Convergent synthesis of potent COX-2 inhibitor inotilone

Article abstract of DOI:10.1016/j.tetlet.2007.03.166

The first synthesis of potent COX-2 inhibitor inotilone is reported. The convergent route features a Mukaiyama aldol condensation that generates the target without the use of protecting groups or a separate dehydration step. The approach also highlights a

Full text of DOI:10.1016/j.tetlet.2007.03.166

Tetrahedron Letters 48 (2007) 3767–3769
Convergent synthesis of potent COX-2 inhibitor inotilone
Julia L. Shamshina and Timothy S. Snowden*
The University of Alabama, Department of Chemistry, Box 870336, Tuscaloosa, AL 35487-0336, United States
Received 22 March 2007; accepted 30 March 2007
Available online 4 April 2007
Abstract—The first synthesis of potent COX-2 inhibitor inotilone is reported. The convergent route features a Mukaiyama aldol
condensation that generates the target without the use of protecting groups or a separate dehydration step. The approach also high-
lights a superior regioselective preparation of 1-bromo-2,4-pentanedione involving a bis(silyl enol ether) and NBS.
Ó 2007 Elsevier Ltd. All rights reserved.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are
popular treatments for prevalent inflammatory ailments
including arthritis and musculoskeletal pain. In recent
years, a specific class of NSAIDs, the cyclooxygenase-
2 (COX-2) inhibitors, has sparked intense clinical
investigation because of their remarkable cancer chemo-
preventive activity versus colorectal,1 breast,2 and
several other cancer cell types.3 COX-2 inhibitors also
elicit potentiation of tumor response to radiation ther-
apy and may ultimately find use as an adjuvant treat-
ment.4 Celecoxib, the most prescribed selective COX-2
inhibitor in the United States, has also shown efficacy
in the treatment of Lou Gehrig’s disease.5 Despite the
promising, and in some cases singular, medical benefits
offered by COX-2 inhibitors, several have indicated
increased cardiovascular risk that warrants caution for
applications involving chemoprevention. Recent studies
suggest that cardiovascular risk may not be a class effect
and that the risk is likely dose dependent.6 Hence,
potent and highly selective COX-2 inhibitors are desired
as safer alternatives to the COX inhibitors currently
available.
hydroxysteroid dehydrogenase, xanthine oxidase, and
displayed an order of magnitude lower IC50 value for
COX-2 than COX-1. Thus, its potency, selectivity,
and low molecular weight make it an attractive target
for further investigation.
Our goal was to synthesize inotilone using a convergent
approach conducive to analog preparation. Winkler’s
route to 5-alkyl-3-furanones (3) seemed particularly
attractive as we envisioned the comparable furanone
portion of inotilone could be readily coupled with 3,4-
dihydroxy benzaldehyde under acidic conditions to
afford 1 without phenol protection (Scheme 1).10
Winkler et al. also showed that the silyl enol ether of 3
could undergo addition with various aldehydes using
one of several Lewis acids, thus portending a promising
outcome to our planned late stage coupling step.
Although inspired by the protocol highlighted in
Scheme 1, the preparation of the 5-methyl-3(2H)-fura-
none (8) featured in inotilone necessitated important
modifications from those reported to furnish 3. We were
initially dissatisfied with published routes to 1-halo-2,4-
diones. The chloride could be prepared in one step using
acetone lithium enolate and ethyl chloroacetate in only
Hertweck and co-workers recently reported several new
phenylpropanoid polyketide metabolites from the
mushroom Inonotus sp.7 An unusual 5-methyl-3(2H)-
furanone derivative, inotilone (1), showed a COX-2
enzyme assay IC50 value of 0.03 lM (Fig. 1). This
potency rivals that of the marketed inhibitors meloxi-
cam and nimesulide8 and is superior to rofecoxib.9
Importantly, inotilone proved a poor inhibitor of
O
O
HO
OH
1
*
Corresponding author. Tel.: +1 205 348 8550; fax: +1 205 348
9104; e-mail: snowden@bama.ua.edu
Figure 1. Potent and selective COX-2 inhibitor inotilone.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.166

3768
J. L. Shamshina, T. S. Snowden / Tetrahedron Letters 48 (2007) 3767–3769
OH
O
O
Mukaiyama
aldol
O
O
R
DBU
Cl
O
O
C6H13
C6H13
C6H13
2
3
4
Scheme 1. The Winkler et al. approach to 3(2H)-furanone 3 and its use in Mukaiyama aldol reactions.10
poor yield (<40%).11 Meanwhile attempted regioselec-
tive bromination of 2,4-pentanedione using hexabromo-
cyclopentadiene resulted in an assortment of 1- and
3-bromoacetylacetone and polybrominated products
that were difficult to separate.12 Direct iodination also
furnished an unacceptable mixture of sensitive regioiso-
meric iodo-2,4-diones.13 However, treatment of bis(silyl
enol ether) 614 with NBS afforded the desired 1-bromo-
2,4-pentanedione 7 in quantitative yield (Scheme 2). The
reaction proceeds rapidly and is equally efficient on
scales from 1 to 25 g.
aromatic C6 hydrogen in the (E)-diastereomer of 1. All
characterization data and NOESY correlations of syn-
thetic 1 coincide with those reported by Hertwick.7
Herein we described the first synthesis of potent COX-2
inhibitor inotilone. The natural product was prepared
from commercially available materials in six steps and
ꢀ50% overall yield. The approach is amenable to
scale-up, conducive to analog preparation, and features
a high yielding new method for 1-bromoacetylacetone
(7) preparation. The synthesis and biological activities
of numerous inotilone analogs will be reported once
completed.
Attempted cyclization of 7 using DBU proved problem-
atic, primarily due to the moderate volatility of 8 and
the arduous removal of the hydrophilic product from
water during work-up. We modified Winkler’s protocol
by conducting the cyclization with K2CO3 in ether.
Rapid filtration of the crude reaction mixture through
Celite and rotary evaporation of the filtrate at 23 °C
provided pure 8 without the need for aqueous work-up
or purification. The furanone was subsequently treated
with LDA and TMSCl to give 9, which may be purified
by simple distillation if desired.
Acknowledgements
The authors thank The University of Alabama for fund-
ing and Dr. Ken Belmore for assistance with NOESY
spectroscopy.
Supplementary data
The Mukaiyama aldol reaction between trimethyl-
silyloxyfuran 9 and 3,4-dihydroxy benzaldehyde was
realized using 4.0 equiv of BF3ÆEt2O in THF at
À30 °C. Fewer equivalents led to poor conversion, as
did employment of Ti(OiPr)4 or Et2AlCl as the Lewis
acid. The reaction can also be conducted at room tem-
perature with only a modest decrease in yield (60%)
while temperatures lower than À30 °C offer no advan-
tage. Elimination of the intermediate b-hydroxyl group
occurs in situ or during work-up, as the crude reaction
mixture shows no evidence of the hydroxyl functionality
by 1H NMR. It is notable that the (Z)-alkene is the only
observed isomer, presumably because of the destabiliz-
ing interaction between the furanone carbonyl and the
Experimental procedures, NMR spectra, and HRMS
data are provided for compounds 1 and 7–9. Supple-
mentary data associated with this article can be found,
in the online version, at doi:10.1016/j.tetlet.2007.03.166.
References and notes
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O
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HO
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(70%)
O
(89-94%)
O
OH
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1
9
Scheme 2. Route to the total synthesis of inotilone.

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