Stereoselective total synthesis of ent-El-1941-2 and epi-ent-El-1941-2

Article abstract of DOI:10.1021/ol0481479

(Chemical equation presented) The first asymmetric total syntheses of ent-El-1941-2 and epi-ent-El-1941-2 have been accomplished, starting from a chiral epoxy iodoquinone 6, a key intermediate in our total syntheses of epoxyquinols A and B. A key step in

Full text of DOI:10.1021/ol0481479

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4535-4538
Stereoselective Total Synthesis of
ent-EI-1941-2 and Epi-ent-EI-1941-2
Mitsuru Shoji, Takao Uno, and Yujiro Hayashi*
Department of Industrial Chemistry, Faculty of Engineering, Tokyo UniVersity of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
hayashi@ci.kagu.tus.ac.jp
Received September 14, 2004
ABSTRACT
The first asymmetric total syntheses of ent-EI-1941-2 and epi-ent-EI-1941-2 have been accomplished, starting from a chiral epoxy iodoquinone
6, a key intermediate in our total syntheses of epoxyquinols A and B. A key step in the preparation of ent-EI-1941-2 is an intramolecular
carboxypalladation via a 6-endo cyclization mode, followed by
of epi-ent-EI-1941-2.
â
-hydride elimination, while carboxymercuration is a key step in the synthesis
Interleukin-1â (IL-1â) converting enzyme (ICE) is a cysteine
protease that cleaves a biologically inactive 31 KDa precursor
to biologically active IL-1â,1 an important mediator in the
pathogenesis of rheumatoid arthritis, septic shock, inflam-
mation, and other physiological conditions.2 Therefore, it is
thought that ICE inhibitors would be useful as antiinflam-
matory drugs. Koizumi and co-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.3 Just recently, the relative
and absolute stereochemistries of EI-1941-1 and -2 have been
determined by X-ray crystallographic analysis of the p-
bromobenzoyl ester of EI-1941-2.4
Structurally, EI-1941-1 and EI-1941-2 (Figure 1) have an
epoxyquinone core, and due to our interest in the synthesis
of such epoxyquinone derivatives, including ECH5 and its
dimers, epoxyquinols A and B,6 we set out to accomplish
the first asymmetric total synthesis of ent-EI-1941-2, the
achievement of which will be disclosed in this paper.
A retrosynthetic analysis of EI-1941-2 is depicted in
Scheme 1. At the time that we started this project, their
(4) Koizumi, F.; Takahashi, Y.; Ishiguro, H.; Tanaka, R.; Ohtaki, S.;
Yoshida, M.; Nakanishi, S.; Ikeda, S. Tetrahedron Lett. 2004, 45, 7419.
(5) Kakeya, H.; Miyake, Y.; Shoji, M.; Kishida, S.; Hayashi, Y.; Kataoka,
T.; Osada, H. Bioorg. Med. Chem. Lett. 2003, 13, 3743.
(1) (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.
(2) (a) Dinarello, C. A. Blood 1991, 77, 1627. (b) Dinarello, C. A.; Wolff.
S. M. N. Engl. J. Med. 1993, 328, 106.
(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: (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) Li, C.; Bardhan, S.; Pace, E. A.;
Liang, M.-C.; Gilmore, T. D.; Porco, J. A., Jr. Org. Lett. 2002, 4, 3267. (h)
Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 3569. (i) Mehta, G.; Islam,
K. Tetrahedron Lett. 2004, 45, 3611.
(3) (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.
10.1021/ol0481479 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/23/2004

Scheme 2. Synthesis of 4t
Figure 1. Structures of EI-1941-1, -2, -3, ECH, and epoxyquinols
A and B.
relative and absolute stereochemistries 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 a synthetic route by which the two
diastereomers (EI-1941-2 and epi-EI-1941-2) can be gener-
ated with high optical purity was undertaken in order to
determine the relative and absolute stereochemistries. EI-
1941-2 and its epimer were to be prepared from diene
carboxylic acid 4 via 6π-electrocyclization8 or carboxy
metalation via the 6-endo mode. 4 was to be synthesized
from iodo compound 5 via the Suzuki coupling reaction,
while we planned to produce 5 from the R-iodocyclohex-
anone derivative 6, a key chiral intermediate in our total
synthesis of epoxyquinols A and B, which is prepared by a
sequence in which the Diels-Alder reaction of furan is one
of the key steps.6c,d
(Scheme 2). Cleavage of the acetonide on acid treatment gave
diol 7. Selective oxidation of the primary alcohol with excess
MnO2 in CH3CN gave aldehyde 8, the secondary alcohol of
which was protected using TBSOTf and 2,6-lutidine, afford-
ing 9 in 72% yield over two steps. Oxidation of this aldehyde
to the carboxylic acid was successfully performed under
Kraus’ conditions.9 The carboxylic acid was protected as its
para-methoxybenzyl ester 10 in 85% yield. Introduction of
the side chain by a Suzuki coupling reaction with (E)-1-
pentenylborate10 and Ag2O in the presence of a catalytic
amount of Pd(PhCN)2Cl2 and Ph3As11 afforded 11t in 97%
yield. Acid treatment then gave carboxylic acid 4t in
excellent yield. The isomer with the (Z)-side chain 4c was
prepared in good yield by a Stille coupling reaction using
(Z)-1-tributylpentenylstannane12 in the presence of a catalytic
amount of Pd(PhCN)2Cl2 and Ph3As,13 followed by the acid
treatment (eq 1).
Scheme 1. Retrosynthetic Analysis of ent-2 and Epi-ent-2
The synthesis starts from the chiral iodocyclohexenone 6,
easily prepared in a large quantity by our reported method6c,d
(7) (a) Terremutin: Miller, M. W. Tetrahedron 1968, 24, 4839. (b)
Isoepoxydon: Nagasawa, H.; Suzuki, A.; Tamura, S. Agric. Biol. Chem.
1978, 42, 1303. (c) Eupenoxide: Duke, R. K.; Rickards, R. W. J. Org.
Chem. 1984, 49, 1898. Liu, Z.; Jensen, P. R.; Fenical, W. Phytochemistry
2003, 64, 571. (d) Bromoxone: Higa, T.; Okuda, R. K.; Severns, R. M.;
Scheur, P. J.; He, C.-H.; Changfu, X.; Clardy, J. Tetrahedron 1987, 43,
1063. (e) Panepoxydon: Erkel, G.; Anke, T.; Sterner, O. Biochem. Biophys.
Res. Commun. 1996, 226, 214. (f) Cycloepoxydon: Gehrt, A.; Erkel, G.;
Anke, H.; Anke, T.; Sterner, O. Nat. Prod. Lett. 1997, 9, 259. Gehrt, A.;
Erkel, G.; Anke, T.; Sterner, O. J. Antibiot. 1998, 51, 455.
Next we examined the key cyclization of diene carboxylic
acid 4t via the 6-endo mode, and the results under several
(8) Marvell, E. N. Thermal Electrocyclic Reactions; Academic Press:
New York, 1980.
(9) (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.
4536
Org. Lett., Vol. 6, No. 24, 2004

acid 4t or ester 11t (eq 3). On the basis of this assumption,
4t and 11t were refluxed in toluene, but this led to complete
recovery of the starting materials (entry 1). Acid catalyst
does not promote the 6π-electrocyclization, and once again
the starting material was completely recovered (entry 2). The
conversion of carboxylic acid 4t to its sodium carboxylate
resulted in decomposition of the starting material (entry 3).
As we had found that the 6π-electrocyclization of 4t scarcely
proceeds at all, intramolecular additions of the carboxylic
acid onto the alkene activated with iodine or metal salts were
examined, though diastereoselectivity and alternate reaction
modes such as 6-endo or 5-exo are possible problems with
this approach. In fact, iodolactonization proceeded in the
6-endo mode with low yield (entry 4), while in the case of
carboxymercuration using Hg(OTf)2,14 the 6-endo cyclized
product was obtained in excellent yield as a single isomer,15
albeit with the incorrect side-chain relative stereochemistry
for the natural product in the reaction of (E)-isomer 4t (vide
infra, entry 5), while the undesired 5-exo cyclization was
observed in that of the (Z)-isomer 4c (entry 6). Unlike these
unsuccessful results, the 7,8-dihydro-6H-isochromen-1,5-
dione structure 16 was formed when palladium(II) was used
as a catalyst. That is, when 4t was treated with p-
benzoquinone and a catalytic amount of Pd(PhCN)2Cl2,16
carboxypalladation proceeded, followed by the â-hydride
elimination, affording 16 in 70% yield (entry 7).
Table 1. Intramolecular Cyclization of 4t and 4c
The remaining steps are reduction of the double bond and
deprotection. Hydrogenation of 16 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 17 and 18 in 91% yield and equal amounts,17
which were separated by column chromatography. Hydro-
genation of R-alcohol 17 proceeded smoothly and stereose-
lectively, affording an inseparable mixture of 19 and 20 in
excellent yield (95%) and with 6.7:1 diastereoselectivity,
which was oxidized with MnO2, affording ketones 21 and
22 in 92% yield in the same ratio. Though hydrogenation of
â-alcohol 18 proceeded slowly, the reduced products 23 and
24 were obtained in 96% yield with the desired isomer
predominating (4.6:1 diastereoselectivity). Oxidation of al-
cohols 23 and 24 with MnO2 gave 21 and 22 in 75% yield
a Starting material. b No reaction. c TFA/CH2Cl2 ) 1:10. d 10 mol % was
employed.
reaction conditions are summarized in Table 1. In our
previous syntheses of epoxyquinols A and B, the key step
is a biomimetic cascade reaction composed of sequential
oxidation, 6π-electrocyclization, and Diels-Alder dimeri-
zation6c (eq 2).
(10) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370.
(11) Ruel, F. S.; Braun, M. P.; Johnson, C. R. Org. Synth. 1997, 75, 69.
(12) Asao, N.; Liu, J.-X.; Sudoh, T.; Yamamoto, Y. J. Org. Chem. 1996,
61, 4568.
(13) Farina, V.; Krishnamurphy, V.; Scott, W. Org. React. 1997, 50, 1.
(14) (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.; Takahashi, K.; Takao, T.;
Imagawa, H.; Sugihara, T. Heterocycles 2000, 54, 629.
(15) Origin of the stereoselective formation of 14 is not clear at the
moment.
(16) (a) Korte, D. E.; Hegedus, L. S.; Wirth, R. K. J. Org. Chem. 1977,
42, 1329. (b) Minami, T.; Nishimoto, A.; Hanaoka, M. Tetrahedron Lett.
1995, 36, 9505.
(17) Stereochemistries of the alcohols 17 and 18 were determined by
the modified MTPA method; see: Ohtani, I.; Kusumi, T.; Kashman, Y.;
Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
On the basis of the facile 6π-electrocyclization observed for
a dienal,6e,f we expected that the same type of 6π-electro-
cyclization would proceed in the case of diene carboxylic
Org. Lett., Vol. 6, No. 24, 2004
4537

Scheme 3. Total Synthesis of ent-EI-1941-2
Scheme 4. Total Synthesis of Epi-ent-EI-1941-2
In summary, we have accomplished the first asymmetric
total synthesis of ent-EI-1941-2 and epi-ent-EI-1941-2,
starting from the chiral epoxy iodoquinone 6, a key inter-
mediate in our total synthesis of epoxyquinols A and B. A
key step is the intramolecular, metal-mediated carboxylation
of an alkene via the 6-endo cyclization mode, in which
Pd(II) gave a 2H-pyran-2-one via â-hydride elimination,
affording ent-EI-1941-2 after stereoselective hydrogenation,
while Hg(OTf)2 afforded a carboxymercurated product of
side-chain relative stereochemistry opposite to that of the
natural product, leading eventually to epi-ent-EI-1941-2 with
high diastereoselectivity. We are currently investigating the
synthesis of the natural enantiomer EI-1941-2, as well as
that of EI-1941-1, the full accounts of which will be
described shortly.
in a 4.6:1 ratio, and these were easily separated by thin-
layer chromatography.
Removal of the TBS group of 21 afforded ent-EI-1941-2
in 86% yield. Synthetic ent-EI-1941-2 exhibited properties
identical to those of the natural product except for the optical
rotation, which was of opposite sign, indicating that the
synthetic compound is the enantiomer of EI-1941-2.3,4
Epi-ent-EI-1941-2 was also prepared stereoselectively from
carboxymercurated derivative 14. Though conventional de-
mercuration using Bu3SnH in the presence of AIBN18 did
not work, affording 4t, we found that the treatment of 14
with Zn powder in MeOH and AcOH19 gave â,γ-unsaturated
lactone 25. After removal of the TBS group, to give alcohol
26, treatment of this with a catalytic amount of amine
isomerized the double bond to provide epi-ent-EI-1941-2 in
67% yield (Scheme 4).
Acknowledgment. This work was partially supported by
a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
Supporting Information Available: Detailed experi-
1
mental procedures, full characterization, and copies of H
and 13C NMR and IR spectra of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Whitesides, G. M.; San Filippo, J., Jr. J. Am. Chem. Soc. 1970, 92,
6611.
(19) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis; John Wiley
and Sons: New York, 1967; Vol. 1, pp 1276.
OL0481479
4538
Org. Lett., Vol. 6, No. 24, 2004