Enantio- and diastereoselective total synthesis of EI-1941-1, -2, and -3, inhibitors of interleukin-1β converting enzyme, and biological properties of their derivatives

Article abstract of DOI:10.1021/jo0516436

The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1β converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a key intermediate in our total synthesis of epoxyquinols A and B.

Full text of DOI:10.1021/jo0516436

Enantio- and Diastereoselective Total Synthesis of EI-1941-1, -2,
and -3, Inhibitors of Interleukin-1â Converting Enzyme, and
Biological Properties of Their Derivatives
Mitsuru Shoji,† Takao Uno,† Hideaki Kakeya,‡ Rie Onose,‡ Isamu Shiina,§
Hiroyuki Osada,‡ and Yujiro Hayashi*,†
Department of Industrial Chemistry, Faculty of Engineering, and Department of Applied Chemistry,
Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan, and
Antibiotics Laboratory, Discovery Research Institute, RIKEN, 2-1 Hirosawa, Wako,
Saitama 351-0198, Japan
hayashi@ci.kagu.tus.ac.jp
Received August 5, 2005
The first asymmetric total synthesis of EI-1941-1, -2, and -3, inhibitors of the interleukin-1â
converting enzyme (ICE), has been accomplished, starting from a chiral epoxy iodoquinone 11, a
key intermediate in our total synthesis of epoxyquinols A and B. Despite a failure to synthesize
the inhibitors by our postulated biosynthetic route, we were able to diastereoselectively synthesize
them via an intramolecular carboxypalladation with the key steps being a 6-endo cyclization mode
followed by â-hydride elimination. The investigation of the biological properties of EI-1941-1, -2,
and -3 and their derivatives disclosed them to be potent and effective ICE inhibitors with less
cytotoxicity than EI-1941-1 and -2 in a cultured cell system.
Introduction
workers have isolated EI-1941-1 (1), EI-1941-2 (2), and
EI-1941-3 (3) from culture broths of Farrowia sp., the
first two of which selectively inhibit human recombinant
ICE activity with IC50 values of 0.086 and 0.006 µM,
respectively, whereas the last is inactive at concentra-
tions up to 10 µM in an in vitro system.4 EI-1941-2 also
has weak antimicrobial activities against Gram-positive
Interleukin-1â (IL-1â) is an important mediator of
pathogenesis of rheumatoid arthritis, septic shock, in-
flammation, and other physiological conditions.1 IL-1â
converting enzyme (ICE) is a cysteine protease, which
cleaves a biologically inactive 31 kDa precursor to
biologically active IL-1â.2 IL-1â is released from mac-
rophage-like cells in an inflammatory situation, and is
the major form of IL-1 in diseases. ICE inhibitors have
been shown to prevent inflammation in several acute
models,3 suggesting that ICE inhibitors would be useful
as antiinflammatory drugs. Recently, Koizumi and co-
(2) (a) Thornberry, N. A.; Bull, H. G.; Calaycay, J. R.; Chapman, K.
T.; Howard, A. D.; Kostura, M. J.; Miller, D. K.; Molineaux, S. M.;
Weidner, J. R.; Aunins, J.; Elliston, K. O.; Ayala, J. M.; Casano, F. J.;
Chin, J.; Ding, G. J.-F.; Egger, L. A.; Gaffney, E. P.; Limjuco, G.;
Palyha, O. C.; Raju, S. M.; Roland, A. M.; Salley, J. P.; Yamin, T.-T.;
Lee, J. A.; Shively, J. E.; Maccross, M.; Mumford, R. A.; Schmidt, J.
A.; Tocci, M. J. Nature 1992, 356, 768. (b) Gerretti, D. P.; Kozlosky, C.
J.; Mosley, B.; Nelson, N.; Ness, K. V.; Greenstreet, T. A.; March, C.
J.; Kronheim, S. R.; Druck, T.; Cannizzaro, L. A.; Huebner, K.; Black,
R. A. Science 1992, 256, 97.
(3) Ku, G.; Faust, T.; Lauffer, L. L.; Livingston, D. J.; Harding, M.
W. Cytokine 1996, 8, 377.
(4) (a) Koizumi, F.; Matsuda, Y.; Nakanishi, S. J. Antibiot. 2003,
56, 464. (b) Koizumi, F.; Ishiguro, H.; Ando, K.; Kondo, H.; Yoshida,
M.; Matsuda, Y.; Nakanishi, S. J. Antibiot. 2003, 56, 603.
* Phone: +81 3-5228-8318. Fax: +81 3-5261-4631.
† Department of Industrial Chemistry, Faculty of Engineering,
Tokyo University of Science.
§ Department of Applied Chemistry, Faculty of Science, Tokyo
University of Science.
‡ RIKEN.
(1) (a) Dinarello, C. A. Blood 1991, 77, 1627. (b) Dinarello, C. A.;
Wolff, S. M. N. Engl. J. Med. 1993, 328, 106.
10.1021/jo0516436 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/03/2005
J. Org. Chem. 2005, 70, 9905-9915
9905

Shoji et al.
FIGURE 1. Natural products of epoxyquinol monomers and dimers.
bacteria, and moderate activity against Proteus vulgaris.4
A more potent and effective ICE inhibitor would be
desired, and EI-1941-1 and -2 would be suitable lead
compounds for the study of the structure-activity rela-
tionship.
tions were made on the basis of the crystallographic
analysis of the p-bromobenzoyl ester of EI-1941-2 and
the chemical correlation between EI-1941-1 and -2.
These results indicate that the compounds we have
synthesized are opposite enantiomers of the natural EI-
1941-2 and its epimer, which was communicated in a
previous letter.9
As for the biosynthesis, we postulated the following
path: Oxidation of alcohol 4 would afford aldehyde 5,
from which 6π-electrocyclization10 proceeds to generate
2H-pyran 6. Hydration and isomerization would afford
EI-1941-1, the oxidation of which would provide EI-
1941-2 (eq 1). Another possible path involves the oxida-
tion of alcohol 4 to carboxylic acid 7, from which 6π-
electrocyclization proceeds to generate hydroxy-2H-pyran
8 (eq 2). Isomerization would afford EI-1941-2, the
reduction of which would provide EI-1941-1. Similar 2H-
pyran 10 is a key intermediate of our biomimetic total
synthesis of epoxyquinols A, B, and C, and epoxytwinol
A, which was generated by the oxidation of ECH followed
by the 6π-electrocyclization.6c,f,g
Structurally, EI-1941-1 and EI-1941-2 have an ep-
oxyquinone core and a side chain. We have been inter-
ested in the synthesis and biology of epoxyquinone
derivatives such as ECH ((2R,3R,4S)-2,3-epoxy-4-hy-
droxy-5-hydroxymethyl-6-(1E)-propenylcyclohex-5-en-1-
one),5 an inhibitor of Fas-mediated apoptosis, and its
dimer, epoxyquinols A, B, and C, and epoxytwinol A,
angiogenesis inhibitors.6 At the time that we started this
project, the relative and absolute stereochemistries of EI-
1941-1, -2, and -3 were not known. As most of the
epoxyquinol natural products have a trans relationship
between the epoxide and the 4-hydroxy group on the
cyclohexenone,7 work on a synthetic route by which the
two diastereomers (EI-1941-2 and epi-EI-1941-2) can
be generated with high optical purity was undertaken
in order to determine the relative stereochemistries. As
for the absolute stereochemistry, with the structural
similarity between EI-1941 and ECH, we tried to syn-
thesize the (1R,5S,6R)-1,6-epoxy-5-hydroxycyclohexenone
derivative as our first target.
(7) (a) Epiepoformin: Nagasawa, H.; Suzuki, A.; Tamura, S. Agric.
Biol. Chem. 1978, 42, 1303. (b) Epiepoxydon: Ichihara, A.; Kimura,
R.; Oda, K.; Koichi, M.; Sakamura, S. Tetrahedron Lett. 1976, 4741.
Nagasawa, H.; Suzuki, A.; Tamura, S. Agric. Biol. Chem. 1978, 42,
1303. Sekiguchi, J.; Gaucher, G. M. Biochem. J. 1979, 182, 445. (c)
Harveynone: Nagata, T.; Ando, Y.; Hirota, A. Biosci. Biotechnol.
Biochem. 1992, 56, 810. Kawazu, K.; Kobayashi, A.; Oe, K. JP
03041075, 1991; Chem. Abstr. 1991, 115, 181517. (d) Tricholomenyn
A: Garlaschelli, L.; Magistrali, E.; Vidari, G.; Zuffardi, O. Tetrahedron
Lett. 1995, 36, 5633. (e) Panepoxydon, Isopanepoxydon: Kis, Z.; Closse,
A.; Sigg, H. P.; Hruban, L.; Snatzke, G. Helv. Chim. Acta 1970, 53,
1577. Erkel, G.; Anke, T.; Sterner, O. Biochem. Biophys. Res. Commun.
1996, 226, 214. (f) Cycloepoxydon: Gehrt, A.; Erkel, G.; Anke, T.;
Sterner, O. J. Antibiot. 1998, 51, 455. Gehrt, A.; Erkel, G.; Anke, H.;
Anke, T.; Sterner, O. Nat. Prod. Lett. 1997, 9, 259. (g) Terremutin:
Miller, M. W. Tetrahedron 1968, 24, 4839. Read, G.; Ruiz, V. M. J.
Chem. Soc. C 1970, 1945. (h) Bromoxone: Higa, T.; Okuda, R. K.;
Severns, R. M.; Scheuer, P. J.; He, C.-H.; Changfu, X.; Clardy, J.
Tetrahedron 1987, 43, 1063. (i) Chaloxone: Fex, T.; Trofast, J.;
Wickberg, B. Acta Chem. Scand. B 1981, 35, 91. Fex, T.; Wickberg, B.
Acta Chem. Scand. B 1981, 35, 97. Grewe, R.; Kersten, S. Chem. Ber.
1967, 100, 2546. (j) Jesterone: Li, J. Y.; Strobel, G. A. Phytochemistry
2001, 57, 261. (k) Epoxyquinomycin C, D: Matsumoto, N.; Tuchida,
T,; Umekita, M.; Kinoshita, N.; Iinuma, H.; Sawa, T.; Hamada, M.;
Takeuchi, T. J. Antibiot. 1997, 50, 900. Matsumoto, N.; Tuchida, T.;
Sawa, R.; Iinuma, H.; Nakamura, H.; Naganawa, H.; Sawa, T.;
Takeuchi, T. J. Antibiot. 1997, 50, 912. For reviews, see: Marco-
Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev. 2004, 104, 2857.
(8) Koizumi, F.; Takahashi, Y.; Ishiguro, H.; Tanaka, R.; Ohtaki,
S.; Yoshida, M.; Nakanishi, S.; Ikeda, S. Tetrahedron Lett. 2004, 45,
7419.
When we had nearly finished the synthesis of the
targeted isomer of EI-1941-2 and its epimer, the abso-
lute and relative stereochemistries of EI-1941-1 and -2
were reported (see Figure 1),8 whereas those of EI-
1941-3 were not determined because of its low avail-
ability from the fermentation broth. Those determina-
(5) Kakeya, H.; Miyake, Y.; Shoji, M.; Kishida, S.; Hayashi, Y.;
Kataoka, T.; Osada, H. Bioorg. Med. Chem. Lett. 2003, 13, 3743.
(6) Isolation: (a) Kakeya, H.; Onose, R.; Koshino, H.; Yoshida, A.;
Kobayashi, K.; Kageyama, S.-I.; Osada, H. J. Am. Chem. Soc. 2002,
124, 3496. (b) Kakeya, H.; Onose, R.; Yoshida, A.; Koshino, H.; Osada,
H. J. Antibiot. 2002, 55, 829. Total syntheses by our group, see: (c)
Shoji, M.; Yamaguchi, J.; Kakeya, H.; Osada, H.; Hayashi, Y. Angew.
Chem., Int. Ed. 2002, 41, 3192. (d) Shoji, M.; Kishida, S.; Takeda, M.;
Kakeya, H.; Osada, H.; Hayashi, Y. Tetrahedron Lett. 2002, 43, 9155.
(e) Shoji, M.; Kishida, S.; Kodera, Y.; Shiina, I.; Kakeya, H.; Osada,
H.; Hayashi, Y. Tetrahedron Lett. 2003, 44, 7205. (f) Shoji, M.; Imai,
H.; Shiina, I.; Kakeya, H.; Osada, H.; Hayashi, Y. J. Org. Chem. 2004,
69, 1548. (g) Shoji, M.; Imai, H.; Mukaida, M.; Sakai, K.; Kakeya, H.;
Osada, H.; Hayashi, Y. J. Org. Chem. 2005, 70, 79. Other groups’ total
syntheses, see: (h) Li, C.; Bardhan, S.; Pace, E. A.; Liang, M.-C.;
Gilmore, T. D.; Porco, J. A., Jr. Org. Lett. 2002, 4, 3267. (i) Mehta, G.;
Islam, K.; Tetrahedron Lett. 2003, 44, 3569. (j) Mehta, G.; Islam, K.
Tetrahedron Lett. 2004, 45, 3611. (k) Kuwahara, S.; Imada, S.
Tetrahedron Lett. 2005, 46, 547. (l) Li, C.; Porco, J. A., Jr. J. Org. Chem.
2005, 70, 6053.
(9) Shoji, M.; Uno, T.; Hayashi, Y. Org. Lett. 2004, 6, 4535.
(10) Marvell, E. N. Thermal Electrocyclic Reactions; Academic
Press: New York, 1980.
9906 J. Org. Chem., Vol. 70, No. 24, 2005

Total Synthesis of EI-1941-1, -2, -3
TABLE 1. Calculated TS Energy and Relative Energy
between Diene Carbonyl Compound and r- and â-Methyl
2H-Pyran Derivatives
starting
material
TS energy
(kcal mol-1
relative energya
entry
)
(kcal mol-1
)
isomerb
1
2
3
4
5
6
7
8
13
13
14
14
15
15
16
16
17.74
15.50
25.34
8.83
25.65
10.23
22.50
9.46
-4.16
-4.18
+5.78
+6.26
+9.24
+8.66
+1. 73
+1. 58
R
â
R
â
R
â
R
â
a The values are relative energies between the diene carbonyl
compound and 2H-pyran in the 6π-electrocyclization. b R indicates
the R-methyl isomer, whereas â indicates the â-methyl isomer.
In this full paper we will describe the highly stereo-
selective, asymmetric total synthesis of the natural
enantiomers of EI-1941-1, -2, and -3 in a full account,
including an attempted total synthesis based on a bio-
mimetic route with the theoretical calculation of 6π-
electrocyclization of dienecarboxylic acid derivatives. We
also describe the biological properties of EI-1941-1, -2,
and -3 and their derivatives, including the finding of a
more superior ICE inhibitor that is less cytotoxic than
EI-1941-1 and -2.
difficult reaction.10 According to the recent theoretical
calculation of 2,4-pentadienal, a simple dienal, 6π-elec-
trocyclization is an equilibrium that shifts to the starting
material, and 2H-pyran is more energetically unstable
than the parent aldehyde with a TS energy of 3.44 kcal/
mol versus 21.52 kcal/mol.13 In the case of ECH, however,
an electron-withdrawing keto group on cyclohexane
reduces the TS energy with the stabilization of the 2H-
pyran intermediate 10 (eq 3).6f As 6π-oxa-electrocycliza-
tion has been investigated only for the diene-aldehydes
without a systematic study of that for diene-carboxylic
acids or esters, the theoretical calculations for the
substrates having a propenyl side chain and functional
groups such as aldehyde 13, carboxylic acid 14, methyl
ester 15, and acid chloride 16 were performed at the
B3LYP/6-31G* level with the program package TITAN
1.0.5 including DFT engine Jaguar 3.5.042.2.14 For all
the transition-state searches, vibrational frequencies
were computed after completion of the optimization from
analytic second derivatives.
Results and Discussion
Synthetic Study Based on Our Postulated Bio-
synthetic Pathway. As described in the Introduction,
EI-1941-1 would be generated by the hydration and
isomerization of 2H-pyran 6, and we already found that
the similar 2H-pyran 10, generated by the oxidation of
ECH, dimerized gradually under neat conditions or in a
rather condensed solution (eq 3).6c,f,g We thought the vinyl
ether moiety of 6 would react with H2O before it dimer-
izes when 2H-pyran 6 was treated with acid in a dilute
solution. Epoxycyclohexenol 4, the starting material, was
synthesized from the chiral iodocyclohexenone 11,6c,d,g an
enantiomer of the intermediate of our total synthesis of
epoxyquinols, by the Suzuki coupling reaction with (E)-
1-pentenylborate11 and Ag2O in the presence of a catalytic
amount of Pd(PhCN)2Cl2 and Ph3As,12 followed by cleav-
age of the acetonide on acid treatment (eq 4). 2H-Pyran
derivative 6 was isolated after the oxidation of alcohol 4
with MnO2, followed by 6π-electrocyclization. Though 2H-
pyran 6 was treated with several acids such as PPTS,
TsOH‚H2O, and CF3CO2H in several dilute aqueous
solvents, a complex mixture was obtained without isola-
tion of the desired product (eq 5), which prompted us to
examine the 6π-electrocyclization of a diene carboxylic
acid derivative.
There are two isomers for the 6π-oxa-electrocyclized
products such as R- and â-methyl derivatives (eq 6). The
transition-state energies for both R- and â-methyl-2H-
pyran derivatives, and the relative energies between
diene carbonyl derivatives and 2H-pyran derivatives, are
calculated with the results summarized in Table 1. We
have experimentally demonstrated the facile electrocy-
clization of diene aldehyde 13, which is supported by the
calculation showing that the 6π-electrocyclized product
is more stable than the starting material with the low
transition-state energies of 17.74 and 15.50 kcal/mol to
R- and â-methyl 2H-pyran derivatives, respectively (en-
Despite the facile 6π-electrocyclization of dienal 5, 6π-
electrocyclization has generally been regarded as a
(13) Rodriguez-Otero, J. J. Org. Chem. 1999, 64, 6842.
(14) TITAN 1.0.5. Schrodinger, Inc.: Irvine, CA, and Wavefunction,
Inc.: Portland, OR, 2000. http://www.schrodinger.com; http://
www.wavefun.com.
(11) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370.
(12) Ruel, F. S.; Braun, M. P.; Johnson, C. R. Org. Synth. 1997, 75,
69.
J. Org. Chem, Vol. 70, No. 24, 2005 9907

Shoji et al.
SCHEME 1. Synthesis of 23t and 23c
tries 1, 2). Diene carboxylic acid derivatives 14, 15, and
16 showed results different from those of diene aldehyde
13. 6π-Electrocyclization might proceed, judging from the
low transition-state energy to the â-methyl isomer,
whereas that to the R-methyl isomer is too high for the
6π-electrocyclization to proceed at room temperature. As
for the relative energies between the starting materials
and the 2H-pyran derivatives, 2H-pyran derivatives are
very unstable except for the acid chloride 16, indicating
that the equilibrium shifts mostly to the starting mate-
rial, and the concentration of the 2H-pyran derivatives
would be quite low. Even in the case of acid chloride 16,
though the 2H-pyran derivative is slightly more unstable
(1.58 kcal/mol) than the starting material, the equilib-
rium also shifts to the starting material with the low
concentration of 2H-pyran.
Synthesis of Carboxylic Acid Derivatives. With
the calculation results in hand, we examined the 6π-oxa-
electrocyclization of several derivatives. Before describing
the results of 6π-oxa-electrocyclization, we will briefly
mention the synthesis of carboxylic acid 23t (see Scheme
1). Cleavage of the acetonide of the chiral iodocyclohex-
enone 11 with an acid treatment gave diol 17. Selective
oxidation of the primary alcohol with excess MnO2 in
CH3CN gave aldehyde 18; the secondary alcohol was
protected by the use of TBSOTf and 2,6-lutidine, afford-
ing 19 in 72% yield over two steps. Oxidation of this
aldehyde to the carboxylic acid was successfully per-
formed under Kraus’ conditions.15 The carboxylic acid was
protected as its p-methoxybenzyl ester 21 by the reaction
with 4-methoxybenzyl trichloroacetimidate16 in 85% yield.
The introduction of a side chain by the Suzuki coupling
reaction with (E)-1-pentenylborate and Ag2O in the
presence of a catalytic amount of Pd(PhCN)2Cl2 and Ph3-
As afforded 22t in 97% yield. Acid treatment then gave
carboxylic acid 23t in excellent yield. The isomer with
the Z side chain, 23c, was prepared in good yield by the
Stille coupling reaction using (Z)-tributyl-1-pentenyl-
stannane in the presence of a catalytic amount of Pd-
(PhCN)2Cl2 and Ph3As, followed by the acid treatment.
With the starting materials in hand, we investigated
the 6π-electrocyclization of dienecarboxylic acid. No reac-
tion proceeded even at reflux in toluene, with the
recovery of the starting materials in the cases of car-
boxylic acid 23t and ester 22t. When acid chloride
generated from carboxylic acid 23t with oxalyl chloride
and a catalytic amount of DMF was gently heated to 60
°C in CDCl3, a complex mixture was obtained. Only
decomposition occurred when acid chloride was treated
with AlCl3 to generate the acylium ion.
As all our trials using 6π-electrocyclization as a key
step were in vain, we pursued another synthetic route
using intramolecular carboxymetalation.
Intramolecular Carboxymetalation. Intramolecu-
lar addition of the carboxylic acid onto the alkene
activated with iodine or metal salts was examined,
though diastereoselectivity and alternate reaction modes
such as 6-endo or 5-exo are possible problems with this
approach (Table 2). In fact, iodolactonization proceeded
(15) (a) Kraus, G. A.; Taschner, M. J. J. Org. Chem. 1980, 45, 1175.
(b) Bal, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron 1981,
37, 2091.
(16) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 4139.
9908 J. Org. Chem., Vol. 70, No. 24, 2005

Total Synthesis of EI-1941-1, -2, -3
TABLE 2. Intramolecular Cyclization of 23t and 23c
as a single isomer, albeit with the incorrect side-chain
relative stereochemistry at C7 in the reaction of E isomer
23t (vide infra, entry 2). Undesired 5-exo cyclization was
observed in that of the Z isomer 23c (entry 3). Unlike
these unsuccessful results, the 7,8-dihydro-6H-iso-
chromen-1,5-dione structure 28 was formed when palla-
dium(II) was used as a catalyst. That is, when 23t was
treated with p-benzoquinone and a catalytic amount of
Pd(PhCN)2Cl2,18 carboxypalladation proceeded, followed
by the â-hydride elimination, affording 28 in 70% yield
(entry 4).
The remaining steps are reduction of the double bond
and deprotection (see Scheme 2). Hydrogenation of 28
under an H2 atmosphere in the presence of Pd/C or Pd-
(OH)2 did not proceed. As the keto group might be the
cause of this reluctance to undergo hydrogenation, it was
reduced with NaBH4 in MeOH to afford alcohols 29 and
30 in 98% yield and equal amounts, which were sepa-
rated by column chromatography. The relative stereo-
chemistry is determined by the modified MTPA-ester
method19 of 29. Hydrogenation of R-alcohol 29 proceeded
smoothly and stereoselectively, affording an inseparable
mixture of 31 and 32 in excellent yield (95%) and with
high diastereoselectivity (95:5). It should be noted that
the concentration is important for the diastereoselectiv-
ity. Whereas excellent diastereoselectivity (95:5) was
obtained at 0.01 M, lower selectivity (87:13) was observed
at a higher concentration (0.1 M).9,20 The mixture of 31
and 32 was oxidized with MnO2, affording ketones 33 and
34 in 92% yield (95:5), which were easily separated by
thin-layer chromatography (TLC). Though hydrogenation
of â-alcohol 30 proceeded slowly, the reduced products
35 and 36 were obtained in 96% yield with the desired
isomer stereoselectivity (97:3). In this hydrogenation, the
concentration is also crucial. Excellent diastereoselectiv-
a Starting material. b Ten mole percent was employed.
in the 6-endo mode with low yield (entry 1), whereas in
the case of carboxymercuration using Hg(OTf)2,17 the
6-endo cyclized product was obtained in excellent yield
SCHEME 2. Synthesis of EI-1941-2 (2)
J. Org. Chem, Vol. 70, No. 24, 2005 9909

Shoji et al.
SCHEME 3. Synthesis of Epi-EI-1941-2 (39)
SCHEME 4. Synthesis of EI-1941-1 (1) and EI-1941-3 (3)
ity (97:3) is observed at low concentration (0.01 M) in
contrast to the lower selectivity (83:17) at higher con-
centration (0.1 M).9 Oxidation of alcohols 35 and 36 with
MnO2 gave 33 and 34 in 91% yield in a 97:3 ratio, and
these were separated by TLC.
of 26 with Zn powder in MeOH and AcOH22 gave â,γ-
unsaturated lactone 37. After removal of the TBS group,
treatment with a catalytic amount of amine isomerized
the double bond to provide epi-EI-1941-2 (39) in 67%
yield (Scheme 3).
Removal of the TBS group of 33 afforded EI-1941-2
(2) quantitatively. Synthetic EI-1941-2 (2) exhibited
properties identical to those of the natural product,4b,8
including the optical rotation.
epi-EI-1941-2 was also prepared stereoselectively from
carboxymercurated derivative 26. Though conventional
demercuration using Bu3SnH in the presence of AIBN21
did not work, affording 23t, we found that the treatment
Synthesis of EI-1941-1 and -3. EI-1941-1 was
synthesized (see Scheme 4) from R-alcohol 31 and â-al-
cohol 35, the intermediates of EI-1941-2, as follows:
When R-alcohols 31 and 32 (31:32 ) 95:5) were treated
with DIBAL-H in CH2Cl2 at low temperature (-90 °C),
(18) (a) Korte, D. E.; Hegedus, L. S.; Wirth, R. K. J. Org. Chem.
1977, 42, 1329. (b) Minami, T.; Nishimoto, A.; Hanaoka, M. Tetrahe-
dron Lett. 1995, 36, 9505.
(17) (a) Nishizawa, M.; Takenaka, H.; Nishida, H.; Hayashi, Y.
Tetrahedron Lett. 1983, 24, 2581. (b) Nishizawa, M.; Morikuni, E.;
Asoh, K.; Kan, Y.; Uenoyama, K.; Imagawa, H. Synlett 1995, 169. (c)
Imagawa, H.; Shigaraki, T.; Suzuki, T.; Takao, T.; Yamada, H.;
Sugihara, T.; Nishizawa, M. Chem. Pharm. Bull. 1998, 46, 1341. (d)
Nishizawa, M.; Kashima, T.; Sakakibara, M.; Wakabayashi, A.; Ta-
kahashi, K.; Takao, T.; Imagawa, H.; Sugihara, T. Heterocycles 2000,
54, 629.
(19) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
(20) The reason for the effect of the concentration on the diastereo-
selectivity is not clear.
(21) Whitesides, G. M.; San Filippo, J., Jr. J. Am. Chem. Soc. 1970,
92, 6611.
(22) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John
Wiley and Sons: New York, 1967; Vol. 1, p 1276.
9910 J. Org. Chem., Vol. 70, No. 24, 2005

Total Synthesis of EI-1941-1, -2, -3
TABLE 3. Summary of IC50 Values of Test Compounds
on IL-1â Secretion from LPS-Stimulated THP-1 Cells and
on Cell Viability of THP-1 Cells
of the TBS group on acid treatment in MeOH, in good
yields (eqs 7 and 8).
IC50 valuesa on IL-1â
secretion (µM)
IC50 valuesb on cell
viability (µM)
compound
EI-1941-1 (1)
EI-1941-2 (2)
ent-2
56
15
>100
40
10
68
EI-1941-3 (3)
45
>100
>100
74
>100
>100
>100
20
ent-45
46
14
10
ent-46
30
a Concentration of 50% inhibitory activity on LPS-stimulated
IL-1â secretion. b Concentration of 50% inhibitory activity on cell
viability.
lactone was reduced stereoselectively to lactols 40 and
41, which were separated by TLC (76% 40, 4% 41).
Oxidation of 40 with MnO2 gave ketone 42 in excellent
yield (95%). â-Alcohols 35 and 36 were also reduced with
DIBAL-H to afford lactols 43 and 44, which were
separated by TLC (68% 43, 2% 44). Oxidation of 43 gave
the same ketone 42 in 95% yield. Deprotection with HF‚
pyridine afforded EI-1941-1 (1) in good yield.
Compounds 1 and 2 inhibited IL-1â secretion in a dose-
dependent manner; IC50 values of 1 and 2 in our assay
system were 56 and 15 µM, respectively. IC50 values of 1
and 2 on cell viability were >100 and 40 µM, respectively.
Compound 3, which has been reported as an inactive
compound in an in vitro system,4 was inactive in THP-1
cells. These results indicate that an epoxide ring in 2 is
essential for exhibiting the biological activities of 2.
Moreover, IC50 values of ent-2 on IL-1â secretion and cell
viability were 10 and 68 µM, respectively, which was a
most effective derivative because the differences in IC50
values against IL-1â secretion and cell viability were
greatly significant. The inhibition of IL-1â secretion by
hydroxy carboxylic acids 45 and ent-45 was weak (IC50
values of >100 and 74 µM, respectively), suggesting that
a three-fused-ring system was important for the biological
activity. Moreover, IC50 values of tetrahydro isocoumarin
derivatives 46 and ent-46 on IL-1â secretion were 14 and
10 µM, respectively. However, these two compounds 46
and ent-46 also affected the cell viability at IC50 values
of 20 and 30 µM, respectively. These results indicate that
the enantiomer of EI-1941-2 (ent-2) is a more potent and
effective ICE inhibitor than natural EI-1941-2 in a
cultured cell system.
23
Reduction of the epoxide with SmI2 at low tempera-
ture (-90 °C) cleanly converted EI-1941-2 into EI-
1941-3 nearly quantitatively. Synthetic EI-1941-1, -2,
and -3 exhibited properties identical to those of the
natural products, including the optical rotation, which
indicate that natural enantiomers were successfully
synthesized. Comparison of the optical rotation of EI-
1941-3 (synthetic 3: [R]30 -88.7, natural 3:4b,8 [R]23
D
D
-87.5) determined its absolute stereochemistry.
Biological Evaluation. We evaluated the effects of
EI-1941-1 (1), -2 (2), and -3 (3) and their derivatives
on the extracellular release of IL-1â from THP-1 cells and
cell viability in THP-1 cells, with the results summarized
in Table 3 and Figure 2. The derivatives examined are
ent-EI-1941-2 (ent-2), hydroxy carboxylic acid 45 and its
enantiomer ent-45, and tetrahydro isocoumarin deriva-
tive 46 and its enantiomer ent-46. Hydroxy carboxylic
acid 45 and tetrahydro isocoumarin derivative 46 were
easily prepared from 23t and 28, respectively, by removal
FIGURE 2. Effect of EI-1941-1 (1), -2 (2), and -3 (3) and their derivatives on IL-1â secretion from LPS-stimulated THP-1
cells and on cell viability of THP-1 cells. Symbols indicate IL-1â secretion (closed circle) and percentage of viable cells (open
circle).
J. Org. Chem, Vol. 70, No. 24, 2005 9911

Shoji et al.
(1S,2S,6R)-2-(tert-Butyldimethylsiloxy)-4-iodo-5-oxo-7-
oxabicyclo[4.1.0]hept-3-ene-3-carboxylic Acid (20). To a
solution of siloxy aldehyde 19 (100 mg, 0.25 mmol), NaH2PO4
(40 mg, 0.25 mmol), and 2-methyl-2-butene (0.1 mL, 1.11
mmol) in tert-BuOH (1.8 mL) and H2O (0.5 mL) was added
NaClO2 (78 mg, 0.86 mmol) at 0 °C, and the reaction mixture
was stirred for 1 h under an argon atmosphere. The reaction
mixture was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (MeOH/
CHCl3 ) 1:10) to afford carboxylic acid 20 (104 mg, 97%) as a
colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.07 (3H, s), 0.14
(3H, s), 0.84 (9H, s), 3.62 (1H, br-d, J ) 3.0 Hz), 3.69 (1H,
br-s), 3.79 (1H, br-s), 5.18 (1H, br-s); 13C NMR (100 MHz,
CDCl3) δ -4.6, -4.56, 18.0, 25.6, 51.0, 56.8, 66.7, 103.2, 152.9,
170.8, 189.1; FT-IR (neat) ν 3199, 2954, 2929, 2858, 1689, 1604,
1389, 1259, 839, 781, 756, 501 cm-1; HRMS (FAB) [M + Na]+
Conclusion
We have accomplished the first asymmetric total
synthesis of EI-1941-1, -2, and -3, starting from the
chiral epoxy iodoquinone 11, a key intermediate in our
total synthesis of epoxyquinols A and B. A key step is
the intramolecular, metal-mediated carboxylation of an
alkene via 6-endo cyclization, in which Pd(II) gave 2H-
pyran-2-one via â-hydride elimination, affording EI-
1941-2 after stereoselective hydrogenation. Hg(OTf)2
afforded a carboxymercurated product of a side-chain
relative stereochemistry opposite to that of the natural
product, leading eventually to epi-EI-1941-2 with high
diastereoselectivity. EI-1941-1 was synthesized stereo-
selectively from the intermediate of EI-1941-2, whereas
EI-1941-3 was synthesized in one step from EI-1941-
2. By using this asymmetric total synthesis, we deter-
mined the absolute stereochemistry of EI-1941-3. The
structure-activity relationship of EI-1941-1, -2, and -3
and their synthetic derivatives revealed that an enanti-
omer of EI-1941-2 is a more potent ICE inhibitor than
EI-1941-2, as it is less cytotoxic.
calcd for [C13H19IO5Si + Na]+ 432.9944, found 432.9938; [R]23
D
+26.1 (c 0.12, MeOH).
(1S,2S,6R)-2-(tert-Butyldimethylsiloxy)-4-iodo-5-oxo-7-
oxabicyclo[4.1.0]hept-3-ene-3-carboxylic Acid 4-Meth-
oxybenzyl Ester (21). To a solution of carboxylic acid 20 (50
mg, 0.12 mmol) in CH2Cl2 was added PMBOC(dNH)CCl3 (102
mg, 0.24 mmol) at 0 °C, and the reaction mixture was stirred
for 1 h under an argon atmosphere. The reaction mixture was
quenched with pH 7.0 phosphate buffer, and diluted with
AcOEt. The organic phase was washed with saturated aqueous
NaCl, dried over anhydrous Na2SO4, and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (AcOEt/hexane ) 1:3-1:10) to afford
PMB ester 21 (55 mg, 85%) as a yellow oil: 1H NMR (400 MHz,
CDCl3) δ 0.01 (3H, s), 0.11 (3H, s), 0.83 (9H, s), 3.62 (1H, dd,
J ) 1.3, 3.7 Hz), 3.64 (1H, dd, J ) 1.0, 3.7 Hz), 3.79 (3H, s),
5.04 (1H, m), 5.21 (2H, dd, J ) 11.7, 18.4 Hz), 6.87 (2H, m),
7.35 (2H, m); 13C NMR (100 MHz, CDCl3) δ -5.1, -4.6, 17.9,
25.4, 50.9, 55,3, 57.0, 66.8, 68.2, 103.8, 114.0, 126.3, 131.0,
151.3, 160.1, 166.0, 188.6; FT-IR (neat) ν 2954, 2858, 1699,
1516, 1241, 1107, 1034, 841, 781 cm-1; HRMS (FAB) [M]+ calcd
for C21H27IO6Si 530.0622, found 530.0637; [R]22D +19.9 (c 0.158,
MeOH).
Experimental Section
(1R,5S,6R)-5-Hydroxy-4-hydroxymethyl-3-iodo-7-
oxabicyclo[4.1.0]hept-3-ene-2-one (17). To a solution of
acetonide 11 (100 mg, 0.311 mmol) in CH2Cl2 (3.1 mL) was
added trifluoroacetic acid (3.1 mL) at 0 °C, and the reaction
mixture was stirred for 1 h. The reaction mixture was
concentrated under reduced preaaure. The residue was puri-
fied by silica gel column chromatography (AcOEt/hexane ) 1:1)
to afford diol 18 (84 mg, 96%) as a yellow oil: 1H NMR (400
MHz, CD3OD) δ 3.63 (1H, dd, J ) 1.6, 3.6 Hz), 3.85 (1H, dd,
J ) 1.4, 3.6 Hz), 4.44 (2H, d, J ) 3.2 Hz), 4.98 (1H, br-s); 13C
NMR (100 MHz, CD3OD) δ 52.5, 57.4, 64.6, 69.6, 102.1, 163.2,
189.8; FT-IR (neat) ν 3392, 1682, 1591, 1273, 1228, 1080, 1051,
931, 856, 758, 525 cm-1; HRMS (FAB) [M + Na]+ calcd for
(1S,2S,6R)-2-(tert-Butyldimethylsiloxy)-5-oxo-4-pentyl-
7-oxa-bicyclo[4.1.0]hept-3-ene-3-carboxylic Acid 4-Meth-
oxybenzyl Ester (22t). To a solution of PMB ester 21 (48 mg,
0.09 mmol), (E)-1-pentenylborate (16 mg, 0.136 mmol), Ag2O
(33.6 mg, 0.145 mmol), and Ph3As (2.8 mg, 0.009 mmol) in
THF.H2O (8:1, 0.45 mL) was added Pd(PhCN)2Cl2 (1.7 mg,
0.0045 mmol) at room temperature in the dark, and the
reaction mixture was stirred for 14 h under an argon atmo-
sphere. The reaction mixture was quenched with saturated
aqueous NH4Cl, and stirred for 30 min at that temperature.
The reaction mixture was filtered through a pad of Celite, and
the organic materials were extracted with AcOEt. The organic
phase was washed with saturated aqueous NaCl, dried over
anhydrous Na2SO4, and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (AcOEt/hexane ) 1:5∼1:20) to afford dienone
22t (42 mg, 97%) as a yellow oil: 1H NMR (400 MHz, CDCl3)
δ 0.00 (3H, s), 0.09 (3H, s), 0.82 (9H, s), 0.84 (3H, t, J ) 7.3
Hz), 1.32 (2H, sextet, J ) 7.3 Hz), 1.90-2.02 (2H, m), 3.54
(1H, d, J ) 4.0 Hz), 3.60 (1H, dd, J ) 1.9, 4.0 Hz), 3.79 (3H,
s), 5.10 (2H, d, J ) 11.8 Hz), 5.20-5.23 (2H, m), 6.23 (1H, td,
J ) 6.6, 15.9 Hz), 6.36 (1H, d, J ) 15.9 Hz), 6.86-6.88 (2H,
m), 7.29-7.32 (2H, m); 13C NMR (100 MHz, CDCl3) δ -4.8,
-4.7, 13.7, 17.9, 21.8, 25.5, 35.9, 53.6, 55.3, 56.0, 65.7, 67.2,
114.0, 121.7, 127.0, 130.7, 135.5, 136.2, 142.1, 160.0, 167.2,
195.7; FT-IR (neat) ν 2956, 2931, 2359, 1716, 1699, 1516, 1244,
1101, 1078, 839, 779 cm-1; HRMS (FAB) [M + H]+ calcd for
[C7H7IO4 + Na]+ 304.9287, found 304.9301; [R]23 -31.7 (c
0.212, MeOH).
D
(1S,2S,6R)-2-(tert-Butyldimethylsiloxy)-4-iodo-5-oxo-7-
oxabicyclo[4.1.0]hept-3-ene-3-carbaldehyde (19). To a
solution of diol 17 (81 mg, 0.287 mmol) in CH3CN (2.9 mL)
was added MnO2 (624 mg, 7.18 mmol) at 0 °C under an argon
atmosphere, and the reaction mixture was stirred for 10 min
at that temperature. The reaction mixture was filtered through
a pad of Celite, and concentrated in vacuo. The residue was
filtered through a pad of silica gel (AcOEt/hexane ) 1:3) to
afford aldehyde 18, and the crude product was used for the
next reaction without further purification. To a solution of
aldehyde 18 (170 mg, 0.606 mmol) and TBSOTf (481 mg, 1.82
mmol) in CH2Cl2 (6.1 mL) was added 2,6-lutidine (0.23 mL,
1.94 mmol) at 0 °C, and the mixture was stirred for 1 h under
an argon atmosphere. The reaction mixture was quenched with
saturated aqueous NH4Cl, and diluted with AcOEt. The
organic phase was washed with saturated aqueous NaCl, dried
over anhydrous Na2SO4, and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (AcOEt/hexane ) 1:10) to afford siloxy alde-
hyde 19 (170 mg, 72%, 2 steps) as a yellow oil: 1H NMR (400
MHz, CDCl3) δ 0.08 (3H, s), 0.22 (3H, s), 0.82 (9H, s), 3.73
(2H, d, J ) 1.2 Hz), 5.21 (1H, br-s), 9.79 (1H, s); 13C NMR
(100 MHz, CDCl3) δ -4.8, 18.0, 25.6, 51.8, 56.2, 63.5, 117.9,
148.2, 190.6, 197.0; FT-IR (neat) ν 2954, 2929, 2858, 1705,
C26H37O6Si 473.2359, found 473.2385; [R]23 -14.5 (c 0.078,
D
1689, 1581, 1471, 1340, 1255, 1167, 1049, 839, 781, 511 cm-1
;
MeOH).
HRMS (FAB) [M + H]+ calcd for C13H20IO4Si 395.0176, found
(1S,2S,6R)-2-(tert-Butyldimethylsiloxy)-5-oxo-4-pent-
1-enyl-7-oxabicyclo[4.1.0]hept-3-ene-3-carboxylic Acid
(23t). To a solution of 22t (32 mg, 0.068 mmol) in CH2Cl2 (0.7
mL) was added trifluoroacetic acid (0.07 mL) at room temper-
395.0178; [R]22 -3.2 (c 0.56, MeOH).
D
(23) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 2596.
9912 J. Org. Chem., Vol. 70, No. 24, 2005

Total Synthesis of EI-1941-1, -2, -3
ature, and the reaction mixture was stirred for 1 h. The
reaction mixture was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
(AcOEt/hexane ) 1:1-1:3) to afford carboxylic acid 23t (23 mg,
98%) as a colorless oil: 1H NMR (400 MHz, CD3OD) δ 0.14
(3H, s), 0.21 (3H, s), 0.90 (9H, s), 0.92 (3H, t, J ) 7.3 Hz), 1.44
(2H, sextet, J ) 7.3 Hz), 1.99-2.21 (2H, m), 3.53 (1H, d, J )
3.9 Hz), 3.72 (1H, dd, J ) 3.9 Hz), 5.21 (1H, br-s), 6.32 (1H,
td, J ) 6.8 Hz, 16.0 Hz), 6.46 (1H, d, J ) 16.0 Hz); 13C NMR
(100 MHz, CD3OD) δ -4.7, -4.7, 13.7, 17.9, 21.8, 25.5, 36.1,
53.6, 55.7, 65.6, 122.1, 134.5, 137.9, 143.4, 172.6, 196.3; FT-
IR (neat) ν 3375, 2929, 2858, 1693, 1680, 1464, 1338, 1099,
781, 741 cm-1; HRMS (FAB) [M + Na]+ calcd for [C18H28O5Si
+ Na]+ 375.1604, found 375.1577; [R]22D -61.4 (c 0.11, MeOH).
NMR (125 MHz, CDCl3) δ 13.5, 17.9, 25.7, 29.6, 50.0, 51.3,
62.7, 67.3, 104.7, 117.2, 149.8, 162.5, 166.9; FT-IR (neat) ν
3419, 2927, 2856, 1726, 1651, 1585, 1464, 1254, 1080, 974, 839,
781 cm-1; HRMS (FAB) [M]+ calcd for C18H28O5Si 352.1706,
found 352.1680; [R]23 +104.1 (c 0.08, MeOH). 30: 1H NMR
D
(400 MHz, CDCl3) δ 0.12 (3H, s), 0.22 (3H, s), 0.85 (9H, s),
0.95 (3H, t, J ) 7.4 Hz), 1.67 (2H, sextet, J ) 7.4 Hz), 2.44
(2H, t, J ) 7.4 Hz), 3.47 (1H, dd, J ) 2.5, 4.3 Hz), 3.59 (1H,
dd, J ) 2.2, 4.3 Hz), 4.79 (1H, d, J ) 8.8 Hz), 5.12 (1H, d, J )
2.2 Hz), 6.29 (1H, s); 13C NMR (100 MHz, CDCl3) δ -5.0, -4.6,
13.5, 18.1, 20.2, 25.8, 29.7, 35.8, 53.1, 54.4, 62.4, 66.1, 101.4,
117.2, 149.4, 162.3, 165.4; FT-IR (neat) ν 3410, 2929, 2856,
1722, 1645, 1574, 1464, 1252, 1117, 1065, 920, 839, 777 cm-1
;
HRMS (FAB) [M]+ calcd for C18H28O5Si 352.1706, found
352.1689; [R]23 +81.3 (c 0.21, MeOH).
D
(2S,3S,7R,8S,11R)-3-(tert-Butyldimethylsiloxy)-8-chlo-
rmercurio-7-propyl-1,6-dioxatricyclo[8.1.0.04,9]undec-4-
en-5,10-dione (26). To a solution of carboxylic acid 23t (21.0
mg, 0.06 mmol) in EtCN (2.1 mL) were added MS4A (6.3 mg,
30 wt %) and Hg(OTf)2/MeCN (0.25 mL, 0.071 mmol) at -78
°C, and the reaction mixture was stirred for 3 min. The
reaction mixture was quenched with saturated aqueous NaH-
CO3 and saturated aqueous NaCl (1:1). The organic materials
were extracted with AcOEt, washed with saturated aqueous
NaCl, dried over anhydrous Na2SO4, and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (AcOEt/hexane ) 1:3) to afford 26
(35.0 mg, 99%) as a colorless solid: 1H NMR (400 MHz, CDCl3)
δ 0.12 (3H, s), 0.24 (3H, s), 0.87 (9H, s), 0.96 (3H, t, J ) 7.3
Hz), 1.49-1.70 (2H, m), 1.77-1.93 (2H, m), 2.82 (1H, br-d, J
) 11.6 Hz), 3.70 (1H, br-d, J ) 3.8 Hz), 3.75 (1H, dd, J ) 1.9,
3.8 Hz), 4.55 (1H, ddd, J ) 3.5, 7.9, 11.6 Hz), 5.43 (1H, br-s);
13C NMR (150 MHz, CDCl3) δ -4.9, -4.5, 13.7, 18.2, 25.6, 29.7,
38.8, 42.4, 53.1, 55.4, 61.9, 80.6, 136.5, 142.2, 164.2, 196.9; FT-
IR (neat) ν 2958, 2929, 2858, 2360, 1714, 1680, 1252, 1090,
839, 781 cm-1; HRMS (FAB) [M + H]+ calcd for C18H28ClHgO5-
(2S,3S,7S,10R,11S)-3-(tert-Butyldimethylsiloxy)-10-hy-
droxy-7-propyl-1,6-dioxatricyclo[8.1.0.04,9]undec-4-en-5-
one (31) and (2S,3S,7R,10R,11S)-3-(tert-Butyldimethyl-
siloxy)-10-hydroxy-7-propyl-1,6-dioxatricyclo[8.1.0.04,9]-
undec-4-en-5-one (32). To a solution of 29 (10.0 mg, 0.0284
mmol) in AcOEt (2.8 mL) was added 10% Pd/C (3.0 mg, 0.0028
mmol) at room temperature, and the reaction mixture was
stirred for 3 h under an H2 atmosphere. The reaction mixture
was filtered through a pad of Celite, and concentrated under
reduced pressure. The residue was purified by preparative
thin-layer chromatography (AcOEt/hexane ) 1:3) to afford an
inseparable mixture of 31 and 32 (9.5 mg, 95%, 95:5 diaste-
reoselectivity) as a colorless oil. 31: 1H NMR (400 MHz, CDCl3)
δ 0.12 (3H, s), 0.22 (3H, s), 0.85 (9H, s), 0.91 (3H, t, J ) 7.3
Hz), 1.37-1.58 (2H, m), 1.74-1.79 (1H, m), 2.29-2.34 (1H,
m), 2.38 (1H, dd, J ) 4.9, 18.0 Hz), 2.62 (1H, dd, J ) 8.4, 18.0
Hz), 3.34-3.36 (1H, m), 3.43-3.45 (1H, m), 4.32 (1H, br-d, J
) 8.7 Hz), 4.45-4.51 (1H, m), 5.03 (1H, d, J ) 2.4 Hz); 13C
NMR (100 MHz, CDCl3) δ -5.0, -4.7, 13.7, 17.9, 18.2, 25.7,
32.0, 36.4, 50.3, 51.8, 62.2, 67.5, 124.3, 148.6, 163.9; FT-IR
(neat) ν 3423, 2958, 2931, 2858, 1716, 1254, 1084, 868, 839,
779 cm-1; HRMS (FAB) [M + H]+ calcd for C18H31O5Si
355.1941, found 355.1948.
Si 589.1101, found 589.1074; [R]23 +48.8 (c 0.087, MeOH).
D
(2R,3S,11S)-3-(tert-Butyldimethylsiloxy)-7-propyl-1,6-
dioxatricyclo[8.1.0.04,9]undec-4,7-dien-5,10-dione (28). To
a solution of carboxylic acid 23t (100.0 mg, 0.567 mmol) in
THF (5.7 mL) was added p-benzoquinone (26.2 mg, 2.84 mmol)
and Pd(PhCN)2Cl2 (12.4 mg, 0.0567 mmol) at room tempera-
ture, and the reaction mixture was stirred for 20 h. The
reaction mixture was filtered through a pad of Celite, and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (AcOEt/hexane ) 1:3-
1:5) to afford 28 (70.0 mg, 70%) as a yellow oil: 1H NMR (400
MHz, CDCl3) δ 0.15 (3H, s), 0.26 (3H, s), 0.85 (9H, s), 0.96
(3H, t, J ) 7.5 Hz), 1.68 (2H, sextet, J ) 7.5 Hz), 2.47 (2H, t,
J ) 7.5 Hz), 3.63 (1H, br-d, J ) 3.9 Hz), 3.77 (1H, dd, J ) 2.0,
3.9 Hz), 5.29 (1H, br-s), 6.28 (1H, br-s); 13C NMR (100 MHz,
CDCl3) δ -4.9, -4.6, 13.5, 20.1, 25.7, 35.8, 52.6, 56.7, 61.9,
98.1, 125.4, 139.6, 139.6, 162.3, 166.9, 192.9; FT-IR (neat) ν
2956, 2929, 2856, 1732, 1705, 1641, 1577, 1464, 1257, 1086,
839, 781 cm-1; HRMS (FAB) [M]+ calcd for C18H26O5Si
(2S,3S,7S,11R)-3-(tert-Butyldimethylsiloxy)-7-propyl-
1,6-dioxatricyclo[8.1.0.04,9]undec-4-en-5,10-dione (33). To
a solution of 31 and 32 (10.0 mg, 0.0283 mmol) in CH2Cl2 (1.0
mL) was added MnO2 (61.3 mg, 0.705 mmol) at 0 °C under an
argon atmosphere, and the reaction mixture was stirred for 1
h at that temperature. The reaction mixture was filtered
through a pad of Celite, and concentrated in vacuo. The residue
was purified by preparative thin-layer chromatography (AcOEt/
hexane ) 1:5) to afford 33 (9.2 mg, 92%; 95:5 diastereoselec-
tivity) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.14
(3H, s), 0.45 (3H, s), 0.85 (9H, s), 1.33-1.58 (3H, m), 1.81-
1.72 (1H, m), 2.52 (1H, dd, J ) 4.6, 18.1 Hz), 2.63 (1H, dd, J
) 7.9, 18.1 Hz), 3.56 (1H, br-d, J ) 3.9 Hz), 3.71 (1H, dd, J )
1.9, 3.9 Hz), 4.48-4.54 (1H,m), 5.16 (1H, br-s); 13C NMR (100
MHz, CDCl3) δ -4.8, -4.75, 13.7, 18.1, 18.2, 25.7, 29.7, 36.2,
52.3, 56.4, 61.9, 135.8, 139.5, 163.5, 194.4; FT-IR (neat) ν 2927,
350.1550, found 350.1579; [R]23 -14.1 (c 0.17, MeOH).
2854, 1726, 1695, 1464, 1252, 1240, 1101, 1084, 839, 781 cm-1
;
D
HRMS (FAB) [M + H]+ calcd for C18H29O5Si 353.1784, found
(2S,3S,10R,11S)-3-(tert-Butyldimethylsiloxy)-10-hy-
droxy-7-propyl-1,6-dioxatricyclo[8.1.0.04,9]undec-4,7-dien-
5-one (29) and (2S,3S,10S,11S)-3-(tert-Butyldimethylsil-
oxy)-10-hydroxy-7-propyl-1,6-dioxatricyclo[8.1.0.04,9]un-
dec-4,7-dien-5-one (30). To a solution of 28 (43.0 mg, 0.123
mmol) in MeOH (1.3 mL) was added NaBH4 (14.0 mg, 0.368
mmol) at 0 °C, and the reaction mixture was stirred for 20
min at that temperature. The reaction mixture was quenched
with saturated aqueous NH4Cl. The organic materials were
extracted with AcOEt, washed with saturated aqueous NaCl,
dried over anhydrous Na2SO4, and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (CHCl3) to afford 29 and 30 (42.0 mg, 98%,
50:50 diastereoselectivity) as a colorless oil. 29: 1H NMR (400
MHz, CDCl3) δ 0.13 (3H, s), 0.25 (3H, s), 0.86 (9H, s), 0.96
(3H, t, J ) 7.5 Hz), 3.43 (1H, m), 3.52 (1H, m), 4.55 (1H, br-d,
J ) 10.2 Hz), 5.23 (1H, d, J ) 2.8 Hz), 5.94 (1H, br-s); 13C
353.1782; [R]22 -10.5 (c 0.12, MeOH).
D
(2R,3S,7S,11R)-3-Hydroxy-7-propyl-1,6-dioxatricyclo-
[8.1.0.04,9]undec-4-en-5,10-dione (EI-1941-2 (2)). To a solu-
tion of 33 (16.6 mg, 0.0471 mmol) in CH3CN (1.9 mL) was
added HF‚Pyr (0.5 mL) at 0 °C, and the reaction mixture was
stirred for 4 h at that temperature. The reaction mixture was
quenched with saturated aqueous NaHCO3. The organic
materials were extracted with AcOEt, washed with saturated
aqueous NaCl, dried over anhydrous Na2SO4, and then con-
centrated under reduced pressure. The residue was purified
by preparative thin-layer chromatography (AcOEt/hexane )
1:1) to afford EI-1941-2 (2) (11.2 mg, quant.) as a colorless
powder: 1H NMR (400 MHz, CD3CN) δ 0.93 (3H, t, J ) 7.3
Hz), 1.35-1.51 (2H, m), 1.57-1.66 (1H, m), 1.69-1.78 (1H,
m), 2.46 (1H, ddd, J ) 1.0 9.7, 18.1 Hz), 2.54 (1H, ddd, J )
1.3, 4.6, 18.1 Hz), 3.56 (1H, dd, J ) 1.0, 3.7 Hz), 3.85 (1H, dd,
J. Org. Chem, Vol. 70, No. 24, 2005 9913

Shoji et al.
J ) 1.6, 3.7 Hz), 4.46-4.53 (1H, m), 4.97 (1H, br-s); 13C NMR
(100 MHz, CD3CN) δ 12.5, 17.3, 25.3, 35.6, 51.8, 55.8, 60.4,
77.1, 135.1, 140.0, 163.7, 193.9; FT-IR (neat) ν 3448, 2960,
2873, 1716, 1695, 1417, 1244, 1124, 1099, 1041 cm-1; HRMS
(FAB) [M + H]+ calcd for C12H15O5 239.0920, found 239.0932;
temperature. The reaction mixture was quenched with satu-
rated aqueous Rochelle salt. The organic materials were
extracted with AcOEt, washed with saturated aqueous NaCl,
dried over anhydrous Na2SO4, and then concentrated under
reduced pressure. The residue was purified by preparative
thin-layer chromatography (AcOEt/hexane ) 1:3) to afford 40
(6.9 mg, 80%, 95:5 diastereoselectivity) as a colorless oil: 1H
NMR (400 MHz, CDCl3) δ 0.14 (3H, s), 0.17 (3H, s), 0.89 (9H,
s), 0.91 (3H, t, J ) 7.2 Hz), 1.32-1.60 (2H, m), 1.80 (1H, dd,
J ) 1.9, 15.5 Hz), 1.88 (1H, br-d, J ) 11.1 Hz), 2.32 (1H, dd,
J ) 11.1, 17.4 Hz), 2.62 (1H, br-d, J ) 5.3 Hz), 3.23-3.24 (1H,
m), 3.38-3.39 (1H, m), 3.93 (1H, ddt, J ) 4.3, 7.5, 11.1 Hz),
4.18 (1H, br-d, J ) 9.9 Hz), 4.59 (1H, br-s), 5.37 (1H, d, J )
4.9 Hz); 13C NMR (100 MHz, CDCl3) δ -4.9, -4.5, 14.0, 18.0,
18.5, 25.8, 33.3, 37.2, 52.5, 52.7, 63.3, 65.8, 67.4, 88.8, 129.1,
131.6; FT-IR (neat) ν 3410, 2956, 2929, 2858, 2364, 2341, 1259,
1082, 1059, 1003, 974, 837, 779 cm-1; HRMS (FAB) [M]+ calcd
for C18H32O5Si 356.2019, found 356.2004; [R]22D -7.13 (c 0.70,
MeOH).
[R]22 -299.9 (c 0.48, MeOH).
D
(2S,3S,7R,11R)-3-(tert-Butyldimethylsiloxy)-7-propyl-
1,6-dioxatricyclo[8.1.0.04,9]undec-8-en-5,10-dione (37). To
a solution of 26 (5.0 mg, 0.009 mmol) in MeOH (0.1 mL) were
added zinc powder (2.8 mg, 0.045 mmol) and AcOH (0.002 mL)
at 0 °C, and the reaction mixture was stirred for 10 min. The
reaction mixture was quenched with saturated aqueous NaH-
CO3. The reaction mixture was filtered through a pad of Celite,
and the organic materials were extracted with AcOEt. The
organic phase was washed with saturated aqueous NaCl, dried
over anhydrous Na2SO4, and then concentrated under reduced
pressure. The residue was purified by preparative thin-layer
chromatography (AcOEt/hexane ) 1:5) to afford 37 (2.7 mg,
90%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.07 (1H,
s), 0.12 (1H, s), 0.78 (1H, s), 0.93 (3H, t, J ) 7.2 Hz), 1.39-
1.53 (2H, m), 1.66-1.76 (2H, m), 3.47 (1H, d, J ) 4.1 Hz), 3.52
(1H, q, J ) 3.0 Hz), 3.61 (1H, t, J ) 4.1 Hz), 5.06 (1H, t, J )
3.0 Hz), 7.05 (1H, t, J ) 3.0 Hz); 13C NMR (100 MHz, CDCl3)
δ -4.1, -4.8, 14.0, 18.2, 25.9, 38.8, 40.7, 54.8, 56.6, 67.5, 79.5,
127.9, 135.1, 168.3, 190.7; FT-IR (neat) ν 2927, 2856, 1743,
1709, 1655, 1464, 1389, 1117, 839, 781 cm-1; HRMS (FAB)
(2R,3R,7R,11S)-3-(tert-Butyldimethylsiloxy)-5-hydroxy-
7-propyl-1,6-dioxatricyclo[8.1.0.04,9]undec-4-en-10-one (42).
To a solution of 40 (10.5 mg, 0.0295 mmol) in CH2Cl2 (1.0 mL)
was added MnO2 (64.0 mg, 0.736 mmol) at 0 °C under an argon
atmosphere, and the reaction mixture was stirred for 1 h at
that temperature. The reaction mixture was filtered through
a pad of Celite, and concentrated in vacuo. The residue was
purified by preparative thin-layer chromatography (AcOEt/
hexane ) 1:5) to afford 42 (10.0 mg, 95%; 95:5 diastereose-
lectivity) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 0.17
(3H, s), 0.19 (3H, s), 0.89 (9H, s), 0.91 (3H, t, J ) 7.3 Hz),
1.38-1.61 (2H, m), 2.06 (1H, dd, J ) 10.8, 17.6 Hz), 2.18 (1H,
br-d, J ) 17.6 Hz), 2.80 (1H, br-s), 3.47 (1H, dd, J ) 1.0, 3.6
Hz), 3.61 (1H, dd, J ) 1.0, 3.6 Hz), 3.86-3.92 (1H, m), 4.82
(1H, br-s), 5.56 (1H, s); 13C NMR (100 MHz, CDCl3) δ -4.8,
-4.3, 13.9, 18.0, 18.4, 25.6, 27.7, 37.1, 52.6, 57.6, 63.3, 66.3,
88.0, 129.8, 146.0, 193.4; FT-IR (neat) ν 3431, 2956, 2931, 2860,
1684, 1464, 1259, 1074, 866, 739 cm-1; HRMS (FAB) [M + H]+
[M + H]+ calcd for C18H29O5Si 353.1784, found 353.1791; [R]23
-31.6 (c 0.113, MeOH).
D
(2R,3S,7R,11R)-3-Hydroxy-7-propyl-1,6-dioxatricyclo-
[8.1.0.04,9]undec-8-en-5,10-dione (38). To a solution of 37 (3.5
mg, 0.01 mmol) in CH3CN (0.2 mL) was added HF‚Pyr (0.05
mL) at room temperature, and the reaction mixture was
stirred for 6 h at that temperature. The reaction mixture was
quenched with saturated aqueous NaHCO3. The organic
materials were extracted with AcOEt, washed with saturated
aqueous NaCl, dried over anhydrous Na2SO4, and then con-
centrated under reduced pressure. The residue was purified
by preparative thin-layer chromatography (AcOEt/hexane )
1:1) to afford 38 (2.4 mg, quant.) as a colorless oil: 1H NMR
(400 MHz, CDCl3) δ 0.95 (3H, t, J ) 7.4 Hz), 1.38-1.60 (2H,
m), 1.67-1.79 (2H, m), 3.52-3.55 (2H, m), 3.79 (1H, dd, J )
3.8, 3.6 Hz), 5.14 (1H, dd, J ) 3.1, 3.6 Hz), 7.13 (1H, t, J ) 3.5
Hz); 13C NMR (100 MHz, CDCl3) δ 13.6, 18.1, 37.0, 41.1, 54.0,
55.3, 65.0, 79.6, 127.3, 135.9, 169.0, 189.7; FT-IR (neat) ν 2956,
calcd for C18H32O5Si 356.2019, found 356.1990; [R]21 -137.2
D
(c 0.593, MeOH).
(2R,3R,7R,11S)-3,5-Dihydroxy-7-propyl-1,6-dioxatri-
cyclo[8.1.0.04,9]undec-4-en-10-one (EI-1941-1 (1)). To a
solution of 42 (6.0 mg, 0.0169 mmol) in CH3CN (0.5 mL) was
added HF‚Pyr (0.05 mL) at room temperature, and the reaction
mixture was stirred for 4 h. The reaction mixture was
quenched with saturated aqueous NaHCO3. The organic
materials were extracted with AcOEt, washed with saturated
aqueous NaCl, dried over anhydrous Na2SO4, and then con-
centrated under reduced pressure. The residue was purified
by preparative thin-layer chromatography (AcOEt/hexane )
1:1) to afford EI-1941-1 (1) (3.2 mg, 94% based on conversion)
as a brownish oil: 1H NMR (400 MHz, CD3CN) δ 0.92 (1H, t,
J ) 7.2 Hz), 1.35-1.54 (4H, m), 1.96 (1H, br-dd, J ) 11.1, 17.7
Hz), 2.09 (1H, ddd, J ) 1.8, 3.2, 17.7 Hz), 3.43 (1H, dd, J )
1.0, 3.7 Hz), 3.74 (1H, dd, J ) 1.3, 3.7 Hz), 3.85 (1H, m), 4.59
(1H, br-s), 5.51 (1H, s); 13C NMR (100 MHz, CD3CN) δ 14.2,
19.2, 28.3, 37.9, 53.4, 57.7, 62.9, 66.3, 88.2, 129.9, 148.3, 194.9;
FT-IR (neat) ν 3419, 2960, 2933, 2873, 1682, 1456, 1281, 1028,
874, 725 cm-1; HRMS (FAB) [M + H]+ calcd for C12H17O5
2927, 2854, 1743, 1709, 1655, 1250, 1117, 1061, 839, 781 cm-1
;
HRMS (FAB) [M + H]+ calcd for C12H15O5 239.0920, found
239.0909; [R]32 +37.4(c 0.113, MeOH).
D
(2R,3S,7R,11R)-3,5-Dihydroxy-7-propyl-1,6-dioxatri-
cyclo[8.1.0.04,9]undec-4-en-10-one (epi-EI-1941-2 (39)). To
a solution of 38 (5.8 mg, 0.024 mmol) in CH2Cl2 (0.24 mL) was
added Et3N (1.7 µL, 0.012 mmol) at room temperature, and
the reaction mixture was stirred for 2 h. The reaction mixture
was quenched with buffer, and diluted with AcOEt. The
organic phase was washed with saturated aqueous NaCl, dried
over anhydrous Na2SO4, and then concentrated under reduced
pressure. The residue was purified by preparative thin-layer
chromatography (AcOEt/hexane ) 1:1) to afford epi-EI-1941-2
(39) (3.5 mg, 67%) as a colorless powder: 1H NMR (400 MHz,
CD3CN) δ 0.95 (3H, t, J ) 7.3 Hz), 1.55-1.38 (2H, m), 1.77-
1.62 (2H, m), 2.88 (1H, dd, J ) 3.4, 18.1 Hz), 3.59 (1H, dd, J
) 1.0, 3.6 Hz), 3.84 (1H, dd, J ) 1.5, 3.6 Hz), 4.35-4.42 (1H,
m), 5.11 (1H, br-s); 13C NMR (100 MHz, CD3CN) δ 14.1, 18.7,
26.3, 36.3, 53.3, 57.0, 61.3, 78.7, 136.5, 141.3, 165.5, 194.4; FT-
IR (neat) ν 3438, 2958, 2871, 1716, 1697, 1417, 1124, 1113,
1246, 1041 cm-1; HRMS (FAB) [M + H]+ calcd for C12H15O5
241.1076, found 241.1075; [R]20 -188.8 (c 0.16, MeOH).
D
(3R,7R,8R)-7,8-Dihydroxy-3-propylisochromene-1,5-di-
one (EI-1941-3 (3)). To a solution of EI-1941-2 (2) (4.6 mg,
0.0193 mmol) in THF (0.39 mL) was added a THF solution of
SmI2 (0.1 M, 0.58 mL, 3.0 mmol) at -90 ° C under an argon
atmosphere, and the reaction mixture was stirred for 20 min
at that temperature. The reaction mixture was quenched with
pH 7.0 phosphate buffer, and diluted with AcOEt. The organic
phase was washed with saturated aqueous NaCl, dried over
anhydrous Na2SO4, and then concentrated under reduced
pressure. The residue was purified by preparative thin-layer
chromatography (AcOEt/hexane ) 1:0) to afford EI-1941-3 (3)
(4.5 mg, 98%) as a reddish oil: 1H NMR (400 MHz, CD3CN) δ
0.94 (3H, t, J ) 7.3 Hz), 1.35-1.56 (1H, m), 1.60-1.69 (1H,
239.0920, found 239.0922; [R]23 -29.5 (c 0.087, MeOH).
D
(2R,3R,7R,10S,11R)-3-(tert-Butyldimethylsiloxy)-7-pro-
pyl-1,6-dioxatricyclo[8.1.0.04,9]undec-4-en-5,10-diol (40).
To a solution of 31 and 32 (9.0 mg, 0.0254 mmol) in CH2Cl2
(0.9 mL) was added a hexane solution of DIBAL-H (0.94 M,
0.09 mL, 0.0787 mmol) at -90 °C under an argon atmosphere,
and the reaction mixture was stirred for 20 min at that
9914 J. Org. Chem., Vol. 70, No. 24, 2005

Total Synthesis of EI-1941-1, -2, -3
m), 1.71-1.80 (1H, m), 2.26 (1H, br-dd, J ) 11.3, 18.2 Hz),
2.51 (1H, dd, J ) 4.0, 16.7 Hz), 2.76 (1H, ddd, J ) 1.4, 3.9,
18.2 Hz), 2.93 (1H, dd, J ) 3.0, 16.7 Hz), 3.38 (1H, br-s), 3.76
(1H, br-s), 4.22 (1H, q, J ) 3.2 Hz), 4.42-4.49 (1H, m); 13C
NMR (100 MHz, CD3CN) δ 14.1, 18.9, 26.3, 37.4, 41.7, 66.7,
70.5, 79.0, 136.9, 143.6, 167.0, 197.7; FT-IR (neat) ν 3419, 2960,
2933, 2873, 1716, 1693, 1410, 1230, 1024 cm-1; HRMS (FAB)
760 cm-1; HRMS (FAB) [M]+ calcd for C12H12O5 236.0685,
found 236.0664; [R]24 -96.1 (c 0.43, MeOH).
D
Measurement of Interleukin-1â) Secretion. THP-1 cells
were suspended in RPMI1640 medium (Sigma, St. Louis, MO)
supplemented with 10% fetal bovine serum, and seeded on 48-
well plates (5 × 104 cells/well). The cells were differentiated
with 30 nM of pharbol-12-myristate-13-axetate (PMA) for 72
h. After the plate was rinsed with serum-free RPMI1640
medium to remove unadherent cells, adherent cells were
stimulated with 100 µg/ml of lipopolysaccharide (LPS; Sigma)
for 4 h in the presence of various concentrations of test
compounds. The culture media were harvested, and mature
IL-1â was measured by an ELISA method using an IL-1â assay
kit (Amersham Biosciences, Tokyo, Japan).
[M + H]+ calcd for C12H17O5 241.1076, found 241.1076; [R]30
D
-88.7 (c 0.28, MeOH).
(1S,2S,6R)-2-Hydroxy-5-oxo-4-pent-1-enyl-7-oxabicyclo-
[4.1.0]hept-3-ene-3-carboxylic Acid (45). To a solution of
23t (5.0 mg, 0.014 mmol) in MeOH (0.05 mL) was added Dowex
50W-X4 (10.0 mg), and the mixture was stirred at room
temperature for 24 h. The reaction mixture was filtered, and
the filtrate was concentrated in vacuo. The residue was
purified by preparative thin-layer chromatography (MeOH/
CHCl3 ) 1:10) to afford carboxylic acid 45 (2.3 mg, 93%) as a
colorless oil: 1H NMR (400 MHz, CD3OD) δ 0.92 (3H, t, J )
7.3 Hz), 1.45 (2H, sextet, J ) 7.3 Hz), 2.11 (2H, q, J ) 6.9
Hz), 3.54 (1H, d, J ) 3.9 Hz), 3.77 (1H, d, J ) 3.9 Hz), 5.00
(1H, br-s), 6.33 (1H, dt, J ) 6.9, 16.1 Hz), 6.45 (1H, d, J )
16.1 Hz); 13C NMR (100 MHz, CD3OD) δ 13.9, 23.1, 36.9, 55.0,
57.3, 65.9, 123.5, 134.1, 141.3, 143.0, 174.6, 197.2; FT-IR (neat)
ν 3342, 2960, 2925, 2873, 2854, 2360, 1695, 1633, 1576, 1261,
1041, 970, 739 cm-1; HRMS (FAB) [M + H]+ calcd for
[C12H14O5 + H]+ 239.0919, found 239.0934; [R]25D -73.8 (c 0.32,
MeOH).
Measurement of Cell Viability. THP-1 cells (2.5 × 104
cells/well) were differentiated with 30 nM PMA as described
above. The differentiated cells were then treated with test
compounds for 4 h. The cell number was evaluated by the
subsequent color reaction. WST-8 solution 2-(2-methoxy-4-
nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetra-
zolium, monosodium salt (Nacalai tesque, Kyoto, Japan), was
added to the medium, and the cells were further incubated
for 3 h at 37 °C. The absorbance (A450) of each well was
measured using a plate reader (Wallac 1420 multilabel
counter; Amersham Biosciences). Cell viability (%) was calcu-
lated as (experimental absorbance - background absorbance)/
(control absorbance - background absorbance) × 100.
(2R,3S,11S)-3-Hydroxy-7-propyl-1,6-dioxatricyclo-
[8.1.0.04,9]undec-4,7-dien-5,10-dione (46). To a solution of
28 (3.6 mg, 0.0074 mmol) in MeOH (0.05 mL) was added
Dowex 50W-X4 (7.2 mg), and the mixture was stirred at room
temperature for 24 h. The reaction mixture was filtered, and
the filtrate was concentrated in vacuo. The residue was
purified by preparative thin-layer chromatography (AcOEt/
hexane ) 1:5) to afford 46 (1.7 mg, 97%) as a yellow oil: 1H
NMR (400 MHz, CDCl3) δ 0.96 (3H, t, J ) 7.5 Hz), 1.67 (2H,
sextet, J ) 7.5 Hz), 2.50 (2H, t, J ) 7.5 Hz), 3.66 (1H, d, J )
3.5 Hz), 3.94 (1H, dd, J ) 1.4, 3.5 Hz), 5.28 (1H, br-s), 6.38
(1H, s); 13C NMR (100 MHz, CDCl3) δ 13.4, 20.2, 35.8, 52.8,
56.6, 61.4, 98.2, 125.7, 139.1, 163.4, 166.9, 191.4; FT-IR (neat)
ν 3431, 2964, 2931, 2875, 1722, 1705, 1641, 1577, 1045, 852,
Acknowledgment. We thank Dr. Fumito Koizumi
at Kyowa Hakko Kogyo Co., Ltd., for the NMR charts
of EI-1941-1, -2, and -3. This work was partially
supported by a Grant-in-Aid for Scientific Research on
Priority Areas 16073219 from The Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT).
Supporting Information Available: Copies of 1H and 13
C
NMR and IR spectra of all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0516436
J. Org. Chem, Vol. 70, No. 24, 2005 9915