An ynolate-initiated tandem process giving cyclopentenones: Total synthesis of cucumin E

Article abstract of DOI:10.1016/S0040-4039(02)01015-8

A total synthesis of cucumin E, a novel type of triquinane natural product, has been accomplished. The strategy is based on an ynolate-initiated tandem [2+2] cycloaddition-Dieckmann condensation, followed by decarboxylation, giving cyclopentenones.

Full text of DOI:10.1016/S0040-4039(02)01015-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5039–5041
An ynolate-initiated tandem process giving cyclopentenones:
total synthesis of cucumin E
Mitsuru Shindo,a,b,* Yusuke Satoa and Kozo Shishidoa
aInstitute for Medicinal Resources, University of Tokushima, Sho-machi 1, Tokushima 770-8505, Japan
bPRESTO, JST, Japan
Received 7 May 2002; revised 28 May 2002; accepted 29 May 2002
Abstract—A total synthesis of cucumin E, a novel type of triquinane natural product, has been accomplished. The strategy is
based on an ynolate-initiated tandem [2+2] cycloaddition–Dieckmann condensation, followed by decarboxylation, giving
cyclopentenones. © 2002 Elsevier Science Ltd. All rights reserved.
Since developing a new method for the synthesis of
ynolate anions,1 we have demonstrated their synthetic
utility.2 Recently, we reported a tandem [2+2] cycload-
dition–Dieckmann condensation initiated by ynolates
(i.e. 1), followed by decarboxylation of the intermediate
bicyclic b-lactones (2), to furnish substituted cyclopen-
tenones (3) as well as cyclohexanones (Scheme 1).3 If
this novel process were applied to the preparation of
carbocyclic frameworks composed of fused five- and
six-membered rings, various kinds of natural products,
like triquinane sesquiterpenes, could be efficiently
synthesized.
sesquiterpenoids have aroused a great deal of interest
among synthetic chemists in recent decades due to their
unique structure and promising biological activity.5
Many syntheses of these compounds have been
reported. However, syntheses of cucumins, which are a
new kind of linear triquinane-type sesquiterpenoid, are
not as well represented in the literature.6 We describe
herein the total synthesis of cucumin E using an yno-
late-initiated tandem reaction for the construction of
the cyclopentenone unit.
Cucumin E (4) was isolated from the mycelial cultures
of the agaric Macrocystidia cucumis (Pers. ex Fr.), and
in 1998, its structure and stereochemistry were deter-
mined by Steglich and Anke.4 Linear triquinane-type
Scheme 1. Ynolate-initiated [2+2] cycloaddition–Dieckmann condensation.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01015-8

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M. Shindo et al. / Tetrahedron Letters 43 (2002) 5039–5041
Since cucumin E possesses a 2-cyclopenten-1-one unit,
we envisaged the ynolate-initiated tandem reaction of
the s-symmetric bicyclo[3.3.0]octan-2,4-dione (5) occur-
ing in the final stage of the total synthesis. First, we
attempted the synthesis of the precursor (5) directly
from the known compound (7).
reaction using NHMDS and 16 equiv. of ethyl bro-
moacetate at room temperature was found to furnish
the desired a-alkylated product (13) in 45% yield as a
single stereoisomer (Scheme 3).11 The stereochemistry
of (13), determined by NOE experiments of 5, can be
explained by the attack of the alkylating reagent on the
convex face of the dienolate. This compound was sub-
jected to oxidative cleavage of exo-olefin to yield the
desired diketone (5) in 85% yield.12
With the diketone (5) in hand, we next examined the
ynolate-initiated tandem reaction. Under the usual con-
ditions (1.2 equiv. of ynolate at −78 to −40°C), the
reaction did not proceed, probably due to steric hin-
drance of the ketone. However, after screening reaction
conditions, using 3 equiv. of ynolates at −20°C for 1 h,
we succeeded in obtaining the adduct (15), the infrared
spectrum of which displays absorptions at 1830 cm−1,
indicating the presence of the b-lactone. This adduct
was decarboxylated by refluxing in toluene in the pres-
ence of silica gel to afford cucumin E (4) in 54% yield
from the diketone (5). The spectral properties were
identical in all respects to those of the natural product
(1H and 13C NMR, IR, MS, elemental analysis).13
As shown in Scheme 2, the bicyclic anhydride (7),
prepared from 4,4-dimethylcyclohexenone according to
the literature procedures,7,8 was reacted with Et2CuLi
to afford the ketocarboxylic acid (8). We attempted the
Lewis acid-mediated cyclization of the corresponding
mixed anhydride and the base induced cyclization of
the methyl ester, but failed to obtain the desired bicy-
clo[3.3.0]octane skeleton (9).
Next, we tried to prepare the precursor (5) from 3,4,7,7-
tetramethylbicyclo[3.3.0]oct-3-en-2-one (12). According
to the literature, 4,4-dimethylcyclopentane-1,2-dicar-
boxylic acid (6) was converted to the diketone (10) by
addition of MeLi which was then cyclized to give the
bicyclo[3.3.0]octenone (11).9 This enone was bromi-
nated and dehydrobrominated, and the resulting bro-
moenone was converted to the bromoacetal, which was
treated with t-BuLi followed by methyl iodide, to
provide, after hydrolysis, the enone (12).10 Regioselec-
tive alkylation of the dienolate derived from the enone
(12) was then examined. When the enone was treated
with LHMDS and an excess of ethyl bromoacetate was
added at room temperature, the undesired g-alkylation
predominated (a:g=1:9). Use of KHMDS increased the
a-regioselectivity up to 1:1.7. Since counter-cations of
the dienolate seemed to influence the regioselectivity,
we therefore decided to use NHMDS as a base. When
3 equiv. of ethyl bromoacetate was added to the sodium
dienolate, the a/g ratio was improved to 1:1.2, and after
several attempts to find the optimum conditions, the
In conclusion, we have achieved a total synthesis of the
new triquinane natural product cucumin E. The strat-
egy of five-membered ring construction via ynolate-ini-
tiated tandem reaction has demonstrated the feasibility
of a short access to triquinane sesquiterpenoids.
Acknowledgements
We are grateful to Professor Steglich for providing us
with a sample of natural cucumin E and its spectra.
This work was supported in part by a Grant-in-Aid for
Scientific Research on Priority Areas (A) ‘Exploitation
of Multi-Element Cyclic Molecules’ from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan, and a research grant from the Faculty of Phar-
maceutical Sciences, the University of Tokushima.
Scheme 2. Reagents and conditions: (a) (i) Pd–C, H2, AcOEt, rt, 13 h, 98%; (ii) Me2CO3 (5.2 equiv.), NaH (2.2 equiv.), DME,
reflux, 3 h, 75%; (b) (i) Br2 (1.0 equiv.), CHCl3, 0°C–rt, 1 h, quant.; (ii) KOH (4.3 equiv.), H2O, 0°C–rt, 30 h, 87%; (c) Ac2O (1.1
equiv.), pyridine (4.0 equiv.), toluene, reflux, 60 h, 78%; (d) EtLi (3.0 equiv.), CuI (1.5 equiv.), ether, −40°C, 80%.

M. Shindo et al. / Tetrahedron Letters 43 (2002) 5039–5041
5041
Scheme 3. Reagents and conditions: (a) MeLi (4.4 equiv.), ether, 0°C–rt, 17 h, 72%; (b) t-BuOK (0.2 equiv.), t-BuOH, 0°C–rt, 3
h, 78%; (c) (i) Br2 (1.1 equiv.), CCl4, 0°C 3 h then Et3N, 83%; (ii) ethylene glycol (5.0 equiv.), pTsOH (0.1 equiv.), benzene, reflux,
70 h, 75%; (iii) t-BuLi (3.0 equiv.); MeI (12 equiv.), HMPA (2.9 equiv.), THF, −78°C, 2 h, then 10% HCl, 99%; (d) NHMDS (1.5
equiv.), BrCH2CO2Et (16 equiv.), rt, 1.5 h, 45%; (e) RuCl3 (0.1 equiv.), NaIO4 (4.1 equiv.), rt, 10 h, 85%; (f) lithium ynolate (1)
(3 equiv.), THF, −20°C, 1 h; (g) silica gel (cat.), toluene, reflux, 13 h, 54% for two steps.
References
6. For reviews, see: (a) Mehta, G.; Srikrishna, A. Chem.
Rev. 1997, 97, 671–719; (b) Singh, V.; Thomas, B. Tetra-
hedron 1998, 54, 3647–3692.
1. (a) Shindo, M. Tetrahedron Lett. 1997, 38, 4433–4436; (b)
Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron 1998, 54,
2411–2422; (c) Shindo, M.; Koretsune, R.; Yokota, W.;
Itoh, K.; Shishido, K. Tetrahedron Lett. 2001, 42, 8357–
8360.
7. Liu, H.-J.; Browne, E. N.; Chew, S. Y. Can. J. Chem.
1988, 66, 2345–2347.
8. Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.; Stull, P. D.
J. Org. Chem. 1989, 54, 817–824.
9. Miyano, K.; Ohfune, Y.; Azuma, S.; Matsumoto, T.
2. (a) Shindo, M.; Sato, Y.; Shishido, K. Tetrahedron Lett.
1998, 39, 4857–4860; (b) Shindo, M.; Oya, S.; Sato, Y.;
Shishido, K. Heterocycles 1998, 49, 113–116; (c) Shindo,
M.; Sato, Y.; Shishido, K. J. Org. Chem. 2000, 65,
5443–5445; (d) Shindo, M.; Oya, S.; Murakami, R.; Sato,
Y.; Shishido, K. Tetrahedron Lett. 2000, 41, 5943–5946;
(e) Shindo, M.; Oya, S.; Murakami, R.; Sato, Y.;
Shishido, K. Tetrahedron Lett. 2000, 41, 5947–5950; (f)
Shindo, M.; Matsumoto, K.; Sato, Y.; Shishido, K. Org.
Lett. 2001, 3, 2029–2031. For reviews, see: (g) Shindo, M.
Chem. Soc. Rev. 1998, 27, 367–374; (h) Shindo, M. J.
Syn. Org. Chem. Jpn. 2000, 58, 1155–1166; (i) Shindo, M.
Yakugaku Zasshi 2000, 120, 1233–1246.
3. (a) Shindo, M.; Sato, Y.; Shishido, K. J. Am. Chem. Soc.
1999, 121, 6507–6508; (b) Shindo, M.; Sato, Y.; Shishido,
K. J. Org. Chem. 2001, 66, 7818–7824.
4. Hellwig, V.; Dasenbrock, J.; Schumann, S.; Steglich, W.;
Leonhardt, K.; Anke, T. Eur. J. Org. Chem. 1998, 73–79.
5. The first total synthesis of cucumin E: Mehta, G.;
Umarye, J. D. Tetrahedron Lett. 2001, 42, 1991–1993.
Tetrahedron Lett. 1974, 1545–1548.
10. (a) Tobe, Y.; Yamashita, D.; Takahashi, T.; Inata, M.;
Sato, J.; Kakiuchi, K.; Kobiro, K.; Odaira, Y. J. Am.
Chem. Soc. 1990, 112, 775–779; (b) Smith, A. B.; Branca,
S. J.; Guaciaro, M. A.; Wovkulich, P. M.; Korn, A. Org.
Synth. Coll. Vol. VII 1990, 271–275.
11. The g-alkylated product was also isolated in 47% yield.
1
12. Diketone (5): H NMR (400 MHz, CDCl3) l: 1.00 (3H,
s), 1.11 (3H, s), 1.19 (3H, s), 1.20 (3H, t, J=7.2 Hz), 1.56
(2H, m), 2.08 (2H, m), 2.91 (2H, s), 3.55 (2H, ddd,
J=2.8, 4.4, 10.0 Hz), 4.03 (2H, q, J=6.8 Hz). 13C NMR
(75 MHz, CDCl3) l: 14.0 (q), 22.7 (q), 26.0 (q), 28.0 (q),
42.6 (t), 43.2 (s), 45.1 (t), 52.8 (d), 53.3 (s), 61.4 (t), 171.3
(s), 219.3 (s). IR (CHCl3): 1762, 1713 cm−1. MS m/z: 266
(M+), 267 (M+1), 193 (M+−COOCH2CH3, 100%).
HRMS (EI) calcd for C15H22O4 (M+) 266.1518, found:
266.1514.
13. Mp 121.3–121.8°C (hexane) for racemic form (lit., mp
108°C for optically pure form).