An approach for the enantioselective synthesis of biologically active furanones from a Morita-Baylis-Hillman adduct

Article abstract of DOI:10.1016/j.tet.2010.06.077

Herein, we disclose an approach for the asymmetric synthesis of both enantiomers of an anti-inflammatory furanone. The approach is based on the utilization of a Morita-Baylis-Hillman adduct as starting material and has as key step a selective epoxide-opening/benzylic oxidation mediated by Palladium (II). This sequence afforded an advanced intermediate, which was used to accomplish the total synthesis. Experimental evidences allowed us to suggest a mechanistic proposal for the oxidation Palladium(II)-mediated.

Full text of DOI:10.1016/j.tet.2010.06.077

Tetrahedron 66 (2010) 6749e6753
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An approach for the enantioselective synthesis of biologically active furanones
from a MoritaeBayliseHillman adduct
*
Giovanni W. Amarante, Fernando Coelho
Universidade de Campinas, Instituto de Química, Laboratório de Síntese de Produtos Naturais e Fármacos, Caixa Postal 6154, 13083-970, Campinas, SP, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 May 2010
Received in revised form 26 June 2010
Accepted 28 June 2010
Available online 3 July 2010
Herein, we disclose an approach for the asymmetric synthesis of both enantiomers of an anti-
inflammatory furanone. The approach is based on the utilization of a MoritaeBayliseHillman adduct as
starting material and has as key step a selective epoxide-opening/benzylic oxidation mediated by Pal-
ladium (II). This sequence afforded an advanced intermediate, which was used to accomplish the total
synthesis. Experimental evidences allowed us to suggest a mechanistic proposal for the oxidation Pal-
ladium(II)-mediated.
Keywords:
MoritaeBayliseHillman
Furanones
Ó 2010 Elsevier Ltd. All rights reserved.
Palladium
anti-Inflammatory
Asymmetric synthesis
1. Introduction
4-methanesulfonylphenyl-2(5H)-furanone (DFP), showed the best
activity (Fig. 1).
The inflammatory process is a sophisticated and complex
sequence of events triggered by the human body to fight injuries. It
is directly associated with several diseases, such as asthma, cancer,
immunological response, and degenerative processes (arthritis and
arthrosis).1
Some years ago, a new isoform of the cyclooxygenase enzyme,
namely COX-2 was discovered and isolated.2 As a result this new
enzyme has been identified as target for the development of new
and safer anti-inflammatory drugs. This inducible isoform appears
to play a major role in the inflammatory process through the pro-
duction of prostaglandins.3 Two selective inhibitors, VioxxÒ and
CelebraÒ have been successively launched into the market
(Fig. 1).4,5 However, clinical phase IV assays have demonstrated that
VioxxÒ increases significantly the risk of cardiovascular issues in
patients taking a daily dose.6 VioxxÒ has been voluntary withdrawn
from the market in 2004.
Most recently, COX-2 was identified as a target for the devel-
opment of new compounds to treat some types of cancer7 and
neurodegenerative diseases like Alzheimer8 and Parkinson.9
In a structureeactivity relationship study, Leblanc et al.10 found
some furanones as promising anti-inflammatory agents. Among the
furanones tested those derived from 5,5-dimethyl-3-(2-propoxy)-
Figure 1. COX-2 selective inhitors and anti-inflammatory furanones.
Substituents at C3 and C5 and particularly isoproxy at C5 were
found to improve the pharmacokinetic profile of this type of
compounds (Fig. 1).11
Thus, we became interested in the total synthesis of new anti-
inflammatory agents exhibiting the furanone motif. There are two
reports describing the total synthesis of 1.11,12 However they are
limited on the possible substitution patterns on aromatic ring.
The MoritaeBayliseHillman (MBH) is known to be a green
atom-efficient chemical transformation13,14 producing multi-
functionalized adducts, which are versatile synthons for the prep-
aration of natural products and drugs.15
In this paper we describe a new approach for the synthesis of 1
through a MoritaeBayliseHillman adduct. Furthermore, we dis-
close a mechanistic proposal to explain our results concerning the
* Corresponding author. E-mail address: coelho@iqm.unicamp.br (F. Coelho).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.077

6750
G.W. Amarante, F. Coelho / Tetrahedron 66 (2010) 6749e6753
consecutive epoxide opening followed by a Palladium(II)-mediated
benzylic oxidation.
Recently interest in Palladium(II)-catalyzed oxidation reaction
with molecular oxygen has increased exponentially. This amazing
method, which embraces the also known palladium oxidase catal-
ysis, allows the preparation of carbonyl compounds and diols21 from
alcohols and epoxides and the formation of new CeC and CeN single
bonds from alkenes in good yields and under mild experimental
conditions.22
Despite these developments, the palladium(II)-mediated oxida-
tion of epoxides directly to acyloins has been barely available in
literature. To our knowledge the only report was described by
Sommerlade and Richter some years ago.23 This result inspired us to
test this method to open chiral epoxide 3 and subsequently oxidize
the benzylic position. Thus, after reduction of the primary alcohol
function of 3 to the corresponding methyl group by conventional
transformations, the resulting epoxide 8 was treated with Palladium
(II) acetate in the presence of water, O2, and bathocuproine to give
acyloin 2, as sole compoundin 55%yield (Scheme 2). Thesynthesis of
1 was then completed by esterification of 2 with 2-isoproxy acetic
acid24 in the presence of DPC and DMAP to give ketoester 9 in 70%,
followed by treatment of 9 with isopropyl trifluoroacetate and DBU
in refluxing acetonitrile, providing the desired anti-inflammatory
agent 1. All spectroscopic data are in complete agreement to those
2. Results and discussion
We envisioned the asymmetric synthesis of 1 to be accomplished
by esterification of chiral keto-alcohol 2 with isopropoxy acetic acid,
followed by a Knoevenagel condensation to form the lactone. Keto-
alcohol 2 in turn can be synthesized from chiral epoxide 3, through
a regioselective opening/benzylic oxidation sequence. Asymmetric
Sharpless epoxidation with allylic alcohol 4 should provide 3, which
could be prepared from its corresponding MoritaeBayliseHillman
adduct (Scheme 1).
O
O
O
O
OH
OH
O
(S)
(S)
R
R
S
O O
1
3, R= SCH3
2, R= SO2CH3
OH
O
OH
O
described in literature. However [
but opposite rotation. The measured [a]
D
a
]D value had the same magnitude,
R1
R
4, R= SCH3
5, R= SCH3
value for our synthetic
compound was þ17.2 (c 1.02, MeOH) while that described for the S
Scheme 1. Retrosynthetic analysis toward the synthesis of DFP analog 1.
isomer was ꢀ19 (c 1.02, MeOH).12
This result was disappointing, because in a undefined point of
our strategy a configurational inversion had occurred. Trying to
understand it, we have carefully evaluated the whole synthetic
strategy. At first glance, two steps could be responsible for this
inversion. It is very unlikely that a configurational inversion had
occurred during esterification reaction and Knoevenagel conden-
sation steps. So, the inversion should have occurred either during
the Sharpless asymmetric epoxidation or during the palladium-
mediated opening of the epoxide.
Utilizing our previously reported process the MBH adduct 5 was
prepared from thioanisaldehyde in 79% yield.16,17 Acetylation fol-
lowed by treatment of the resulting allylic ester with lithium
dimethylcopper in ether furnished the cinnamate derivative 6.18
a,
b-Unsaturated methyl ester was then reduced with DIBAL-H, to
afford allylic alcohol 4, in 37% overall yield after three steps
(Scheme 2).
OR1
O
O
O
Sharpless epoxidation is a well established methodology and
based on its stereochemical rationalization we can assume no
inversion had occurred at this step. Despite these considerations,
a,b
O
c
O
R
R
R
5, R1 =H;
7, R1= Ac
we did the Sharpless reaction again, but using
L
-(þ)-DIPT (71%
6, R= SCH3
yield, 80% ee, confirmed by HPLC, Scheme 3).19 The obtained
epoxide 3a was then investigated by NOE experiment in order to
confirm its stereochemistry. The singlet resonance at 4.32 ppm
(benzylic hydrogen) was initially irradiated. We observed a net
increment of 1.75% on the methylene absorption centered at
3.90 ppm, and thus confirming the syn relative stereochemistry of
the asymmetric centers. As expected, the accepted model works
nicely and no inversion had occurred.
R= SCH3
d
O
O
(R)
R1
OH
g
e, f
OH
(S)
(R)
R
R
R
3, R= SO2CH3; R1= CH2OH
8, R= SO2CH3; R1= CH3
4, R= SCH3
2, R= SO2CH3
h
O
O
O
O
O
O
O
(R)
i
irradiated at
(R)
4.32 ppm
S
1.75%
R
O O enant-1
9, R= SO2CH3
H
O
(S)
O
1
a
(S)
b
Scheme 2. Synthesis of enantiomeric 1. Reagents and conditions: a. Methyl acrylate,
DABCO, ultrasound, 48 h, 79%; b. AcCl, Et3N, DMAP, CH2Cl2, 0 ꢁC, 12 h, 88%; c. CH3Li,
CuI, ꢀ20 to ꢀ40 ꢁC, 10 h, 60%. d. DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 2 h, 89%; e. (ꢀ)-DIPT, Ti
(OiPr)4, TBHP, CH2Cl2, ꢀ40 to ꢀ20 ꢁC, 70%, 76% ee f. (i) MsCl, Et3N, CH2Cl2, 0 ꢁC, 10 min;
(ii) LiAlH4, THF, 0 ꢁC, 30 min, 70% (for two steps); g. 20 mol % Pd(OAc)2, bathocuproine
(20 mol %), H2O, O2, 100 ꢁC, 30 h, 55%; h. DPC, DMAP, 2-isoproproxy acetic acid, DCE,
70%; i. CF3CO2iPr, DBU, CH3CN, reflux, 10 h, 85%.
OH
2
(R)
4
(S)
R
R
3a, R= SO2CH3
8a, R= SO2CH3
c
O
O
O
O
(S)
OH
d,e
(S)
Allylic alcohol 4 was then treated with (D)-diisopropyl tartrate
at low temperature to give epoxide 3, in 70% yield and 76% ee. As
expected, the thioether moiety was also oxidized to the sulfone in
this step. Several modifications (temperature, equivalents of tar-
trate, etc.) were tested in order to improve enantioselectivity,
however we did not succeed.19 To improve the enantioselectivity of
this transformation we also employed Shi’s chiral dioxirane,
resulting in both lower yield and the enantiomeric excess.20
S
O O
S
O O
1
2a, R= SO2CH3
Scheme 3. Reagents and conditions: a. L-(þ)-DIPT, Ti(OiPr)4, TBHP, CH2Cl2, ꢀ40 to
ꢀ20 C, 71%, 80% ee b. (i) MsCl, Et3N, CH2Cl2, 0 ꢁC, 10 min; (ii) LiAlH4, THF, 0 ꢁC, 30 min,
70% (for two steps); c. 20 mol % Pd(OAc)2, bathocuproine (20 mol %), H2O, O2, 100 ꢁC,
30 h, 55%; d. DPC, DMAP, 2-isopropoxy acetic acid, DCE, 70%; e. CF3CO2iPr, DBU, CH3CN,
reflux, 10 h, 85%.

G.W. Amarante, F. Coelho / Tetrahedron 66 (2010) 6749e6753
6751
Now we turn our attention to the palladium mediated epoxide
4. Experimental section
4.1. General
ring opening and benzylic oxidation step. A careful inspection
shows that the epoxide opening can occur either at the benzylic or
at homobenzylic position (C1 and C2, respectively, see Scheme 3).
Attack at the homobenzylic position of 8a (C2) would form
a product in which the configuration of the new stereogenic center
would be inverted. On the other hand, attack at C1 would result in
retention of configuration at C2.15e However, C2 is quaternary center
and from a steric point of view, it is most likely to be more difficult
to be attacked by a nucleophile than C1. The presence of a strong
electron-withdrawing group at the para position of the aromatic
ring could compromise C1, if a positive charge (formal or transient)
is formed during the ring opening process. Apparently, the latter
effect seems to overweigh steric arguments in this case and
explains the observed inversion of configuration. Based on these
considerations we restarted the synthetic sequence. Allylic alcohol
4 underwent the Sharpless asymmetric epoxidation to afford 3a.
Treatment of 8a with Palladium(II) acetate, molecular oxygen
(O2), and bathocuproine afforded acyloin 2a, which was esterified
and cyclized as before to lead to the chiral lactone 1, which was
purified by column chromatography and recrystallized twice from
ethyl acetate/hexane (30:70).
The 1H and 13C spectra were recorded on a Brucker at 250 MHz
and 62.5 MHz, respectively. The 1H and 13C spectra were also
recorded on an Inova instrument at 500 MHz and 125 MHz,
respectively. The high resolution mass spectra were recorded using
a Q-TOF Micromass equipment (Waters, UK). Manipulations and
reactions were not performed under dry atmospheres or employing
dry solvents, unless otherwise specified. In those cases CH2Cl2, DMF,
and triethylamine were dried over CaH2 and distilled. Purification
and separations by column chromatography were performed on
silica gel, using normal or flash chromatography. TLC visualization
was achieved by spraying with 5% ethanolic phosphomolybdic acid
and heating. All the reactions, the MoritaeBayliseHillman reactions
were sonicated in an ultrasonic cleaner (81 W, 40 MHz).
4.1.1. Preparation of (ꢂ)-methyl 2-{hydroxy[4-(methylsulfanyl)phe-
nyl]methyl}acrylate (5). A mixture of 4-thiomethylbenzaldehyde
(4.0 g, 26.3 mmol), methyl acrylate (11.3 g,131.5 mmol), and DABCO
(1.9 g, 17.1 mmol) in acetonitrile (10 mL) was sonicated in an
ultrasound bath for 48 h. Next, excess methyl acrylate and aceto-
nitrile was removed under vacuum. The crude residue was diluted
in ethyl acetate (25 mL) and washed with distilled water (15 mL),
brine (2ꢃ15 mL) then dried over anhydrous Na2SO4 and the solvent
removed under vacuum. The residue was purified by flash silica gel
column chromatography (ethyl acetate/hexanesd30:70) to pro-
vide 4.95 g of the MBH adduct 5, as a white solid. Yield 79%, white
solid. Mp: 60e62 ꢁC; IR (film, nmax): 3456,1712,1434 cmꢀ1; 1H NMR
To our delight all spectroscopic and physical data were iden-
tical to those reported in literature. The observed [
this compound was ꢀ17.4 (c 1.02, MeOH). The specific rotation
described in literature for this compound was [
a] value for
D
a
]
D
ꢀ19 (c 1.02,
MeOH). After two recrystallizations the enantiomeric purity was
increased to 94% ee.
This evidence confirm the hypothesis that inversion of configu-
ration at C2 occurs in the epoxide opening. The electronic influence
exerted by the SO2CH3 group seems to be pivotal in the opening
process. Based on these experimental data we have proposed
a mechanism to explain the palladium(II)-catalyzed oxidation with
molecular oxygen (Scheme 4).
(300 MHz, CDCl3),
6.04 (s, 1H), 5.68 (s, 1H), 3.89 (s, 3H), 3.23 (s, 1H, OH), 2.65 (s, 3H);
13C NMR (75.4 MHz, CDCl3),
ppm: 166.5, 141.8, 138.1, 137.9, 127.0,
d ppm: 7.46 (m, 2H), 7.39 (m, 2H), 6.50 (s, 1H),
d
126.8, 126.4, 125.7, 72.5, 51.8, 15.6; HRMS (ESI-TOF) calcd for
C12H14O3S [MþNa]þ: 261.0562. Found: 261.0537.
4.1.2. Preparation of (ꢂ)-methyl 2-{(acetyloxy)[4-(methylsulfanyl)
phenyl]methyl}acrylate (7). To a solution of MBH adduct 5 (1.5 g,
6.3 mmol) in a mixture of dry dichloromethane (30 mL) and dry
Et3N (1.2 mL, 8.2 mmol), under an argon atmosphere, was added
a catalytic amount of DMAP. The resulting solution was cooled to
0 ꢁC and then acetyl chloride (0.64 g, 0.7 mL, 8.2 mmol) was slowly
added. The reaction was stirred for 12 h and upon completion, the
solvent was removed under vacuum. The crude residue was diluted
with ethyl acetate (30 mL) and the organic layer washed with water
(20 mL), brine (2ꢃ20 mL), dried over anhydrous Na2SO4, and con-
centrated under vacuum. The residue was purified by flash silica gel
column chromatography (ethyl acetate/hexanesd25:75) to pro-
vide 1.55 g of the acylated MBH adduct 7. Yield 88%, light yellow oil;
Scheme 4. Mechanistic proposal for the epoxide opening and benzylic oxidation
Palladium(II)-mediated.
IR (film, nmax): 2950, 1736, 1437, 1225 cmꢀ1
CDCl3), ppm: 7.35 (m, 2H), 7.26 (m, 2H), 6.69 (s, 1H), 6.44 (s, 1H),
5.94 (s, 1H), 3.75 (s, 3H), 2.50 (s, 3H), 2.14 (s, 3H); 13C NMR
(75.4 MHz, CDCl3), ppm: 169.1, 165.1, 139.3, 138.8, 134.3, 128.0,
;
1H NMR (300 MHz,
In the first step, palladium coordinates the oxygen promoting
d
nucleophilic attack by water.
b-Elimination hydride delivers the
oxidized product and palladium hydride, which after re-oxidation
in the presence of O2, restarts the catalytic cycle (Scheme 4).
d
126.1, 125.3, 72.6, 51.8, 20.9, 15.3; HRMS (ESI-TOF) calcd for
C14H16O4S [MþNa]þ: 303.0667. Found: 303.0726.
3. Conclusion
4.1.3. Preparation of methyl (2E)-2-[4-(methylsulfanyl)benzylidene]
butanoate (6). A freshly prepared solution of 7 (0.6 g, 2.1 mmol) in
dry diethyl ether (50 mL) was kept under stirring at ꢀ40 ꢁC. In an-
other flask, a suspension of CuI (0.48 g, 2.5 mmol) in dry ethyl ether
(10 mL) wasprepared. Theresulting suspensionwas stirredandthen
cooled to 0 ꢁC and then a 1.6 mol Lꢀ1 solution of methyllithium
(0.112 g, 3.2 mL) was slowly added. The resulting solution was stir-
red for 10 min at 0 ꢁC and immediately after it was cooled to ꢀ40 ꢁC
and transferred via cannula to the solution of 7 at ꢀ40 ꢁC. The yellow
mixture was stirred for 8 h at ꢀ40 ꢁC. The medium was diluted with
In summary, we have developed a newstrategy, which allows the
syntheses of both enantiomers of the anti-inflammatory agent DFP
analog 1. The syntheses were accomplished in 10 steps, in 6% overall
yield, from commercially available thioanisaldehyde. This approach
demonstrates the synthetic utility of the MoritaeBayliseHillman
and the palladium-(II)/O2 oxidation reactions.
Further studies are ongoing in our laboratory in order to dem-
onstrate the generality of this synthetic strategy and will be pub-
lished in due time.

6752
G.W. Amarante, F. Coelho / Tetrahedron 66 (2010) 6749e6753
ethyl ether (20 mL) and a solution of NH4Cl/NH4OH 1:1 (5 mL) was
added. The mixture was stirred until an intense blue coloration had
appeared. The organic layer was washed with water (10 mL), brine
(2ꢃ15 mL), dried over anhydrous Na2SO4, and concentrated under
vacuum. The crude product was purified by flash silica gel column
chromatography (ethyl acetate/hexanesd20:80) to afford 0.3 g of
olefin 6, as a sole isomer. Yield 60%, light yellow oil; IR (film, nmax):
procedure was used to prepare enantiomeric epoxide 3, however
(ꢀ)-diisopropyl tartrate was used instead. Epoxide (R,R)-3 (42 mg)
was obtained as a viscous oil, in 70% yield and 88:12 er. The en-
antiomeric purity of both epoxide was determined by HPLC.
25
(S,S)-3a[
a
]
D
þ16.0 (c 1.2, MeOH); for the enantiomer (R, R)-3
25
[
a
]
ꢀ15.0 (c 1.2, MeOH); IR (film, nmax): 3432, 2970, 2921, 1299,
D
1148 cmꢀ1
;
1H NMR (300 MHz, CDCl3),
d
ppm: 7.94 (d, J¼8.4 Hz,
2966, 1708, 1234 cmꢀ1
;
1H NMR (300 MHz, CDCl3),
d
ppm: 7.59 (s,
2H), 7.53 (d, J¼8.4 Hz, 2H), 4.32 (s,1H), 3.90 (q, 2H), 3.08 (s, 3H),1.80
1H), 7.31 (m, 2H), 7.25 (m, 2H), 3.82 (s, 3H), 2.56 (q, J¼7.5 Hz, 2H),
(br s, 1H), 1.40 (m, 2H), 0.82 (t, J¼7.8 Hz, 3H); 13C NMR (75.4 MHz,
2.51 (s, 3H),1.18 (t, J¼7.5 Hz, 3H); 13C NMR (75.4 MHz, CDCl3),
d
ppm:
CDCl3), d ppm: 142.2, 139.6, 127.3, 127.1, 67.3, 62.1, 59.5, 44.5, 20.8,
168.7, 139.3, 137.9, 134.0, 132.2, 129.6, 125.9, 51.9, 20.9, 15.5, 13.8;
HRMS (ESI-TOF) calcd for C13H16O2S [MþH]þ: 237.0949. Found:
237.0918.
8.98; HRMS (ESI-TOF) calcd for C12H16O4S [MþNa]þ: 279.0667.
Found: 279.0732.
4.1.6. Preparation of (S,R)-2-ethyl-2-methyl-3-[4-(methylsulfonyl)
4.1.4. Preparation of (2E)-2-[4-(methylsulfanyl)benzylidene]butan-1-ol
(4). To a solution of cinnamate ester 6 (0.4 g, 1.7 mmol) in dry
dichloromethane (12 mL), at ꢀ78 ꢁC under an inert gas atmosphere,
was added, a 1.5 mol Lꢀ1 solution of DIBAL-H in hexane (2.5 equiv,
2.8 mL). The reaction was stirred for 2 h at ꢀ78 ꢁC and then meth-
anol (six drops) was added. The mixture was warmed to 0 ꢁC fol-
lowed by the addition of 10 mL of a saturated solution of sodium
acetate. The mixture was stirred until the formation of a gel, which
was filtered on pad of Celite. The organic layer was separated, dried
over anhydrous Na2SO4, and concentrated under vacuum. The crude
product shows a purity grade high enough to be used in the next step
without additional purification. Yield 89% (0.32 g), light yellow oil; IR
(film, nmax): 3350, 2962, 1491, 1091 cmꢀ1; 1H NMR (300 MHz, CDCl3),
phenyl]oxirane (8a). To
0.41 mmol) in dry dichloromethane (12 mL), at 0 ꢁC and under ar-
gon atmosphere, was added triethylamine (77 L, 0.53 mmol) and
mesyl chloride (38 L, 0.53 mmol). After stirring for 10 min, dis-
a solution of epoxide 3a (0.106 g,
m
m
tilled water (8 mL) was added and the organic layer was separated.
The aqueous layer was extracted with dichloromethane (3ꢃ20 mL).
The organic layers were combined, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The crude product was
used for the next step without purification.
(S,S)-{2-ethyl-3-[4-(methylsulfonyl)phenyl]oxiran-2-yl}methyl
methanesulfonate. Yield >99% (0.13 g), viscous tinged yellow oil; IR
(film, nmax): 3000, 1351, 1295, 1171, 1148, 958, 852 cmꢀ1 1H NMR
;
(300 MHz, CDCl3),
d
ppm: 7.96 (d, J¼7.8 Hz, 2H), 7.54 (d, J¼7.8 Hz,
d
ppm: 7.30 (m, 2H), 7.26 (m, 2H), 6.52 (s, 1H), 4.30 (d, J¼0.8 Hz, 2H),
2.56 (s, 3H), 2.40 (q, J¼6.0 Hz, 2H), 1.91 (s, 1H, OH), 1.19 (t, J¼6.0 Hz,
3H); 13C NMR (75.4 MHz, CDCl3),
ppm: 143.2, 136.4, 134.3, 128.9,
2H), 4.43 (q, 2H), 4.23 (s, 1H), 3.14 (s, 3H), 3.09 (s, 3H), 1.42 (m, 2H),
0.90 (t, J¼7.8 Hz, 3H); 13C NMR (75.4 MHz, CDCl3),
d ppm: 140.7,
d
140.0, 127.4, 127.3, 69.8, 64.4, 61.2, 44.5, 38.0, 20.3, 8.79.
126.4, 124.3, 66.7, 21.9, 16.0, 13.1; HRMS (ESI-TOF) calcd for C12H16OS
A solution of the above mesylate (0.103 g, 0.32 mmol) in dry
THF, at 0 ꢁC, under an argon atmosphere, was added to a stirred
suspension of LiAlH4 (0.06 g, 1.55 mmol) in dry THF (5 mL). The
reaction was stirred for 30 min. Then, a 10% solution of NaOH
(1.0 mL) was slowly added at 0 ꢁC. [Caution: A very exothermic and
vigorous reaction occurs during this addition and should therefore be
carefully controlled]. The resulting mixture was slowly warmed to
room temperature and stirred until formation of a white solid. The
mixture was filtered on a pad of Celite and the cake was washed
with ethyl acetate (3ꢃ20 mL). The organic layers were combined,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure. The crude residue was purified by flash silica gel column
chromatography (ethyl acetate/hexanesd50:50) to provide 50 mg
[MþNa]þ: 231.0820. Found: 231.0781.
4.1.5. Preparation of {2-ethyl-3-[4-(methylsulfonyl)phenyl]oxiran-2-
yl}methanol (3). rac-3: To a stirred solution of allylic alcohol 4 (0.1 g,
0.48 mmol) in dichloromethane (15 mL), at 0 ꢁC, was added, m-
chloroperbenzoic acid 70% (4.0 equiv, 0. 47 g, 1.92 mmol). The
resulting mixture was stirred for 12 h at room temperature and upon
completion, the reaction was quenched with a saturated solution of
sodium bisulfite (8 mL). The mixture was diluted with dichloro-
methane (15 mL) and the phases were separated. The aqueous layer
was washed with dichloromethane (3ꢃ20 mL) and the combined
organic layers were dried over anhydrous Na2SO4 and concentrated
under vacuum. The crude product was purified by flash silica gel
column chromatography (ethyl acetate/hexanesd80:20) to give
0.104 g of racemic epoxide 3, as a viscous oil, in 90% yield.
of epoxide 8a, as a viscous colorless oil, in 70% yield for two steps.
25
(S,R)-3a: [
a
]
25 þ11.0 (c 1.0, MeOH); for the enantiomer (R,S)-3: [
a]
D
D
ꢀ10.0 (c 1.0, MeOH); IR (film, nmax): 2974, 1308, 1149 cmꢀ1; 1H NMR
Chiral 3 (S,S) and (R,R): To a stirred suspension of 4 Å molecular
sieves (60 mg) in dry dichloromethane (1.0 mL), at ꢀ40 ꢁC, under
an inert gas atmosphere, was added a solution of titanium tetra-
(250 MHz, CDCl3),
d
ppm: 7.93 (d, J¼8.7 Hz, 2H), 7.52 (d, J¼8.7 Hz,
2H), 3.94 (s, 1H), 3.05 (s, 3H), 1.49 (s, 3H), 1.30 (m, 2H), 0.84 (t,
J¼7.8 Hz, 3H); 13C NMR (62.5 MHz, CDCl3),
d ppm: 143.0, 139.4,
127.4, 127.1, 65.1, 64.0, 44.5, 24.6, 21.4, 9.16; HRMS (ESI-TOF) calcd
isopropoxide (73
m
L, 0.27 mmol) and (þ)-diisopropyl tartrate
(36 L, 0.17 mmol) dissolved in dry CH2Cl2 (1.0 mL). The mixture
m
for C12H16O3S [MþH]þ: 241.0898. Found: 241.0901.
was stirred for 1 h. Next, a 5 mol Lꢀ1 solution tert-butyl-hydroper-
oxide in nonane (0.32 mL, 1.6 mmol) was added. After 15 min. of
stirring, a solution of allylic alcohol 4 (0.05 g, 0.24 mmol) in dry
dichloromethane (3,0 mL) was cannulated to the reaction mixture.
The final mixture was warmed to ꢀ20 ꢁC and stirred for 30 h. After
that time, the reaction mixture was warmed to 0 ꢁC and diluted
with dichloromethane (10 mL) and distilled water (5 mL). The
stirred mixture was slowly warmed to room temperature and then
a 10% solution of NaOH was added (2.0 mL). The mixture was fil-
tered over a pad of Celite and the cake was washed with
dichloromethane (15 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated under vacuum. The crude
product was purified by flash silica gel column chromatography
(ethyl acetate/hexanesd80:20) as the eluent to provide epoxide (S,
S)-3a (43 mg), as a viscous oil, in 71% yield and 90:10 er. The same
4.1.7. Preparation of (S)-2-hydroxy-2-methyl-1-[4-(methylsulfonyl)
phenyl]butan-1-one (2a). A mixture of palladium acetate (0.0041 g,
20 mol %) and bathocuproine (0.0067 g, 20 mol %) in distilled water
(3.0 mL) was stirred for 24 h. To this final mixture, epoxide 3a
(0.018 g, 0.075 mmol) was added and the reaction was warmed to
100 ꢁC, under an oxygen atmosphere. The reaction was stirred for
30 h at 100 ꢁC. Then the mixture was cooled to room temperature
and diluted with ethyl acetate (10 mL). The organic layer was washed
with water (5 mL), brine (2ꢃ5 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The crude product was
purified by flash silica gel column chromatography (ethyl acetate/
hexanesd55:45) to provide 10 mg of hydroxyketone 2a, as a viscous
oil, in 55% yield. (S)-2a: [
a
]
25 ꢀ18.0 (c 1.0, MeOH); for the enantiomer
D

G.W. Amarante, F. Coelho / Tetrahedron 66 (2010) 6749e6753
6753
25
(R)-2: [
a
]
þ17.0 (c 1.0, MeOH); IR (film, nmax): 3493, 2970, 2929,
References and notes
D
1683, 1307, 1148 cmꢀ1
;
1H NMR (250 MHz, CDCl3),
d ppm: 8.15 (m,
1. (a) Inflammation: Basic Principles and Clinical Correlates, 3rd ed.; Gallin, J. E., Sny-
derman, R., Eds.; Lippincott William & Wilkins: Washington, DC, 1999; (b) Physi-
ology of Inflammation; Ley, K., Ed.; American Physiological Sociey: Bethesda, 2001.
2. (a) Vane, J. R.; Bakhle, Y. S.; Botting, R. M. Annu. Rev. Pharmacol. Toxicol. 1998, 98,
97e120; (b) Mitchell, J. A.; Akarasereenont, P.; Thiemermann, C.; Flowers, R. J.;
Vane, J. R. Proc. Natl. Acad. Sci. U.S.A. 1994, 90, 11693e11697 and references cited
therein; (c) Taketo, M. M. J. Cancer Res. 1998, 90, 1529e1534.
3. (a) Kennedy, B. P.; Chan, C. C.; Culp, S. A.; Cromlish, W. A. Biochem. Biophys. Res.
Commun. 1993, 197, 494e500; (b) Masferrer, J. L.; Zweifel, B. S.; Manning, P. T.;
Hauser, S. D.; Leahy, K. M.; Smith, W. G.; Isakson, P. C.; Seibert, K. Proc. Natl.
Acad. Sci. U.S.A. 1994, 91, 3228e3232; (c) Vane, J. R.; Mitchell, J. A.; Appleton, I.;
Tomlinson, A.; Bishop-Bailey, D.; Croxtall, J.; Willoughby, D. A. Proc. Natl. Acad.
Sci. U.S.A. 1994, 91, 2046e2050; (d) Harada, Y.; Hatanaka, K.; Saito, M.; Majima,
M.; Ogino, M.; Kawamura, M.; Ohno, T.; Yang, Q.; Katori, M.; Yamamoto, S.
Biomed. Res. 1994, 15, 127e130.
2H), 8.04 (m, 2H), 3.08 (s, 3H), 1.93 (m, 2H), 1.59 (s, 3H), 0.88 (t,
J¼6.2 Hz, 3H); 13C NMR (62.5 MHz, CDCl3),
d ppm: 204.3,143.7,139.4,
130.0, 127.5, 80.0, 44.3, 33.7, 26.4, 7.86; HRMS (ESI-TOF) calcd for
C12H16O4S [MþNa]þ: 279.0667. Found: 279.0656.
4.1.8. (S)-2-Methyl-1-[4-(methylsulfonyl)phenyl]-1-oxobutan-2-yl
(propan-2-yloxy)acetate (9a). To a mixture of isopropyl acetic acid
(5.3 mg, 0.045 mmol) and a catalytic amount of DMAP in di-
chloroethane (3.0 mL), at 0 ꢁC, was added
a-hydroxyketone 2a
(8.0 mg, 0.03 mmol) and then diisopropyl carbodiimide (5.7 mg,
0.045 mmol) during 3 h. The resulting mixture was stirred for 10 h
at room temperature and then the excess of dichloroethane was
removed under vacuum. The crude residue was diluted with ethyl
acetate (10 mL) and the organic layer was washed with water
(10 mL), brine (2ꢃ5 mL), dried over anhydrous Na2SO4, and con-
centrated under vacuum. The crude product was purified by flash
silica gel column chromatography (ethyl acetate/hexanesd55:45)
to provide the ester 53 (8.0 mg, 0.022 mmol) as a white solid in
4. Vioxx ís
a registered trademark of Merck while Celebrex is a registered
trademark of Pfizer.
5. For the development of celecoxib, see: Penning, D. T.; Talley, J. J.; Bettensahw, S.
R.; Carter, J. S.; Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;
Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E.
G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.;
Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347e1365.
6. Flower, R. J. Nature Rev. Drug Discov 2003, 2, 179e191.
7. (a) Subbaramaiah, K.; Dannenberg, A. J. Trends Pharmacol. Sci. 2003, 24, 96e102;
(b) Iniguez, M. A.; Rodriguez, A.; Volpert, O. V.; Fresno, M.; Redondo, J. M. Trends
Mol. Med. 2003, 9, 73e78.
a 70% yield. (S)-9a: [
MeOH); for the enantiomer (R)-9: [
NMR (250 MHz, CDCl3),
a
]
25 ꢀ19.0 (c 1.0, MeOH); lit. [
a]
25 ꢀ19.3 (c 1.0,
D
D
25
a]
þ18.8 (c 1.0, MeOH); 1H
D
8. Xiang, Z.; Ho, L.; Valdellon, J.; Borchelt, D.; Kelley, K.; Spielman, L.; Aisen, P. S.;
Pasinetti, G. M. Neurobiol. Aging 2002, 23, 327e334.
d ppm: 8.15 (m, 2H), 7.99 (m, 2H), 3.99 (d,
J¼2.5 Hz, 2H), 3.46 (hept, J¼6.0 Hz, 1H), 3.07 (s, 3H), 2.27 (m, 1H),
9. (a) Feng, Z. H.; Wang, T. G.; Li, D. D.; Fung, P.; Wilson, B. C.; Liu, B.; Ali, S. F.;
Langenbach, R.; Hong, J. S. Neurosci. Lett. 2002, 329, 354e358; (b) Michaux, C.;
de Leval, X.; Julémont, F.; Dogné, J.-M.; Pirotte, B.; Durant, F. Eur. J. Med. Chem.
2006, 41, 1446e1455.
10. (a) Beley, M.; Gauthier, J.Y.; Grimm, E.; Leblanc, Y.; Li, C.-S.; Therien, M.; Black,
C.; Lau, C. -K.; Prasit, P.; Roy, P. International Patent WO 1997/14691, April 24th,
1997; Chem. Abstr. 1997, 127, 384238; (b) Leblanc, Y.; Roy, P.; Boyce, S.; Brideau,
C.; Chan, C. C.; Charleson, S.; Gordon, R.; Grimm, E.; Guay, J.; Léger, S.; Li, C. S.;
Riendeau, D.; Visco, D.; Wang, Z.; Webb, J.; Xu, L. J.; Prasit, P. Bioorg. Med. Chem.
Lett. 1999, 9, 2207e2212.
11. Leblanc, Y.; Roy, P.; Wang, Z.; Li, C. S.; Chauret, N.; Nicoll-Griffith, D. A.; Silva, J. M.;
Aubin, Y.; Yergey, J. A.; Chan, C. C.; Riendeau, D.; Brideau, C.; Gordon, R.; Xu, L.;
Webb, J.; Visco, D. M.; Petpiboon, P. Bioorg. Med. Chem. Lett. 2002, 12, 3317e3320.
12. (a) Tan, L.; Chen, C.-Y.; Chen, W.; Frey, L.; King, A. O.; Tillyer, R. D.; Xu, F.; Zhao,
D.; Grabowski, E. J. J.; Reider, P. J.; O’Shea, P.; Dagneu, P.; Wang, X. Tetrahedron
2002, 58, 7403e7410.
13. (a) Almeida, W. P.; Coelho, F. Quim. Nova 2001, 23, 98e101; (b) Basavaiah, D.;
Rao, K. V.; Reddy, R. J. Chem. Soc. Rev. 2007, 36, 1581e1588; (c) Singh, V.; Batra,
S. Tetrahedron 2008, 64, 4511e4574.
14. (a) Santos, L. S.; Pavam, C. H.; Almeida, W. P.; Coelho, F.; Eberlin, M. N. Angew. Chem.,
Int. Ed. 2004, 43, 4330e4333; (b) Amarante, G. W.; Milagre, H. M. S.; Gontigo, B. V.;
Ferreira, B. R. V.; Eberlin, M. N.; Coelho, F. J. Org. Chem. 2009, 74, 3031e3037.
15. (a) Masunari, A.; Ishida, E.; Trazzi, G.; Almeida, W. P.; Coelho, F. Synth. Commun.
2001, 31, 2127e2136; (b) Coelho, F.; Veronese, D.; Pavam, C. H.; de Paula, V. I.;
Buffon, R. Tetrahedron 2006, 62, 4563e4572; (c) Dunn, P. J.; Fournier, J.-F.;
Hughes, M. L.; Searle, P. M.; Wood, A. S. Org. Process Res. Dev. 2003, 7, 244e253;
(d) Reddy, L. R.; Fournier, J.-F.; Reddy, B. V. S.; Corey, E. J. Org. Lett. 2005, 7,
2699e2701; (e) Silveira, G. P. C.; Coelho, F. Tetrahedron Lett. 2005, 46,
6477e6481; (f) Mateus, C. R.; Coelho, F. J. Braz. Chem. Soc. 2005, 16, 386e396.
16. (a) Coelho, F.; Almeida, W. P.; Veronese, D.; Mateus, C. R.; Lopes, E. C. S.; Rossi, R. C.;
Silveira, G. P. C.; Pavam, C. H. Tetrahedron 2002, 58, 7437e7447; (b) Almeida, W. P.;
Coelho, F. Tetrahedron Lett. 1998, 39, 8609e8612.
2.05 (m, 1H), 1.72 (s, 3H), 1.11 (two d, 6H), 1.00 (t, J¼7.5 Hz, 3H); 13C
NMR (62.5 MHz, CDCl3),
d ppm: 197.9, 170.1, 143.4, 139.4, 129.2,
127.5, 87.5, 72.8, 65.8, 44.3, 30.6, 21.7, 21.6, 21.2, 7.6; HRMS (ESI-
TOF) calcd for C17H24O6S [MþNa]þ: 379.1191. Found: 379.1032.
4.1.9. (S)-5-Ethyl-3-isopropoxy-5-methyl-4-[4-(methylsulfonyl)phe-
nyl]furan-2(5H)-one (1). To a solution of ester (S)-9a (0.005 g,
0.014 mmol) in dry and degassed CH3CN (1.5 mL) was added i-
PrOOCCF3 (2.5 mL, 0.017 mmol) and DBU (3.2 mL, 0.021 mmol). The
mixture was refluxed for 10 h. Then, the reaction medium was
cooled to room temperature and neutralized with a 1 mol Lꢀ1 so-
lution of HCl (six drops). The solvent was removed under vacuum.
The crude product was diluted with distilled water (3 mL) and the
aqueous phase was extracted with ethyl acetate (3ꢃ4 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated under vacuum. The residue was purified by flash silica
gel column chromatography (ethyl acetate/hexanesd50:50) and
recrystallized twice to provide 4 mg of lactone 1, as a white solid, in
25
85% yield. (S)-1: [
a
]
D
ꢀ17.4 (c 1.02, MeOH); lit. [
a
]
25 ꢀ19.0 (c 1.02,
D
25
MeOH); for the enantiomer (R)-1: [
(film, nmax): 2978, 2931, 1754, 1152 cmꢀ1
CDCl3),
a
]
þ17.2 (c 1.02, MeOH); IR
D
;
1H NMR (250 MHz,
d
ppm: 8.00 (m, 2H), 7.85 (m, 2H), 5.32 (hept, J¼6.2 Hz, 1H),
3.10 (s, 3H), 2.07 (dq, J¼14.8, 7.4 Hz, 1H), 1.94 (dq, J¼14.7, 7.3 Hz,
1H), 1.65 (s, 3H),1.30 (d, J¼3.5 Hz, 3H),1.28 (d, J¼6.0 Hz, 3H), 0.83 (t,
17. (a) Lin, Y.-S.; Lin, C.-Y.; Liu, C.-W.; Tsai, T. Y. R. Tetrahedron 2006, 62, 872e877;
(b) Lin, Y.-S.; Liu, C.-W.; Tsai, T. Y. R. Tetrahedron Lett. 2005, 46, 1859e1861.
18. (a) The double bond configuration was determined as being E by NOE exper-
iments; (b) For more details, see: Basavaiah, D.; Sarma, P. K. S.; Bhavani, A. K. D.
J. Chem. Soc., Chem. Commun. 1994, 1091e1092.
J¼7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3),
d ppm: 167.0,141.6,140.4,
139.3, 135.9, 128.7, 127.7, 85.9, 73.8, 44.4, 31.5, 25.9, 22.7, 7.6; HRMS
(ESI-TOF) calcd for C17H22O5S [MþH]þ: 339.1266. Found: 339.1214.
19. The enantiomeric excess of epoxide 3 was determined by chiral HPLC using
a Chiralcel column OJ-H, 0.46 cm of diameterꢃ25 cm purchased by DAICEL
Chemical Eluent: hexanes/isopropyl alcohol 35%, isocratic elution.
20. Shi, Y. Acc. Chem. Res. 2004, 37, 488e496 and references cited therein.
21. Yu, X.-Q.; Yoshimura, F.; Ito, F.; Sasaki, M.; Hirai, A.; Tanino, K. Angew. Chem., Int.
Ed. 2008, 47, 750e754; (b) Kjellgren, J.; Aydin, J.; Wallner, O. A.; Saltanova, I. V.;
Szabo, K. J. Chem.dEur. J. 2005, 1, 5260e5268; (c) Miyashita, M.; Mizutani, T.;
Tadano, G.; Iwata, Y.; Miyazawa, M.; Tanino, K. Angew. Chem., Int. Ed. 2005, 44,
5094e5097; (d) Yu, X.-Q.; Hirai, A.; Miyashita, M. Chem. Lett. 2004, 33,
764e765; (e) Hirai, A.; Yu, X.-Q.; Tonooka, T.; Miyashita, M. Chem. Commun.
2008, 2482e2483.
22. (a) Gligorich, K. M.; Sigman, M. S. Chem. Commun. 2009, 3854e3867; (b) Stahl,
S. S. Angew. Chem., Int. Ed. 2004, 43, 3400e3420; (c) Rogers, M. M.; Kotov, V.;
Chatwichien, J.; Stahl, S. S. Org. Lett. 2007, 9, 4331e4334 and references cited
therein; (d) Muzart, J. Tetrahedron 2003, 59, 5789e5816.
23. Sommerlade, R.H.; Richter, I. PCT WO 2006/005682 A2 01.19.2006.
24. 2-Isoproxy acetic acid can be easily prepared from commercially available
methyl bromoacetate in two steps and 92% overall yield. See: Padakanti, S.; Pal,
M.; Yeleswaparu, K. R. Tetrahedron 2003, 59, 7915e7920.
Acknowledgements
Authors thank FAPESP for fellowship (to GWA) and grant (FC). FC
thanks CNPq for scientific fellowship and financial support. The
authors are grateful to Prof. Carol H. Collins for English revision of
this manuscript.
Supplementary data
Spectra of all compounds are supplied as Supplementary data.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.06.077. These data include
MOL files and InChIKeys of the most important compounds
described in this article.