Total synthesis of euplectin, a natural product with a chromone fused lndenone

Article abstract of DOI:10.1021/ol901817r

The first total synthesis of euplectin, a rare metabolite with a chromone annulated indenone motif, has been accomplished In 17 steps. This has been possible through Interplay among three key reactions: a Hauser sulfoxide annulation, a new chromone format

Full text of DOI:10.1021/ol901817r

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4398-4401
Total Synthesis of Euplectin, a Natural
Product with a Chromone Fused
Indenone
Dipakranjan Mal* and Saroj Ranjan De
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
dmal@chem.iitkgp.ernet.in
Received August 6, 2009
ABSTRACT
The first total synthesis of euplectin, a rare metabolite with a chromone annulated indenone motif, has been accomplished in 17 steps. This
has been possible through interplay among three key reactions: a Hauser sulfoxide annulation, a new chromone formation and a late-stage
retro-Diels-Alder reaction. The entire regiochemical integrity of the successful route is established by an iodine-catalyzed aromatization of
a cyclohexane-1,3-dione and the Hauser annulation.
The natural products with annulated chromone nuclei are
an emerging class of metabolites. In recent years, members
like 6-methoxycomapavin 1,1 isonigerone 2,2 and pluramycin
33 (Figure 1) have gained enormous attention due to their
antitumor, antibacterial, and enzyme inhibitory activities. Their
synthetic chemistry has duly been advanced by many research
groups: namely, Dallavalle,4 Danishefsky,5 Hauser,6 Hecht,7
Kozlowski,8 Krohn,9 McDonald,10 Suzuki,11 Tietze,12 and
Uno13 groups. More specifically, 5-hydroxychromones, annu-
(8) Kozlowski, M. C.; Dugan, E. C.; DiVirgilio, E. S.; Maksimenka,
K.; Bringmann, G. AdV. Synth. Catal. 2007, 349, 583–594.
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10.1021/ol901817r CCC: $40.75
Published on Web 09/08/2009
 2009 American Chemical Society

droxyindenone (Scheme 1). Hence, the formulation of the
retrosynthesis was focused on three stages: (i) formation of
indenone skeleton with free OH groups, (ii) formation of
Scheme 1. Retrosynthesis of Euplectin (5a)
Figure 1. Representative structures of naturally occurring annulated
chromones.
pyrone moiety, and (iii) construction of naphthol unit. Since
2,3-unsubstituted indenones are known to dimerize in both
acidic and basic conditions,18 the creation of the indenone
double bond was considered the last step. It was expected
to be achieved by the retro-Diels-Alder reaction of hexacy-
cle 8, construction of which was planned from 9 via a
chromone synthesis, which, in turn, should be obtainable
from 10 through functional group interconversion. The BCD
ring, i.e., benz[f]indan scaffold of 10 was envisaged to be
assembled by annulation19 of thiophthalide 11 with masked
cyclopentadienone 12. Among the various methods20 known
in the literature for naphthol annulation, the reaction between
11 and 12 was chosen because such a reaction allows
introduction of the 9-hydroxy group of benz[f]indenones,
concomitant with the benzannulation.21 Moreover, the com-
monly conceived 1,4-dipolar synthons like ortho toluate
lated to a quinone represented by topopyrones 4 have begun
to receive attention due to their promising topoisomerase
inhibitory activity.14 Euplectin (5a), one of the five related
but rare natural products15 (Figure 2), with an indenone
Figure 2. Structures of naturally occurring hydroxychromone[f]in-
denones.
(18) Davis, B. R.; Johnson, S. J.; Woodgate, P. D. Aust. J. Chem. 1987,
40, 1017–1021.
(19) Mal, D.; Hazra, N. K.; Murty, K. V. S. N.; Majumdar, G. Synlett
1995, 1239–1240.
moiety fused to a 5-hydroxychromone, was isolated in 2000
and reported to exhibit cytotoxicity against the growth of
murine P-815 mastocytoma cells.16 The bioactivity of the
congener, coneuplectin (6a) could not be evaluated due to
the paucity of the material obtained from the natural source.
Our interest in these molecules stemmed from the intriguing
fact that a 2,3-unsubstituted indenone like 5a survives the
harsh processes of a scheme of isolation, while the simplest
indenone easily polymerizes at ordinary temperatures even
in diffuse light.17
In part, the interest was reinforced owing to our conjecture
that euplectin (5a) could be an artifact of 8-hydroxyconeu-
plectin. Herein, we disclose the first successful route leading
to the total synthesis of euplectin (5a).
Inspection of the structure of euplectin (5a) revealed fusion
of two prominent motifs: a hydroxychromone and a hy-
(20) (a) Dodsworth, D. J.; Calcagno, M.-P.; Ehrmann, E. U.; Devadas,
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10790. For reviews on the Hauser phthalide annulation, see: (a) Mal, D.;
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Org. Lett., Vol. 11, No. 19, 2009
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sulfoxides and homophthalic anhydrides do not undergo
anionic cycloaddition with the tricyclic enone 12.19,22
Synthesis of the required thiophthalide 11 commenced with
the reported regioselective preparation23 of 13a from methyl
acetoacetate and methyl crotonate (Scheme 2). The corre-
sulfoxide donors.25 However, the recent report26 on the
remarkable effect [yield: 0% (THF)26 and 5% (THF);25 31%
(THF-DMSO)26] of DMSO on such annulations prompted
us to examine the reactivity of the toluate sulfoxide 19 toward
enone 12. Benzyl bromide 14 was reacted with PhSH-Et3N
followed by K2CO3-MeOH to furnish phenyl sulfide 20 in
83% yield. Phenyl sulfide 20 was reacted with MOMCl-i-
Pr2NEt to give MOM ether 21 in 86% yield. Oxidation of
the SPh group in 21 with NaIO4 afforded the requisite
sulfoxide 19 in 64% yield. An initial cursory attempt at
condensation of the sulfoxide 19 with enone 12 in THF under
commonly employed conditions (t-BuOLi, THF, -60 to 0
°C) failed to produce the desired product 22. When carried
out in the mixed solvent, i.e., 3:1 THF-DMSO, the same
reaction afforded the product 22 in 51% yield (Scheme 3).
Scheme 2. Synthesis and Annulation of Thiophthalide 11
Scheme 3. Model Studies with the Hauser Sulfoxide Annulation
sponding acetate 13b was brominated with NBS to give
bromide 14 in 78% yield. This was treated with thiourea
followed by aq NaHCO3 solution to afford thiophthalide 15
in 61% yield. For further elaboration, the free OH of 15 was
protected as methyl ether with CH3I-K2CO3 affording 16a.
NBS bromination of 16a to 16b followed by reaction with
PhSH-Et3N yielded the desired thiophthalide 11 in 92%
yield. This was then annulated with the tricyclic enone 12
in the presence of t-BuOLi in THF to furnish benzo[b]fluo-
renone 10 in good yield. To construct the pyrone ring on
10, selective demethylation of 10 to phenol 17 was examined.
Unfortunately, all attempts (BBr3, AlCl3, HBr-AcOH, TMSI,
Ph2S2-CaH2, etc.) failed to furnish the desired phenol 17.
Flash vacuum pyrolysis of 10 provided benz[f]indenone 18,
but it was not amenable to further elaboration due to its
instability to acidic conditions.
Frustratingly, all standard attempts (BF3·OEt2, PPTS, or dilute
HCl) to remove MOM ether in 22 caused severe decomposi-
tion of the pentacycle 22. This compound slowly decomposed
even upon storage at rt under ambient conditions. Although
further work on utilization of the MOM ether 22 was
discontinued, this study established the viability of the Hauser
sulfoxide annulation in fabrication of the euplectin core.
Lessons learned from the preceding schemes led us to
examine the chromanone sulfoxide 23 route (Scheme 4). The
sulfoxide was prepared from toluate sulfide 20 via (i)
chromanone formation (20 f 24), (ii) oxidation of sulfide
to sulfoxide (24 f 25), and (iii) protection of keto carbonyl
group as a 1,3-dithiane (25 f 23).
Annulation of the sulfoxide 23 with the enone 12 under
the conditions t-BuOLi, THF-DMSO, -60 to 0 °C, yielded
the expected product 26 in 25-28% yield. Remarkable
improvement in the yield (88%) of the process was met by
heating the reaction mixture at reflux for 2 h before
quenching. The dithiane group of 26 was smoothly removed
under the standard protocol27 (HgCl2, aq CH3CN) to give
Next, we resorted to the Hauser sulfoxide annulation24a
which furnishes R-naphthols. Although its compatibility with
cycloalkenone acceptors or unsaturated lactones24f is unpre-
dictable, we demonstrated that such a reaction is achievable
with the base-stable cyclic enone acceptor 12 and a furan-
derived sulfoxide donor.22 We also showed that the annu-
lation of 12 does not work with ortho toluate derived
(22) (a) Mal, D.; Murty, K. V. S. N.; Datta, K. Tetrahedron Lett. 1994,
35, 9617–9618. (b) Bandyopadhyay, M.; Datta, K.; Mal, D. J. Indian Chem.
Soc. 1999, 76, 551–556
.
(23) Mal, D.; Pahari, P.; De, S. R. Tetrahedron 2007, 63, 11781–11792.
(24) Hauser sulfoxide annulation for naphthol synthesis: (a) Hauser,
F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178–180. (b) Mohanakrishnan,
A. K.; Srinivasan, P. C. Tetrahedron Lett. 1993, 34, 1343–1346. (c) Mal,
D.; Bandyopadhyay, M.; Ghorai, S. K.; Datta, K. Tetrahedron Lett. 2000,
41, 3677–3680. (d) Hauser, F. M.; Liao, H.; Sun, Y. Org. Lett. 2002, 4,
2241–2243. (e) Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D. Synthesis 2006,
2556–2562. (f) Sperry, J.; Yuen, T. Y.; Brimble, M. A. Synthesis 2009,
2561–2569.
(25) Hazra, N. K. Ph.D. Thesis, 1999, Indian Institute of Technology,
Kharagpur.
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Org. Lett., Vol. 11, No. 19, 2009

was considered for introduction of the chromone double
bond. But this strategy also posed serious problems. At-
tempted R-iodination of 27a by I2-Selectfluor28 resulted in
the nuclear iodination product 27b rather than the desired
product. At last, hexacycle 27a was derivatized to the acetate
27c, controlled reaction of which with I2-Selectfluor af-
forded the requisite product 29 in moderate yield (60%). This
was treated with DBU to give annulated chromone 28 (62%)
along with a small amount of the corresponding deacetylated
product. O-Demethylation of 28 was possible after rigorous
and controlled experimentation. Treatment of 28 with BBr3
furnished 8 in respectable yield (78%). Flash vacuum
pyrolysis (FVP) of 8, though daunting, could be effected at
550 °C and 0.01 Torr to furnish euplectin (5a) in 64% yield.
Both 1H and 13C NMR spectral data of the synthetic 5a were
in complete agreement with the original16 data.
Scheme 4. Total Synthesis of Euplectin (5a)
In conclusion, we have accomplished the first total
synthesis of euplectin (5a) in 17 steps from commercially
available chemicals. The synthesis thus confirms the origi-
nally assigned structure of euplectin. The crucial steps include
an optimized Hauser sulfoxide annulation and a new
chromone formation via selective R-iodination of ketone.
Further application of this strategy to the other members of
euplectin-type natural products is under investigation.
Acknowledgment. We thank the Council of Scientific &
Industrial Research (CSIR), New Delhi, for generous finan-
cial support of this work. S.R.D. is thankful to the CSIR for
his research fellowship. S.R.D. is also thankful to Mr. Subrata
Pore and Mr. Uttam Dash, IICT Hyderabad, for some spectral
data. The NMR facility was supported by the FIST program
of DST, New Delhi.
Supporting Information Available: General experimental
methods, experimental procedures, and 1H, 13C, and DEPT-
135 NMR spectra of the new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
annulated chromanone 27a in 84% yield. Transformation of
chromanone 27a to chromone 28 was not a trivial problem.
Attempts at dehydrogenation using DDQ were not feasible.
This failure was anticipated based upon the literature
background and the well-known sensitivity of naphthol
moieties. Alternatively, selective iodination at the R-position
to the pyrone carbonyl group followed by dehydroiodination
OL901817R
(28) Jereb, M.; Stavber, S.; Zupan, M. Tetrahedron 2003, 59, 5935–
5940.
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