Total synthesis of the novel antifungal agent (±)-jesterone

Article abstract of DOI:10.1021/ol0499699

A total synthesis of the novel, biologically active epoxyquinone natural product (±)-jesterone has been accomplished from the readily accessible Diels-Alder adduct of cyclopentadiene and prenylated-p-benzoquinone. The approach delineated here is notable f

Full text of DOI:10.1021/ol0499699

ORGANIC
LETTERS
2
004
Vol. 6, No. 5
11-813
Total Synthesis of the Novel Antifungal
Agent (±)-Jesterone
8
Goverdhan Mehta* and Subhas Chandra Pan
Department of Organic Chemistry, Indian Institute of Science,
Bangalore 560 012, India
gm@orgchem.iisc.ernet.in
Received January 5, 2004
ABSTRACT
A total synthesis of the novel, biologically active epoxyquinone natural product (±)-jesterone has been accomplished from the readily accessible
Diels−Alder adduct of cyclopentadiene and prenylated-p-benzoquinone. The approach delineated here is notable for its conceptual simplicity
and efficient orchestration of a series of chemo-, regio-, and stereoselective operations.
1
a
In 2001, Li and Strobel reported the isolation and structure
determination of novel epoxyquinone natural products jes-
terone 1 and its hydroxy derivative 2 from a new endophytic
fungus Pestalotiopsis jesteri from the Southern Highland
Province of Papua New Guinea.1b Besides its highly func-
tionalized architecture and mixed polyketide-isoprenoid
biogenesis, 1 has attracted attention on account of the
selective biological activity (minimum inhibitory concentra-
tion values 6-25 µg/mL) it displays against the oomycetous
fungi, which are some of the most pathogenic of all disease-
“jesterone dimer” 4 derived from the related quinone 3 via
an intermolecular Diels-Alder reaction. Interestingly, the
dimer 4 not only exhibits substantially enhanced anti-cancer
activity against human cancer cell lines but also blocks
activation of the transcription factor NF-κB by inhibiting the
3
inhibitor of the κB kinase. These promising observations
have further stimulated interest in the synthesis of jesterone
1
and related compounds. As part of our continuing efforts
4
causing fungi.1a More recently, jesterone 1 was found to
in the area, we report here a total synthesis of racemic 1,
following a strategy that is simple, flexible, and amenable
to diversity generation.
exhibit activity against human breast and human leukemia
2
cell lines. The first total synthesis of (-)-jesterone 1 was
achieved by the group of Porco, who also described a
2
The starting material in our synthetic route to (()-jesterone
was the prenylated p-benzoquinone 7, which in turn is
1
(
1) (a) Li, J. Y.; Strobel, G. A. Phytochemistry 2001, 57, 261. (b) Strobel,
G.; Li, J. Y.; Worapong, J.; Baird, G.; Hess, W. M. Mycotaxon 2000, 76,
57.
2) Hu, Y.; Li, C.; Kulkarni, B. A.; Strobel, G.; Lobkovsky, E.;
Torczynski, R. M.; Porco, J. A., Jr. Org. Lett. 2001, 3, 1649.
(3) Liang, M.-C.; Bardhan, S.; Li, C.; Pace, E. A.; Porco, J. A., Jr.;
Gilmore, T. D. Mol. Pharmacol. 2003, 64, 123.
(4) Mehta, G.; Islam, K. Tetrahedron Lett. 2003, 44, 3569.
(5) Bouzbouz, S.; Kirschleger, B. Synthesis 1994, 714.
2
(
1
0.1021/ol0499699 CCC: $27.50 © 2004 American Chemical Society
Published on Web 02/05/2004

easily available from p-methoxyphenol 5 via 4-methoxy-2-
prenylphenol 6 (Scheme 1).5
Scheme 2 a
Scheme 1 a
a
Reagents and conditions: (a) TBSCl, imidazole, DMAP, DMF,
0
°C, 90%; (b) DBU, 35% formalin, THF, 0 °C, 36 h, 80%; (c)
a
Reagents and conditions: (a) prenyl bromide, Na, ether, reflux,
NaBH
min, 98%.
4
, methanol, -5 °C, 1 h, 84%; (d) diphenyl ether, 220 °C, 6
8
7%; (b) CAN, CH
3
CN-H
2
O (1:1), 0 °C, 45 min, 85%; (c)
CO , 30%
, acetone, 0 °C, 40 min, 92%; (e) DBU, 35% formalin, THF,
°C, 2 h, 92%.
cyclopentadiene, methanol, 0 °C, 2 h, 98%; (d) 10% Na
2
3
H
0
2 2
O
of 8 in the presence of base was both regio- and stereo-
selective to furnish a single epoxide 9 in excellent yield
Diels-Alder reaction between 7 and cyclopentadiene was
regioselective and furnished the endo-adduct 8 in almost
6
Scheme 3 a
quantitative yield. Hydrogen peroxide-mediated epoxidation
(
6) All new compounds were fully characterized on the basis of spectral
data (IR, H, C NMR, and HRMS). Selected spectral data: 9: 1H NMR
300 MHz, CDCl3) δ 6.05 (s, 2H), 4.92 (t, 1H, J ) 7.5 Hz), 3.50-3.41 (m,
H), 3.35 (s, 1H), 3.27 (br s, 2H), 2.65 (dd, 1H, J ) 6.9, 15.6 Hz), 2.54
dd, 1H, J ) 8.1, 15.9 Hz), 1.68 (s, 3H), 1.59 (s, 3H), 1.48 (d, 1H, J ) 8.7
1
13
(
2
(
1
3
Hz), 1.29 (d, 1H, J ) 8.4 Hz); C NMR (75 MHz, CDCl3) δ 205.3, 205.2,
37.0, 136.6, 115.2, 66.9, 62.0, 50.5, 50.1, 46.7, 43.3, 43.1, 25.8, 25.7,
1
1
2
)
1
1
+
8.0; HRMS (ES) m/z calcd for C16H18NaO3 [M + Na] 281.1154, found
1
81.1134. 12: H NMR (300 MHz, CDCl3) δ 5.96 (s, 2H), 4.82 (t, 1H, J
7.2 Hz), 4.08-3.82 (m, 4H), 3.40 (dd, 1H, J ) 3.0, 9.6 Hz), 3.29 (s,
H), 3.05 (s, 1H), 2.98 (s, 1H), 2.66 (dd, 1H, J ) 7.5, 15.3 Hz), 2.40 (dd,
H, J ) 6.6, 15.3 Hz), 1.61 (s, 3H), 1.52 (br s, 4H), 1.23 (d, 1H, J ) 9.3
13
Hz), 0.83 (s, 9H), 0.01 (s, 6H); C NMR (75 MHz, CDCl3) δ 206.6, 206.3,
1
4
38.5, 138.2, 136.6, 115.4, 68.1, 67.6, 66.5, 62.8, 62.7, 61.8, 50.6, 50.1,
2.7, 26.1, 25.7, 25.6, 18.1, 17.9, -5.7, -5.8; HRMS (ES) m/z calcd for
+
1
C24H36NaO5Si [M + Na] 455.2230, found 455.2205. 14: H NMR (300
MHz, CDCl3) δ 5.18 (t, 1H, J ) 7.2 Hz), 4.68 (d, 1H, J ) 5.7 Hz), 4.56
(
1
1
dd, 1H, J ) 4.8, 14.4 Hz), 4.47-4.37 (m, 3H), 3.55 (br s, 1H), 3.48 (br s,
H), 3.34 (s, 1H), 2.91 (dd, 1H, J ) 7.8, 15.6 Hz), 2.43 (dd, 1H, J ) 7.2,
5.3 Hz), 1.73 (s, 3H), 1.65 (s, 3H), 0.85 (s, 9H), 0.06 (s, 6H); 13C NMR
(
5
75 MHz, CDCl3) δ 195.2, 154.2, 136.7, 131.7, 116.5, 67.8, 65.1, 62.3,
8.2, 56.1, 28.9, 25.8, 25.7, 18.1, 18.0, -5.4, -5.5; HRMS (ES) m/z calcd
for C19H32NaO5Si [M + Na] 391.1917, found 391.1935. 15: 1H NMR
+
(
1
300 MHz, CDCl3) δ 10.55 (s, 1H), 5.21 (br s, 1H), 5.14 (s, 1H), 4.82 (d,
H, J ) 14.4 Hz), 4.65 (d, 1H, J ) 14.7 Hz), 3.46 (s, 1H), 2.98 (br s, 1H),
2
.48 (br s, 1H), 1.77 (s, 3H), 1.69 (s, 3H), 0.88 (s, 9H), 0.09 (s, 6H); 13
C
NMR (75 MHz, CDCl3) δ 196.4, 194.5, 143.1, 141.9, 136.3, 115.6, 64.2,
6
2.8, 57.7, 56.3, 28.3, 25.2, 25.0, 17.4, -6.1, -6.2; HRMS (ES) m/z calcd
for C19H30NaO5Si [M + Na] 389.1760, found 389.1746. 17b: 1H NMR
+
(
300 MHz, CDCl3) δ 6.65 (dd, 1H, J ) 1.2, 15.6 Hz), 6.41-6.29 (m, 1H),
6
1
3
.32 (s, 1H), 5.07 (t, 1H, J ) 8.1 Hz), 4.52 (d, 1H, J ) 12 Hz), 4.41 (d,
H, J ) 12 Hz), 3.38 (s, 1H), 2.57-2.43 (m, 2H), 2.05 (s, 3H), 1.88 (dd,
H, J ) 1.5, 6.6 Hz), 1.72 (s, 3H), 1.59 (s, 3H), 0.85 (s, 9H), 0.04 (s, 6H);
C NMR (75 MHz, CDCl3) δ 195.5, 169.9, 145.6, 136.6, 135.6, 131.8,
27.5, 115.8, 66.1, 61.7, 57.1, 55.8, 29.0, 25.8, 20.9, 19.6, 18.2, 18.0, -5.2,
1
3
1
-
4
a
+
Reagents and conditions: (a) TEMPO [TEMPO ) 2,2,6,6-
5.3; HRMS (ES) m/z calcd for C23H36NaO5Si [M + Na] 443.2230, found
1
43.2246. 1: H NMR (300 MHz, CDCl3) δ 6.09 (d, 1H, J ) 15.9 Hz),
.92-5.81 (m, 1H), 5.06 (t, 1H, J ) 7.2 Hz), 4.93 (s, 1H), 4.75 (d, 1H, J
tetramethylpiperidin-1-oxyl], O
Ac
2
, CuCl, DMF, rt, 3 h, 90%; (b)
5
)
1
2
O, pyridine, DMAP, DCM, 0 °C, 3 h, 98%; (c) C
BuOK, THF, 0 °C, 65%; (d) hυ, Pyrex, 450 W (Hannovia), I
CDCl , 1.5 h, 95%; (e) LiOH, methanol, 0 °C, 2 h, 65%; (f) TPAP,
2 5 3
H PPh Br,
14.4 Hz), 4.48 (d, 1H, J ) 14.4 Hz), 3.67 (d, 1H, J ) 1.8 Hz), 3.20 (d,
t
2
,
H, J ) 3.9 Hz), 2.78 (dd, 1H, J ) 8.1, 15.6 Hz), 2.55 (dd, 1H, J ) 6.6,
5.6 Hz), 2.18 (br s, 1H), 1.84 (dd, 3H, J ) 1.5, 6.6 Hz), 1.71 (s, 3H), 1.65
3
1
1
3
NMMO, MS 4 Å, DCM, rt, 4 h, 92%; (g) HF, pyridine, THF, 0
°C, 7 h, 90%; (h) DIBAL-H (2 equiv), THF, -78 °C, 10 min, 84%.
(
s, 3H); C NMR (75 MHz, CDCl3) δ 195.0, 145.5, 136.0, 134.9, 131.5,
1
22.2, 116.5, 65.3, 63.1, 60.1, 59.5, 26.6, 25.8, 19.2, 18.0; HRMS (ES)
+
m/z calcd for C15H20NaO4 [M + Na] 287.1259, found 287.1255.
812
Org. Lett., Vol. 6, No. 5, 2004

(
Scheme 1). Mono-hydroxymethylation of 9 with aq HCHO
With the key stereochemical issue resolved, functional
group readjustments were now attended to, en route to target
1. Acetate deprotection of 17b to obtain 18 and further TPAP
in the presence of DBU was efficient as well as regioselec-
tive, furnishing a 9:1 mixture in which the desired isomer
1
as TBS derivative 11 and repetition of the hydroxymethy-
lation protocol exclusively furnished 12 with chemodiffer-
entiated sidearms on the epoxyquinone moiety. The free
hydroxyl group, the epoxy oxygen functionality, and the exo-
propensity of the norbornyl scaffold were now fully exploited
6
8
6
0 predominated. Protection of the primary hydroxyl group
oxidation led to the epoxyquinone 19 (Scheme 3). TBS
deprotection of 19 furnished 20 and set the stage for the
hydroxyl and epoxy-directed regio- and stereoselective
2
reduction. Indeed, DIBAL-H reduction of 20 furnished
1
13
exclusively jesterone 1 whose H and C NMR data were
identical with those reported for the natural product.1a
for the regio- and stereoselective reduction of 12 to furnish
In short, we have achieved a synthesis of jesterone 1 from
easily available prenylated benzoquinone 7 through a series
of simple, efficient, and highly chemo-, regio-, and stereo-
selective steps. This approach should enable access to many
analogues of this biologically active natural product and
efforts in this direction as well as toward a chiral version of
the synthesis are in progress.
6
13 (Scheme 2). Retro-Diels-Alder reaction of 13 was
smooth and led to the chemodifferentiated monocyclic
6
precursor 14 of jesterone 1 (Scheme 2).
7
Chemoselective TEMPO oxidation of the primary hy-
droxyl group in 14 led to the hydroxyaldehyde 15; its
secondary hydroxyl group was now protected as the acetate
6
1
6 (Scheme 3). Wittig ethylidenation of 16 was nonstereo-
selective and 17 was obtained as a cis:trans (3:1) mixture in
which only the minor trans-isomer was serviceable. Efforts
to improve the cis:trans stereoselectivity in the Wittig
olefination, through variation of reaction regimes, were not
very productive. Recourse was therefore taken to photo-
chemical cis:trans equilibration of the dienone chromophore
present in 17 and this indeed proved rewarding. Irradiation
of the mixture 17a and 17b with a 450-W Hannovia Hg lamp
resulted in complete isomerization to the desired trans-isomer
Acknowledgment. This work was supported by the
Chemical Biology Unit of JNCASR, Bangalore. We thank
S. Ramesh and K. Islam for useful discussions and A. Medda
and P. Maity for the preparation of starting materials.
1
Supporting Information Available: Spectral data ( H,
C NMR, and HRMS) of all the compounds. This material
13
is available free of charge via the Internet at http://pubs.acs.org.
7b (Scheme 3).6
OL0499699
1
(
7) Semmelhack, M. F.; Schmid, C. R.; Cortes, D. A.; Chou, C. S. J.
(8) Ley, S. V.; Marsden, S. P.; Norman, J.; Griffith, W. P. Synthesis
1994, 639.
Am. Chem. Soc. 1984, 106, 3374.
Org. Lett., Vol. 6, No. 5, 2004
813