaction and an intramolecular aldol condensation. It also involves efficient epimerization through a retro-Michael reaction-Michael addition and will be applicable to the total synthesis of 1.

Full text of DOI:10.1016/j.tetlet.2011.04.092

Tetrahedron Letters 52 (2011) 3379–3381
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic study of yonarolide: stereoselective construction of the tricyclic core
⇑
Yohei Ueda, Hideki Abe, Kazuo Iguchi, Hisanaka Ito
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Stereoselective construction of the tricyclic core of yonarolide (1), a marine norditerpenoid, was achieved.
This synthetic route includes a Diels–Alder reaction and an intramolecular aldol condensation. It also
involves efficient epimerization through a retro-Michael reaction–Michael addition and will be applica-
ble to the total synthesis of 1.
Received 9 March 2011
Revised 21 April 2011
Accepted 22 April 2011
Available online 5 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Yonarolide
Diels–Alder reaction
Intramolecular aldol condensation
Tricyclic core
Retro-Michael–Michael addition
1. Introduction
the diketone derivative 6 by intramolecular aldol condensation.
Compound 6 would be obtained by an intermolecular Diels–Alder
Soft coral of the genus Sinuralia has been a rich source of bioac-
tive natural products, including various terpenoidal metabolites.
Yonarolide (1), isolated in 1995 from the Okinawan soft coral of
the genus Sinuralia, is a tetracyclic norditerpenoid.1 The structure
of yonarolide (1) was assigned based on 2D-NMR spectra, HSQC,
HMBC, and 1H–1H COSY and NOESY analysis to be a tricy-
clo[7.5.0.03,7]tetradecane (named the yonarane skeleton) tethered
reaction of the c-lactone derivative 7 with the diene derivative 8
using a Lewis acid promoter.
The synthesis of the target molecule 5 was initiated with the
construction of the dihydroisobenzofuran-1,5-dione framework
via a Diels–Alder reaction. First, the
c-lactone derivative playing
the role of the dienophile (compound 7) was synthesized as shown
in Scheme 2. Protection of the ketone group of commercially avail-
able 9 gave ethylene acetal 10 in excellent yield.7 A one pot reac-
tion involving reduction of the methyl ester moiety using
DIBALH, followed by vinylation of the resultant aldehyde with
to a
c-lactone ring (Fig. 1), which was unprecedented in natural
products. The stereochemistry at the C11 position of the seven-
membered ring in 1 has not been identified, and no pharmacologic
effects have been reported for 1. More recently, sinulochmodin C
(2)2 and scabrolide A (3)3–6 and B (4)3 have been identified as nat-
ural products isolated from soft corals of the genus Sinuralia that
also possess the same yonarane skeleton. The structural features
render 1 an ideal target for a total synthesis. To the best of our
knowledge, there is no report to date of any synthetic study of
these norditerpenoids possessing the yonarane skeleton. Herein
we describe the stereoselective construction of the tricyclic lactone
of yonarolide (1) based on an intramolecular aldol condensation as
the first entry in the synthetic study of these natural products.
O
H
O
O
O
H
H
O
11
H
H
H
H
H
O
O
O
O
yonarolide (1)
sinulochmodin C (2)
O
H
O
O
O
H
HO
H
HO
H
2. Results and discussion
H
H
H
Our strategy for the synthesis of the tricyclic lactone 5 is out-
lined in Scheme 1. The target compound 5 would be derived from
H
O
H
O
O
O
scabrolide A (3)
scabrolide B (4)
⇑
Corresponding author. Tel.: +81 42 676 5473; fax: +81 42 676 7282.
E-mail addresses: itohisa@toyaku.ac.jp, itohisa@ls.toyaku.ac.jp (H. Ito).
Figure 1. Structures of yonarolide (1) and related compounds.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.092

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Y. Ueda et al. / Tetrahedron Letters 52 (2011) 3379–3381
O
H
O
O
TBSO
OTBS
a
O
+
O
O
H
H
Intramolecular
aldol condensation
13
7
H
H
O
O
O
O
O
O
O
6
5
b
H
H
Diels–Alder reaction
O
H
H
O
O
O
O
O
O
O
OR OR
+
O
14
6
O
O
8
Scheme 3. Reagents and conditions: (a) Tf2CH2, Me3Al, (CH2Cl)2, rt, 1 h, 57%; (b) p-
TsOH, acetone, 50 °C, 2 h, 92%.
7
Scheme 1. Strategy for the synthesis of tricyclic core 5.
O
a
O
O
O
H
H
7a
CO2Me
CO2Me
O
4
3a
3
10
9
O
1'
H
H
H
H
O
O
b
c
OH
d
H
O
O
: NOE was observed
14
11
Figure 2. Selected NOE correlations for the Diels–Alder adduct 14.
O
O
O
O
O
O
O
O
on the side chain in this configuration were far apart. It was nec-
essary for construction of the target molecule 5 to reverse the ste-
reochemistry of the C3 position before forming the cyclopentene
unit via an aldol condensation. To execute this inversion at the
C3 position, our proposed strategy involved a retro-Michael reac-
tion–Michael addition sequence followed by a subsequent intra-
molecular aldol condensation under basic or acidic conditions.
Although synthesis of 5 from 6 under several basic conditions
(t-BuOK, Et3N, DBU, K2CO3) was unsuccessful,12 treatment of 6
with trifluoroacetic acid13 in toluene produced the desired com-
pound 514 in 55% yield in Scheme 4. The structure of 5 was as-
signed by NMR experiments as depicted in Figure 3.
Three observed key NOE interactions between 2a-H and 7b-H
and 7a-H and 7b-H in the NOESY analysis of 5 disclosed that the
stereochemical relationships between all of the bridgehead pro-
tons were each of the syn configuration, and these experimental
facts revealed that the retro-Michael reaction–Michael addition–
intramolecular aldol condensation proceeded smoothly under
strong acidic conditions to afford the desired tricyclic lactone 5,
one of the core structures of yonarolide (1).
7
12
Scheme 2. Reagents and conditions: (a) ethyleneglycol, p-TsOH, toluene, reflux,
2 h, 91%; (b) DIBALH, toluene, ꢀ78 °C, 2 h ? ꢀ50 °C, 0.5 h, then vinylmagnesium
chloride, ꢀ78 ? 0 °C, 0.5 h, 85%; (c) acryloyl chloride, Et3N, CH2Cl2, 0 °C, 2 h, 85%;
(d) Grubbs-2nd, toluene, 100 °C, 0.5 h, 99%.
vinylmagnesium chloride yielded allyl alcohol 11 (85%). After
esterification of 11 with acryloyl chloride, ring closing metathesis
of 12 using the Grubbs second generation catalyst produced the
furanone derivative 7 in 84% over all yield.
With compound
7
in hand, construction of the
dihydroisobenzofuran-1,5-dione framework via the Diels–Alder
reaction between dienophile 7 and diene 138 (readily prepared
from acetylacetone) was studied as shown in Scheme 3. After sev-
eral attempts (heated condition or combination of trifluorome-
thanesulfonamide and dimethylaluminum chloride9), use of a
combination of trimethylaluminum and bis(trifluoromethanesul-
fonyl)methane10 as the Lewis acid catalyst provided the best result,
with the desired Diels–Alder adduct 14 obtained in 57% yield as a
single diastereomer.11 Treatment of 14 with p-TsOH in acetone led
to cleavage of the acetal moiety in 14 to give the aldol condensa-
tion precursor diketone derivative 6 in good yield.
A proposed mechanism accounting for the construction of 5 is
depicted in Scheme 5. Intramolecular aldol reaction of enol 17 gen-
erated from 3a-6 to produce the tricyclic lactone 18 was not able
to proceed, because the aldol reaction donor (the C4 carbon in
the cyclic enol group) and the acceptor (the C20 carbonyl group
on the C3 side chain) are located too far away from each other in
The structure of 14 was confirmed by NMR experiments as de-
picted in Figure 2, wherein clear NOE interactions between 3a-H
and 7a-H, 3a-H and 4a
-H, 3-H and 4b-H, and 3a-H and 10-H,
respectively, were observed. These results indicated that the ste-
reochemical relationships between C3 and C3a and C3a and C7a
in 14 were anti and syn, respectively.
With the stereoselective synthesis of the aldol condensation of
precursor 6 achieved, our interest then turned to the next stage.
The relative configuration at the C3 position in 6 was contrary to
that of yonarolide (1). Additionally, construction of the tricyclic
compound from 6 was expected to be excessively difficult because
the two reaction points at the C4 position and the carbonyl group
O
H
O
TFA
H
H
toluene
90 °C, 18 h
(55%)
H
H
O
O
O
O
O
6
5
Scheme 4. Construction of the tricyclic lactone 5 from 6.

Y. Ueda et al. / Tetrahedron Letters 52 (2011) 3379–3381
3381
accomplished from the methyl ester 9 in a total of eight steps
and in 29% overall yield. This synthetic methodology involved
the following features: (i) intermolecular Diels–Alder reaction be-
tween the furanone derivative 7 and diene 13, (ii) intramolecular
aldol condensation involving epimerization via a retro-Michael
reaction–Michael addition. This concise synthetic methodology
will be applicable to the total synthesis of yonarolide (1), a project
that is now in progress in our laboratory.
H
H
H
7b
2a
7a
O
O
: NOE was observed
5
O
Figure 3. Selected NOE correlations of the tricyclic lactone 5.
Acknowledgments
This work was supported in part by a grant for private univer-
O
sities and
a Grant-in-Aid for Scientific Research (C) (No.
21590024) from MEXT of Japan.
H
References and notes
H
OH
O
O
1. Iguchi, K.; Kajiyama, K.; Yamada, Y. Tetrahedron Lett. 1995, 36, 8807–8808.
2. Tseng, Y.-J.; Ahmed, A. F.; Dai, C.-F.; Chiang, M. Y.; Sheu, J.-H. Org. Lett. 2005, 7,
3813–3816.
Michael
addition
retro-Michael
reaction
15
H+
H+
3. Sheu, J.-H.; Ahmed, A. F.; Shiue, R.-T.; Dai, C.-F.; Kuo, Y.-H. J. Nat. Prod. 2002, 65,
1904–1908.
4. Ahmed, A. F.; Shiue, R.-T.; Wang, G.-H.; Dai, C.-F.; Kuo, Y.-H.; Sheu, J.-H.
Tetrahedron 2003, 59, 7337–7344.
O
O
5. Rudi, A.; Shmul, G.; Benayahu, Y.; Kashman, Y. Tetrahedron Lett. 2006, 47, 2937–
2939.
6. Tseng, Y.-J.; Ahmed, A. F.; Hsu, C.-H.; Su, J.-H.; Dai, C.-F.; Sheu, J.-H. J. Chin.
Chem. Soc. 2007, 54, 1041–1044.
7. (a) Boisse, T.; Rigo, B.; Millet, R.; Hénichart, J.-P. Tetrahedron 2007, 63, 10511–
10520; (b) Cavallaro, R. A.; Filocamo, L.; Galuppi, A.; Galione, A.; Brufani, M.;
Genazzani, A. A. J. Med. Chem. 1999, 42, 2527–2534.
8. (a) Ward, D. E.; Shen, J. Org. Lett. 2007, 9, 2843–2846; (b) Denmark, S. E.;
Heemstra, J. R., Jr. J. Org. Chem. 2007, 72, 5668–5688.
H
H
H
H
O
O
O
O
O
O
6
16
9. Saito, A.; Ito, H.; Taguchi, T. Org. Lett. 2002, 4, 4619–4621.
10. (a) Yanai, H.; Takahashi, A.; Taguchi, T. Tetrahedron 2007, 63, 12149–12159; (b)
Yanai, H.; Takahashi, A.; Taguchi, T. Tetrahedron Lett. 2007, 48, 2993–2997.
O
O
H
O
O
11. Experimental procedures. Preparation of 14. To
a solution of bis(trifluoro
O
HO
methanesulfonyl)methane (183 mg, 0.65 mmol) in dichloroethane (3 mL) was
added dropwise trimethylaluminum (1.03 M in hexane solution, 0.82 mL,
0.85 mmol) at room temperature under argon. After stirring for 0.5 h, this
mixture was added to a solution of 7 (200 mg, 1.09 mmol) and 13 (535 mg,
1.63 mmol) in dichloroethane (3 mL), and the reaction mixture stirred at room
temperature for 0.5 h. The reaction mixture was then quenched with aqueous
1 M HCl, extracted three times with CHCl3. The combined organic layers were
washed with brine, dried over MgSO4 and the solvent removed. The residue was
purified by flash column chromatography (hexane–AcOEt, 1:1) to afford 14
HO
H
H
H
H
H
O
17
19
O
O
(495 mg, 57%) as white crystals. IR (KBr) 2988, 2912, 1774, 1730, 1671 cmꢀ1 1H
;
NMR (300 MHz, CDCl3) d 1.31 (3H, s), 1.95 (1H, dd, J = 14.9, 5.0 Hz), 2.03 (1H, dd,
J = 14.9, 6.3 Hz), 2.12 (3H, s), 2.40 (2H, dd, J = 16.9, 7.0 Hz), 2.93 (1H, quint,
J = 6.7 Hz), 3.36 (1H, d, J = 3.8 Hz), 3.83–3.98 (4H, m), 4.31 (1H, q, J = 6.0 Hz), 6.00
(1H, br s); 13C NMR (75 MHz, CDCl3) d 22.3, 24.3, 35.8, 40.0, 42.2, 44.5, 64.5, 64.6,
79.5, 107.8, 128.4, 152.3, 172.5, 195.4; HRMS (ESI–TOF) calcd for C14H19O5
[(M+H)+] 267.1232, found 267.1245.
H
H
H
H
H
H
O
O
O
O
12. Treatment of 5 with several bases gave the aromatic compound along with a
complex mixture. This aromatization reaction likely results from a slower
reaction rate for the Michael addition of the unsaturated ketone on the side
chain resulting from the retro-Michael reaction versus the reaction rate for the
5
18
Scheme 5. Proposed mechanism for the construction of tricyclic lactone 5.
formation of the conjugated enol ether via deprotonation at the
in the retro-Michael product.
c position (C3)
enol 17. On the other hand, the retro-Michael reaction of 3a-6 and
13. Use of acetic acid instead of trifluoroacetic acid gave trace amount of 5 along
with a complex mixture including the enone 15.
6 leads to generation of enone 15, which undergoes an intramolec-
ular Michael addition reaction to produce compound 16, which has
the side chain at the b position. Compounds 6 and 15 and 15 and 16
are in equilibrium with one another. Consequently, epimerization
at the C3 side chain results in the acceptor part gaining access to
the donor part, and the intramolecular aldol reaction occurs in enol
19 (generated from 16) to give the desired target tricyclic com-
pound 5 as a single diastereoisomer.
14. Spectral data for (2aR⁄,7aR⁄,7bS⁄)-3,6-dimethyl-7,7a-dihydroindeno[1,7-bc]furan-
2,5(2aH,7bH)-dione 5. Colorless needles; mp 125–127 °C (from hexane–AcOEt);
IR (KBr) 2935, 1754, 1655 cmꢀ1 1H NMR (300 MHz, CDCl3) d 2.08 (3H, br s),
;
2.23 (3H, d, J = 1.1 Hz), 2.73 (1H, d, J = 19.0 Hz), 2.96 (1H, ddquint, J = 19.0, 4.4,
1.6 Hz), 3.38 (1H, d, J = 8.2 Hz), 3.95–4.06 (1H, m), 5.03 (1H, t, J = 4.6 Hz), 6.00
(1H, quint, J = 1.3 Hz); 13C NMR (75 MHz, CDCl3) d 15.4, 23.5, 45.5, 46.0, 51.0,
80.9, 127.4, 130.1, 148.9, 152.3, 172.3, 185.7; HRMS (ESI–TOF) calcd for
C
12H13O3 [(M+H)+] 205.0865, found 205.087.
In conclusion, the stereoselective construction of the tricyclic
core of yonarolide (1) and related natural products (2–4) was