Short synthesis of COX-2 inhibitor inotilone

Article abstract of DOI:10.1080/00397910903047778

An efficient three-step synthesis of COX-2 inhibitor inotilone from acetaldoxime is described. The structure of inotilone was elucidated via an aldol reaction between 5-methyl-3(2H)-furanone and 3,4-dihydroxybenzaldehyde. This approach describes a convenient pathway to 5-alkyl-3-furanones through isoxazole chemistry.

Full text of DOI:10.1080/00397910903047778

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Short Synthesis of COX-2 Inhibitor
Inotilone
Saleh Al-Busafi a , Muna Al-Belushi a & Khalid Al-Muqbali a
a Department of Chemistry , College of Science, Sultan Qaboos
University , Muscat, Oman
Published online: 04 Mar 2010.
To cite this article: Saleh Al-Busafi , Muna Al-Belushi & Khalid Al-Muqbali (2010) Short Synthesis
of COX-2 Inhibitor Inotilone, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 40:7, 1088-1092, DOI: 10.1080/00397910903047778
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Synthetic Communications1, 40: 1088–1092, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903047778
SHORT SYNTHESIS OF COX-2 INHIBITOR INOTILONE
Saleh Al-Busafi, Muna Al-Belushi, and Khalid Al-Muqbali
Department of Chemistry, College of Science, Sultan Qaboos University,
Muscat, Oman
An efficient three-step synthesis of COX-2 inhibitor inotilone from acetaldoxime is
described. The structure of inotilone was elucidated via an aldol reaction between
5-methyl-3(2H)-furanone and 3,4-dihydroxybenzaldehyde. This approach describes a
convenient pathway to 5-alkyl-3-furanones through isoxazole chemistry.
Keywords: COX-2 inhibitor; 3(2H)-furanone; inotilone; isoxazol ring
In 2006, Wangun and coworkers[1] reported the isolation and structure elucidation of
an unusual 5-methyl-3(2H)-furanone derivative, inotilone 1, along with several
phenylpropanoid-derived polyketides from the fruiting body of the mushroom
Inonotus sp. (Fig. 1).[1]
When evaluated for its inhibitory activities in COX (cyclooxygenase) assays,
inotilone 1 showed a potent COX-2 inhibitory activity with IC50 value of
0.03 mM.[1] The selective inhibition of COX-2 showed by inotilone 1 is comparable
to those of the already marketed selective inhibitors meloxicam and nimesulide.[2]
Therefore, the selective inhibitory potency of inotilone along with its unique struc-
ture inspired us to design a simple synthetic route to prepare inotilone and possibly
its analogs. Inotilone can be synthesized via aldol reaction between 5-methyl-3
(2H)-furanone 2 and 3,4-dihydroxybenzaldehyde 3 (Scheme 1).
In 2007, Shamshina and Snowden[3] first reported the synthesis of inotilone in
six steps, starting from 2,4-pentanedione, by applying the Mukaiyama aldol reaction
between trimethylsilyloxyfuran and 3,4-dihydroxybenzaldehyde in the last step. One
of the main goals of our current research is to exploit the isoxazole ring in the total
synthesis of natural products that contain the 3(2H)-furanone ring. Studies showed
that catalytic hydrogenation of isoxazole ring under mild conditions broke the NꢀO
bond, thus providing b-iminoenol, which can be converted in situ to 3(2H)-furanone
by acidic treatment followed by basic treatment (Scheme 2).[4]
Received April 3, 2009.
Address correspondence to Saleh Al-Busafi, Department of Chemistry, College of Science, Sultan
Qaboos University, PC 123, Muscat, Oman. E-mail: saleh1@squ.edu.om
1088

SYNTHESIS OF COX-2 INHIBITOR INOTILONE
1089
Figure 1. Inotilone 1.
Scheme 1. Retrosynthetic strategy.
Scheme 2. Conversion of isoxazole ring to 3(2H)-furanone.
RESULTS AND DISCUSSION
The synthesis of inotilone (Scheme 3) started with the preparation of
3-methyl-5-(isoxazolyl) methanol 4 from acetaldoxime 6, according to the method
of Chimichi and coworkers.[5] Therefore, acetaldoxime was treated with sodium
hypochlorite and triethylamine to form nitrile oxide, which reacted insitu with
propargyl alcohol in a [3 þ 2] cycloaddition reaction to form compound 4 in 64%
yield. Catalytic hydrogenation of compound 4 in the presence of 10% palladium
on charcoal in MeOH occurred smoothly, giving a white solid, which was subse-
quently subjected to acidic hydrolysis with hydrochloric acid (1 M, pH < 1) followed
by treatment with saturated bicarbonate solution to afford 5-methyl-3(2H)-furanone
2 in 80% yield. Compound 2 was converted to the enol form after standing, as
1
confirmed by H NMR (CDCl3). As depicted in the retrosynthetic analysis outlined
in Scheme 1, we envisioned inotilone through an aldol reaction between

1090
S. AL-BUSAFI, M. AL-BELUSHI, AND K. AL-MUQBALI
Scheme 3. Synthesis of inotilone. Reagents and conditions: (i) Propargyl alcohol, Et3N, NaOCl, CHCl3,
0 ꢂC; (ii) (a) H2=Pd-C, MeOH, room temperature; (b) HCl (1 M), then sat. NaHCO3; (iii) 3,4-dihydroxy-
benzaldehyde, K2CO3, THF, room temperature.
3(2H)-furanone 2 and 3,4-dihydroxybenzaldehyde 3. In this context, the reaction of
freshly prepared sample of compound 2 with 3,4-dihydroxybenzaldehyde in tetrahy-
drofuran (THF) in the presence of aqueous potassium carbonate afforded inotilone
1 in 70.9% yield.
In conclusion, we have described a quick synthesis of COX-2 inhibitor inoti-
lone 1 in only three steps with 36.4% overall yield starting from commercially avail-
able acetaldoxime. This work highlights the utility of the isoxazole ring as a
precursor for the 3(2H)-furanone ring.
EXPERIMENTAL
General
The reagents and solvents were obtained from Aldrich and used without
further purification. Infrared (IR) spectra were obtained with a Nicolet Magna
560 spectrometer. NMR spectra were recorded on a Bruker Avance 400 (1H:
400 MHz; 13C: 100.6 MHz). The internal standard used was tetramethylsilane
(TMS). Data are reported as chemical shift (multiplicity, number of protons, coup-
ling constant). Mass spectra were measured using a Quatro Ultima PT (Waters
Corp., MA, USA) instrument.
3-Methyl-5-(isoxazolyl)methanol 4
Propargyl alcohol (5.72 g, 0.102 mol), triethylamine (0.69 g, 0.0068 mol), and
sodium hypochlorite (5%, 40.0 mL) were mixed in 200 mL of chloroform. Acetaldox-
ime 5 (1.0 g, 0.0169 mol) was added dropwise to the cooled reaction mixture. The
reaction mixture was further stirred in the ice bath for 45 min. The heterogeneous
mixture was separated, and the aqueous layer was extracted with chloroform
(2 ꢁ 10 mL). The organic layer was dried, filtered, and concentrated under vacuum.
The resulting yellow oil was purified by column chromatography on silica gel using
EtOAc=hexanes for elution to give compound 4. Yield 64%: IR (KBr) nmax in cmꢀ1
:
1
=
=
3369 (OꢀH), 1610 (C C), 1560 (C N aromatic); H NMR (400 MHz, CDCl3) d in
ppm: 2.29 (s, 3H), 3.47 (s, 1H), 4.72 (s, 2H), 6.09 (s, 1H); 13C NMR (100.4 MHz,
CDCl3) d in ppm: 11.26, 56.30, 102.43, 159.78, 171.08. HPLC-MS m=z calcd. for
C5H8NO2, 114.11; found 114.11 (MHþ).

SYNTHESIS OF COX-2 INHIBITOR INOTILONE
1091
5-Methyl-3(2H)-furanone 2
A mixture of 3-methyl-5-(isoxazolyl)methanol 4 (2.59 g, 0.023 mol) and Pd=
C 10% (1.14 g) in methanol (40.7 ml) was hydrogenated for 6 h. The reaction mix-
ture was filtered and washed with methanol, and the solvent was removed under
vacuum to yield a white solid. The white solid was dissolved in HCl (1 M), and
the mixture was stirred for 4 h, then neutralized with saturated NaHCO3. The
product was extracted with diethyl ether (3 ꢁ 10 mL), dried, filtered, and concen-
trated to give compound 2. Yield 80%: IR (KBr) nmax in cmꢀ1: 1694 (C O),
=
1600 (C C), 1289 (CꢀO); 1H NMR (400 MHz, CDCl3) d in ppm: 2.25 (s,
=
3H), 4.50 (s, 2H), 5.49 (s, 1H); 13C NMR (100.4 MHz, CDCl3) d in ppm:
17.16, 75.87, 105.31, 191.97, 203.26. HPLC-MS m=z calcd. for C5H7O2, 99.04;
found 99.05 (MHþ).
Inotilone 1
A solution of K2CO3 (2.2 g) in water (10 mL) was added to a solution of
5-methyl-3(2H)-furanone 2 (0.77 g, 7.9 mmol) and 3,4-dimethoxybenzyladehyde 3
(1.30 g, 7.8 mmol) in THF (10 mL). The reaction mixture was stirred under
reflux for 3 h, and the product was extracted with dichloromethane (3 ꢁ 10 mL).
The organic layer was separated, dried, filtered, and concentrated under vacuum,
and the residue was purified by column chromatography on silica gel using
EtOAc=hexane for elution to give compound 1 as orange solid. Yield 1.22 g,
70.9%; mp: 177.4ꢂC. nmax(KBr)=cmꢀ1 3340 (OꢀH), 1678 (C O), 1606 (C C),
=
=
1
1256 (CꢀO); H NMR (400 MHz, DMSO-d6) 2.40 (s, 3H), 5.58 (s, 1H), 6.53 (s,
1H), 6.82 (d, 1H, J 8.3 Hz), 7.19 (dd, 1H, J 1.9 Hz and 8.3 Hz), 7.38 (d, 1H, J
1.9 Hz); 13C NMR (100.4 MHz, DMSO-d6) d in ppm: 16.61, 106.39, 112.87,
116.83, 118.87, 123.86, 125.67, 145.27, 146.41, 149.09, 181.42, 187.59. HPLC-MS
m=z calcd. for C12H10O4, 218.06; found 218.0 (Mþ). These data compare favorably
with the published data.[1,3]
ACKNOWLEDGMENTS
We acknowledge, with thanks, the financial support from the Sultan Qaboos
University. The authors are also grateful to Professor M. Khan (Sultan Qaboos
University) for extremely helpful discussions.
REFERENCES
1. Wangun, H. V. K.; Ha¨rtl, A.; Kiet, T. T.; Hertweck, C. Inotilone and related phenylpro-
panoid polyketides from Inonotus sp. and their identification as potent COX and XO
inhibitors. Org. Biomol. Chem. 2006, 4, 2545–2548.
2. Vane, J. R.; Bakhle, Y. S.; Botting, R. M. Cyclooxygenases 1 and 2. Ann. Rev. Pharmacol.
Toxicol. 1998, 38, 97–120.
3. Shamshina, J. L.; Snowden, T. S. Convergent synthesis of potent COX-2 inhibitor inotlone.
Tetrahedron Lett. 2007, 48, 3767–3769.

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S. AL-BUSAFI, M. AL-BELUSHI, AND K. AL-MUQBALI
4. Chimichi, S.; Boccalini, M.; Cosimelli, B.; Viola, G.; Vedaldi, D.; Dall, F. New geiparvarin
analogues from 7-(2-oxoethoxy)coumarins as efficient in vitro antitumoral agents.
Tetrahedron Lett. 2002, 43, 7473–7476.
5. Chimichi, S.; Boccalini, M.; Cosimelli, B.; Viola, G.; Vedaldi, D.; Dall, F.
New 5-(2-ethenylsubstituted)-3(2H)-furanones with in vitro antiproliferative avtivity.
Tetrahedron 2003, 59, 5215–5223.