Asymmetric synthesis of Sulindac esters by enantioselective sulfoxidation in the presence of chiral titanium complexes

Article abstract of DOI:10.1016/j.tetasy.2006.12.002

High ee values (up to 94-96% ee) and moderate isolated yields (48-50%) were achieved in the preparation of Sulindac alkyl esters. These molecules are simple and straightforward precursors of Sulindac, an anti-inflammatory drug that has also been recently

Full text of DOI:10.1016/j.tetasy.2006.12.002

Tetrahedron: Asymmetry 17 (2006) 3226–3229
Asymmetric synthesis of Sulindac esters by enantioselective
sulfoxidation in the presence of chiral titanium complexes
Francesco Naso,a,b Cosimo Cardellicchio,a,* Francesco Affortunatob
and Maria Annunziata M. Capozzic
aConsiglio Nazionale delle Ricerche, Istituto di Chimica dei Composti Organometallici (ICCOM), c/o Dipartimento di Chimica,
`
Universita di Bari, via Orabona 4, 70126 Bari, Italy
`
`
Dipartimento di Scienze Agro-Ambientali, Chimica e Difesa Vegetale, Universita di Foggia, via Napoli 25, 71100 Foggia, Italy
b
Dipartimento di Chimica, Universita di Bari, via Orabona 4, 70126 Bari, Italy
c
Received 5 October 2006; accepted 13 December 2006
Abstract—High ee values (up to 94–96% ee) and moderate isolated yields (48–50%) were achieved in the preparation of Sulindac alkyl
esters. These molecules are simple and straightforward precursors of Sulindac, an anti-inflammatory drug that has also been recently
investigated in anti-cancer therapy. The key step of the overall procedure was the enantioselective hydroperoxide oxidation of the Sul-
indac sulfide alkyl esters in the presence of chiral complexes of titanium with either (S,S)- or (R,R)-hydrobenzoin. Various reaction con-
ditions were investigated in order to obtain the best balance between yield and enantioselectivity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
presence of a complex between titanium and diethyl tar-
trate was unsuccessful.7 The difficulties were partially over-
come by oxidising a smaller, less substituted indenic sulfide
intermediate with the above procedure (54–56% yield, 88–
90% ee).7 This intermediate was then transformed into
Sulindac by reacting it with glyoxylic acid (28–30% yield).7
Important progress was made by Bolm et al., who applied
an iron catalysed methodology to the oxidation of the same
indenic sulfide intermediate (69–71% yield).8 The proce-
dure that permitted the synthesis of both enantiomers of
Sulindac in up to 92% ee has the advantages of using an
environmentally friendly metal and mild reaction
conditions.
Sulindac1,2 {(Z)-5-fluoro-2-methyl-1-[p-(methylsulfinylbenz-
ylidene]indene-3-acetic acid)} is a well-known non-steroi-
dal anti-inflammatory drug. Recently, different research
lines have focussed on the application of Sulindac and its
derivatives in cancer research. Attention was devoted to
the action of these molecules on the enhancement of cyto-
toxicity of anti-cancer drugs,3 the induction of apoptosis
on tumour cell lines4,5 and inhibition of the proliferation
of colorectal carcinoma cells.6 Obviously, investigations
on the biological activity of Sulindac and its metabolites re-
quire both enantiomers of this molecule. However, only a
few successful works have been reported on this topic,
the crucial step being represented by an enantioselective
metal-7,8 or bio-catalysed9,10 oxidation of sulfides.
2. Results and discussion
The asymmetric oxidation of sulfides in the presence of
metal complexes is an established and straightforward
procedure11 that was also applied to biologically active
molecules.12 In the case of Sulindac, oxidation of the corre-
sponding sulfide with cumene hydroperoxide (CHP) in the
Due to our interest in enantioselective routes to sulfox-
ides,13 we chose a different approach to the synthesis of
Sulindac, with the aim of avoiding the low yield reaction
with glyoxylic acid. Sulindac alkyl esters were considered
as convenient precursors, since they can be easily converted
into the target molecule by an almost quantitative hydroly-
sis.1 Herein, we report the asymmetric synthesis of these
compounds by an enantioselective oxidation of the corre-
sponding sulfides with hydroperoxides (Table 1), in the
*
Corresponding author. Tel.: +39 0805442077; fax: +39 0805442924;
e-mail: cardellicchio@ba.iccom.cnr.it
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.12.002

F. Naso et al. / Tetrahedron: Asymmetry 17 (2006) 3226–3229
3227
Table 1. Enantioselective oxidation of Sulindac sulfides alkyl esters with hydroperoxides in the presence of a titanium/hydrobenzoin complex
COOR
F
COOR
F
TBHP or CHP
Ti(Oi-Pr)4/HB
S
*
O
S
1a, 1b
2a, 2b
1a, 2a R = Me. 1b, 2b R = tert-Bu
HB = (S,S) or (R,R)-hydrobenzoin
Entry
Substrate
Oxidant
Ligand
Temperature
Watera
t (h)
Solvent
Product
Yield (%)
eeb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
CHP
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(S,S)
(R,R)
(S,S)
(S,S)
(S,S)
(R,R)
rt
rt
rt
rt
rt
rt
rt
0°
rt
rt
rt
rt
rt
rt
rt
0
0
0
0.5
0
0
0
0
0
0
42
44
4
48
44
46
4
48
46
28
43
47
46
6
n-Hexane
Toluene
Toluene
Toluene
CH2Cl2
CCl4
CCl4
CCl4
Toluene
CCl4
CCl4
(R)-2a
(R)-2a
(R)-2a
(R)-2a
(R)-2a
(R)-2b
(R)-2a
(R)-2a
(R)-2a
(R)-2a
(S)-2a
(R)-2b
(R)-2b
(R)-2b
(S)-2b
29c (31)d
47c (33)d
(40:47:13)e
49c
88
88
76
88
52
96
77
71
53
32
94
94
95
76
96
59f
49c (38)d
(34:52:14)e
64c
9
20c (50)d
28f
10
11
12
13
14
15
CHP
TBHP
TBHP
TBHP
TBHP
TBHP
0
0
0
0
50c
Toluene
CCl4
CCl4
49c
48c
54c
0
46
CCl4
49c
a Water/sulfide ratio.
b Determined by HPLC [(R,R)-Whelk O1 column, eluent n-hexane/i-propanol/methylene chloride 6:3:1), or NMR [upon addition of (R)-3,5-dinitro-N-(1-
phenylethyl)benzamide].
c Isolated yields of the sulfoxide.
d Isolated yield of the corresponding sulfone.
e Ratios between 1a:2a:3a (yields not determined).
f Chromatographic yield.
presence of a complex between titanium and (S,S)-hydro-
benzoin (HB). This oxidation system had been applied by
us to prepare (R)-benzyl p-bromophenyl sulfoxide (85%
yield, >98% ee) that represents a general precursor of dial-
kyl sulfoxides,14 and aryl b-ketosulfoxides (70–94% yield,
92–>98% ee).15 Another group has adopted the same meth-
odology in the preparation of an anti-HIV-1 agent.16 Here-
in, we oxidise Sulindac sulfide methyl ester 1a1,17 to yield
sulfoxide 2a1,2,18 (Table 1) by adding 1.3 equiv of tert-butyl
hydroperoxide (TBHP) to 1 equiv of sulfide 1a, in the pres-
ence of 0.1 equiv of a 1:2 complex between titanium(IV)
i-propoxide and (S,S)-hydrobenzoin, according to our
procedure.14,15 The products in the crude reaction mixture
were separated by column chromatography on silica gel
(eluent ethyl acetate/petroleum ether 1:1).
1, entry 2). After 44 h, only 6% of the starting substrate 1a
was still present and sulfoxide (+)-2a was obtained with
47% isolated yield and with 88% ee, together with the cor-
responding sulfone 3a (33% isolated yield). In order to shed
light on the mechanism of the formation of sulfoxide 2a,
the same reaction was stopped after 4 h (Table 1, entry
3). The ratios between compounds 1a:2a:3a were
40:47:13, sulfoxide 2a having a 76% ee value. The presence
of large amounts of sulfone (Table 1, entry 2) and the
observation that the ee value increased over time were
indications that the asymmetric synthesis of sulfoxide 2a
followed a two-step mechanism; the first step being the
enantioselective oxidation of sulfide 1a, and the second
one a further enantiomeric enrichment of sulfoxide 2a,
due to a kinetic resolution in the process leading to sulfone
3a. A couple of reactions in which a kinetic resolution step
increases the ee of the produced sulfoxides were recently
investigated for different sulfides and catalysts.19–21
When the oxidation was performed in n-hexane, the sulfide
reacted sluggishly (Table 1, entry 1). After 42 h, sulfoxide
(+)-2a was produced with a high ee value (88% ee), but
in low isolated yield (29%). Almost 40% of the starting sul-
fide 1a was still present. Furthermore, at variance with
other previous cases,14,15 we observed large amounts of
the corresponding sulfone 3a (31% isolated yield). There-
fore, we decided to change the solvent and to perform
the same oxidation in toluene at room temperature (Table
At this stage, the role of water in the reaction was investi-
gated, since its presence is sometimes reported to be crucial
in titanium catalysed oxidations.11 The reaction of entry 2
was repeated by adding 0.5 equiv of water (with respect to
the sulfide) during the formation of the titanium catalyst
(Table 1, entry 4). Since the result was similar to those of

3228
F. Naso et al. / Tetrahedron: Asymmetry 17 (2006) 3226–3229
entry 2, the other reactions were performed without adding
water.
reaction was repeated in carbon tetrachloride (48% yield,
95% ee). If this reaction was stopped after 6 h (Table 1,
entry 14), sulfoxide 2b was produced in a slightly higher
isolated yield (54%), but in lower enantiomeric purity
(76% ee). Thus, the presence of sulfone 3b and the increase
of the ee values of sulfoxide 2b with time suggest that a two
step mechanism (enantioselective oxidation/kinetic resolu-
tion) was also active in the asymmetric synthesis of Sulin-
dac tert-butyl ester. The use of (R,R)-hydrobenzoin
(Table 1, entry 15), as expected, yielded the enantiomeric
sulfoxide (ꢀ)-2b with the same yields and ee values as the
(+)-counterpart.
After these experiments, we chose to test chlorinated sol-
vents in the oxidation. Methylene chloride was found to
be unsuitable since a decrease in the ee value (52%) of sulf-
oxide 2a was observed (Table 1, entry 5), as occurred in a
previous work.14 Better results were obtained when carbon
tetrachloride was used. After 46 h, sulfoxide (+)-2a was ob-
tained (49% yield, 96% ee) together with sulfone 3a (38%)
(Table 1, entry 6). Only small amounts of sulfide 1a were
recovered (7%). The observation of the composition of
the same reaction mixture after only 4 h showed that com-
pounds 1a:2a:3a were in 34:52:14 ratios and sulfoxide 2a
had 77% ee (Table 1, entry 7). From these results, the
mechanistic considerations concerning entry 2 could also
be extended to this reaction, that is, a combined mecha-
nism (enantioselective oxidation of sulfide 1a, followed by
a kinetic resolution of sulfoxide 2a) was acting. The oxida-
tion was then repeated under the same reaction conditions,
but at 0 °C for 48 h (Table 1, entry 8). Sulfoxide 2a was
formed (64% yield, 71% ee), together with low amounts
of sulfone 3a (<5%). This experiment was considered of
special mechanistic interest, because it showed that it was
possible to inhibit the kinetic resolution process, even at
longer reaction times, by lowering the temperature. Thus,
the sulfoxide could be obtained in a better yield, although
with a lower enantiomeric purity. The inhibition of the
kinetic resolution step at 0 °C had some precedent in the
literature.22,23
As far as the configurations of the Sulindac alkyl esters are
concerned, sulfoxides (+)-2a and (+)-2b were obtained by
the TBHP-oxidation, when (S,S)-hydrobenzoin was used
as a ligand of titanium. Sulfoxide (+)-2a (95% ee) was trea-
ted with 1 M sodium hydroxide ethanol/water solution1
leading to (+)-Sulindac in an almost quantitative yield
(98%) and without the loss of enantiomeric excess (95%
ee, as determined by NMR, upon addition of (R)-3,5-
dinitro-N-1-phenylethyl)benzamide). Since the (R)-configu-
ration was attributed to (+)-Sulindac,7–11 the (R)-configu-
ration should also be attributed to esters (+)-2a that
originated in the (+)-acid. As a further confirmation, an
enantioenriched mixture of (+)-2a or (+)-2b was treated
with (R)-(methoxy)phenylacetic acid, according to a mod-
el25 that we had previously used.14,15 Since the methyl sig-
nal of the more abundant enantiomer showed upfield shift,
the (R)-configuration was confirmed.
In further tests, we used cumene hydroperoxide as the oxi-
dant, in the presence of the same titanium/hydrobenzoin
complex. When the reaction was performed in toluene
(Table 1, entry 9), small quantities of sulfoxide 2a were
obtained with a lower enantiomeric purity (20% yield,
53% ee), accompanied by rather large amounts of sulfone
3a (50%) that, at variance with the previous reactions,
was produced to a significant extent even with an early
reaction time. A low ee value for sulfoxide 2a (32% ee)
was obtained, when the same reaction was performed in
carbon tetrachloride (Table 1, entry 10). Due to this result,
the use of this oxidant was abandoned.
Sulindac methyl ester 2a: mp 86–88 °C (n-hexane/ethanol).
25
(R)-2a ½aꢁD ¼ þ61:5 ðc 1:0; CHCl3Þ for a 96% ee sam-
25
ple. (S)-2a ½aꢁD ¼ ꢀ60:4 ðc 1:0; CHCl3Þ for a 94% ee sam-
ple. Sulindac tert-butyl ester 2b: mp 47–49 °C (n-hexane/
25
acetone). (R)-2b ½aꢁD ¼ þ42:2 ðc 1:0; CHCl3Þ for
a
25
95% ee sample. (S)-2b ½aꢁD ¼ ꢀ42:8 ðc 1:0; CHCl3Þ for a
96% ee sample. Sulindac: mp 174–176 °C (n-hexane/ethyl
25
acetate). (R)-Sulindac ½aꢁD ¼ þ56:6 ðc 0:5; CH3OHÞ for a
96% ee sample.
3. Conclusion
Finally, we performed the oxidation of 1a with TBHP in
the presence of a complex between titanium and (R,R)-
hydrobenzoin (Table 1, entry 11), according to the reaction
conditions of entry 7, that should lead to a fair balance be-
tween isolated yield and enantioselectivity. The enantio-
meric (ꢀ)-2a was obtained with 50% yield and 94% ee.
The results reported herein show that by using the appro-
priate reagent, catalyst, solvent and reaction conditions,
the preparation of both enantiomers of Sulindac alkyl
esters could be achieved with high ee values (94–96% ee)
and in satisfactory isolated yield (48–50%) by a straightfor-
ward and effective synthetic strategy, without resorting to
difficult or low-yielding reactions.
Further experiments were performed by using a different
Sulindac sulfide alkyl ester. For this purpose, we decided
to oxidise the Sulindac sulfide tert-butyl ester 1b, in which
a larger alkyl group was present, to obtain sulfoxide 2b.24
We observed a reactivity similar to the behaviour of methyl
ester 2a. When the reaction was performed in toluene (Ta-
ble 1, entry 12), sulfoxide (+)-2b was obtained with a slight
increase of enantioselectivity (49% yield, 94% ee) with re-
spect to the reaction of 1a in the same solvent. The corre-
sponding sulfone 3b was also present in this reaction. A
similar trend (Table 1, entry 13) was observed when the
Moreover, the reactivity picture that emerged from the
present work was as equally interesting as the synthetic
aspects. As mentioned in Table 1, if Sulindac sulfide alkyl
esters were oxidised by controlling the reaction time or
reaction temperature, that is, in reaction conditions that
were able to inhibit the formation of large amounts of
sulfone, Sulindac alkyl esters were produced in higher
yields but in lower enantioselectivities (54–64% yields,
71–77% ee). These results were similar to those reported
for the oxidation of a simple aryl methyl sulfide (58–63%

F. Naso et al. / Tetrahedron: Asymmetry 17 (2006) 3226–3229
3229
yield, 69–80% ee),22 under analogous reaction conditions
(0 °C, 2 h reaction time). Thus, Sulindac sulfide alkyl
esters, that is, large molecules bearing various functional
groups, behaved similarly to small aryl methyl sulfides.
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presence of a complex between titanium and hydrobenzoin
seems to be substrate sensitive. In the first case, a genuine
enantioselective oxidation occurs, as observed in the prep-
aration of aryl benzyl sulfoxides14 or aryl b-ketosul-
foxides.15 High ee values and high yields, due to the
presence of only negligible amounts of the corresponding
sulfone, are obtained. Thus, it is useless to perform the
reaction at 0 °C, or with a short reaction time, since the
over-oxidation of the sulfoxide is marginal, even at longer
reaction times. On the other hand, enantioselective oxida-
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or complex, as Sulindac sulfide alkyl esters) follows a two-
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Even if more work on this topic seems to be needed, the
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minary reactivity framework that should be useful in future
application of this oxidation system to the synthesis of
other bioactive chiral sulfoxides.
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Acknowledgements
17. Meneghin, M. European Patent EP0206241, 1986.
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This work was financially supported, in part, by the MIUR
Rome (National Project ‘Stereoselezione in Sintesi Orga-
nica. Metodologie e Applicazioni’), by the FIRB project
(‘Progettazione, preparazione e valutazione biologica e far-
macologica di nuove molecole organiche quali potenziali
farmaci innovativi’) and by the Ministero della Salute-
Regione Puglia project (‘Farmacoprevenzione nei pazienti
con mieloma multiplo. Inibizione dell’angiogenesi e della
crescita tumorale con inibitori della COX-2’). Thanks are
due to Dr. Nicola Caldarola for preliminary works.
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