Total synthesis of (±)-hibiscone C

Article abstract of DOI:10.1016/j.tetlet.2011.01.111

A total synthesis of (±)-hibiscone C, one member of the furanosteroid family of natural products that also includes viridin and wortmannin, is reported. Two new pathways for formation of the key diacyl furan subunit are described.

Full text of DOI:10.1016/j.tetlet.2011.01.111

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Tetrahedron Letters 52 (2011) 1509–1511
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Tetrahedron Letters
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Total synthesis of ( )-hibiscone C
⇑
Sinziana Ungureanu, Maggie Meadows, Joel Smith, David B. Duff, James M. Burgess, Brian C. Goess
Furman University, Department of Chemistry, 3300 Poinsett Highway, Greenville, SC 29613, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A total synthesis of ( )-hibiscone C, one member of the furanosteroid family of natural products that also
includes viridin and wortmannin, is reported. Two new pathways for formation of the key diacyl furan
subunit are described.
Received 11 December 2010
Revised 21 January 2011
Accepted 25 January 2011
Available online 1 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Furanosteroid
Hibiscone C
Oxidative aromatization
Total synthesis
The sesquiterpene furanosteroid family of natural products
includes hibiscone C, viridin, wortmannin, and halenaquinone.1
The key structural similarity shared by each member of this family
is a furan ring flanked by two conjugated carbonyl groups. The
electrophilicity of such diacylheteroaryl systems coupled with
the ring strain caused by the fusion of many contiguous sp2-
hybridized carbons within a polycyclic ring system confers to the
furanosteroids an enhanced reactivity towards nucleophiles that
accounts for their varied and often potent biologic activities. For in-
stance, wortmannin, which has attracted the most interest based
on its antiproliferative activity,2 inhibits the PI-3 kinase, an en-
zyme responsible in part for cell growth and differentiation. The
timing of the installation of this sensitive functional group has
been referred to as the ‘greatest strategic conundrum’ in the syn-
thesis of furanosteroids.2
covery of a new strategy for the synthesis of diacylated furans exe-
cuted on hibiscone C, one of the structurally less complex members
of this family of natural products. In addition we report related
reactivity of some synthetic intermediates that provide additional
insights into furanosteroid construction (Fig. 1).
To date two total syntheses of hibiscone C have been reported.3
In planning our approach we were attracted in particular to the
elegant synthesis of Kraus and Wan,3b which utilizes many classi-
cal organic transformations to rapidly construct the fused polycy-
clic skeleton. The only drawback we saw to their approach was
the expense of the starting material, 1,3-cyclohexanedione (3).4
We developed a scalable five-step sequence of reactions that pre-
pares 3 from isobutyraldehyde in high yield without requiring
purification of any intermediates (Scheme 1). An aldol dehydration
of acetone and isobutyraldehyde yields enone 1,5 which undergoes
a Michael addition with diethylmalonate to yield ketone 2.6 An
annulation followed by ester hydrolysis and decarboxylation yields
As part of a program to investigate the mechanism of action of
various furanosteroids and their analogs, we report herein our dis-
O
O
O
O
O
H
H3C
H3C
O
O
O
O
O
H3C
H3C
O
H
H3C
HO
O
AcO
O
O
O
O
CH3
OCH3
OCH3
O
hibiscone C
viridin
wortmannin
halenaquinone
Figure 1. Four members of the furanosteroid family of natural products.
⇑
Corresponding author. Tel.: +1 864 294 2318; fax: +1 864 295 3559.
E-mail address: brian.goess@furman.edu (B.C. Goess).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.111

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1510
S. Ungureanu et al. / Tetrahedron Letters 52 (2011) 1509–1511
O
O
OH
H3C
H3C
OH
H3C
H3C
OH
O
CH3
CH3
OH
OH
a,b
c
H3C
H3C
H3C
CO2Et
H
[O]
H
H
CH3
CH3
CH3 CO2Et
2
5
O
O
1
CH3
CH3
O
O
4
9
10
d,e
OH
OH
H3C
H3C
OH
O
OH
H3C
H3C
O
H3C
H3C
OH
O
CH3
CH3
[O]
3
H
H
(a) acetone, NaOH, H2O, 5 → 23 oC; (b) p-TsOH, Na2SO4 benzene, 80 oC;
(c) CH2(CO2Et)2, NaOEt, EtOH, 80 oC; (d) KOH, H2O, 90 oC; (e) H2SO4,
H2O, 90 oC, 62% (five steps)
O
O
CH3
CH3
11
8
Scheme 1. Preparation of 1,3-cyclohexane dione (3) from inexpensive starting
materials.
Scheme 3. Proposed pathway for the conversion of 5–8 mediated by K2OsO4/
K3Fe(CN)6.
dione 3 in 62% isolated overall yield following column chromatog-
raphy. As would be expected from a 1,3-dione, NMR analysis of 3
indicates it exists primarily as its enol tautomer 4. Of note, this
modular approach to 3 would allow preparation of hibiscone C
analogs that bear different side chains on the cyclohexane ring,
depending on the identity of the starting aldehyde.
With an efficient route to 3 in hand, we utilized the strategy of
Kraus and Wan to prepare dienone 5; however, in our hands stan-
dard dihydroxylation reaction conditions did not yield desired triol
6. Instead, we obtained only pentaol 7 in 71% yield (Scheme 2). This
result occurred regardless of whether or not the stock solution of
OsO4 used in the reaction was freshly prepared.
As there is literature evidence that some conjugated dienes un-
dergo exhaustive dihydroxylation with OsO4/NMO,7 we felt it
would be advantageous to employ a different set of reagents
(K2OsO4/K3Fe(CN)6) that has been found to mediate regioselective
dihydroxylations on a range of conjugated dienes.8 Under these
conditions we were surprised to isolate cyclized diol 8 in 86% yield
instead of desired triol 6 (Scheme 3).9 Our hypothesis is that fol-
lowing initial regioselective dihydroxylation to yield 9 an elimina-
tion takes place to generate dienone 10, which undergoes a second
regioselective dihydroxylation to yield 11, which then cyclizes to
produce stable hemiketal 8.
H3C
Ac2O
Et3N
DMAP
OAc
f
(see Scheme 5)
H
H3C
5
No reaction
O
CH2Cl2
0 oC
80%
CH3
12
Scheme 4. Mechanistic probe of the conversion of 5–8.
OH
O
OH
H3C
H3C
H3C
H3C
O
O
f
g
H
H
5
O
O
CH3
CH3
8
( )-hibiscone C
h
We designed a mechanistic probe of this unusual oxidation cas-
cade reaction (Scheme 4). Primary alcohol 5 was acetylated with
the intent of precluding cyclization, and resulting acetate 12 was
then exposed to the same reagents that generate 8 from 5 (Scheme
OH
H3C
H3C
O
H
O
CH3
H3C
OH
13
OsO4
(f) K3Fe(CN)6, K2CO3, NaHCO3, CH3SO2NH2, K2OsO4 (12 mol%),
tBuOH, H2O, 86%; (g) COCl2, DMSO, Et3N, CH2Cl2, -78 oC, quant.;
(h) toluene, 110 oC, 57% combined (41% 13 + 16% hibiscone C)
Ref. 3b
5 steps
NMO
H
3
H3C
O
(CH3)2CO : H2O
71%
CH3
Scheme 5. Two routes for the preparation of hibiscone C from 5.
5
OH
OH
H3C
H3C
OH
OH
H3C
H3C
OH
OH
5, conditions f). No reaction was observed even after extended
reaction times, indicating that the primary hydroxyl likely has a
strong rate-accelerating effect on the dihydroxylation reaction.
Molecule 8 requires only an oxidation and aromatizing elimina-
tion to generate hibiscone C, which occur simultaneously and in
quantitative yield upon its exposure to Swern oxidation conditions
(Scheme 5). Proton and carbon NMRs of the isolated product
matched recently published revised assignment data.10
OH
H
H
OH
O
O
CH3
CH3
6, not observed
7
Scheme 2. Double dihydroxylation of dienone 5.

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S. Ungureanu et al. / Tetrahedron Letters 52 (2011) 1509–1511
1511
Interestingly, we found that heating 8 in refluxing toluene open
to the atmosphere induced both an elimination to yield alcohol 13
(41% yield) and a subsequent heteroarylic oxidation to generate
hibiscone C (16% yield) directly from 8 without the use of any man-
ufactured oxidizing agents (Scheme 5, path h). Heating 8 in an oxy-
gen-free sealed tube generates primarily 13 with only trace
amounts of hibiscone C detectable by crude 1H NMR. Both routes
to hibiscone C illustrated in Scheme 5 represent new pathways
for furanosteroid construction.
In summary, we have accomplished a total synthesis of furanos-
teroid hibiscone C from inexpensive starting materials. Key fea-
tures of this synthesis include an unusual oxidation–cyclization
cascade to yield 8 and a tandem elimination/oxidation of 8 to yield
the natural product.
for all intermediates between compounds 3 and 5 (Scheme 2)3b
)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.01.111.
References and notes
1. Hanson, J. R. Nat. Prod. Rep. 1995, 12, 381–384.
2. (a) Wipf, P.; Halter, R. J. Org. Biomol. Chem. 2005, 3, 2053–2061; (b) Cravatt, B.
F.; Sorensen, E. J.; Drahl, C. Angew. Chem., Int. Ed. 2005, 44, 5788–5809.
3. (a) Smith, A. B., III; Koft, E. R. J. Am. Chem. Soc. 1982, 104, 5568–5570; (b) Kraus,
G. A.; Wan, Z. Synlett 2000, 363–364.
4. $25/g from Sigma–Aldrich.
5. Tanaka, K.; Kobayashi, T.; Mori, H.; Katsumura, S. J. Org. Chem. 2004, 69, 5906–
5925.
6. Frank, R. K.; Hall, H. K., Jr. J. Am. Chem. Soc. 1950, 72, 1645–1648.
7. (a) Park, C. Y.; Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 1003–
1006; (b) Kolb, H. C.; VanNieuwenhze, M. J.; Sharpless, K. B. Chem. Rev. 1994,
94, 2483–2547.
Acknowledgments
8. Xu, D.; Crispino, G. A.; Sharpless, K. B. J. Am. Chem. Soc. 1992, 114, 7570–7571.
9. Procedure:
A biphasic mixture of 5 (1 equiv), K3Fe(CN)6 (3 equiv), K2CO3
(3 equiv), CH3SO2NH2 (3 equiv), K2OsO4 (0.12 equiv), and 3:5 tBuOH: H2O
(0.14 M) was stirred vigorously at room temperature for two days. Following
extractive work-up between EtOAc and H2O, 8 was obtained as a clear oil after
purification through a SiO2 column (1:1 EtOAc: hexanes). 1H NMR (400 MHz,
CDCl3): d 0.87 (d, J = 7.2 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 1.21 (d, J = 7.6 Hz, 3H),
1.58 (dt, J = 12.8, 4.8 Hz, 1H), 1.82–1.92 (m, 2H), 1.96–2.08 (m, 1H), 2.22–2.32
(m, 2H), 2.37 (dd, J = 19.2, 4.0 Hz, 1H), 2.45 (br s, 1H), 2.64–2.74 (m, 1H), 3.00
(br s, 1H), 3.72 (d, J = 2.4 Hz, 1H), 4.71 (dd, J = 13.2, 2.8 Hz, 1H), 4.88 (dd, J = 9.2,
4.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 16.5, 17.1, 21.3, 27.1, 31.1, 32.0, 33.4,
37.5, 47.8, 71.0, 75.4, 108.1, 134.2, 158.9, 196.2. IR (neat, cmÀ1) 3372, 2959,
2934, 2876, 1669. HRMS (EI+) Calcd 266.1519 (M+), Found 266.1518. Relative
stereochemistry was not determined.
Financial support from the National Institutes of Health(INBRE:
2P20-RR01641-05) and the Howard Hughes Medical Institute
Undergraduate Science Education program are gratefully acknowl-
edged. The authors acknowledge important preliminary contribu-
tions from Justin Goodwin, Billy Grimes, and Ashley Windrum.
Supplementary data
Supplementary data (1H NMR, 13C NMR, IR, and HRMS spectra
are provided for hibiscone C, for compounds 5, 7, 8, and 13, and
10. Zhang, X.; Zhang, S.; Xuan, L. Heterocycles 2008, 75, 661–668.