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The ee of our catalyst system was comparable with the
original results reported by Bolm, so we decided to investigate
its scope in the oxidation of a variety of other alkyl aryl sulfides
(Scheme 2), and our results are reported in Table 1. The ee
values are remarkably consistent, and indicate the utility of the
catalyst. Some overoxidation to the sulfone was observed in the
case of 3d (13%) and 3g (22%), but in all other cases the amount
of sulfone was less than 5%.
Scheme 2 Asymmetric oxidation of alkyl aryl sulfides.
Table 1 Asymmetric oxidation of alkyl aryl sulfides
We thank EPSRC for the award of a research grant (GR/
M13633), GlaxoSmithKline and the EPSRC for an Industrial
CASE studentship (S. D. G.), and the Commission of the
European Union (IHP Network HPRN-CT-2000-00014) for
support of a studentship (C. M.).
Sulfide R1
R2
Sulfoxide Conversiona ee (%)a
3a
3b
3c
3d
3e
3f
3g
3h
3i
Ph
Ph
Ph
CH3
Et
Pr
CH3
CH3
CH3
CH3
CH3
CH3
4a
4b
4c
4d
4e
4f
4g
4h
4i
100%
96%
90%
85%
90%
70%
61%
90%
87%
64
64
57
63
58
53
64
45
72
4-CH3OC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-NCC6H4
2-Naphthyl
Notes and references
‡ General procedure for solid phase asymmetric oxidation of sulfides. The
solid phase ligand (0.015 mmol) was weighed into an Altech tube.
Anhydrous CH2Cl2 (2.0 ml) was added, followed by the metal salt (0.05
mmol). After 20 min, the resin was filtered, and anhydrous CH2Cl2 (2.0 ml)
was added to wash the resin. After one min the resin was filtered. A dry
reaction tube with a magnetic stirrer was purged and filled with nitrogen
three times. Then the resin was added in the reaction tube, followed by
distilled CH2Cl2 (2.0 ml), the sulfide (1 mmol), and 30% H2O2 in water (1.1
mmol) and the mixture was stirred for 5–16 h, depending on the substrate.
A sample (1–2 ml) was then removed, and diluted with 10% IPA–heptane,
for analysis by HPLC.† To isolate the products, the reaction was worked up
by quenching with 10% Na2SO3 solution (5 ml). The reaction mixture was
extracted with Et2O (2 3 10 ml), and the extracts were combined and dried
(MgSO4); the solvent was removed under reduced pressure. The crude
product was purified by silica flash chromatography (Et2O–MeOH 95+5) to
leave the product as a white solid.
a Conversions and ee values were measured using chiral phase HPLC.
HPLC conditions are provided in the supplementary material.
conversion. Clearly the low rate of the background reaction is
important. Schiff-base titanium complexes are effective for
sulfur oxidation,8–10 and very recently it has been reported that
Ti(salen) complexes can be very effective in the same process
using hydrogen peroxide as the oxidant.11
Since the behaviour of solid-supported ligands and their
solution phase counterparts can differ, we converted the
optimum ligand into the corresponding methyl ester 6 by
treatment with NEt3 in DMF–MeOH. Use of this solution phase
ligand gave an identical 64% ee in the oxidation of methyl
phenyl sulfide 3a to the solid phase analogue (which is therefore
a superior catalyst from a practical point of view).
§ We found that use of Wang-Tle- Thr*-DtBS also gave an improved ee of
18%, but since resin loading of tert-leucine is less straightforward, we used
commercially available Fmoc-L-phenylalanine resin for the subsequent
libraries.
1 P. Pitchen, E. Dunach, M. N. Deshmukh and H. B. Kagan, J. Am. Chem.
Soc., 1984, 106, 8188.
2 F. Di Furia, G. Modena and R. Seraglia, Synthesis, 1984, 325.
3 C. Bolm and F. Bienewald, Angew. Chem., Int. Ed. Engl., 1995, 34,
2640.
4 For applications and modifications of this process, see: C. Bolm, G.
Schlingloff and F. Bienewald, J. Mol. Catal. A: Chem., 1997, 117, 347;
C. Bolm and F. Bienewald, Synlett, 1998, 1327; D. A. Cogan, G. C. Liu,
K. J. Kim, B. J. Backes and J. A. Ellman, J. Am. Chem. Soc., 1998, 120,
8011; A. H. Vetter and A. Berkessel, Tetrahedron Lett., 1998, 39, 1741;
J. Skarzewski, E. Ostrycharz and R. Siedlecka, Tetrahedron: Asym-
metry, 1999, 10, 3457; N. N. Karpyshev, O. D. Yakovleva, E. P. Talsi,
K. P. Bryliakov, O. V. Tolstikova and A. G. Tolstikov, J. Mol. Catal. A:
Chem., 2000, 157, 91.
Rather than screening all our previous libraries in the
titanium-catalysed oxidation reaction, we tested the correspond-
ing serine, threonine and O-tert-butyl threonine derivatives,
Wang-
D
-Phe-Ser-DtBS (27% ee), Wang-
D-Phe-Thr-DtBS
(23% ee) and Wang-
D-Phe-Thr(t-Bu)-DtBS (0% ee) in the
titanium-catalysed oxidation of methyl phenyl sulfide 3a. These
results confirm both the importance of the free hydroxyl group
and the influence of the stereogenic centre at C-3 of the allo-
threonine residue.
In order to establish how strongly the titanium was com-
plexed to the solid phase ligand, we incubated a solution of
Ti(Oi-Pr)4 in CH2Cl2 with the ligand 5. The resin was then
washed 5 times, and the titanium concentration in each of the
washings was measured by ICP-AES. While some residual
titanium was detectable in the first washing, in all the four
subsequent washings the titanium concentration was below the
background level ( < 1 ppm). This suggested that leaching of
titanium from the resin was minimal, and that as a consequence
the catalyst combination of ligand 5 and Ti might be reusable.
5 H. B. Kagan, ‘Asymmetric Oxidation of Sulfides’, in Catalytic
Asymmetric Synthesis, ed. I. Ojima, Wiley, VCH, New York, 2000, p.
327.
6 S. Dahmen and S. Bräse, Synthesis, 2001, 1431.
7 B. M. Cole, K. D. Shimizu, C. A. Krueger, J. P. A. Harrity, M. L.
Snapper and A. H. Hoveyda, Angew. Chem., Int. Ed. Engl., 1996, 35,
1668; K. D. Shimizu, B. M. Cole, C. A. Krueger, K. W. Kuntz, M. L.
Snapper and A. H. Hoveyda, Angew. Chem., Int. Ed. Engl., 1997, 36,
1703; K. D. Shimizu, M. L. Snapper and A. H. Hoveyda, Chem., Eur. J.,
1998, 4, 1885; J. R. Porter, W. G. Wirschun, K. W. Kuntz, M. L.
Snapper and A. H. Hoveyda, J. Am. Chem. Soc., 2000, 122, 2657; S. J.
Degrado, H. Mizutani and A. H. Hoveyda, J. Am. Chem. Soc., 2001,
123, 755; J. R. Porter, J. F. Traverse, A. H. Hoveyda and M. L. Snapper,
J. Am. Chem. Soc., 2001, 123, 984; C. A. Luchaco-Cullis, H. Mizutani,
K. E. Murphy and A. H. Hoveyda, Angew. Chem., Int. Ed., 2001, 40,
1456.
8 A. Colombo, G. Marturano and A. Pasini, Gazz. Chim. Ital., 1986, 116,
35.
9 S. Colonna, A. Manfedi, M. Spadoni, L. Casella and M. Gullotti, J.
Chem. Soc., Perkin Trans. 1, 1987, 71.
10 K. Nakajima, C. Sasaki, M. Kojima, T. Aoyama, S. Ohba, Y. Saito and
J. Fujita, Chem. Lett., 1987, 2189.
Provided the resin was not allowed to dry out, the catalyst could
be reused without erosion of conversion or ee (first run, 62% ee,
second run, 64% ee), although the ee did degrade with
subsequent runs with the same sample of catalyst.
11 B. Saito and T. Katsuki, Tetrahedron Lett., 2001, 42, 3873.
Chem. Commun., 2001, 2594–2595
2595