Total synthesis of the novel NF-κB inhibitor (-)-cycloepoxydon

Article abstract of DOI:10.1021/ol036521j

An enantioselective total synthesis of the novel, biologically active epoxyquinone natural product (-)-cycloepoxydon has been accomplished from the readily available Diels-Alder adduct of cyclopentadiene and p-benzoquinone. A new cycloepoxydon related heptacyclic dimer has been prepared and characterized.

Full text of DOI:10.1021/ol036521j

ORGANIC
LETTERS
2004
Vol. 6, No. 5
807-810
Total Synthesis of the Novel NF-KB
Inhibitor (−)-Cycloepoxydon
Goverdhan Mehta* and Kabirul Islam
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, India
gm@orgchem.iisc.ernet.in
Received December 29, 2003
ABSTRACT
An enantioselective total synthesis of the novel, biologically active epoxyquinone natural product (−)-cycloepoxydon has been accomplished
from the readily available Diels−Alder adduct of cyclopentadiene and p-benzoquinone. A new cycloepoxydon related heptacyclic dimer has
been prepared and characterized.
Polyketide-derived natural products, embodying an ep-
oxyquinone core, are surfacing with increasing frequency
from diverse natural sources, and have been found to exhibit
promising, wide-ranging biological activity.1 Cycloepoxydon
1 from a deuteromycete strain,1c jesterone 2 from the fungal
species P. jesteri,1f panepoxydone 3 from basidiomycete
Lentinus crinitus,1b and yanuthone A 4 from a marine isolate
of Aspergillus niger1d constitute representative recent ex-
amples of the monomeric epoxyquinones encountered in
nature. Among these, cycloepoxydon 1 has been shown to
inhibit activation of NF-κB, an inducible, ubiquitous tran-
scription factor that regulates the expression of various
cellular genes involved in immune and inflammation re-
sponses and apoptosis.1c
Thus, 1 and its analogues have the potential for broad
applications as novel therapeutic agents. As a result, synthetic
protocols providing access to 1 through simple, flexible
strategies from readily available building blocks hold special
appeal. The research group of Porco has recently ac-
complished2 the first total synthesis of (-)-cycloepoxydon
1 in which tartrate-mediated asymmetric epoxidation through
nucleophilic addition was an important step. As part of our
ongoing interest3 in the synthesis of epoxyquinone natural
products, we describe here a total synthesis of (-)-cyclo-
epoxydon 1.
Recently, we have achieved convenient access to (+)-5
via enzymatic desymmetrization of 6,4 which in turn has been
prepared from the readily available Diels-Alder adduct 7
of cyclopentadiene and benzoquinone.3a Our synthetic pursuit
(1) (a) Oloigosporons: Anderson, M. G.; Jarman, T. B.; Rickards, R.
W. J. Antibiot. 1995, 48, 391. (b) Panepoxydon: Erkel, G.; Anke, T.;
Sterner, O. Biochem. Biophys. Res. Commun. 1996, 226, 214. (c) Cycloe-
poxydon: 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. (d) Yanuthones: Bugni, T. S.; Abbanat, D.; Bernan, V. S.;
Maiese, W. M.; Greenstein, M.; Van Wagoner, R. M.; Ireland, C. M. J.
Org. Chem. 2000, 65, 7195. (e) Ambuic acid: Li, J. Y.; Harper, J. K.;
Grant, D. M.; Tombe, B. O.; Bashyal, B.; Hess, W. M.; Strobel, G. A.
Phytochemistry 2001, 56, 463. (f) Jesterone: Li, J. Y.; Strobel, G. A.
Phytochemistry 2001, 57, 261.
(2) Li, C.; Pace, E. A.; Liang, M.-C.; Lobkovsky, E.; Gilmore, T. D.;
Porco, J. A., Jr. J. Am. Chem. Soc. 2001, 123, 11308.
(3) (a) Mehta, G.; Islam, K. Tetrahedron lett. 2003, 44, 3569. (b) Mehta,
G.; Ramesh, S. S. Tetrahedron Lett. 2004, 45, 1985.
(4) Mehta, G.; Islam, K. To be submitted for publication.
10.1021/ol036521j CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/05/2004

of 1 emanated from the enantiomerically pure epoxyquinone
(+)-5, which had two strategically placed and chemo-
differentiated sidearms on the epoxyquinone core.
Scheme 1 a
Dibal-H reduction in (+)-5 was both regio- and stereo-
selective to furnish (-)-9 through a chelation-controlled
process involving the intermediacy of an aluminum chelate5
8 and hydride delivery from the same face as the epoxide
ring (Scheme 1).6 TEMPO-mediated oxidation7 in (-)-9 was
chemoselective and exclusively furnished the aldehyde (-)-
106 through the oxidation of the allylic primary hydroxyl
group. The secondary hydroxy group in (-)-10 was protected
at this stage to give diacetate (-)-11 (Scheme 1). Four-carbon
Wittig olefination in (-)-11 was chemoselective and engaged
only the allylic aldehyde group but the stereoselectivity in
this reaction was unsatisfactory and led to a cis:trans mixture
of diastereomers 12a,b (2.6:1) (Scheme 1). Since only the
(5) Kiyooka, S.-I.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett. 1986,
27, 3009.
(6) All new compounds were fully characterized on the basis of spectral
1
data (IR, H and 13C NMR, mass). Selected spectral data: (-)-9: [R]23
D
1
(-)176 (c 4.5, CHCl3); H NMR (300 MHz, CDCl3) δ 4.99 (1H, s), 4.88
(1H, d, J ) 12.3 Hz), 4.77 (1H, d, J ) 12.0 Hz), 4.55 (2H, br s), 4.04 (1H,
s), 3.84 (1H, s), 3.56 (1H, s), 3.46 (1H, s), 2.02 (3H, s); 13C NMR (75
MHz, CDCl3) 193.2, 171.6, 154.5, 127.5, 64.3, 61.2, 56.6, 56.1, 52.6, 20.8;
HRMS (ES) m/z calcd for C10H12NaO6 [M + Na]+ 251.0532, found
251.0536. (-)-10: [R]24 (-)305 (c 2.36, CHCl3); 1H NMR (300 MHz,
D
a Reagents and conditions: (a) DIBALH (2 equiv), THF, -78
°C, 74%; (b) TEMPO, O2, CuCl, DMF, rt, 77%; (c) Ac2O, pyridine,
DMAP, DCM, 0 °C, 71%; (d) n-C4H9PPh3Br, t-BuOK, THF, 0
°C, 54%; (e) hυ, 450 W (Hanovia), I2, CDCl3, 2 h, quant.
CDCl3) δ 10.33 (1H, s), 5.21 (1H, d, J ) 12.6 Hz), 5.20 (1H, s), 5.14 (1H,
d, J ) 12.6 Hz), 3.88 (1H, d, J ) 3.9 Hz), 3.66 (1H, d, J ) 3.6 Hz), 2.05
(3H, s); 13C NMR (75 MHz, CDCl3) 194.5, 192.7, 170.4, 144.0, 134.7,
60.8, 55.7, 54.8, 52.8, 20.6; HRMS (ES) m/z calcd for C10H10NaO6 [M +
Na]+ 249.0375, found 249.0369. (-)-12b: [R]24D (-)194 (c 1.09, CHCl3);
1H NMR (300 MHz, CDCl3) δ 6.44 (1H, d, J ) 15.9 Hz), 6.35 (1H, s),
6.29-6.21 (1H, m), 5.02 (1H, d, J ) 11.7 Hz), 4.85 (1H, d, J ) 11.7 Hz),
3.75 (1H, m), 3.57 (1H, d, J ) 3.9 Hz), 2.21 (2H, q, J ) 7.2 Hz), 2.13
(3H, s), 2.05 (3H, s), 1.47 (2H, sextate, J ) 7.2 Hz), 0.92 (3H, t, J ) 7.2
Hz); 13C NMR (75 MHz, CDCl3) 193.1, 170.7, 169.9, 145.7, 142.5, 128.2,
125.0, 63.2, 56.4, 53.0, 52.0, 35.9, 21.9, 20.8, 20.7, 13.5; HRMS (ES) m/z
trans-isomer 12b was considered serviceable for further
elaboration to the natural product 1, considerable effort was
expended toward improving the stereoselectivity of the Wittig
reaction but without much success. However, a solution to
this problem was devised by exploiting the possibility of
photochemical cis-trans isomerization of the disubstituted
double bond in the dienone chromophore present in 12a,b.
When the mixture of diastereomers 12a,b was irradiated from
a 450-W Hg lamp through Pyrex in the presence of iodine,
it cleanly and quantitatively furnished the desired trans-
isomer (-)-12b (Scheme 1).6
Acetate hydrolysis in (-)-12b led to the diol (-)-13 and
the primary hydroxyl group was selectively protected as the
TBS derivative (-)-14 (Scheme 2).6 Epoxidation of the trans
double bond in the side chain with m-chloroperbenzoic acid
in aqueous buffer was stereoselective and occurred exclu-
sively from the face opposite to the neighboring secondary
hydroxyl group to deliver the γ,δ-epoxyenone (-)-15,6 an
outcome along the lines previously observed by Porco et al.2
When (-)-15 was exposed to 40% HF in acetonitrile to
remove the TBS protecting group, concomitant hydroxy-
mediated endo-epoxide opening was also encountered to
furnish (-)-cycloepoxydon 1 as the predominant product.6,8
Our synthetic (-)-1 had spectral data (1H and 13C NMR)
identical with that reported in the literature1c for the natural
product and had an [R]D value of -135° (CHCl3-CH3OH
90:10), lit. [R]D -145° (CHCl3-CH3OH 95:5).1c
calcd for C16H20NaO6 [M + Na]+ 331.1158, found 331.1161. (-)-13: [R]24
D
(-)231 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.56-6.48 (2H, m),
5.04 (1H, s), 4.37 (2H, s), 3.87 (1H, dd, J ) 1.2, 3.6 Hz), 3.5 (1H, dd, J )
0.6, 3.6 Hz), 2.29-2.21 (2H, m), 1.51 (2H, sextate, J ) 7.2 Hz), 0.95 (1H,
t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) 196.2, 148.9, 143.4, 129.5,
125.2, 63.1, 55.8, 55.5, 52.4, 36.0, 22.0, 13.7; HRMS (ES) m/z calcd for
C12H16NaO4 [M + Na]+ 247.0946, found 247.0950. (-)-15: [R]23 (-)-
D
140 (c 0.72, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.64 (1H, d, J ) 12.6
Hz), 4.43 (1H, d, J ) 12.3 Hz), 4.36 (1H, br s), 3.97 (1H, d, J ) 2.4 Hz),
3.78 (1H, dd, J ) 1.5, 3.6 Hz), 3.53 (1H, dd, J ) 0.6, 3.6 Hz), 3.19-3.15
(2H, m), 1.79-1.73 (1H, m), 1.68-1.46 (3H, m), 0.99 (3H, t, J ) 7.2 Hz),
0.86 (9H, s), 0.02 (3H, s); 13C NMR (75 MHz, CDCl3) 192.2, 150.4, 134.3,
61.5, 60.2, 56.4, 55.6, 55.5, 52.7, 33.9, 25.8 (3 C), 19.1, 18.2, 13.8, -5.2,
-5.4; HRMS (ES) m/z calcd for C18H30NaO5Si [M + Na]+ 377.1760, found
1
377.1743. (-)-1: [R]23 (-)135 (c 0.55, CHCl3:MeOH 90:10); H NMR
D
[300 MHz, CDCl3:MeOH-d4 90:10] δ 4.92 (1H, s), 4.51 (1H, dd, J ) 2.1,
17.1 Hz), 4.07-4.04 (2H, m), 3.77 (1H, dd, J ) 1.2, 3.6 Hz), 3.40 (1H,
dd, J ) 0.9, 3.6 Hz), 3.30 (1H, m), 1.72 (1H, m), 1.52 (1H, m), 1.44-1.32
(2H, m), 0.9 (3H, t, J ) 7.2 Hz); 13C NMR [75 MHz, CDCl3:MeOH-d4
90:10] 191.9, 150.5, 129.3, 77.7, 64.9, 62.0, 59.9, 57.0, 52.2, 33.9, 18.5,
13.9‚ (-)-19: [R]25D (-)159 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 6.61-6.51 (1H, m), 6.31 (1H, d, J ) 16.2 Hz), 4.57 (1H, dd, J ) 6.9,
12.9 Hz), 4.44 (1H, dd, J ) 5.1, 12.6 Hz), 3.89 (1H, d, J ) 4.2 Hz), 3.86
(1H, d, J ) 3.9 Hz), 2.40 (1H, t, J ) 6.3 Hz), 2.23 (2H, q, J ) 7.2 Hz),
1.88 (2H, sextate, J ) 7.2 Hz), 0.94 (3H, t, J ) 7.2 Hz); 13C NMR (75
MHz, CDCl3) 193.8, 192.9, 147.4, 141.6, 137.0, 120.5, 57.3, 54.0, 53.7,
36.5, 21.8, 13.7; HRMS (ES) m/z calcd for C12H14NaO4 [M + Na]+
245.0790, found 245.0779. (+)-24: [R]23D (+)144 (c 0.90, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.89 (1H, s), 5.68 (1H, s), 4.37 (1H, q, J ) 4.8 Hz),
4.18 (1H, t, J ) 6.3 Hz), 3.88 (1H, d, J ) 3.6 Hz), 3.84 (1H, d, J ) 4.2
Hz), 3.82 (1H, d, J ) 3.6 Hz), 3.67 (1H, d, J ) 3.6 Hz), 3.28 (1H, s), 2.64
(1H, d, J ) 2.7 Hz), 1.35-1.17 (8H, m), 0.89-0.83 (6H, m); 13C NMR
(75 MHz, CDCl3) 199.9, 187.7, 187.6, 187.0, 159.3, 145.0, 143.5, 112.3,
81.4, 71.4, 69.5, 60.6, 55.7, 54.6, 54.2, 49.9, 38.8, 36.9, 36.4, 35.0, 18.9,
18.5, 13.8, 13.4; HRMS (ES) m/z calcd for C24H24NaO8 [M + Na]+
463.1369, found 463.1360.
It has been demonstrated recently that dimeric products
derived from epoxyquinones, both of natural as well as
synthetic origin, exhibit a notable and sometimes enhanced
(7) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.; Chou, C. S. J.
Am. Chem. Soc. 1984, 106, 3374.
808
Org. Lett., Vol. 6, No. 5, 2004

related dimer. Consequently, (-)-14 was oxidized with TPAP
to the epoxyquinone (-)-18 and the TBS deprotection led
to (-)-19 (Scheme 4).6 Dess-Martin oxidation11 furnished
the intermediate aldehyde 20, which underwent concomitant
6π electron cyclization to 21 and 22 and further endo-
selective intermolecular Diels-Alder heterodimerization (see
23) led to the “cycloepoxydon dimer” (+)-24 (Scheme 4).6
The stereostructure of (+)-24 follows from similar endo-
dimerizations documented in the literature12-14 wherein the
two alkyl chains are positioned to minimize steric interac-
tions.
Scheme 2 a
Scheme 4 a
a Reagents and conditions: (a) LiOH, MeOH, 0 °C, 66%; (b)
TBSCl, imidazole, DMAP, DCM, 0 °C, 92%; (c) MCPBA, DCM,
pH 7, rt, 86%; (d) 40% HF, CH3CN, 0 °C, 2 h, 69%.
biological activity profile.9 For example, a “jesterone dimer”
17, prepared from epoxyquinone 16 via a 6π electrocycliza-
tion, [4+2]-cycloaddition cascade (Scheme 3), has been
Scheme 3
a Reagents and conditions: (a) TPAP, NMMO, mol. Sieve, DCM,
rt, 82%; (b) HF‚Py, CH3CN, 0 °C, 91%; (c) Dess-Martin
periodinane, DCM, rt; (d) SiO2, DCM, rt, 70% (in two steps).
In summary, we have achieved a simple and effective
enantioselective synthesis of the novel epoxyquinone natural
(9) (a) Torreyanic acid: Lee, J. C.; Strobel, G. A.; Lobkovsky, E.; Clardy,
J. J. Org. Chem. 1996, 61, 3232. (b) Epoxyquinol A: Kakeya, H.; Onose,
R.; Koshino, H.; Yoshida, A.; Kobayashi, K.; Kageyama, S.-I.; Osada, H.
J. Am. Chem. Soc. 2002, 124, 3496. (c) Epoxyquinol B: Kakeya, H.; Onose,
R.; Yoshida, A.; Koshino, H.; Osada, H. J. Antibiot. 2002, 55, 829. (d)
Panepophenanthrin: Sekiizawa, R.; Ikeno, S.; Nakamura, H.; Naganawa,
H.; Matsui, S.; Iinuma, H.; Takeuchi, T. J. Nat. Prod. 2002, 65,
1491.
(10) (a) Hu, Y.; Li, C.; Kulkarni, B. A.; Strobel, G.; Lobkovsky, E.;
Torczynski, R. M.; Porco, J. A., Jr. Org. Lett. 2001, 3, 1649. (b) Liang,
M.-C.; Bardhan, S.; Li, C.; Pace, E. A.; Porco, J. A., Jr.; Gilmore, T. D.
Mol. Pharmacol. 2003, 64, 123.
shown to exhibit impressive anti-cancer activity against
human breast and leukemia cell lines.10 In light of such
observations, it was of interest to prepare a cycloepoxydon-
(8) Porco et al.2 have reported the formation of 1 and regioisomeric exo-
cyclized product isocycloepoxydon i in a ratio of 3:2 during the hydroxyl-
mediated opening of the epoxide closely related to (-)-15. However, in
our case, employing (-)-15 and slightly different reaction conditions, 1
was obtained as the major product with isocycloepoxydon i constituting
about 10% of the reaction mixture.
(11) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. (b)
Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(12) Li, C.; Johnson, R. P.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003,
125, 5095-5106.
(13) Transition state calculations12,14 for the Diels-Alder dimerization
of several model epoxyquinones related to 21 and 22, as well as mechanistic
studies, support the assignment of endo-anti dimeric structure (+)-24.
(14) Shoji, M.; Kishida, S.; Kodera, Y.; Shiina, I.; Kakeya, H.; Osada,
H.; Hayashi, Y. Tetrahdron. Lett. 2003, 44, 7205.
Org. Lett., Vol. 6, No. 5, 2004
809

product (-)-cycloepoxydon from the readily available Di-
els-Alder adduct of cyclopentadiene and p-benzoquinone.
A cycloepoxydone related dimer with biological potential
has also been prepared.
Acknowledgment. K.I. thanks CSIR, India for the award
of a research fellowship. This work was supported by the
Chemical Biology Unit of JNCASR, Bangalore.
OL036521J
810
Org. Lett., Vol. 6, No. 5, 2004