A general carbometalation, three component coupling strategy for the synthesis of α,β-unsaturated γ-sultines including thio-rofecoxib, a selective COX-2 inhibitor

Article abstract of DOI:10.1016/j.bmcl.2005.02.056

Magnesium mediated carbometalation (Grignard addition) to appropriate propargyl alcohols to synthesize a cross-section of variably substituted α,β-unsaturated γ-sultines is described. Thio-rofecoxib, a selective COX-2 inhibitor (12), is synthesized by thi

Full text of DOI:10.1016/j.bmcl.2005.02.056

Bioorganic & Medicinal Chemistry Letters 15 (2005) 2057–2060
A general carbometalation, three component coupling strategy
for the synthesis of a,b-unsaturated c-sultines including
thio-rofecoxib, a selective COX-2 inhibitor
David V. Smil,c Fabio E. S. Souzab and Alex G. Fallisa,*
aDepartment of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, ON, Canada K1N 6N5
bAlphora Research Inc., 2395 Speakman Drive, Mississauga, ON, Canada L5K 1B3
c
´
Methyl Gene Inc., 7220 Frederick Banting, Montreal, Quebec, Canada H4S 2A1
Received 4 January 2005; revised 16 February 2005; accepted 17 February 2005
Available online 16 March 2005
Abstract—Magnesium mediated carbometalation (Grignard addition) to appropriate propargyl alcohols to synthesize a cross-sec-
tion of variably substituted a,b-unsaturated c-sultines is described. Thio-rofecoxib, a selective COX-2 inhibitor (12), is synthesized
by this method and its IC50, lM COX-1 and COX-2 inhibition, and whole blood stability values reported.
Ó 2005 Elsevier Ltd. All rights reserved.
Cyclic sulfinates (sultines) constitute a class of heterocy-
clic compounds whose chemistry continues to be of
interest.1 There appears to be only one report of a sul-
tine natural product, 3-propyl-c-sultine from the yellow
passion fruit (Passiflora edulis f. flavicarpa).2 Neverthe-
less sultines have a long chemical history3 and several
methods exist for their synthesis.1,4 Sultines are versatile
synthetic intermediates, applications include ring-open-
ing reactions (to generate ortho-quinodimethanes5 or
biradicals6), alkylation,7 and oxidation at sulfur to give
sultones.8 In addition, the stereogenic center at sulfur
has the potential to play a role in subsequent asymmet-
ric transformations. More recently, there has been in-
creased interest in five membered sulfur heterocycles
such as sultines because of their cancer chemopreventa-
tive effects. They function as glutathione S-transferase
inducers and may have medicinal potential.9 Additional
reports suggest that thio-acetals such as 1,2-dithiolanes
and 1,2-dithianes hold promise as HIV type 1 replica-
tion inhibitors.10
pounds generated in a single reaction, for a variety of
objectives. These reactions have included the regio-
and stereoselective generation of diene–halides, diene–
diols, enediynes, furans, furanones, taxo intermediates,
and palladium(0) cross-couplings for dienes, and the
stereospecific synthesis of (Z)-tamoxifen.12
The common feature of this chemistry is the reaction of
a propargyl alcohol either directly or in situ with a Grig-
nard reagent, subsequent generation of the magnesium
chelate, followed by reaction with an appropriate elec-
trophile. In the case of furans the substitution pattern
may be controlled for all the ring substituents and five
bonds are formed in one reaction vessel (Scheme 1).
We wish to report an extension of this chemistry for the
synthesis of 3,4-disubstituted a,b-unsaturated c-sultines.
It was anticipated that the putative chelate 3 that arises
from addition of the Grignard reagent 2 to the propar-
gylic alcohol 1 could be trapped with thionyl chloride to
We have previously described some of the attributes and
versatility of the magnesium mediated carbometalation
of propargyl alcohols11 to assemble several diverse com-
R
R2
R
R2
R
1
R
MgCl
Li
(1) R CHO
(2) R2MgCl
(3) R3CN
R
R1
R3
Keywords: Carbometalation; Propargyl alcohols; Sultines; Cox-2
inhibitor.
Mg
R1
O
O
OM
*
Corresponding author. Tel.: +1 613 562 5732; fax: +1 613 562
5170; e-mail: afallis@science.uottawa.ca
Scheme 1. Magnesium mediated carbometalation route to furans.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.02.056

2058
D. V. Smil et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2057–2060
R1
S
R2
R1
R2
OH
THF/toluene
reflux, 18 h
SOCl2
+
R2MgCl
R1
-78 ºC-rt
Mg
1
2
O
O
O
4
3
Scheme 2. Carbometalation of propargyl alcohols with thionyl chloride quench to sultines.
SO2Me
yield variably disubstituted c-sultines of type 4 (Scheme
2).
Me
SO2NH2
The carbometalation of several propargylic alcohols (1)
were conducted with a variety of Grignard reagents 2.
However, initial attempts to trap the intermediate che-
late 3 at 0 °C with thionyl chloride resulted in complex
product mixtures. This difficulty was overcome by con-
N
N
O
O
CF3
ducting the quench at À78 °C to afford the desired c-sul-
Celebrex®
Me
Vioxx® (5)
(6)
tines cleanly with minimal contamination. These results
are summarized in Table 1. The yields were reproducible
and the products were of sufficient purity, determined by
1H NMR analysis, that further purification was usually
not required.
SO2NH2
SO2NH2
N
The cyclooxygenases (COX-1 and COX-2) play an
important role in human health due to their important
role as catalysts for the conversion of arachidonic acid
to initiate the prostaglandin cascade. It is now estab-
lished that cyclooxygenages exist as two isoforms with
different functions. COX-1, via prostaglandins, helps
mediate gastric cytoprotection and platelet aggregation.
In contrast COX-2 is up-regulated in response to inflam-
matory stimuli. This has led to a new family of COX-2
selective inhibitors that are potent anti-inflammatory
agents with improved gastrointestinal features com-
pared to non-selective drugs (NSAIDS) (Fig. 1). The po-
tential of more efficient drugs for the treatment of
osteoarthritis and reduction of acute pain with less acute
gastrointestinal problems stimulated the discovery of
several novel coxib drugs with improved efficacy. Prom-
inent among these were refecoxib (5, VioxxÒ), celecoxib
(6, CelebrexÒ) valdecoxib (7, BextraÒ), and etoricoxib
(8, ArcoxiaÒ). In a very short time frame these became
billion dollars drugs. It is interesting to note the similar-
ity in structures, particularly of the first generation,
based on a five membered ring heterocyclic framework
that contained both phenyl and most importantly a
N
N
Me
O
Cl
Arcoxia®
Brextra®
(7)
(8)
Figure 1. Selective COX-2 inhibitor drugs.
phenylsulfonyl
functionality.
methyl
or
phenylsulfonamide
Our research was completed before the current contro-
versy regarding heart complications with VioxxÒ was
verified. However, further research and human ingenu-
ity will eventually generate compounds with improved
therapeutic profiles. Previously we developed a two-step
synthesis of the COX-2 anti-inflammatory drug VioxxÒ
(5) with our carbometalation strategy (Scheme 3).11c In
view of the widespread interest in COX-2 inhibitors
and the success of the results above the opportunity to
synthesize a C2 sulfur analog of the butenolide nick-
named ‘‘thio-Vioxx’’ (12) was particularly appealing.13
Standard quenching conditions at À78 °C afforded the
sultine 11 from addition of thioanisole magnesium chlo-
ride (9) to phenylpropargyl alcohol (10) in modest yield
(29%). Oxidation of sultine 11 with exactly 2 equiv of m-
CPBA afforded 12 in 99% yield. The differentially oxi-
dized analogs 13 and 14 were prepared via modification
of the oxidation conditions.
Table 1. Sultine 4 substitution patterns and yields
Compound
R1
R2
Yielda (%)
4a
4b
4c
4d
4e
4f
Me
Me
Ph
Allyl
Ph
57
60
82
95
92
89
86
82
83
91
Me
Ph
Ph
Vinyl
Isopropenyl
Allyl
Ph
Treatment of 11 with 1 equiv of m-CPBA afforded the
methyl sulfoxide 13, while with 3 equiv of oxidant 14
was produced. The preferential oxidation of the thio-
methyl ether 11 is noteworthy, as no competing oxida-
tion of the intra-annular sulfur was observed in the
preparation of either 12 or 13.
Ph
Ph
4g
4h
4i
TMS
TMS
TMS
Vinyl
Vinyl
Ph
4j
a Yields are for isolated products.

D. V. Smil et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2057–2060
2059
SMe
SO2Me
a)
SMe
CO2
m-CPBA
ClMg
SOCl2
b)
9
S
O
O
OH
O
O
11
10
Vioxx® (5)
m-CPBA
3eq.
m-CPBA, 2eq.
m-CPBA
1eq.
SOMe
SO2Me
SO2Me
S
S
O
O
S
O
O
O
O
O
"thio-Vioxx" (12)
14
13
Scheme 3. Synthesis of Ôthio-rofecoxibÕ = Ôthio-VioxxÕ 12.
At the outset, we wanted to evaluate the metabolic sta-
bility of sultine 12. This was accomplished by incubating
12 in rat plasma at room temperature and subsequently
analyzing the incubations for levels of parent drug.
Thus, at different time points, the rat plasma incubation
sample was treated with acetonitrile to precipitate the
plasma proteins and, after centrifugation, the resulting
materials were analyzed by HPLC–UV. We were
pleased to note that the concentration of 12 in the plas-
ma samples, as measured by LC–UV, remained un-
changed even after 24 h incubation. Encouraged by
this finding, we next evaluated the in vitro coxib profile
of 12 in a microsomal enzyme assay. Results of this as-
say revealed that sultine 12 is a selective COX-2 inhibi-
tor. The IC50 of 12 on COX-1 was found to be >100 lM
(13% inhibition at 100 lM). Interestingly, the titration
curve for the COX-2 assay plateaued at approximately
40% inhibition with an inflection point of 0.86 lM.
The reason for this plateau effect in the COX-2 assay
is unclear, although this phenomenon with other classes
of COX-2 inhibitors has been reported in the
literature.14
to previously unavailable c-sultines with novel substitu-
tion patterns. In addition, thio-rofecoxib, which displays
selective COX-2 inhibitor was prepared in a straightfor-
ward manner. Based on these results, extension of this
chemistry to the synthesis of glutathione peroxidase cat-
alysts such as 1,2-oxaselenane Se-oxide16 may be
feasible.
After submission of this manuscript it was suggested
that the conjugate base of rofecoxib was a possible con-
tributor to the human toxicity observed during long
term treatment with rofecoxib.17 Air oxidation of anion
15, generated from rofecoxib on treatment with either n-
BuLi or LiOH in THF, afforded a small amount of 16
and the corresponding maleic anhydride 17 (Scheme
4). If anhydride 17 were to be generated in vivo and if
it was a long live metabolite, it was speculated that
nucleophilic attack from amino groups would be
possible.17
A reviewer asked us to comment on the potential rela-
tionship with these observations and the anticipated
behavior of thio-rofecoxib 12.
A select number of 3,4-disubstituted a,b-unsaturated c-
sultines have been reported.15 However, our magnesium
mediated carbometalation approach offers a very flexi-
ble 3-component coupling method for efficient access
These are very different molecules and the sultine is not
capable of enolization in the manner of the butenolide.
Indeed, the most likely oxidation product from 12 is
SO2Me
SO2Me
SO2Me
+
OH
O
O
O
O
O
O
O
15
17
16
Scheme 4. Possible in vitro oxidation pathway from rofecoxib alkoxide.

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D. V. Smil et al. / Bioorg. Med. Chem. Lett. 15 (2005) 2057–2060
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Acknowledgements
We are grateful to the National Sciences and Engineer-
ing Research Council of Canada (NSERC) for financial
support of this research. In addition, we thank Marc
Ouellett and Claudio Sturino (Merck-Frosst, Montreal)
for kindly conducting the microsomal COX assay and
for the plasma stability measurements, respectively.
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