Enantioselective total synthesis of enokipodins A-D, antimicrobial sesquiterpenes produced by the mushroom, Flammulina velutipes

Article abstract of DOI:10.1271/bbb.69.374

The first enantioselective total synthesis of enokipodins A, B, C and D, highly oxidized α-cuparenone-type sesquiterpenoids possessing antimicrobial activity, was accomplished in 8-28% overall yields from methyl (2,5-dimethoxy-4-methylphenyl)acetate by ap

Full text of DOI:10.1271/bbb.69.374

Biosci. Biotechnol. Biochem., 69 (2), 374–381, 2005
Enantioselective Total Synthesis of Enokipodins A–D, Antimicrobial
Sesquiterpenes Produced by the Mushroom, Flammulina velutipes
y
Mana SAITO and Shigefumi KUWAHARA
Laboratory of Applied Bioorganic Chemistry, Graduate School of Agricultural Science, Tohoku University,
Tsutsumidori-Amamiyamachi, Aoba-ku, Sendai 981-8555, Japan
Received September 27, 2004; Accepted October 30, 2004
The first enantioselective total synthesis of enokipo-
dins A, B, C and D, highly oxidized ꢀ-cuparenone-type
sesquiterpenoids possessing antimicrobial activity, was
accomplished in 8–28% overall yields from methyl (2,5-
dimethoxy-4-methylphenyl)acetate by applying Meyers’
diastereoselective alkylation protocol for the construc-
tion of their C7-quaternary asymmetric center. The
present synthesis confirmed the absolute configuration
of the enokipodins, and also constitutes a formal
enantioselective synthesis of (S)-1,4-cuparenediol and
(S)-cuparene-1,4-quinone.
Key words: enokipodin; terpenoid; antibiotic; cuparene
Cuparene-type sesquiterpenoids constitute a family of
natural products featuring a p-tolylcyclopentane frame-
work bearing two contiguous quaternary asymmetric
centers on the cyclopentane ring, and, quite interestingly
from a biosynthetic viewpoint, some of them are known
Fig. 1. Structures of Enokipodins A–D and Related Compounds.
to exist in both enantiomeric forms in nature [e.g., (R)-
cuparene ((R)-3a)1) and (S)-ꢀ-cuparenone ((S)-3b)2,3)
from higher plants; (S)-cuparene ((S)-3a)4,5) and (R)-ꢀ-
cuparenone ((R)-3b)6) from liverworts] (Fig. 1). Since
the isolation of (R)-(þ)-cuparene in 1958 as the first
example of this class of terpenoids from the heartwood
extracts of some conifers,1) the sterically congested
molecular architecture of cuparenoids has attracted
considerable interest by synthetic chemists, and many
reports concerning the synthesis of cuparenoids, either
in racemic or optically active forms, have appeared in
the literature to date.7) Most of the synthetic efforts,
however, have been focused on two simple cuparenes,
3a and 3b,7,8) while the syntheses of cuparenes bearing
oxygen functionalities on the aromatic ring did not
appear in the literature until two recent reports on the
synthesis of (ꢀ)-HM-1 methyl ether (methyl ether of
3c),9) (ꢀ)-1,4-cuparenediol (3d)10) and (ꢀ)-cuparene-
1,4-quinone (4).10) Most recently, Srikrishna and Rao
have reported the synthesis of (ꢀ)-enokipodins A and B
(1a and 2a, respectively),11) isolated in 2000 by
Ishikawa and co-workers from a culture broth of an
edible mushroom (Flammulina velutipes, called ‘‘eno-
kitake’’ in Japanese).12) These two cuparenoids and two
additional ꢀ-cuparenone derivatives isolated later from
the same mushroom [enokipodin C (1b) and enokipo-
din D (2b), which correspond to C8-oxidation products
of 1a and 2a, respectively]13) showed significant
antimicrobial activity against a fungus (Cladosporium
herbarum) and Gram-positive bacteria (Bacillus subtilis
and Staphylococcus aureus). To the best of our knowl-
edge, enokipodins C and D are the first examples of
naturally occurring cuparenones whose cyclopentanone
ring and aromatic portion are both oxidized. This
structural uniqueness coupled with the fact that no
enantioselective synthesis of cuparenes bearing oxygen
functionalities on the aromatic ring has been reported so
far, as well as our 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, and quite recently we suc-
ceeded in the first enantioselective total synthesis of
these natural products.14) We report here a full account
of our synthetic study on 1a, 1b, 2a, and 2b.
y
To whom correspondence should be addressed. Tel/Fax: +81-22-717-8783; E-mail: skuwahar@biochem.tohoku.ac.jp

Enantioselective Total Synthesis of Enokipodins A–D
375
Results and Discussion
of its C8–C9 double bond would produce the corre-
sponding saturated cyclopentanone intermediate which
could be converted into 1a through oxidation and
reduction via 2a, while the stereoselective introduction
of a hydroxy group to the C8-position of B would afford
A that is suitable for transformation into 2b and 1b. Key
intermediate B should be obtainable by dimethylation of
C, the C7-quaternary stereocenter of which could be
installed from E through D by applying Meyers’ well-
established protocol for the synthesis of chiral cyclo-
pentenone derivatives.15) Keto acid E was considered to
be easily derived from known aromatic ester F.
Scheme 1 represents our synthetic plan for enokipo-
dins A–D. Hoping to obtain all the target compounds by
a single synthetic strategy, we adopted an appropriately
substituted cyclopentenone (B) as the common synthetic
intermediate for enokipodins A–D, since the reduction
According to the synthetic plan just described, our
synthesis began with methallylation of F, which in turn
could readily be obtained from 2,5-dimethoxy-4-meth-
ylbenzaldehyde in 3 steps by following the literature
procedure (Scheme 2).16) The double bond of the
resulting product (5a) obtained in a 98% yield was
cleaved by Lemieux-Johnson oxidation to give keto
ester 5b almost quantitatively. When this oxidative
cleavage was conducted by using ozonolysis, a sub-
stantial degree of undesirable oxidation at the aromatic
1
ring moiety seemed to take place, as judged by the H-
NMR spectrum of the crude product mixture, and
attempted direct alkylation of F with bromoacetone into
5b was unsuccessful due to preferential attack of the
enolate of F (prepared by treating with LDA in THF) on
the carbonyl group of bromoacetone, eventually leading
to a 3:2 mixture of diastereomeric epoxides G in an 81%
yield (Fig. 2). The ester group of 5b was then saponified
to afford keto acid E in a 96% overall yield from 5a. In
order to construct the C7-quaternary stereogenic center
of enokipodins by Meyers’ diastereoselective alkylation
protocol,15) the keto acid (E) was converted in an 85%
yield into chiral bicyclic lactam D as an inseparable 6:5
epimeric mixture at the C7-position by treating with (S)-
Scheme 1. Synthetic Plan for Enokipodins A–D.
Scheme 2. Synthesis of Enokipodins A and B.
Reagents and conditions: a) LDA, methallyl chloride, NaI, THF–HMPA (7:1), ꢁ78 ꢂC, 3.5 h (98%); b) OsO4, NMO, NaIO4, THF–H2O (3:1),
rt, 18 h (98%); c) 2 M aq. KOH, THF, 50 ꢂC, 12 h (98%); d) (S)-valinol, toluene, reflux, 15 h (85%); e) s-BuLi, MeI, THF, ꢁ78 ꢂC, 2 h (88%); f)
Red-Alꢀ, THF, 0 ꢂC 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 6a); 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 B); l) Na2S2O4, EtOH–H2O, rt,
30 min (55%).

376
M. SAITO and S. KUWAHARA
Fig. 2.
valinol17) in refluxing toluene. Judging from the 1H-
NMR chemical shift of the angular methyl signal of each
epimer (ꢁ 1.43 and 1.55 in a ratio of 6:5), the aromatic
moiety of the slightly predominant epimer was consid-
ered to be oriented cis to the angular methyl group, since
the angular methyl of the cis-epimer should be more
strongly shielded by the aromatic moiety as compared to
the corresponding trans-epimer.15) As expected from
literature precedent,15,18) the mixture of lactams was
alkylated with iodomethane with high stereoselectivity,
to give 6a in an 88% isolated yield together with a trace
amount of its C7-epimer (3% yield). The methylated
lactam (6a) was reduced with Red-Alꢀ to give hemi-
Scheme 3. Synthesis of Enokipodins C and D.
Reagents and conditions: a) 30% aq. H2O2, NaOH, MeOH, 60 ꢂC,
6.5 h (51%); b) PhSeSePh, NaBH4, EtOH, AcOH, rt, 1 h (68%); c)
CAN, CH3CN–H2O (3:2), rt, 30 min (78%); d) Na2S2O4, EtOH–
H2O, rt, 30 min (89%).
of intermediate B to enokipodins C (1b) and D (2b)
(Scheme 3). Stereoselective epoxidation of the C8–C9
double bond of B with alkaline hydrogen peroxide in
methanol occurred from the less-hindered ꢀ-face oppo-
site the aromatic ring moiety to give 9 as a single
stereoisomer in a moderate isolated yield of 51%.22) In
this reaction, a prolonged reaction time caused the
formation of H (Fig. 2) which probably resulted from
base-catalyzed epoxide ring-opening of 9 by methanol at
the C9-position with subsequent dehydration.23) Reduc-
tive cleavage of the epoxide ring was carried out by
using Miyashita’s organoselenium chemistry to afford A
in a 68% yield.24) The 1H-NMR spectrum of A was
exactly the same as that of an authentic sample prepared
previously from natural enokipodin C by Ishikawa et
al.13) to determine the absolute configuration of 1b.
Finally, in the same manner as that described for the
synthesis of 1a and 2a, compound A was converted into
1
aminal 6b, whose H-NMR spectrum revealed that 6b
had been obtained, quite interestingly, as a single
stereoisomer, although the orientation of its hydroxyl
group was not assigned. Compound 6b was then treated
with an aqueous solution of tetrabutylammonium dihy-
drogenphosphate to give keto aldehyde 7 which, upon
immediate exposure to aldol condensation conditions
(K2CO3, t-BuOH, reflux),19) furnished cyclopentenone
derivative C in an 82% overall yield from 6a. Di-
methylation of C 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.7,15) In this solvent,
however, substantial amounts of the starting ketone (C)
and the corresponding mono-methylated product re-
mained even after 3 days of heating at 100 ꢂC. On the
other hand, this dimethylation reaction proceeded
smoothly in THF–HMPA (5:1), even at room temper-
ature, to give the desired dialkylation product (B) in a
61% yield. Despite the highly hindered environment of
the double bond, catalytic hydrogenation of B in ethyl
acetate for 16 h at room temperature uneventfully
afforded 8 which, upon oxidation with ceric ammonium
nitrate,20) gave (ꢁ)-enokipodin B (2a) as orange needles
enokipodin D [2b: yellow needles, mp 146–147 ꢂC,
26
½ꢀꢃ
ꢁ130ꢂ (c 0.20, MeOH); lit.13) mp 116.0–117 ꢂC,
½ꢀꢃDD ꢁ130ꢂ (c 0.1, MeOH)]14) and then enokipodin C
24
24
24
[1b: ½ꢀꢃD ꢁ9:2ꢂ (c 0.50, MeOH); lit.13) ½ꢀꢃD ꢁ9:4ꢂ (c
1.0, MeOH)]. The spectral data (1H- and 13C-NMR) for
1b and 2b were identical with those of natural
enokipodins C and D, respectively.
In conclusion, the first enantioselective total synthesis
of enokipodins A, B, C and D was accomplished by
starting from known aromatic ester F in 12, 11, 13 and
12 steps with overall yields of 15%, 28%, 8% and 10%,
respectively. The specific rotation values of synthetic
enokipodins matched those reported for the natural
products, which enable us to confirm the absolute
configuration of enokipodins, while the melting points
of synthetic 1a and 2b were considerably higher than
those of the corresponding natural enokipodins. Since
(ꢀ)-8 has previously been converted into (ꢀ)-3d and
(ꢀ)-4,10,11) this synthesis also constitutes a formal
synthesis of (S)-3d and (S)-4.
22
[mp 146–147 ꢂC, ½ꢀꢃD ꢁ65ꢂ (c 0.40, MeOH); lit.12)
24
semisolid, ½ꢀꢃD ꢁ63ꢂ (c 0.05, MeOH)] in a 79%
overall yield from B. Finally, reduction of the benzo-
quinone moiety with sodium dithionite21) afforded (þ)-
enokipodin A (1a) as colorless prisms (mp 180–182 ꢂC,
23
½ꢀꢃ
þ48ꢂ (c 0.50, MeOH); lit.12) mp 138.5–138.9 ꢂC,
½ꢀꢃDD þ48ꢂ (c 0.5, MeOH)) in a 55% yield. The H-
and 13C-NMR spectra of synthetic 1a and 2a were
respectively identical with those of natural enokipodins
A and B.
23
1
Having completed the synthesis of (þ)-1a and (ꢁ)-
2a, we next turned our attention to the elaboration

Enantioselective Total Synthesis of Enokipodins A–D
377
Experimental
s, ArOCH3), 3.77 (3H, s, ArOCH3), 4.42 (1H, dd, J ¼
9:8, 4.3 Hz, 2-H), 6.65 (1H, s, ArH), 6.70 (1H, s, ArH).
HR-EIMS m=z (Mþ): calcd. for C15H20O5, 280.1311;
found, 280.1313.
IR spectra were measured by a Jasco IR Report-100
spectrometer. NMR spectra were recorded with TMS as
an internal standard in CDCl3 by a Varian Gemini 2000
(300 MHz), Varian Unity Inova 500 (500 MHz), or
Varian Unity Inova 600 (600 MHz) spectrometer.
Optical rotation values were measured with a Horiba
Sepa-300 polarimeter, and mass spectra were obtained
with a Jeol JMS-700 spectrometer operated in the EI
mode. Merck silica gel 60 (70–230 mesh) was used for
column chromatography.
2-(2,5-Dimethoxy-4-methylphenyl)-4-oxopentanoic
acid (E). A mixture of 5b (5.70 g, 20.4 mmol) and 2 M
NaOH aq. (20.5 ml, 41.0 mmol) in THF (56 ml) was
stirred for 12 h at 50 ꢂC. The mixture was extracted once
with ether, and the aqueous layer was acidified with 2 M
HCl aq. The resulting mixture was extracted with ether,
and the ethereal solution was successively washed with
water and brine, dried over Na2SO4 and concentrated in
vacuo. The residue was chromatographed over silica gel
(110 g; hexane–ethyl acetate, 7:3) to give 5.32 g (98%)
of E as a colorless microcrystalline solid, mp 121.0–
122.0 ꢂC. IR ꢂmax (KBr) cmꢁ1: 3150 (m), 1710 (s), 1660
(m), 1510 (s), 1210 (s), 1170 (s), 1045 (s). NMR ꢁH
(300 MHz): 2.17 (3H, s, 5-H3), 2.20 (3H, s, ArCH3),
2.61 (1H, dd, J ¼ 17:7, 4.5 Hz, 3-H), 3.36 (1H, dd,
J ¼ 17:7, 9.8 Hz, 3-H), 3.77 (3H, s, OCH3), 3.78 (3H, s,
OCH3), 4.38–4.48 (1H, m, 2-H), 6.68 (1H, s, ArH), 6.72
(1H, s, ArH). HR-EIMS m=z (Mþ): calcd. for C14H18O5,
266.1155; found, 266.1158.
Methyl 2-(2,5-dimethoxy-4-methylphenyl)-4-methyl-
4-pentenoate (5a). To a stirred solution of LDA, which
had been prepared by treating a solution of diisopropyl-
amine (3.80 ml, 27.1 mmol) in THF (27 ml) with
butyllithium (1.57 M in hexane, 17.2 ml, 27.0 mmol) at
0 ꢂC, was added dropwise a solution of F (3.00 g,
13.4 mmol) in THF (30 ml) at ꢁ78 ꢂC. After 30 min, the
reaction mixture was allowed to warm to 0 ꢂC over 1.5 h,
and then re-cooled to ꢁ78 ꢂC. To the solution was
successively added methallyl chloride (2.65 ml,
26.8 mmol), HMPA (8 ml) and sodium iodide (0.40 g,
2.7 mmol), and the resulting mixture was stirred for 2.5 h
at ꢁ78 ꢂC, then allowed to warm to 0 ꢂC, and finally
quenched with sat. NH4Cl aq. The mixture was
extracted with ether, and the ethereal solution was
successively washed with water and brine, dried over
Na2SO4 and concentrated in vacuo. The residue was
chromatographed over silica gel (80 g; hexane–ethyl
acetate, 15:1) to give 3.65 g (98%) of 5a as a solid,
recrystallization of which from hexane–ethyl acetate
gave colorless prisms, mp 76.5–77.5 ꢂC. IR ꢂmax (KBr)
cmꢁ1: 1720 (s), 1505 (m), 1215 (s), 1040 (m). NMR ꢁH
(300 MHz): 1.73 (3H, s, 4-CH3), 2.20 (3H, s, ArCH3),
2.38 (1H, dd, J ¼ 14:5, 7.0 Hz, 3-H), 2.76 (1H, dd,
J ¼ 14:5, 8.4 Hz, 3-H), 3.65 (3H, s, CO2CH3), 3.78 (3H,
s, ArOCH3), 3.79 (3H, s, ArOCH3), 4.29 (1H, dd,
J ¼ 8:4, 7.0 Hz, 2-H), 4.68 (1H, s, 5-H), 4.72 (1H, s, 5-
H), 6.70 (1H, s, ArH), 6.79 (1H, s, ArH). HR-EIMS m=z
(Mþ): calcd. for C16H22O4, 278.1518; found, 278.1519.
(3S,6S,7aR)-6-(2,5-Dimethoxy-4-methylphenyl)-3-iso-
propyl-6,7a-dimethyltetrahydropyrrolo[2,1-b]oxazol-5-
one (6a). A solution of E (3.00 g, 11.3 mmol) and (S)-
valinol (1.75 g, 17.0 mmol) in toluene (200 ml) was
refluxed for 16 h with azeotropic removal of water. The
mixture was diluted with sat. NH4Cl aq. and extracted
with ether. The ethereal solution was successively
washed with sat. NaHCO3 aq., water and brine, dried
over Na2SO4 and concentrated in vacuo. The residue was
chromatographed over silica gel (70 g; hexane–ethyl
acetate, 10:1) to give 3.18 g (85%) of D as an inseparable
6:5 diastereomeric mixture. IR ꢂmax (film) cmꢁ1: 1715,
(s) 1515 (s), 1505 (s), 1215 (s), 1040 (m). Some of the
1
peaks in the H-NMR spectrum of the diastereomeric
mixture were assigned as follows for ꢁH (300 MHz): 0.93
(3H, d, J ¼ 6:6 Hz, isopropyl-CH3), 1.06 (3H ꢄ 6=11, d,
J ¼ 6:6 Hz, isopropyl-CH3), 1.15 (3H ꢄ 5=11, d, J ¼
6:6 Hz, isopropyl-CH3), 1.43 (3H ꢄ 6=11, s, 7a-CH3),
1.55 (3H ꢄ 5=11, s, 7a-CH3), 1.66–1.81 (1H, m, iso-
propyl-CH), 2.09 (1H ꢄ 5=11, dd, J ¼ 14:0, 4.8 Hz, 7-
H), 2.197 (3H ꢄ 6=11, s, ArCH3), 2.202 (3H ꢄ 5=11, s,
ArCH3), 2.39 (1H ꢄ 6=11, t, J ¼ 12:3 Hz, 7-H), 2.52
(1H ꢄ 6=11, dd, J ¼ 12:3, 8.8 Hz, 7-H), 2.67 (1H ꢄ
5=11, dd, J ¼ 14:0, 10.7 Hz, 7-H), 6.64 (1H ꢄ 6=11, s,
ArH), 6.65 (1H ꢄ 5=11, s, ArH), 6.698 (1H ꢄ 5=11, s,
ArH), 6.704 (1H ꢄ 6=11, s, ArH). To a stirred solution of
D (3.00 g, 9.00 mmol) in THF (270 ml) was added
dropwise a solution of sec-butyllithium (0.96 M in
hexane, 15 ml, 14 mmol) at ꢁ78 ꢂC. After 2 h, iodo-
methane (1.40 ml, 22.5 mmol) was added at the same
temperature, and the resulting mixture was allowed to
warm to ꢁ15 ꢂC over 2 h. The reaction mixture was
quenched with sat. NH4Cl aq. and extracted with ether.
Methyl 2-(2,5-dimethoxy-4-methylphenyl)-4-oxopen-
tanoate (5b). To a stirred solution of 5a (2.40 g,
8.63 mmol) in THF–H2O (3:1, 120 ml) were added 4-
methylmorpholine N-oxide (2.03 g, 17.3 mmol) and a
catalytic amount of OsO4 (ca. 15 mg). After 3 h, NaIO4
(3.70 g, 17.3 mmol) was added, and the mixture was
stirred for 15 h. The reaction mixture was quenched with
sat. Na2S2O3 aq. and extracted with ether. The ethereal
solution was successively washed with water and brine,
dried over Na2SO4 and concentrated in vacuo to give
2.38 g (98%) of 5b. IR ꢂmax (KBr) cmꢁ1: 1725 (s), 1710
(s), 1515 (m), 1500 (m), 1210 (s), 1040 (s). NMR ꢁH
(300 MHz): 2.18 (3H, s, 5-H3), 2.20 (3H, s, ArCH3),
2.59 (1H, dd, J ¼ 17:8, 4.3 Hz, 3-H), 3.35 (1H, dd,
J ¼ 17:8, 9.8 Hz, 3-H), 3.66 (3H, s, CO2CH3), 3.76 (3H,

378
M. SAITO and S. KUWAHARA
The ethereal solution was successively washed with 10%
Na2S2O3 aq., water and brine, dried over Na2SO4 and
concentrated in vacuo. The residue was chromatograph-
ed over silica gel (60 g; hexane–ethyl acetate, 20:1) to
give 2.75 g (88%) of 6a and 86 mg (3%) of its epimer.
for C20H31NO4, 349.2253; found, 349.2254. A portion
of the oil (172 mg, 0.493 mmol) was dissolved in ethanol
(10 ml), and 1 M (n-Bu)4NH2PO4 aq. (10 ml) was added
to the solution at room temperature. After being stirred
for 24 h, the mixture was concentrated in vacuo, diluted
with water, and extracted with ether. The ethereal
solution was successively washed with water and
brine, dried over Na2SO4 and concentrated in vacuo to
give 142 mg of (S)-2-(2,5-dimethoxy-4-methylphenyl)-
2-methyl-4-oxopentanal (7) as an oil. IR ꢂmax (film)
cmꢁ1: 2700 (w), 1715 (s), 1500 (s), 1390 (m), 1215 (s),
1140 (s). NMR ꢁH (300 MHz): 1.51 (3H, s, 2-CH3), 1.97
(3H, s, 5-H3), 2.22 (3H, s, ArCH3), 3.05 (1H, d,
J ¼ 16:2 Hz, 3-H), 3.16 (1H, d, J ¼ 16:2 Hz, 3-H), 3.74
(3H, s, OCH3), 3.82 (3H, s, OCH3), 6.72 (1H, s, ArH),
6.75 (1H, s, ArH), 9.53 (1H, s, 1-H). HR-EIMS m=z
(Mþ): calcd. for C15H20O4, 264.1361; found, 264.1364.
The oil just obtained (142 mg) was dissolved in t-butyl
alcohol (3.5 ml), and K2CO3 (0.37 g, 2.7 mmol) was
added to the solution. The mixture was stirred at reflux
for 4.5 h, diluted with ether, and filtered. The filtrate was
concentrated in vacuo, and the residue was chromato-
graphed over silica gel (5 g; hexane–ethyl acetate, 9:1)
24
Compound 6a: ½ꢀꢃD ꢁ52:4ꢂ (c 5.00, EtOH). IR ꢂmax
(KBr) cmꢁ1: 1710 (s), 1505 (m), 1215 (s), 1040 (s). NMR
ꢁH (600 MHz): 0.92 (3H, d, J ¼ 6:7 Hz, isopropyl-CH3),
1.14 (3H, d, J ¼ 6:7 Hz, isopropyl-CH3), 1.20 (3H, s, 7a-
CH3), 1.52 (3H, s, 6-CH3), 1.69 (1H, dsep, J ¼ 10:4,
6.7 Hz, isopropyl-CH), 2.195 (3H, s, ArCH3), 2.202 (1H,
d, J ¼ 13:5 Hz, 7-H), 2.81 (1H, d, J ¼ 13:5 Hz, 7-H),
3.72 (1H, ddd, J ¼ 10:4, 7.7, 6.5 Hz, 3-H), 3.75 (3H, s,
OCH3), 3.80 (3H, s, OCH3), 3.83 (1H, dd, J ¼ 8:5,
6.5 Hz, 2-H), 4.22 (1H, dd, J ¼ 8:5, 7.6 Hz, 2-H), 6.72
(1H, s, ArH), 6.74 (1H, s, ArH). NMR ꢁC (150 MHz):
16.0, 19.1, 20.7, 24.3, 24.7, 34.0, 48.6, 52.1, 55.6, 55.9,
62.0, 70.7, 97.3, 110.5, 114.8, 125.8, 129.7, 150.4, 151.3,
182.6. HR-EIMS m=z (Mþ): calcd. for C20H29NO4,
23
347.2097; found, 347.2098. Epimer of 6a: ½ꢀꢃD þ41:0ꢂ
(c 1.00, EtOH). IR ꢂmax (KBr) cmꢁ1: 1710 (s), 1505 (m),
1210 (s), 1040 (s). NMR ꢁH (600 MHz): 0.92 (3H, d, J ¼
6:5 Hz, isopropyl-CH3), 1.08 (3H, d, J ¼ 6:5 Hz, iso-
propyl-CH3), 1.57 (3H, s, 7a-CH3), 1.68–1.76 (1H, m,
isopropyl-CH), 1.71 (3H, s, 6-CH3), 2.09 (1H, d, J ¼
13:2 Hz, 7-H), 2.19 (3H, s, ArCH3), 2.66 (1H, d,
J ¼ 13:2 Hz, 7-H), 3.68–3.77 (1H, m, 3-H), 3.71 (3H,
s, OCH3), 3.80 (3H, s, OCH3), 3.90 (1H, dd, J ¼ 8:7,
6.9 Hz, 2-H), 4.31 (1H, seemingly t, J ¼ ca. 8.2 Hz, 2-
H), 6.68 (1H, s, ArH), 6.82 (1H, s, ArH). NMR ꢁC
(150 MHz): 16.3, 19.2, 20.9, 24.7, 27.2, 34.4, 50.0, 50.4,
56.3, 56.4, 62.3, 71.0, 97.1, 110.6, 115.1, 126.4, 130.4,
150.6, 151.5, 183.3. HR-EIMS m=z (Mþ): calcd. for
C20H29NO4, 347.2097; found, 347.2101.
26
to give 95.0 mg (82% from 6a) of C, ½ꢀꢃD þ99:7ꢂ
(c 5.00, EtOH). IR ꢂmax (film) cmꢁ1: 1710 (s), 1500 (m),
1395 (m), 1210 (s), 1040 (s). NMR ꢁH (300 MHz): 1.58
(3H, s, 4-CH3), 2.21 (3H, s, ArCH3), 2.56 (1H, d,
J ¼ 18:7 Hz, 5-H), 2.78 (1H, d, J ¼ 18:7 Hz, 5-H), 3.75
(3H, s, OCH3), 3.79 (3H, s, OCH3), 6.16 (1H, d,
J ¼ 5:6 Hz, 2-H), 6.66 (1H, s, ArH), 6.71 (1H, s, ArH),
7.80 (1H, d, J ¼ 5:6 Hz, 3-H). HR-EIMS m=z (Mþ):
calcd. for C15H18O3, 246.1256; found, 246.1256.
(4R)-4-(2,5-Dimethyl-4-methylphenyl)-4,5,5-trimeth-
yl-2-cyclopentenone (B). To a stirred suspension of NaH
(60% in mineral oil, 1.71 g, 42.8 mmol) in THF (2 ml)
was added dropwise a solution of C (1.06 g, 4.30 mmol)
in THF (5.5 ml)–HMPA (1.5 ml), and the resulting
mixture was stirred for 1 h at room temperature. Iodo-
methane (2.67 ml, 42.9 mmol) was then added, and the
mixture was stirred for 17 h at room temperature. The
reaction mixture was quenched with methanol (1.7 ml)
and diluted with ether. The ethereal solution was
successively washed with water and brine, dried over
Na2SO4 and concentrated in vacuo. The residue was
chromatographed over silica gel (60 g; hexane–ethyl
(4R)-4-(2,5-Dimethoxy-4-methylphenyl)-4-methyl-2-
cyclopentenone (C). To a stirred solution of 6a (1.00 g,
2.88 mmol) in THF (45 ml) was added dropwise a
solution of Red-Alꢀ (65% in toluene, 0.540 ml, 1.80
mmol) at 0 ꢂC. After 30 min, the mixture was allowed to
warm gradually to room temperature and stirred for an
additional 1 h. The reaction mixture was quenched with
methanol and concentrated in vacuo. The residue was
diluted with a mixture of hexane and ether (1:1, 50 ml),
and the resulting solution was successively washed with
15% NaOH aq., water and brine, dried over Na2SO4 and
concentrated in vacuo to give 6b as an oil (1.05 g). IR
ꢂmax (KBr) cmꢁ1: 3500 (m), 1505 (m), 1390 (m), 1215
(s), 1040 (s). NMR ꢁH (300 MHz): 0.85 (3H, d, J ¼
6:6 Hz, isopropyl-CH3), 1.11 (3H, d, J ¼ 6:6 Hz, iso-
propyl-CH3), 1.36 (3H, s, 7a-CH3), 1.43 (3H, s, 6-CH3),
1.50–1.60 (1H, m, isopropyl-CH), 1.77 (1H, d, J ¼
1:9 Hz, OH), 2.19 (3H, s, ArCH3), 2.35 (1H, d,
J ¼ 13:2 Hz, 7-H), 2.58 (1H, d, J ¼ 13:2 Hz, 7-H),
3.18 (1H, q, J ¼ 8:5 Hz, 3-H), 3.65 (1H, t, J ¼ 8:9 Hz,
2-H), 3.80 (3H, s, OCH3), 3.83 (3H, s, OCH3), 4.21 (1H,
dd, J ¼ 8:9, 7.6 Hz, 2-H), 4.90 (1H, br s, 5-H), 6.61 (1H,
s, ArH), 6.72 (1H, s, ArH). HR-EIMS m=z (Mþ): calcd.
28
acetate, 20:1) to give 0.720 g (61%) of B, ½ꢀꢃD ꢁ43:9ꢂ
(c 5.00, EtOH). IR ꢂmax (film) cmꢁ1: 1710 (s), 1600 (m),
1510 (m), 1500 (m), 1210 (s), 1040 (s). NMR ꢁH (300
MHz): 0.67 (3H, s, 5-CH3), 1.27 (3H, s, 5-CH3), 1.49
(3H, s, 4-CH3), 2.22 (3H, s, ArCH3), 3.77 (6H, s,
OCH3 ꢄ 2), 6.12 (1H, d, J ¼ 6:0 Hz, 2-H), 6.54 (1H, s,
ArH), 6.72 (1H, s, ArH), 7.90 (1H, d, J ¼ 6:0 Hz, 3-H).
HR-EIMS m=z (Mþ): calcd. for C17H22O3, 274.1569;
found, 274.1571.
2-Methyl-5-[(S)-1,2,2-trimethyl-3-oxocyclopentyl]-1,4-
benzoquinone (enokipodin B) (2a). A mixture of B

Enantioselective Total Synthesis of Enokipodins A–D
379
(100 mg, 0.365 mmol) and 10% Pd-C (15 mg) in ethyl
acetate (4 ml) was stirred under a hydrogen atmosphere
for 16 h. The mixture was filtered through a pad of
Celiteꢀ, and the filtrate was concentrated in vauo to give
95 mg of (R)-3-(2,5-dimethoxy-4-methylphenyl)-2,2,3-
trimethylcyclopentanone (8). IR ꢂmax (film) cmꢁ1: 1730
(s), 1500 (m), 1215 (s), 1040 (m). NMR ꢁH (300 MHz):
0.70 (3H, s, 2-CH3), 1.23 (3H, s, 2-CH3), 1.38 (3H, s,
3-CH3), 2.01–2.09 (1H, m, 4-H), 2.21 (3H, s, ArCH3),
2.41–2.58 (3H, m, 4-H, 5-H2), 3.72 (3H, s, OCH3), 3.81
(3H, s, OCH3), 6.68 (1H, s, ArH), 6.86 (1H, s, ArH).
HR-EIMS m=z (Mþ): calcd. for C17H24O3, 276.1726;
found, 276.1728. To a stirred solution of 8 just obtained
(95 mg, 0.34 mmol) in acetonitrile (2.1 ml)–water (0.9
ml) was added dropwise a solution of ceric ammonium
nitrate (0.57 g, 1.0 mmol) in acetonitrile–water (1:1,
3 ml) at 0 ꢂC. After 30 min, the mixture was diluted with
water and extracted with dichloromethane. The extract
was successively washed with water and brine, dried
over Na2SO4 and concentrated in vacuo. The residue
was chromatographed over silica gel (5 g; hexane–ethyl
acetate, 9:1) to give 71 mg (79% from B) of 2a as a
solid, recrystallization of which from hexane–ether gave
(1H, s), 6.55 (1H, s). NMR ꢁC (150 MHz): 15.49, 15.50,
16.0, 18.4, 34.7, 38.2, 43.2, 47.3, 109.6, 111.0, 116.8,
122.4, 131.1, 146.1, 147.4. HR-EIMS m=z (Mþ): calcd.
for C15H20O3, 248.1413; found, 248.1418. See ref. 12
1
for assignment of the H- and 13C-NMR signals.
(4R,5S,6S)-4-(2,5-Dimethoxy-4-methylphenyl)-3,3,4-
trimethyl-6-oxa-bicyclo[3.1.0]hexan-2-one (9). To a
stirred solution of B (100 mg, 0.365 mmol) in methanol
(2 ml) was successively added 25% NaOH aq. (0.44 ml,
2.8 mmol) and 30% H2O2 aq. (7.4 ml, 73 mmol) at 0 ꢂC.
The mixture was allowed to warm to 60 ꢂC, and stirred
for 6.5 h. The mixture was diluted with water and
extracted with ethyl acetate. The extract was washed
with brine, dried over Na2SO4 and concentrated in
vacuo. The residue was chromatographed over silica gel
(5 g; hexane–ethyl acetate, 9:1) to give 54.0 mg (51%)
26
of 9, ½ꢀꢃD þ110ꢂ (c 0.55, EtOH). IR ꢂmax (film) cmꢁ1
:
2960, 2925, 1715, 1600, 1510, 1500, 1460, 1390, 1370,
1210, 1045, 860. NMR ꢁH (500 MHz): 0.59 (3H, s, 3-
CH3), 1.17 (3H, s, 3-CH3), 1.63 (3H, s, 4-CH3), 2.21
(3H, s, ArCH3), 3.58–3.60 (4H, br s, OCH3, 5-H), 3.61
(1H, d, J ¼ 2:5 Hz, 1-H), 3.83 (3H, s, OCH3), 6.62 (1H,
s, ArH), 6.85 (1H, s, ArH). HR-EIMS m=z (Mþ): calcd.
for C17H22O4, 290.1518; found, 290.1518.
22
orange needles, mp 146–147 ꢂC, ½ꢀꢃD ꢁ65ꢂ (c 0.40,
MeOH). IR ꢂmax (KBr) cmꢁ1: 1730 (m), 1650 (s), 1630
(w), 1590 (w), 1255 (w), 1120 (w), 1070 (w), 1010 (w),
930 (w). NMR ꢁH (600 MHz): 0.76 (3H, s), 1.23 (3H, s),
1.32 (3H, s), 1.88 (1H, ddd, J ¼ 12:8, 9.0, 2.4 Hz), 2.04
(3H, d, J ¼ 1:5 Hz), 2.27 (1H, ddd, J ¼ 12:8, 10.3,
9.5 Hz), 2.44 (1H, ddd, J ¼ 19:2, 10.3, 9.0 Hz), 2.50
(1H, ddd, J ¼ 19:2, 9.5, 2.4 Hz), 6.57 (1H, q, J ¼
1:5 Hz), 6.69 (1H, s). NMR ꢁC (150 MHz): 14.9, 20.6,
22.1, 23.0, 31.0, 33.7, 48.9, 52.3, 134.1, 135.3, 144.4,
153.4, 187.7, 188.2, 221.0. HR-EIMS m=z (Mþ): calcd.
for C15H18O3, 246.1256; found, 246.1259. See ref. 12
(3R,4R)-3-(2,5-Dimethoxy-4-methylphenyl)-4-hydroxy-
2,2,3-trimethylcyclopentanone (A). To a stirred solution
of PhSeSePh (232 mg, 0.743 mmol) in ethanol (1 ml)
was added NaBH4 (56 mg, 1.5 mmol) at room temper-
ature. After hydrogen evolution had ceased, acetic acid
(5 ml, 0.09 mmol) was added to the mixture at 0 ꢂC. After
5 min, a solution of 9 (54.0 mg, 0.186 mmol) in ethanol
(0.8 ml) was added, and the resulting mixture was stirred
at room temperature for 1 h. The mixture was diluted
with ethyl acetate, and oxygen gas was passed through
the mixture for 5 min. The mixture was diluted with
brine and extracted with ethyl acetate. The extract was
dried over Na2SO4 and concentrated in vacuo. The
residue was chromatographed over silica gel (5 g;
hexane–ethyl acetate, 7:3) to give 36.9 mg (68%) of A,
1
for assignment of the H- and 13C-NMR signals.
(2R,5R)-4,5-Dihydro-5,8,10,10-tetramethyl-2,5-meth-
ano-1-benzoxepin-2,7(3H)-diol (enokipodin A) (1a). To
a stirred solution of 2a (36 mg, 0.15 mmol) in ethanol
(1 ml) was added a solution of Na2S2O4 (51 mg, 0.29
mmol) in water (1 ml) at room temperature. After
30 min, the mixture was diluted with water (1 ml) and
concentrated in vacuo. The residue was diluted with
water and extracted with ether. The ethereal solution
was washed with brine, dried over Na2SO4 and
concentrated in vacuo. The residue was chromatograph-
ed [silica gel–Na2S2O4 (10:1), 11 g; hexane–ethyl
acetate, 4:1) to give 20 mg (55%) of 1a as a solid,
recrystallization of which from hexane–ether gave
23
½ꢀꢃD ꢁ115ꢂ (c 1.00, EtOH). IR ꢂmax (film) cmꢁ1: 3450,
2940, 2960, 2850, 1740, 1510, 1460, 1390, 1210, 1070,
1040. NMR ꢁH (300 MHz): 0.72 (3H, s, 2-CH3), 1.31
(3H, s, 2-CH3), 1.33 (3H, s, 3-CH3), 2.21 (3H, s,
ArCH3), 2.48 (1H, dd, J ¼ 19:0, 10.2 Hz, 5-H), 2.79
(1H, dd, J ¼ 19:0, 8.5 Hz, 5-H), 2.99 (1H, d, J ¼ 3:8 Hz,
OH), 3.80 (3H, s, OCH3), 3.83 (3H, s, OCH3), 5.32 (1H,
ddd, J ¼ 10:2, 8.5, 3.8 Hz, 4-H), 6.77 (1H, s, ArH), 6.86
(1H, s, ArH). HR-EIMS m=z (Mþ): calcd. for C17H24O4,
292.1675; found, 292.1684.
23
colorless prisms, mp 180–182 ꢂC, ½ꢀꢃD þ48ꢂ (c 0.50,
MeOH). IR ꢂmax (KBr) cmꢁ1: 3500 (m), 3380 (m), 1490
(s), 1280 (s), 1200 (s), 1140 (s), 900 (s). NMR ꢁH
(600 MHz): 0.80 (3H, s), 1.09 (3H, s), 1.24 (3H, s), 1.78
(1H, ddd, J ¼ 12:6, 9.4, 4.1 Hz), 1.90 (1H, ddd,
J ¼ 12:6, 11.2, 6.8 Hz), 2.09 (1H, ddd, J ¼ 14:2, 11.2,
4.1 Hz), 2.17 (3H, s), 2.18 (1H, ddd, J ¼ 14:2, 9.4,
6.8 Hz), 2.72 (1H, br s, OH), 4.28 (1H, br s, OH), 6.50
2-Methyl-5-[(1S,5R)-5-hydroxy-1,2,2-trimethyl-3-oxo-
cyclopentyl]-1,4-benzoquinone (enokipodin D) (2b). To
a stirred solution of A (35.0 mg, 0.120 mmol) in
acetonitrile–water (7:3, 1 ml) was added a solution of
ceric ammonium nitrate (0.15 g, 0.27 mmol) in acetoni-
trile–water (1:1, 1 ml) at 0 ꢂC. The mixture was stirred at

380
M. SAITO and S. KUWAHARA
room temperature for 30 min, diluted with water, and
extracted with dichloromethane. The extract was suc-
cessively washed with water and brine, dried over
Na2SO4 and concentrated in vacuo. The residue was
chromatographed over silica gel (5 g; hexane–ethyl
acetate, 7:3) to give 24.5 mg (78%) of 2b as a solid,
recrystallization of which from hexane–ethyl acetate
References
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26
gave yellow needles, mp 146–147 ꢂC, ½ꢀꢃD ꢁ130ꢂ (c
0.20, MeOH). IR ꢂmax (KBr) cmꢁ1: 3550 (m), 3430 (m),
1730 (m), 1650 (s), 1600 (w), 1250 (w), 1070 (w), 925
(w). NMR ꢁH (600 MHz): 0.83 (3H, s), 1.25 (3H, s), 1.29
(3H, s), 2.06 (3H, d, J ¼ 1:6 Hz), 2.44 (1H, dd,
J ¼ 19:2, 9.7 Hz), 2.64 (1H, d, J ¼ 4:7 Hz, OH), 2.84
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4.7 Hz), 6.60 (1H, q, J ¼ 1:6 Hz), 6.87 (1H, s). NMR ꢁC
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To a stirred solution of 2b (12.0 mg, 0.0458 mmol) in
ethanol (120 ml) was added a solution of Na2S2O4
(16 mg, 0.092 mmol) in water (130 ml) at room temper-
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(250 ml) and concentrated in vacuo. The residue was
diluted with water and extracted with dichloromethane.
The extract was washed with brine, dried over Na2SO4
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graphed [silica gel–Na2S2O4 (10:1), 11 g; hexane–ethyl
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recrystallization of which from hexane–ether gave
24
colorless prisms, ½ꢀꢃD ꢁ9:2ꢂ (c 0.50, MeOH). IR
ꢂmax (KBr) cmꢁ1: 3400 (s), 1500 (w), 1420 (w), 1300
(w), 1175 (m), 1070 (m). NMR ꢁH (600 MHz): 0.74 (3H,
s), 1.25 (3H, s), 1.30 (3H, s), 1.93 (1H, d, J ¼ 3:8 Hz,
OH), 2.17 (3H, s), 2.22 (1H, dd, J ¼ 15:1, 2.7 Hz), 2.61
(1H, dd, J ¼ 15:1, 8.0 Hz), 2.86 (1H, br s, OH), 3.89
(1H, ddd, J ¼ 8:0, 3.8, 2.7 Hz), 4.45 (1H, br s, OH), 6.52
(1H, s), 6.56 (1H, s). NMR ꢁH (150 MHz): 11.4, 15.5,
16.7, 19.7, 42.6, 46.5, 51.7, 77.2, 108.7, 111.1, 117.2,
123.4, 128.5, 145.8, 147.8. HR-EIMS m=z (Mþ): calcd.
for C15H20O4, 264.1361; found, 264.1364. See ref. 13
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1
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Acknowledgments
We are grateful to Prof. Tahara (Hokkaido Univer-
sity) for providing copies of the spectra of natural
enokipodins A–D. This work was supported, in part, by
Grant-in-Aid for Scientific Research (B) from the
Ministry of Education, Culture, Sports, Science and
Technology of Japan (No. 16380075). Financial support
given to S. K. by Nagase Science and Technology
Foundation is also greatly appreciated.
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