Catalytic asymmetric oxidation of cyclic dithioacetals: Highly diastereo- and enantioselective synthesis of the S -oxides by a chiral aluminum(salalen) complex

Article abstract of DOI:10.1021/ja106877x

Aluminum(salalen) complex 1 [salalen = half-reduced salen, salen = N,N′-ethylenebis(salicylideneiminato)] was found to be a highly efficient catalyst for asymmetric oxidation of cyclic dithioacetals in the presence of 30% hydrogen peroxide as an oxidant.

Full text of DOI:10.1021/ja106877x

Published on Web 12/10/2010
Catalytic Asymmetric Oxidation of Cyclic Dithioacetals: Highly
Diastereo- and Enantioselective Synthesis of the S-Oxides by
a Chiral Aluminum(salalen) Complex
Junichi Fujisaki,† Kenji Matsumoto,†,§ Kazuhiro Matsumoto,† and
Tsutomu Katsuki*,†,‡
Department of Chemistry, Faculty of Science, Graduate School, and Institute for AdVanced
Study, Kyushu UniVersity, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan
Received August 10, 2010; E-mail: katsuscc@chem.kyushu-univ.jp
Abstract: Aluminum(salalen) complex 1 [salalen ) half-reduced salen, salen ) N,N′-ethylenebis(sali-
cylideneiminato)] was found to be a highly efficient catalyst for asymmetric oxidation of cyclic dithioacetals
in the presence of 30% hydrogen peroxide as an oxidant. In the reaction of a series of 2-substituted 1,3-
dithianes bearing alkyl, alkenyl, alkynyl, and aryl groups as the substituent, the trans-monoxides were
obtained in high yields with 19:1 f >20:1 dr (diastereomeric ratio) and 98-99% ee (enamtiomeric excess).
The reaction of nonsubstituted 1,3-dithiane also proceeded in a highly enantioselective manner to give the
monoxide with a small formation of the trans-1,3-dioxide, an overoxidation product. Five-membered 1,3-
dithiolanes and seven-membered 1,3-dithiepanes also underwent oxidation to give monoxides with high
diastereo- and enantioselectivity. It was found that the equilibrium between the two chairlike conformers of
dithianes has relevance to the observed diastereoselectivity in the first oxidation process, and the dioxide
formation in the oxidation of 1,3-dithiane and its stereochemistry also can be explained by the conformational
equilibrium of the product monoxide.
Introduction
alkyl hydroperoxide as oxidant, a variety of chiral ligands have
been introduced for titanium-catalyzed oxidation.7 Other transi-
Optically active sulfoxides are efficient chiral auxiliaries,
organocatalysts, and ligands for metal complexes utilized in
stereoselective synthesis.1 They are also found in an important
class of biologically active compounds.2 For example, omepra-
zole and derivatives containing a chiral sulfoxide moiety are
present in leading pharmaceuticals.3 A reliable route to this class
of compounds involves asymmetric oxidation of the correspond-
ing sulfides. Thus, the past few decades have witnessed
significant progress in the field of catalytic asymmetric sulfur
oxidation.4 Since the seminal reports by the Kagan group5 and
Modena group6 using titanium/tartrate catalysts together with
tion-metal catalysts based on vanadium,8 manganese,9 iron,10
and so on,11-15 and chemoenzymatic16 methods have also been
(7) For titanium-catalyzed oxidation of sulfides, see: (a) Nakajima, K.;
Sasaki, C.; Kojima, M.; Aoyama, T.; Ohba, S.; Saito, Y.; Fujita, J.
Chem. Lett. 1987, 16, 2189-2192. (b) Komatsu, N.; Nishibayashi,
Y.; Sugita, T.; Uemura, S. Tetrahedron Lett. 1992, 33, 5391–5394.
(c) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1997, 62, 8560–8564.
(d) Donnoli, M. I.; Superchi, S.; Rosini, C. J. Org. Chem. 1998, 63,
9392–9395. (e) Saito, B.; Katsuki, T. Tetrahedron Lett. 2001, 42,
3873–3876. (f) Bryliakov, K. P.; Talsi, E. P. Eur. J. Org. Chem. 2008,
3369–3376.
(8) For vanadium-catalyzed oxidation of sulfides, see: (a) Nakajima, K.;
Kojima, M.; Fujita, J. Chem. Lett. 1986, 15, 1483-1486. (b) Bolm,
C.; Bienewald, F. Angew. Chem., Int. Ed. Engl. 1995, 34, 2640–2642.
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1744. (d) Ohta, C.; Katsuki, T. Tetrahedron Lett. 2001, 42, 3885–
3888. (e) Sun, J.; Zhu, C.; Dai, Z.; Yang, M.; Pan, Y.; Hu, H. J. Org.
Chem. 2004, 69, 8500–8503. (f) Drago, C.; Caggiano, L.; Jackson,
R. F. W. Angew. Chem., Int. Ed. 2005, 44, 7221–7223.
† Department of Chemistry.
‡ Institute for Advanced Study.
§ Current address: Department of Chemistry, Faculty of Science, Kochi
University, 2-5-1 Akebono-cho, Kochi 780-8520, Japan.
(1) (a) Mellah, M.; Voituriez, A.; Schulz, E. Chem. ReV. 2007, 107, 5133–
5209. (b) Pellissier, H. Tetrahedron 2007, 63, 1297–1330. (c) Pellissier,
H. Tetrahedron 2006, 62, 5559–5601. (d) Kobayashi, S.; Ogawa, C.;
Konishi, H.; Sugiura, M. J. Am. Chem. Soc. 2003, 125, 6610–6611.
(2) (a) Ferna´ndez, I.; Khiar, N. Chem. ReV. 2003, 103, 3651–3705. (b)
Legros, J.; Dehli, J. R.; Bolm, C. AdV. Synth. Catal. 2005, 347, 19–
31.
(9) For manganese-catalyzed oxidation of sulfides, see: (a) Palucki, M.;
Hanson, P.; Jacobsen, E. N. Tetrahedon Lett. 1992, 33, 7111-7114.
(b) Noda, K.; Hosoya, N.; Yanai, K.; Irie, R.; Katsuki, T. Tetrahedron
Lett. 1994, 35, 1887–1890. (c) Noda, K.; Hosoya, N.; Irie, R.;
Yamashita, Y.; Katsuki, T. Tetrahedron 1994, 50, 9609–9618. (d)
Kokubo, C.; Katsuki, T. Tetrahedron 1996, 52, 13895–13900.
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Angew. Chem., Int. Ed. 2003, 42, 5487-5489. (b) Legros, J.; Bolm,
C. Angew. Chem., Int. Ed. 2004, 43, 4225–4228. (c) Bryliakov, K. P.;
Talsi, E. P. Angew. Chem., Int. Ed. 2004, 43, 5228–5230. (d) Legros,
J.; Bolm, C. Chem.sEur. J. 2005, 11, 1086–1092. (e) Egami, H.;
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Springer-Verlag: Berlin, Germany, 1999; Vol. II, pp 697-710. (b)
Kagan, H. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.;
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Wojaczyn˜ski, J. Chem. ReV. 2010, 110, 4303–4356.
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S. E.; Maguire, A. R. Synlett 2007, 1501-1506.
(12) For niobium-catalyzed oxidation of sulfides, see: Miyazaki, T.; Katsuki,
T. Synlett 2003, 1046-1048.
(5) Pitchen, P.; Dun˜ach, E.; Deshmukh, M. N.; Kagan, H. B. J. Am. Chem.
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(6) Di Furia, F.; Modena, G.; Seraglia, R. Synthesis 1984, 325–326.
9
56 J. AM. CHEM. SOC. 2011, 133, 56–61
10.1021/ja106877x  2011 American Chemical Society

Asymmetric Oxidation of Cyclic Dithioacetals
A R T I C L E S
Scheme 1. Product Complexity in Oxidation of 2-Substituted
1,3-Dithianes
developed, and high enantioselectivity has already been achieved
in the oxidation of simple substrates such as alkyl aryl sulfides.
However, asymmetric oxidation of cyclic dithioacetals including
1,3-dithiolanes and 1,3-dithianes has been slow to develop,
despite the synthetic utility of the enantiomerically enriched
S-oxides.17 To the best of our knowledge, there are no general
catalysts that achieve high stereoselectivity (more than 20:1 dr
(diastereomeric ratio), more than 95% ee (enamtiomeric excess))
in the oxidation of dithioacetals with a wide substrate spectrum.
Although the titanium/tartrate systems have been applied to the
oxidation of dithiolanes and dithianes, good substrates were
limited with regard to both diastereo- and enantioselectivity.18
Bolm and Bienewald’s vanadium/Schiff base catalysts, which
showed high enantioselectivity in the oxidation of simple
sulfides, also gave insufficient results.19 We reported significant
improvements in the oxidation of 2-substituted cyclic dithio-
acetals by using titanium(salen) complexes as catalyst, but the
stereoselectivity was strongly affected by the substituents on
the 2-position. For example, the oxidation of 2-tert-butyl-1,3-
dithiane produced the S-oxide with only 39% ee.20 Enzymatic
methods have also been developed for the oxidation, but the
substrate scope is inherently narrow.21
Different from simple sulfides, cyclic dithioacetals have four
sulfur lone pairs in one molecule which can participate in
oxidation process, and the presence of a substituent at the
2-position raises the issue of diastereoselectivity as well as
enantioselectivity (Scheme 1). Potentially, four stereoisomers
of the monoxide can be produced. Thus, the discrimination of
the four lone pairs by optically active catalysts is an essential
qualification for achieving highly stereoselective oxidation of
dithioacetals. Moreover, the produced monoxides can undergo
overoxidation to give the 1,3-dioxide (disulfoxide) and 1,1-
dioxide (sulfone), and these overoxidation products can also
undergo further oxidation. In addition, there is a possibility of
kinetic resolution in these overoxidation processes.22 This
complexity has hampered the development of asymmetric
oxidation of cyclic dithioacetals. Consequently, extremely high
stereorecognition ability of catalysts is essential in order to
realize highly stereoselective oxidation of cyclic dithioacetals.
In the preceding papers, we have reported that aluminum-
(salalen) complex 1 (Figure 1) is an effective catalyst for
asymmetric oxidation of sulfur compounds such as acyclic and
cyclic sulfides in the presence of environmentally benign
aqueous hydrogen peroxide as the stoichiometric oxidant23 and
preliminarily demonstrated that a few cyclic 1,3-dithianes
underwent the oxidation to give the monoxides with high
diastereo- and enantioselectivity.23b Here, we report a more
detailed examination of the aluminum-catalyzed asymmetric
oxidation of cyclic dithioacetals.
(13) For molybdenum-catalyzed oxidation of sulfides, see: Basak, A.;
Barlan, A. U.; Yamamoto, H. Tetrahedron: Asymmetry 2006, 17, 508-
511.
(14) For tungsten-catalyzed oxidation of sulfides, see: Thakur, V. V.;
Sudalai, A. Tetrahedron: Asymmetry 2003, 14, 407-410.
(15) For platinum-catalyzed oxidation of sulfides, see: Scarso, A.; Strukul,
G. AdV. Synth. Catal. 2005, 347, 1227-1234.
(16) Dembitsky, V. M. Tetrahedron 2003, 59, 4701-4720. See also, ref
2a.
(17) (a) Page, P. C. B.; McKenzie, M. J.; Allin, S. M.; Klair, S. S.
Tetrahedron 1997, 53, 13149–13164. (b) Page, P. C. B.; McKenzie,
M. J.; Buckle, D. R. Tetrahedron 1998, 54, 14581–14596. (c) Page,
P. C. B.; McKenzie, M. J.; Allin, S. M.; Buckle, D. R. Tetrahedron
2000, 56, 9683–9695. (d) Garc´ıa Ruano, J. L.; Barros, D.; Maestro,
M. C.; Slawin, A. M. Z.; Page, P. C. B. J. Org. Chem. 2000, 65,
6027–6034.
Results and Discussion
I. Preparation of Al(salalen) Complex 1. Al(salalen) complex
1 was prepared from Et2AlCl and the corresponding salalen
ligand according to the reported procedure.23b
II. Development of Al(salalen)-Catalyzed Asymmetric
Oxidation of 1,3-Dithianes. We first examined asymmetric
oxidation of 2-phenyl-1,3-dithiane 2a with Al(salalen) complex
(18) (a) Bortolini, O.; Di Furia, F.; Licini, G.; Modena, G.; Rossi, M.
Tetrahedron Lett. 1986, 27, 6257–6260. (b) Samuel, O.; Ronan, B.;
Kagan, H. B. J. Organomet. Chem. 1989, 370, 43–50. (c) Di Furia,
F.; Licini, G.; Modena, G. Gazz. Chim. Ital. 1990, 120, 165–170. (d)
Page, P. C. B.; Wilkes, R. D.; Namwindwa, E. S.; Witty, M. J.
Tetrahedron 1996, 52, 2125–2154.
(19) Bolm, C.; Bienewald, F. Synlett 1998, 1327–1328.
(20) Tanaka, T.; Saito, B.; Katsuki, T. Tetrahedron Lett. 2002, 43, 3259–
3262.
(21) (a) Alphand, V.; Gaggero, N.; Colonna, S.; Pasta, P.; Furstoss, R.
Tetrahedron 1997, 53, 9695–9706. (b) Zambianchi, F.; Raimondi, S.;
Pasta, P.; Carrea, G.; Gaggero, N.; Woodley, J. M. J. Mol. Catal. B:
Enzym. 2004, 31, 165–171.
Figure 1. Aluminum(salalen) complex 1.
9
J. AM. CHEM. SOC. VOL. 133, NO. 1, 2011 57

A R T I C L E S
Fujisaki et al.
Scheme 2. Asymmetric Oxidation of 2-Phenyl-1,3-dithiane 2a with
Al(salalen) Complex 1
monoxides was determined as the trans-isomers, based on the
1H and 13C NMR analysis.18b,24 The absolute configuration of
trans-2-phenylethynyl-1,3-dithiane 1-oxide 3c was unequivo-
cally determined to be 1S,2S by X-ray crystallographic analysis
(Figure 2).25 In addition to 2-monosubstituted dithioacetals, 2,2-
disubstituted ones are also good substrates for the Al(salalen)-
catalyzed asymmetric oxidation. The reaction of 2,2-dimethyl-
1,3-dithiane 2k produced the monoxide 3k with 99% ee, but
the reaction was slow (entry 13). 2-Methyl-2-phenyl-1,3-dithiane
2l also underwent the oxidation to give the trans-oxide 3l in
79% yield with >20:1 dr and 99% ee (entry 14). Although the
reaction of 2-methyl-2-(2-phenylethyl)-1,3-dithiane 2m fur-
nished the monoxides as a 1.2:1 diastereomer mixture, both the
diastereomers were obtained in high enantiomeric excesses
(entry 15). The cause of this low diastereoselectivity is discussed
in the next section.
Surprisingly, the oxidation of 1,3-dithiane 2n with no
substituent was also highly enantioselective (Scheme 3).26 The
monoxide 3n was obtained in 70% yield with 95% ee. This
high enantioselectivity further emphasizes the high utility of
the Al(salalen)-catalyzed system. It is of note that an overoxi-
dation product, 1,3-dithiane trans-1,3-dioxide 4n, was formed
in 15% yield with 99% ee under the reaction conditions.
Although the dioxide formation was difficult to suppress,
employment of 2.2 equiv of aqueous hydrogen peroxide enabled
the selective formation of the trans-dioxide 4n in 71% yield
with >99% ee (Scheme 4). The dioxide is known as an important
chiral auxiliary, and it can be transformed to a variety of chiral-
modified compounds.27 Although Aggarwal and co-workers
have reported an effective procedure for the preparation in an
enantiopure form using Modena’s protocol [Ti(OiPr)4 (0.5
equiv), DET (2 equiv), and CHP (4 equiv)], the procedure is
indirect and includes the steps of the asymmetric oxidation of
2-carbethoxy-1,3-dithiane and the subsequent hydroxylation and
decarboxylation.28 In contrast, the Al(salalen)-catalyzed system
makes the direct preparation of enantiopure trans-1,3-dithiane
1,3-dioxide 4n possible.
Table 1. Asymmetric Oxidation of 1,3-Dithiane Derivatives
entry substrate
R1
R2 time (h)
dra
yield (%)b
ee (%)c
1d
2
2a
2b
2b
2c
2d
2e
2f
Ph
H
H
H
H
H
H
H
H
H
H
H
H
4.5 >20:1 93
99
99
99
PhCHdCH
PhCHdCH
PhCtC
PhCH2
PhCH2CH2
(CH3)2CH
(CH3)2CH
cC3H5
4
4
>20:1 94
>20:1 95
19:1 72
>20:1 92
>20:1 94
>20:1 98
>20:1 95
>20:1 95
>20:1 98
>20:1 73
>20:1 91
68
3d
4
4
3
4
5
>99 (1S,2S)e
99
5
6
99 (1S,2S)f
>99
7
8d
9
2f
6
>99
2g
2h
2i
2j
2k
2l
11
12
12
3
>99
10
11
12
13
14
15
cC6H11
99
(CH3)3C
(CH3)3Si
CH3
>99 (1S,2S)g
99 (1S,2S)g
99 (S)g
>99
CH3 24
CH3 48
Ph
>20:1 79
2m
PhCH2CH2 CH3
4
1.2:1 47h/38i 98 (1S,2R)j/
99 (1S,2S)j
a Determined by 1H NMR analysis (400 MHz). b Isolated yield.
c Determined by chiral HPLC analysis, see the Supporting Information
for details. d Run on
a 1
mmol scale. e Determined by X-ray
crystallographic analysis. f Determined by comparison of the optical
rotation with the authentic sample prepared from (-)-(S)-1,3-dithiane
1-oxide. g Determined by comparison of the optical rotation with
literature value. h Yield of (1S,2R)-isomer 3m. i Yield of (1S,2S)-isomer
3m′. j Determined by comparison of the optical rotation with the
authentic sample prepared from (+)-(1S,2S)-2-phenylethyl-1,3-dithiane
1-oxide.
III. Mechanistic Consideration of Al(salalen)-Catalyzed
Asymmetric Oxidation of 1,3-Dithianes. We postulate that
Al(salalen) complex 1 and hydrogen peroxide give a hydrop-
1 in the presence of 30% hydrogen peroxide as the oxidant
(Scheme 2). Addition of pH 7.4 phosphate buffer is effective
for increasing the reproducibility. In the course of this study,
ethyl acetate was found to be a more effective solvent with
respect to the reaction rate, though the reaction was conducted
in methanol in the previous study.23b In ethyl acetate, the
dithiane 2a was completely consumed in less than 4 h. Although
only a trace amount of the cis-monoxide and dioxides were
formed under the conditions, the trans-monoxide 3a was
preferentially obtained in 94% yield with 99% ee.
The scope and limitations of cyclic 1,3-dithianes are shown
in Table 1. Most of the 2-substituted 1,3-dithianes examined
gave the monoxides with almost complete diastereo- and
enantioselectivity. 1,3-Dithianes with unsaturated groups such
as cinnamyl and phenylethynyl groups underwent the oxidation
with excellent stereoselectivity (entries 2-4). Substitution with
primary, secondary, and tertiary alkyl groups also led to the
production of the monoxides in a highly stereoselective manner
(entries 5-11), but the reactions with bulkier groups including
cyclopropyl, cyclohexyl, and tert-butyl required longer reaction
times to completion (entries 9-11). A silylated dithiane 2j
smoothly underwent the oxidation with excellent diastereo- and
enantioselectivity (entry 12). These results indicate that the steric
hindrance of the 2-substituents had little impact on the diastereo-
and enantioselectivity. The relative configuration of the major
(22) (a) Phillips, M. L.; Berry, D. M.; Panetta, J. A. J. Org. Chem. 1992,
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(25) CCDC 766991 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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58 J. AM. CHEM. SOC. VOL. 133, NO. 1, 2011

Asymmetric Oxidation of Cyclic Dithioacetals
A R T I C L E S
Figure 2. X-ray structure of trans-2-phenylethynyl-1,3-dithiane 1-oxide 3c. ORTEP view (50% probability).
Scheme 3. Asymmetric Oxidation of 1,3-Dithiane 2n
Scheme 4. Asymmetric Synthesis of trans-1,3-Dithiane 1,3-Dioxide
4n
Figure 3. Reaction sites in 1,3-dithianes: four lone pairs.
Scheme 5. Conformational Issue of 2-Substituted 1,3-Dithiane
1-Oxide (A), 1,3-Dithiane 1-Oxide (B), and 5-tert-Butyl-1,3-dithiane
1-Oxide (C)
eroxo species,23c,29 which oxidizes sulfides to the sulfoxides,
and that the highly elaborated salalen ligand with two binaphthyl
units constructs an effective cavity around the hydroperoxo
species for the asymmetric induction. However, a detailed
discussion regarding the asymmetric induction is difficult
because the actual structure of the active species is unclear at
present. Nonetheless, the observed absolute configuration of the
produced 1,3-dithiane monoxides and its extremely high dias-
tereo- and enantioselectivity indicate that, among the four lone
pairs on the sulfur atoms, the optically active oxidant exclusively
reacts with lone pair a, an equatorial lone pair on the pro-S
sulfur atom, irrespective of substituents at the C2-position
(Figure 3). Axial lone pairs b and ent-b are inherently less
reactive, due to the hyperconjugative interactions with σ*C-H
orbitals,30 and the enantiotopic lone pairs a and ent-a could be
effectively differentiated by the highly elaborated Al(salalen)
complex.
trans-1,3-dioxide in the oxidation of 1,3-dithiane are clearly
explained by the respective conformational equilibriums of 1,3-
dithianes and the monoxides. It is known that 1,3-dithianes take
a chairlike conformation in which substituents prefer to occupy
equatorial positions similar to cyclohexane chemistry.30 In the
oxidation of 2-substituted 1,3-dithianes, lone pair a′ of the
product monoxide which is hypothetically identical to lone pair
a can also participate in the oxidation (Scheme 5A). However,
the chair conformer in which two substituents (R and O-)
occupy axial positions is disfavored. As the result, the second
oxidation is significantly retarded. On the other hand, the oxygen
atom of 1,3-dithiane 1-oxide also tends to occupy the equatorial
If based on the premise that only lone pair a can attack the
optically active oxidant to give the corresponding sulfoxide, not
only the high diastereomer ratio of the produced monoxides
but also almost no formation of overoxidation products in the
oxidation of 2-substituted 1,3-dithiane and the formation of
(29) (a) Rinaldi, R.; Fujiwara, F. Y.; Ho¨lderich, W.; Schuchardt, U. J. Catal.
2006, 244, 92–101. (b) van Vliet, M. C. A.; Mandelli, D.; Arends,
I. W. C. E.; Schuchardt, U.; Sheldon, R. A. Green Chem. 2001, 3,
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9
J. AM. CHEM. SOC. VOL. 133, NO. 1, 2011 59

A R T I C L E S
Fujisaki et al.
Scheme 6. Asymmetric Oxidation of 5-tert-Butyl-1,3-dithiane 2o
Scheme 8. Reaction Pathway in the Oxidation of
2-Methyl-2-(2-phenylethyl)-1,3-dithiane
Scheme 7. Conversion of (1S,2S)-2-(2-Phenylethyl)-1,3-dithiane
1-Oxide 3e to 2-Methyl-2-(2-phenylethyl)-1,3-dithiane 1-Oxide
position, but the energy difference between the equatorial and
axial conformers is rather small. The axial conformer is reported
to be only 7.1 kJ mol-1 higher in energy by theoretical
calculations, and the experimental value of 2.7 kJ mol-1 was
also reported.31 These studies indicate easy ring flipping of 1,3-
dithiane 1-oxide at the reaction temperature. Thus, the lone pair
a′′ of the S+-O- axial conformation (Scheme 5B), which is
identical in a spatial arrangement to lone pair a, participates in
the second oxidation to give the trans-1,3-dioxide with high
diastereo- and enantioselectivity (Schemes 3 and 4).
In order to confirm this assumption, we examined the
oxidation of 5-tert-butyl-1,3-dithiane 2o, where a bulky tert-
butyl group occupies the equatorial position exclusively and
locks the conformation (Scheme 5C). As we expected, no
formation of the dioxides was observed and the monoxide 3o
was obtained in 93% yield with 99% ee (Scheme 6). It was
confirmed that conformational rigidity of 2-substituted 1,3-
dithiane 1-oxides is associated with the suppression of the
overoxidation.
This conformational analysis also elucidates the very low
diastereoselectivity observed in the oxidation of 2-methyl-2-
(2-phenylethyl)-1,3-dithiane 2m (Table 1, entry 15). Treatment
of trans-(1S,2S)-2-phenylethyl-1,3-dithiane 1-oxide 3e, which
was obtained in the asymmetric oxidation of 2-phenylethyl-1,3-
dithiane 2e, with n-butyllithium and then methyl iodide gave a
ca. 1:2 diastereomeric mixture of 2-methyl-2-phenylethyl-1,3-
dithiane 1-oxide, in which the S-stereogenic center is retained
during the process (Scheme 7).32
It is of note that the absolute configurations of both of the
diastereomers obtained with this procedure were identical with
those of the diastereomers obtained in the asymmetric oxidation
of 2-methyl-2-(2-phenylethyl)-1,3-dithiane 2m. Thus, a plausible
reaction pathway based on the accord of the absolute config-
uration can be proposed as illustrated in Scheme 8. The small
difference in the steric requirements of the methyl and phenyl-
ethyl groups allows both of the chairlike conformers to
participate in the oxidation. As the result, the low diastereose-
lectivity was observed. Since, however, the Al(salalen) complex
discriminates only an enantiotopic equatorial lone pair in each
of the conformers as shown in Figure 3, the monoxides with
the same S-stereogenic center were obtained in high enantio-
meric excesses.
The conformational study of 1,3-dithianes explains the
induction of diastereoselectivity in the first oxidation process.
Nevertheless, there is room for discussion on the observed
excellent diastereoselectivity. Considering the small A value of
the phenylethynyl group that indicates a small energy difference
between the two chairlike conformers,33 the diastereomer ratio
of 19:1 observed in the oxidation of 2-phenylethynyl-1,3-
dithiane is higher than expected. Moreover, it has been reported
that the axial conformer of 2-phenylethynyl-1,3-dithiane is
preferred over the equatorial one.34 If based on the above
conformational discussion, the cis-oxide should be obtained
preferentially from the axial conformer. In fact, however, the
trans-oxide was obtained with high diastereo- and enantiose-
lectivity (Table 1, entry 4). In order to explain this result, we
consider that the Curtin-Hammett principle is applicable to this
system, where the equatorial and axial conformers are rapidly
interconvertible and the axial one reacts much slower than the
equatorial one (Scheme 9).35 Bulkier axial substituents might
retard the reaction progress by a steric repulsion with catalyst.
Synergistic combination of high stereorecognition ability of the
aluminum catalyst and conformational flexibility of 2-substituted
1,3-dithianes explains the induction of the excellent diastereo-
selectivity.
IV. Al(salalen)-Catalyzed Asymmetric Oxidation of Other
Dithioacetals. The Al(salalen) complex 1/H2O2 system has a
broad spectrum for cyclic dithioacetals. Five-membered 1,3-
dithiolanes underwent the oxidation with high enantioselectivity
(Scheme 10). The reactions of dithiolanes 5 with 2-phenyl and
2-tert-butyl groups smoothly proceeded to give the trans-
monoxides 6 and small amounts of the trans-1,3-dioxides 7 with
high enantiomeric excesses. Although conformational study of
(31) (a) Von Acker, L.; Anteunis, M. Tetrahedron Lett. 1974, 15, 225–
228. (b) Khan, S. A.; Lambert, J. B.; Hernandez, O.; Carey, F. A.
J. Am. Chem. Soc. 1975, 97, 1468–1473. (c) Juaristi, E.; Guzma´n, J.;
Kane, V. V.; Glass, R. S. Tetrahedron 1984, 40, 1477–1485. (d) Roux,
M. V.; Temprado, M.; Jime´nez, P.; Da´valos, J. Z.; Notario, R.; Mart´ın-
Valca´rcel, G.; Garrido, L.; Guzma´n-Mej´ıa, R.; Juaristi, E. J. Org.
Chem. 2004, 69, 5454–5459. (e) Juaristi, E.; Notario, R.; Roux, M. V.
Chem. Soc. ReV. 2005, 34, 347–354.
(33) A values represent free energy differences between equatorial and axial
substituents on a cyclohexane ring: ∆G°/kJ mol-1 1.7 (CtCH), 7.1
(CHdCH2), 11 (Ph), and 21 (tBu).
j
(34) Arai, K; Iwamura, H.; Oki, M. Bull. Chem. Soc. Jpn. 1975, 48, 3319–
(32) Carey, F. A.; Dailey, O. D., Jr.; Hernandez, O. J. Org. Chem. 1976,
41, 3979–3983.
3323.
(35) Seeman, J. I. Chem. ReV. 1983, 83, 83–134.
9
60 J. AM. CHEM. SOC. VOL. 133, NO. 1, 2011

Asymmetric Oxidation of Cyclic Dithioacetals
A R T I C L E S
Scheme 11. Asymmetric Oxidation of 2-Phenyl-1,3-dithiepane 8
Scheme 9. Stereochemical Course with
2-Phenylethynyl-1,3-dithianes
Scheme 12. Oxidation of an Acyclic Dithioacetal 10
Scheme 10. Asymmetric Oxidation of 1,3-Dithiolanes 5
oselectivity and chelate formation with products delayed the
reaction progress.
Conclusion
We achieved highly diastereo- and enantioselective oxidation
of cyclic dithioacetals with Al(salalen) complex 1 as catalyst
and aqueous hydrogen peroxide as an oxidant. In this study,
we found that a conformational issue of the substrates and
produced monoxides as well as the stereorecognition ability of
the aluminum catalyst is closely connected with the control of
the stereoselectivity.
1,3-dithiolane 1-oxides has been unexplored, the ring conforma-
tion of the 1,3-dithiolane 1-oxides is more flexible than that of
1,3-dithiane 1-oxides.36 The dioxide formation observed in the
oxidation of 1,3-dithiolanes is considered to be due to the
conformational flexibility. A seven-membered substrate, 2-phen-
yl-1,3-dithiepane 8, was also a good substrate for the aluminum-
catalyzed oxidation, and the monoxide 9 was obtained in 96%
yield with >99% ee (Scheme 11).
Acknowledgment. We are grateful to a Grant-in-Aid for
Scientific Research (Specially Promoted Research 18002011) and
the Global COE Program, “Science for Future Molecular Systems”
from MEXT, Japan for generous financial support.
Unfortunately, however, the reaction of acyclic dithioacetals
was sluggish and poorly enantioselective (Scheme 12). We
assumed that conformational flexibility led to the low enanti-
Supporting Information Available: Experimental procedures
and spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(36) Sternson, L. A.; Coviello, D. A.; Egan, R. S. J. Am. Chem. Soc. 1971,
93, 6529–6532.
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