Exploring Chemical Diversity of Epoxyquinoid Natural Products: Synthesis and Biological Activity of (-)-Jesterone and Related Molecules

Article abstract of DOI:10.1021/ol0159367

(matrix presented) Enantioselective syntheses of the potent antifungal agent (-)-jesterone, its hydroxy epimer, and a dimeric quinone epoxide derivative are reported. The synthesis involves diastereoselective epoxidation of a chiral quinone monoketal deri

Full text of DOI:10.1021/ol0159367

ORGANIC
LETTERS
2001
Vol. 3, No. 11
1649-1652
Exploring Chemical Diversity of
Epoxyquinoid Natural Products:
Synthesis and Biological Activity of
(−)-Jesterone and Related Molecules
Yongbo Hu,† Chaomin Li,† Bheemashankar A. Kulkarni,† Gary Strobel,‡
,†
Emil Lobkovsky, Richard M. Torczynski,§ and John A. Porco, Jr.*
Department of Chemistry and Center for Streamlined Synthesis, Metcalf Center for
Science and Engineering, Boston UniVersity, 590 Commonwealth AVenue,
Boston Massachusetts 02215, Department of Plant Sciences, Montana State UniVersity,
Bozeman, Montana, 59717, Department of Chemistry, Baker Laboratory,
Cornell UniVersity, Ithaca, New York 14853-1301, and Cytoclonal Pharmaceutics, Inc.,
9000 Harry Hines BlVd., Dallas, Texas 75235
porco@chem.bu.edu
Received April 4, 2001
ABSTRACT
Enantioselective syntheses of the potent antifungal agent (−)-jesterone, its hydroxy epimer, and a dimeric quinone epoxide derivative are
reported. The synthesis involves diastereoselective epoxidation of a chiral quinone monoketal derivative and regio- and stereoselective reduction
of a quinone epoxide intermediate.
Endophytic fungi from the world’s rainforests have provided
numerous pharmacologically active compounds with a broad
range of biological activities. Recently, a number of novel
compounds have been isolated from Pestalotiopsis spp., a
fungal genus that is well-known for the production of
important secondary metabolites, including taxol.1 For
example, the quinone epoxide dimer torreyanic acid (1),
isolated from the fungal species P. microspora, causes cell
death by apoptosis in human cancer cells.2 We recently
† Boston University.
‡ Montana State University.
reported3 the total synthesis of (()-torreyanic acid using a
biomimetic dimerization of a quinone epoxide precursor
related to the highly functionalized cyclohexenone ambuic
acid (2), also produced by P. microspora.4 The structurally
related monomeric epoxyquinol jesterone (3) was recently
isolated from P. jesteri.5,6 Noteably, jesterone displays
Cornell University.
§ Cytoclonal Pharmaceutics, Inc.
(1) Strobel, G.; Yang, X.; Sears, J.; Kramer, R.; Sidhu, R. S.; Hess, W.
M. Microbiology 1996, 142, 435.
(2) (a) Lee, J. C.; Strobel, G. A.; Lobkovsky, E.; Clardy, J. J. Org. Chem.
1996, 61, 3232. (b) Jarvis, B. B. Chemtracts 1997, 10, 10.
(3) Li, C.; Lobkovsky, E.; Porco, J. A., Jr. J. Am. Chem. Soc. 2000,
122, 10484.
10.1021/ol0159367 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/05/2001

selective biological activity (minimum inhibitory concentra-
tion (MIC) values 6-25 µg/mL) against the oomycetous
fungi, which are some of the most pathogenic of all disease-
causing fungi. On the basis of examples of other anti-
oomycete agents that have antitumor activity (e.g., taxol),1
it was anticipated that jesterone, as an anti-oomycete agent,
may also have cytotoxic activity. Taking a lead from the
biological diVersity of fungal metabolites, we have initiated
a program to explore chemical diVersity through the chemical
synthesis of jesterone and related molecules. In this Letter,
we report the synthesis, stereochemical assignment, and
biological evaluation of (-)-jesterone and related epoxy-
quinoid compounds, including a novel “jesterone dimer”
produced by a tandem oxidation-6π electrocyclization-
dimerization cascade sequence.3
ether 5. Reduction of 5 with NaBH4 afforded an alcohol,
which was silylated (TBDPSCl) and treated with TBAF (0
°C) to effect selective desilylation of the phenolic TBS ether.
Using this procedure, the overall yield of phenol 6 for six
steps was 53%, and multigram (5-10 g) amounts may be
prepared with minimal purification. After considerable
experimentation, we found that the prenyl side chain could
optimally be installed using direct C-prenylation. After
careful consideration of reaction conditions,11 we adopted a
two-step protocol involving prenylation of 6 (0.7 M in
toluene) with NaH and prenyl bromide (-30 °C), which
afforded the desired ortho-prenyl phenol 7 (49%) and prenyl
ether 8 (35%). Rearrangement of 8 to produce further
amounts of 7 was accomplished using Montmorillonite KSF
in benzene12 to afford 7 in an overall yield of 60%.
For the synthesis of jesterone and related epoxyquinoids,
we first devised a synthesis of an ortho-prenyl phenol
intermediate (Scheme 1), which would ultimately be con-
In analogy to our route to (()-torreyanic acid,3 advance-
ment of 7 to jesterone and related structures required
preparation and regio- and stereoselective epoxidation of a
quinone monoketal intermediate (Scheme 2). Hypervalent
Scheme 1a
Scheme 2a
a Reagents and conditions: (a) Br2, CHCl3, rt, 2.5 h, 94%; (b)
TBSCl, imidazole, CH2Cl2, rt, 20 min, 94%; (c) MeI, NaH, THF,
65 °C, 6 h, 72%; (d) NaBH4, EtOH, 0 °C, 0.5 h, 100%; (e)
TBDPSCl, imidazole, DMF, rt, 2 h, 93%; (f) TBAF, THF, 0 °C,
10 min, 93%; (g) NaH, toluene, 50 °C, then prenyl bromide, -30
°C, 4 h; (h) Montmorillonite KSF, benzene, rt, 48 h, 31%.
verted to a quinone monoepoxide. Bromination of com-
mercially available 2,5-dihydroxybenzaldehyde7,8 afforded
2-bromo-3,5-dihydroxybenzaldehyde 4 (94%).9 Regioselec-
tive silylation of the most nucleophilic phenol10 of 4 followed
by methylation of the 5-hydroxyl group provided methyl
a Reagents and conditions: (a) PhI(OAc)2, MeOH, 20 min, rt,
83%; (b) (2S,4S)-(+)-pentanediol, PPTS, benzene, 80 °C, 20 min,
80%; (c) KHMDS, TrOOH, THF, -35 °C, 15 h, 80%; (d) TBAF/
AcOH, THF, rt, 10 h, 91%; (e) 4-bromobenzoyl chloride, DMAP,
pyridine, CH2Cl2, rt, 30 min, 78%; (f) (E)-tributyl-1-propenyl-
stannane, Pd(PPh3)4, toluene, 110 °C, 6 h, 88%; (g) HF, CH3CN,
rt, 4.5 h, 82%.
(4) Li, J. Y.; Harper, J. K.; Grant, D. M.; Tombe, B. O.; Bashyal, B.;
Hess, W. M.; Strobel, G. A. Phytochemistry 2001, 56 , 463.
(5) Li, J. Y.; Strobel, G. A. Phytochemistry. 2001, 57, in press.
(6) For representative structurally related epoxy-cyclohexenone natural
products, see (a) oligosporons: 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) cyclo-
epoxydon: Gehrt, A.; Erkel, Gerhard; Anke, Timm; Sterner, Olov. 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.
iodine oxidation13 of 7 (PhI(OAc)2, room temperature, 30
min) afforded dimethoxyketal 9. In line with established
literature precedent for use of chiral acetals in diastereo-
selective epoxidations of quinone monoketals,12b,14 9 was
transketalized with (2S,4S)-(+)-pentanediol to afford chiral
acetal 10. Epoxidation of 10 with Ph3COOH (KHMDS, -35
°C) afforded monoepoxide 11 as a single diastereomer.
Stereochemical assignment of 11 followed literature analogy
and was based on examination of molecular models of the
(7) Knolker, H.-J.; Hartmann, K. Synlett 1993, 755.
(8) For the synthesis of epoxydons using related starting materials, see:
(a) Ichihara, A.; Oda, K.; Sakamura, S. Tetrahedron Lett. 1972, 23, 5105.
(b) Chou, D. T-W.; Ganem, B. J. Am. Chem. Soc. 1980, 102, 7987.
(9) Narayanan, V. L.; Sausville, E. A.; Kaur, G.; Varma, R. K. PCT Int.
Appl. WO9943636, 1999.
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Org. Lett., Vol. 3, No. 11, 2001

two possible conformers 10a and 10b, which indicate that
the former should be preferred as a result of the presence of
a severe steric interaction between the indicated axial methyl
group in 10b and the allylic silyl ether moiety (Figure 1a).
using metal chelation-based protocols. Gratifyingly, treatment
of 14 using Kiyooka’s conditions19 (2 equiv of Dibal-H, THF,
-78 °C) afforded (-)-jesterone 3 (84%). The structure of 3
was confirmed to be identical to natural (-)-jesterone by
1H and 13C NMR, IR, mass spectrum, [R]D (-202.6° (c )
0.43, CHCl3)) and TLC Rf values in three different solvent
systems. The regio- and stereoselectivity of the reduction
step may be explained by initial formation of aluminum
chelate 15, followed by chelation-controlled reduction to
produce 3. Alternatively, reduction of 14 using NaBH4/
MeOBEt220 afforded hydroxy-epi-jesterone 16 and 3 in a 9:1
ratio (72%) (Scheme 3). In this case, the reduction selectivity
Scheme 3a
Figure 1. (a) Conformations of 1,3-dioxane 10. (b) Chem 3D
representation of the X-ray structure of 12.
Selective formation of 11 thus may be explained by steric
blocking of the â-face of the dienone by the axial methyl
group in conformer 10a. Unambiguous stereochemical as-
signment was achieved by conversion of 11 into p-bromo-
benzoate 12 and single X-ray crystal structure analysis
(Figure 1b). Interestingly, in this structure the conformation
of the chiral 1,3-dioxane is boatlike, presumably to avoid
steric interactions between the emerged epoxide methine and
the axial methyl group in a chair conformation. Stille
coupling of 10 with (E)-tributyl-1-propenyl-stannane in the
presence of Pd(PPh3)4 provided propenyl enone 13, which
was treated with HF in CH3CN to afford the target quinone
monoepoxide intermediate 14.
a Reagents and conditions: (a) 2 equiv Dibal-H, THF, -78 °C,
10 min, 84%; (b) MeOBEt2, NaBH4, THF/MeOH, -72 °C, 3 h,
72%.
may be explained by formation of boron chelate 17 and
preferential activation of the complexed ketone toward
reduction with borohydride.21 The coupling constants ob-
served for 3 and epimer 16 (J1-2 ) 1.6 and 2.8 Hz,
respectively) are also consistent with values reported for
related epoxyquinol compounds.6d, 22
Completion of the synthesis of jesterone required a
hydroxyl-directed reduction to an anti-epoxy alcohol. A
number of stereoselective reduction methods have been
reported to prepare anti-epoxy alcohols from epoxy ketones,
including Zn(BH4)2,15 NaBH4/CeCl3,16 and NaBH4/CaCl2.17
Because of established precedent for chelation-controlled
reduction of quinone monoepoxides using Dibal-H to afford
anti-epoxy quinols12b,18 we first evaluated reduction of 14
In an effort to further explore chemical diversity in the
jesterone series, we prepared a novel “jesterone dimer”
employing the tandem oxidation-6π-electrocyclization proc-
ess previously used to produce torreyanic acid and related
core structures (Scheme 4).3 Dess-Martin oxidation of
quinone epoxide 14 provided a crude product mixture
consisting largely of 2H-pyran diastereomers 18 (1H NMR).
Further treatment with silica gel in CH2Cl2, followed by silica
gel chromatography, led to the production of 19 (84%) as
(10) For selective silylation of 2,5-dihydroxybenzaldehyde, see: Liu, A.;
Dillon, K.; Campbell, R. M.; Cox, D. C.; Huryn, D. M. Tetrahedron Lett.
1996, 37, 3785.
(18) (a) Gautier, E. C. L.; Lewis, N. J.; McKillop, A.; Taylor, R. J. K.
Tetrahedron Lett. 1994, 35, 8759. (b) Alcaraz, L.; Macdonald, G.; Ragot,
J. P.; Taylor, R.J. K.; Alcaraz, L.; Kapfer-Eyer, I.; Macdonald, G.; Wei,
X.; Lewis, N. Synthesis 1998, 15, 775.
(19) Kiyooka, S-i.; Kuroda, H.; Shimasaki, Y. Tetrahedron Lett. 1986,
27, 3009.
(11) For literature discussing conditions for optimization of alkylation
of ambident anions, see: (a) Le Noble, W. J. Synthesis 1970, 2, 1. (b) Bigi,
F.; Casiraghi, G.; Casnati, G.; Sartori, G. Tetrahedron 1983, 39, 169.
(12) (a) Dauben, W. G.; Cogen, J. M.; Behar, V. Tetrahedron Lett. 1990,
31, 3241. (b) Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327
(13) (a) Pelter, A.; Elgendy, S. Tetrahedron Lett. 1988, 29, 677. (b) Fleck,
A. E.; Hobart, J. A.; Morrow, G. W. Synth. Comm. 1992, 22, 179.
(14) Wipf, P.; Kim, Y.; Jahn, H. Synthesis 1995, 12, 1549.
(15) Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1981, 22, 4723.
(16) Li, K.; Hamann, L. G.; Koreeda, M. Tetrahedron Lett. 1992, 33,
6569.
(20) Chen, K.-M.; Hardtmann, G. E.; Prasad, K.; Repic, O.; Shapiro,
M. J. Tetrahedron Lett. 1987, 28, 155.
(21) For sodium borohydride reductions of related epoxyketone systems,
see: (a) Harigaya, Y.; Yamaguchi, H.; Onda, M. Heterocycles 1981, 15,
183 (b) Wipf, P.; Kim, Y.; Jahn, H. Synthesis 1995, 12, 1549.
(22) For synthetic work on panepoxydon and correlations of coupling
constants, see: Shotwell, J. B.; Hu, S.; Medina, E.; Abe, M.; Cole, R.;
Crews, C. M.; Wood, J. L Tetrahedron Lett. 2000, 41, 9639.
(17) Taniguchi, M.; Fujii, H.; Oshima, K.; Utimoto, K. Tetrahedron 1995,
51, 679.
Org. Lett., Vol. 3, No. 11, 2001
1651

synthetic jesterone mimics the antifungal effect of natural
jesterone. In addition, the synthetic compounds, including
14 and 16, retain potent bioactivity against P. cinnamomi
and P. ultimum and exhibit relatively low MIC values against
these important pathogenic fungi. In preliminary studies,
synthetic 3 and dimer 19 have also been tested in several
cell lines derived from human cancers: a human breast
cancer cell line (MDA MB231) and two human leukemia
cell lines (HL60 and U937).23 Noteably, the dimer 19
displays low µM activity against these cell lines and dem-
onstrates the potential for bioactivity of novel epoxyquinoids
(Table 2). Evaluation of this compound against other tumor
Scheme 4
Table 2. Preliminary Evaluation of Jesterone 3 and Jesterone
Dimer 18 against Human Tumor Cell Lines (IC50, µM)
compound
jesterone 3
jesterone dimer 19
HL60
MDA MB 231
U937
150
19
528
2.8
109
1.5
cell lines and mechanism of action studies are warranted and
are in progress.
the sole dimeric product. Selective formation of 19 may be
explained by Diels-Alder dimerization of two diastereomeric
2H-pyran monomers A and B, in which case the methyl
groups of the pyran are anti to one another and the dienophile
(A) approaches the diene (B) anti to the epoxide moiety.3
In effect, 19 is a torreyanic acid analogue, which may be
more cell permeable as a result of the absence of the two
carboxylate groups.
In summary, the synthesis and stereochemical assignment
of the potent antifungal compound (-)-jesterone has been
accomplished. Synthesis of a hydroxy epimer, as well as a
related quinone epoxide precursor and a novel “jesterone
dimer” resulting from Diels-Alder dimerization of a 2H-
pyran intermediate, underscores the possibility to prepare
chemically diverse, bioactive compounds using a natural
product lead. Continued studies of (-)-jesterone and related
epoxyquinoid compounds are in progress and will be reported
in due course.
Evaluation of monomeric and dimeric epoxyquinoid
compounds against various plant pathogens is shown in Table
1.23 These results indicate that the biological activity of
Acknowledgment. We thank Ms. Susan Corona (Cyto-
clonal Pharmaceutics, Inc.) for assays. G.S. thanks HMV
(San Diego, CA), the NSF, and the Montana Agricultural
Experiment Station for partial support.
Table 1. Minimum Inhibitory Concentration (µg/mL) of
(-)-Jesterone and Other Related Compounds for a
Representative Group of Plant Pathogenic Fungi
jesterone
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds,
including X-ray structure of 12 (PDF). X-ray crystallographic
data (CIF). This material is available free of charge via the
Internet at http:// pubs.acs.org.
test fungus
nat
synth
14
50
16
50 >100
12
100 >100
50 50
19
Pythium ultimum
25
25
6
Phytophthora cinnamomi
Sclerotinia sclerotiorum
Rhizoctonia solani
6
100
25
6
6
100 >100
50 50
Geotrichum candidum
Pyricularia oryzae
>100 >100 >100 >100 >100
25 25 50 nd 25
OL0159367
(23) See the Supporting Information for experimental methods.
1652
Org. Lett., Vol. 3, No. 11, 2001