Enantioselective total synthesis of enokipodins A-D

Article abstract of DOI:10.1016/j.tetlet.2004.04.191

The first enantioselective total synthesis of enokipodins A-D, highly oxidized α-cuparenone-type sesquiterpenoids with antimicrobial activity, was accomplished by using Meyers' diastereoselective alkylation protocol for the construction of the C7-quaterna

Full text of DOI:10.1016/j.tetlet.2004.04.191

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5047–5049
Enantioselective total synthesis of enokipodins A–D
Shigefumi Kuwahara* and Mana Saito
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University,
1-1 Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received 31 March 2004; revised 30 April 2004; accepted 30 April 2004
Abstract—The first enantioselective total synthesis of enokipodins A–D, highly oxidized a-cuparenone-type sesquiterpenoids with
antimicrobial activity, was accomplished by using Meyers’ diastereoselective alkylation protocol for the construction of the C7-
quaternary asymmetric center. The present synthesis also constitutes a formal enantioselective synthesis of (S)-1,4-cuparenediol and
(S)-cuparene-1,4-quinone.
Ó 2004 Elsevier Ltd. All rights reserved.
Cuparene-type sesquiterpenoids constitute a family of
natural products featuring a p-tolylcyclopentane frame-
work bearing two contiguous quaternary centers on the
cyclopentane ring, and quite interestingly, are known to
exist in both enantiomeric forms in nature [e.g., (R)-
cuparene [(R)-3a]1 and (S)-a-cuparenone [(S)-3b]2 from
higher plants; (S)-cuparene [(S)-3a]3;4 and (R)-a-cupar-
enone [(R)-3b]5 from liverworts] (Fig. 1). Since the iso-
lation of (R)-(+)-cuparene from the heartwood extracts
of some conifers,1 the sterically congested molecular
architecture of this class of terpenoids has attracted
considerable interest of synthetic chemists, and thereby
many synthetic studies on cuparenes, either as racemic or
as optically active forms, have been reported so far.6
Most of the synthetic efforts, however, have been focused
on two simple cuparenes, 3a and 3b,6;7 while syntheses of
cuparenes bearing oxygen functionalities at the aromatic
ring portion did not appear in the literature until two
recent reports on the synthesis of ( )-HM-1 methyl ether
(methyl ether of 3c),8 ( )-1,4-cuparenediol (3d),9 and ( )-
cuparene-1,4-quinone (4).9 Most recently, Srikrishna and
Rao reported the synthesis of ( )-enokipodins A and B
(1a and 2a, respectively),10 previously isolated by
Ishikawa et al. from a culture broth of an edible mush-
room (Flammulina velutipes, enokitake in Japanese).11
These two cuparenoids and two additional a-cuparene
derivatives isolated later from the same mushroom
[enokipodin C (1b) and enokipodin D (2b)]12 showed
significant antimicrobial activity against a fungus (Clad-
osporium herbarum) and Gram-positive bacteria (Bacillus
subtilis and Staphylococcus aureus). Their structural
uniqueness (both the cyclopentane and the aromatic ring
portions are oxidized) combined with the fact that no
enantioselective synthesis of cuparenes bearing oxygen
functionalities on the aromatic ring moiety has been
reported to date, as well as our own interest in elucidating
the biological activities of enokipodins and their analogs
in detail prompted us to embark on the synthesis of
optically active enokipodins A–D.
X
X
8
7
HO
O
O
1
O
OH
O
1a: X = H (enokipodin A)
1b: X = OH (enokipodin C)
2a: X = H (enokipodin B)
2b: X = OH (enokipodin D)
X
O
Z
Y
O
3a: X, Y = H, Z = H2
4
3b: X, Y = H, Z = O
3c: X = OMe, Y = OH, Z = H2
3d: X, Y = OH, Z = H2
Figure 1. Structures of enokipodins A–D and related compounds.
Keywords: Enokipodin; Terpenoids; Antibiotics; Cuparene.
* Corresponding author. Tel./fax: +81-22-717-8783; e-mail: skuwahar@
biochem.tohoku.ac.jp
Our synthesis began with methallylation of known
aromatic ester 5, which in turn could readily be obtained
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.191

5048
S. Kuwahara, M. Saito / Tetrahedron Letters 45 (2004) 5047–5049
O
O
CO2R
X
N
N
MeO
MeO
7
a, b, c
d
e
MeO
MeO
CO2Me
OMe
O
O
OMe
OMe
OMe
6a: R = Me, X = CH2
6b: R = Me, X = O
6c: R = H, X = O
5
8
9
X
9
8
CHO
f, g
j
h, i
k
l
MeO
MeO
MeO
O
O
O
2a
1a
R
OMe
R
OMe
OMe
12
10
11a: R = H, X = H
11b: R = Me, X = H
11c: R = Me, X = OMe
CO2Me
m
O
MeO
HO
O
OMe
p
o
n
MeO
MeO
O
O
2b
7
1b
OMe
OMe
13
14
Scheme 1. Reagents and conditions: (a) LDA, methallyl chloride, NaI, THF–HMPA (7:1), )78 °C, 3.5 h (98%); (b) OsO4, NMO, NaIO4, THF–H2O
(3:1), rt, 18 h (98%); (c) 2 M aq KOH, THF, 50 °C, 12 h (98%); (d) (S)-valinol, toluene, reflux, 15 h (85%); (e) s-BuLi, MeI, THF, )78 °C, 2 h (88%);
(f) Red-Alâ, THF, 0 °C to rt, 1.5 h; (g) 1 M aq (n-Bu)4NH2PO4, EtOH, rt, 24 h; (h) K2CO3, t-BuOH, reflux, 4.5 h (82% from 9); (i) NaH, MeI, THF–
HMPA (5:1), rt, 17 h (61%); (j) H2, Pd/C, EtOAc, rt, 16 h; (k) CAN, CH3CN–H2O (3:2), rt, 30 min (79% from 11b); (l) Na2S2O4, EtOH–H2O, rt,
30 min (55%); (m) 30% aq H2O2, NaOH, MeOH, 60 °C, 6.5 h (51%); (n) PhSeSePh, NaBH4, EtOH, AcOH, rt, 1 h (68%); (o) CAN, CH3CN–H2O
(3:2), rt, 30 min (78%); (p) Na2S2O4, EtOH–H2O, rt, 30 min (89%).
from 2,5-dimethoxy-4-methylbenzaldehyde in three
steps following the literature procedure (Scheme 1).13
The resulting olefinic product (6a) produced in 98%
yield was subjected to the Lemieux–Johnson oxidation
to give keto ester 6b almost quantitatively. When this
oxidative cleavage was conducted by using ozonolysis, a
substantial degree of undesirable oxidation at the aro-
matic ring moiety took place, and attempted direct
alkylation of 5 with bromoacetone into 6b was unsuc-
cessful due to preferential attack of the enolate of 5 to
the keto group of bromoacetone, leading eventually to a
3:2 mixture of diastereomeric epoxides 7. The ester
group of 6b was then saponified to afford keto acid 6c
(96% overall yield from 6a). In order to construct the
C7-quaternary stereogenic center of enokipodins by
Meyers’ diastereoselective alkylation protocol,14 the
keto acid (6c) was converted in 85% yield into chiral
bicyclic lactam 8 as an inseparable 6:5 epimeric mixture
at the C7 position by treating with (S)-valinol in re-
fluxing toluene.15 The mixture of lactams was alkylated
with iodomethane to give 9 in 88% isolated yield to-
gether with its C7-epimer (3% yield). The methylated
lactam (9) was successively treated with Red-Alâ and an
aqueous solution of tetrabutylammonium dihydrogen-
phosphate to give keto aldehyde 10, which upon expo-
sure to aldol condensation conditions (K2CO3, t-BuOH,
reflux)16 furnished cyclopentenone derivative 11a in 82%
overall yield from 9. Dimethylation of 11a with excess
amounts of iodomethane and sodium hydride was first
attempted in DMF, which had been used as the solvent
for dimethylation of an analogous cyclopentenone
derivative.7;14 In this solvent, however, substantial
amounts of the starting ketone (11a) and the corre-
sponding mono-methylated product remained even after
3 days of heating at 100 °C. On the other hand, this
reaction proceeded smoothly in THF–HMPA (5:1) even
at room temperature, to give the desired dialkylation
product (11b) in 61% yield. Catalytic hydrogenation of
11b afforded 12, which upon oxidation with ceric
ammonium nitrate gave ())-enokipodin B (2a) as orange
22
needles [mp 146–147 °C, ½aꢀ )65 (c 0.40, MeOH); lit.11
D
24
D
from 11b. Finally, reduction of the benzoquinone moi-
semisolid, ½aꢀ )63 (c 0.05, MeOH)] in 79% overall yield
ety with sodium dithionite afforded (+)-enokipodin
23
D
A (1a) as colorless prisms [mp 180–182 °C, ½aꢀ +48 (c
23
0.50, MeOH); lit.11 mp 138.5–138.9 °C, ½aꢀ +48 (c 0.5,
D
1
MeOH)] in 55% yield. The H and 13C NMR spectra of
synthetic 1a and 2a were completely identical with those
of natural enokipodins A and B, respectively.11
Having completed the synthesis of (+)-1a and ())-2a, we
next turned our attention to the elaboration of inter-
mediate 11b to enokipodins C (1b) and D (2b). Stereo-
selective epoxidation of the C8–C9 double bond of 11b
with alkaline hydrogen peroxide in methanol occurred
from the less hindered a-face opposite the aromatic ring
moiety to give 13 as a single stereoisomer in a moderate
isolated yield of 51%.17 In this reaction, prolonged
reaction time caused formation of 11c, which probably
resulted from epoxide ring opening of 13 at the C9 po-
sition by methanol followed by dehydration. Reductive
cleavage of the epoxide ring was carried out by using
Miyashita’s organoselenium chemistry to afford 14 in
1
68% yield.18 The H NMR spectrum of 14 was exactly
the same as that of an authentic sample prepared pre-
viously from natural enokipodin C by Ishikawa et al.12
to determine the absolute configuration of 1b. Finally, in
the same manner as described for the synthesis of 1a and

S. Kuwahara, M. Saito / Tetrahedron Letters 45 (2004) 5047–5049
5049
2. Chetty, G. L.; Dev, S. Tetrahedron Lett. 1964, 73–77.
2a, 14 was converted into enokipodin D [2b: yellow
26
D
needles, mp 146–147°, ½aꢀ )130 (c 0.20, MeOH); lit.12
3. Matsuo, A.; Nakayama, M.; Maeda, T.; Noda, Y.;
Hayashi, S. Phytochemistry 1975, 14, 1037–1040.
4. Toyota, M.; Koyama, H.; Asakawa, Y. Phytochemistry
1997, 46, 145–150.
5. Benesova, V. Collect. Czech. Chem. Commun. 1976, 41,
3812–3814.
6. Pirrung, M. C.; Morehead, A. T., Jr.; Young, B. G. In The
Total Synthesis of Natural Products; Goldsmith, D., Ed.;
John Wiley: New York, 2000; Vol. 11, pp 186–199.
7. Satoh, T.; Yoshida, M.; Takahashi, Y.; Ota, H. Tetra-
hedron: Asymmetry 2003, 14, 281–288, and references cited
therein.
8. Pal, A.; Gupta, P. D.; Roy, A.; Mukherjee, D. Tetrahedron
Lett. 1999, 40, 4733–4734.
9. Paul, T.; Pal, A.; Gupta, P. D.; Mukherjee, D. Tetrahedron
Lett. 2003, 44, 737–740.
10. Srikrishna, A.; Rao, M. S. Synlett 2004, 374–376.
11. Ishikawa, N. K.; Yamaji, K.; Tahara, S.; Fukushi, Y.;
Takahashi, K. Phytochemistry 2000, 54, 777–782.
12. Ishikawa, N. K.; Fukushi, Y.; Yamaji, K.; Tahara, S.;
Takahashi, K. J. Nat. Prod. 2001, 64, 932–934.
13. Coutts, R. T.; Malicky, J. L. Can. J. Chem. 1974, 52, 395–
399.
24
mp 116.0–117 °C, ½aꢀ )130 (c 0.1, MeOH)]19 and
D
24
D
then enokipodin C [1b: ½aꢀ )9.2 (c 0.50, MeOH); lit.12
24
½aꢀ )9.4 (c 1.0, MeOH)]. The spectral data (1H and 13
C
NMR) of 1b and 2b were identical with those of natural
D
enokipodins C and D, respectively.12
In conclusion, the first enantioselective total synthesis of
enokipodins A, B, C, and D was accomplished starting
from known aromatic ester 5 in 12, 11, 13, and 12 steps,
and in overall yields of 15%, 28%, 8%, and 10%,
1
respectively. The H and 13C NMR spectra and specific
rotation values of synthetic enokipodins were matched
those of the natural enokipodins, while the melting
points of synthetic 1a and 2b were considerably higher
than those of the corresponding natural samples of
enokipodins. Since ( )-12 has previously been converted
into ( )-3d and ( )-4,9;10 this synthesis also constitutes a
formal synthesis of (S)-3d and (S)-4.
14. Meyers, A. I.; Lefker, B. A. J. Org. Chem. 1986, 51, 1541–
1544.
15. Judging from the H NMR chemical shift of the angular
Acknowledgements
1
We are grateful to Prof. Tahara (Hokkaido University)
for providing the copies of the spectra of natural eno-
kipodins A–D. This work was supported, in part, by a
Grant-in-Aid for Scientific Research (C) from the
Ministry of Education, Culture, Sports, Science and
Technology of Japan (no. 13660103). Financial support
given to S.K. by Nagase Science and Technology
Foundation is also greatly appreciated.
methyl signal of each epimer (d 1.43 and 1.55 in a ratio of
6:5), the aromatic ring moiety of the slightly predominant
epimer is considered to be oriented cis to the angular
methyl group.14
16. Kuwahara, S.; Ishikawa, J.; Leal, W. S.; Hamade, S.;
Kodama, O. Synthesis 2000, 1930–1935.
17. Kakiuchi, K.; Ue, M.; Tsukahara, H.; Shimizu, T.; Miyao,
T.; Tobe, Y.; Odaira, Y.; Yasuda, M.; Shima, K. J. Am.
Chem. Soc. 1989, 111, 3707–3712.
18. Miyashita, M.; Suzuki, T.; Hoshino, M.; Yoshikoshi, A.
Tetrahedron 1997, 53, 12469–12486.
19. Ishikawa et al. originally reported the specific rotation of
2b to be +130°.12 However, they recently informed us that
the ‘‘+’’ sign was a typing error and the real sign was minus
()).
References and notes
1. Enzell, C.; Erdtman, H. Tetrahedron 1958, 4, 361–368.