Enantioselective Sulfoxidation Catalyzed by a Bisguanidinium Diphosphatobisperoxotungstate Ion Pair

Article abstract of DOI:10.1002/anie.201601574

The first enantioselective tungstate-catalyzed oxidation reaction is presented. High enantioselectivities were achieved for a variety of drug-like phenyl and heterocyclic sulfides under mild conditions with H₂O₂, a cheap and environmentally friendly oxidant. Synthetic utility was demonstrated through the preparation of (S)-Lansoprazole, a commercial proton-pump inhibitor. The active ion-pair catalyst was identified to be bisguanidinium diphosphatobisperoxotungstate using Raman spectroscopy and computational studies.

Full text of DOI:10.1002/anie.201601574

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International Edition: DOI: 10.1002/anie.201601574
German Edition: DOI: 10.1002/ange.201601574
Asymmetric Sulfoxidation
Enantioselective Sulfoxidation Catalyzed by a Bisguanidinium
Diphosphatobisperoxotungstate Ion Pair
Xinyi Ye, Adhitya Mangala Putra Moeljadi, Kek Foo Chin, Hajime Hirao, Lili Zong, and
Choon-Hong Tan*
Abstract: The first enantioselective tungstate-catalyzed oxida-
tion reaction is presented. High enantioselectivities were
achieved for a variety of drug-like phenyl and heterocyclic
sulfides under mild conditions with H2O2, a cheap and
environmentally friendly oxidant. Synthetic utility was dem-
onstrated through the preparation of (S)-Lansoprazole, a com-
mercial proton-pump inhibitor. The active ion-pair catalyst
was identified to be bisguanidinium diphosphatobisperoxo-
tungstate using Raman spectroscopy and computational stud-
ies.
for a growing number of reactions.[10] We have also recently
described how chiral cations including pentanidiums and
other cationic phase transfer catalysts can be used as ion-
pairing catalysts to activate inorganic anionic metal salts.[11]
We demonstrated that by using potassium permanganate salt
in the presence of a chiral dicationic bisguanidinium, highly
enantioselective dihydroxylation and oxohydroxylation of
a,b-unsaturated esters can be achieved (reaction 3 in
Figure 1).[11] This strategy is highly complementary to the
chiral anion ion-pairing catalysis that was demonstrated to be
compatible with a variety of cationic metal species.[12]
S
odium tungstate-catalyzed epoxidation of a,b-unsaturated
acids using H2O2 in water was first demonstrated by Payne in
1959 and was followed up by Sharpless in 1985.[1] Tungstates
are known to be polymeric in aqueous solutions, and the
distribution of the polyoxotungstate species is dependent on
pH and concentration.[2] Peroxotungstate complexes are
known to be the catalytic species in these reactions.[3]
Investigation by Venturello into the role of phosphate in
phase transfer tungstate oxidation reactions, resulted in the
isolation and identification of the heteropolyperoxotungstate,
[PO4{WO(O2)2}4]3À [4]
This peroxotungstate species was also
.
postulated to be the catalytically active species for the
H3PW12O40/H2O2 (Kegginꢀs reagent) oxidation system devel-
oped by Ishii.[5] Subsequently, Noyori developed an efficient
catalyst suitable on a practical scale with high turnover
number.[6] It was found that (aminomethyl)phosphonic acid
or phenylphosphonic acid was effective in accelerating the
reaction. It was proposed that a 1:1 complex between
phosphonic acid and monoperoxotungstate is the active
catalyst.[6c] Using this method, they furnished olefin epoxida-
tion[6a] and sulfoxidation[6d] in high chemoselectivities.
We are interested in the practical preparation of enantio-
pure chiral sulfoxides.[7] While Kagan oxidation is widely
adopted for asymmetric sulfoxidation,[8] there are emerging
methods[9a–d] to prepare chiral sulfoxides, including some
recent breakthroughs utilizing imidodiphosphoric acid,[9e]
binuclear titanium chiral complex,[9f] or pentanidium.[10c]
Pentanidiums belong to a new class of efficient phase-transfer
catalysts that we have developed and have shown to be useful
Figure 1. Enantioselective chiral cation ion-pairing oxidations.
Chiral cationic ion-pairing catalysis using inorganic salts is
well-known. The oxidizing anionic salts can be stoichiometric
as in the epoxidation of chalcone with sodium hypochlorite
using Maruoka catalyst (reaction 1 in Figure 1).[13] Alterna-
tively, the actual oxidant, (hypo)iodite, can be generated
in situ through the use of iodide and stoichiometric oxidant
such as cumene hydroperoxide (CHP) (reaction 2 in
Figure 1). Ishihara demonstrated that enantioselective oxida-
tive cycloetherification can be accomplished with this
approach.[14] Herein, we wish to report the enantioselective
sulfoxidation using catalytic amount of silver tungstate in the
[*] X. Ye, A. M. P. Moeljadi, K. F. Chin, Prof. Dr. H. Hirao, Dr. L. Zong,
Prof. Dr. C.-H. Tan
Division of Chemistry and Biological Chemistry
Nanyang Technological University
21 Nanyang Link, 637371 Singapore (Singapore)
E-mail: choonhong@ntu.edu.sg
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601574.
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presence of chiral dicationic bisguanidinium (reaction 4 in
Figure 1).
At the outset, benzimidazole-derived benzyl sulfide 1a
was chosen as the model substrate to investigate the reaction
conditions (Table 1). In the presence of 2.0 mol% of bisgua-
nidinium BG1 with Et2O as solvent, no reaction was found
when only H2O2 was used; indicating that BG1 alone cannot
Table 1: Optimization of the reaction conditions.
Entry
BG
M2WO4 [mol%]
Solvent
Yield [%][a]
ee [%][b]
1
2
3
4
5
BG1
BG1
BG1
BG1
ent-
BG1
BG1
BG2
BG3
BG4
BG5
Na2WO4 (5)
K2WO4 (5)
(NH4)2WO4 (5)
Ag2WO4 (5)
Ag2WO4 (5)
Et2O
Et2O
Et2O
Et2O
Et2O
36
18
48
83
90
20
À2
42
88
À89
6
7
8
9
Ag2WO4 (2)
Ag2WO4 (2)
Ag2WO4 (2)
Ag2WO4 (2)
Ag2WO4 (2)
iPr2O
iPr2O
iPr2O
iPr2O
iPr2O
96
65
63
52
84
92
63
50
32
8
10
[a] Yield of isolated product. [b] Determined by HPLC analysis on a chiral
stationary phase.
catalyze the reaction. When 5.0 mol% of Na2WO4 was added,
the reaction gave sulfoxide 2a in poor yield and low
enantioselectivity. It is only when 10 mol% NaH2PO4 was
added, the yield of sulfoxide 2a improved significantly to
36% and its ee value improved to 20% (Table 1, entry 1).
When Na2HPO4 and Na3PO4 were used instead, the reactions
were inhibited. Next, a range of commercially available
tungstate salts, such as K2WO4, (NH4)2WO4, and Ag2WO4,
were evaluated (entries 2–4). Sulfoxide 2a was obtained in
83% yield with 88% ee value when Ag2WO4 was used
(entry 4). When the catalyst loading of Ag2WO4 was
decreased to 2.0 mol%, it is necessary to change the solvent
to diisopropyl ether to provide the best results (entry 6).
Other bisguanidiniums BG2–5 featuring different benzyl
groups was unable to improve the results obtained with BG1
(entries 7–10). We also confirm that NaH2PO4 in the absence
of Ag2WO4 did not promote the sulfoxidation reaction.
With the optimized reaction conditions in hand, the
substrate scope of benzimidazole-derived sulfides was exam-
ined (Scheme 1, 2a–2i). The benzimidazole group does not
seem to act as a ligand and inhibit the reaction. Both electron-
donating and electron-withdrawing substitutions on the
benzyl group worked well, affording the corresponding
sulfoxidation products in good to excellent yields with good
levels of enantioselectivities. The oxidation ability of the
catalyst is able to override even a highly electron-withdrawing
group such as pentafluorobenzyl (Scheme 1, 2g). Besides
Scheme 1. Enantioselective sulfoxidation of heterocyclic sulfides. Reac-
tions were carried out on a 0.2 mmol scale in 4.0 mL solvent for 36
hours unless otherwise noted; yield values refer to isolated yields after
purification; ee was determined by chiral-phase HPLC. [a] 5.0 mol% of
Ag2WO4 was used. [b] Et2O as the solvent. [c] 8.0 mL iPr2O was used.
benzyl groups, simple alkyl groups or esters are also tolerated
in this reaction (2h-l). Other heterocyclic systems, such as
benzothiazole (2m–r), pyridine (2s-t), and thiophene (2u),
also worked well, providing products with excellent ee values.
However, thiophene heterocyclic sulfides gave lower yields
with significant amount of sulfone detected. We were also
able to scale the reaction to gram scale (3.5 mmol) to give 2q
in 91% yield and 92% ee. The established strategy was also
successfully applied to the preparation of (S)-Lansoprazole,
a commercial proton-pump inhibitor (Scheme 2).
Scheme 2. Enantioselective synthesis of (S)-lansoprazole.
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To further demonstrate the substrate scope of this new
iv.[15] These complexes assume distorted pentagonal bipyr-
method, several conventional substrates containing phenyl
sulfide moiety were also tested (Scheme 3). For such sub-
strates, a balance between reaction yields and enantioselec-
tivities was achieved by employing a solvent mixture between
dimethyl carbonate (DMC) and ethers. The substrates that
could be tolerated included those with simple alkyl chains to
electron-withdrawing aromatic rings.
amid geometry and obey the 18-electron rule. As a result,
coordination of three or more phosphates to the tungstate
center can be considered to be unlikely. It is also important to
À
note that owing to the short O O bond distances (1.45 to
1.47 Š)[16] in the peroxo group, the oxygen atoms will most
likely lie in the equatorial plane, instead of occupying both
axial and equatorial positions in the complex. Based on these
premises, the four possible configurations of substituted
peroxotungstate species are presented (Figure 2).
Raman spectra of the active species were obtained and
compared with predicted Raman spectra of the four possible
intermediates. Computed Raman spectra were obtained by
performing vibrational frequency analysis on stationary
points optimized at the B3LYP/B1 level of theory in gas
phase, where B1 is a combination of LANL2DZ effective
core potential basis set for W and the 6-31g* basis set for
remaining atoms. A peak was observed experimentally at
711 cmÀ1, which corresponds to the twisting of P-O-H group
in the phosphate ligand (Figure 3 and Table 2; see the
Scheme 3. Enantioselective sulfoxidation of phenyl sulfides. [a] Reac-
tions were carried out on 0.2 mmol scale in a solvent mixture of DMC
(4.0 mL)/ iPr2O (4.0 mL). (DMC=dimethyl carbonate) [b] Reactions
were carried out in a solvent mixture of DMC (4.0 mL)/Et2O (4.0 mL).
During optimization of the reaction conditions, we
realized that the ratio between Ag2WO4 to NaH2PO4 is
crucial to obtaining good yields and enantioselectivities
(Scheme 4). The most significant improvement was achieved
when the ratio of phosphate to tungstate reached 1:2. As the
Figure 3. Experimental Raman spectrum of P2W, [{PO2(OH)2}2{WO-
(O2)2}]2À. For the vibration diagram, see Table 2.
Scheme 4. Influence of phosphate loading.
Table 2: Vibrations of the Raman spectrum of P2W, [{PO2(OH)2}2{WO-
(O2)2}]2À
.
=
=
À
À À
À À
P O H W(O2)
P O W O O O
P O H
amount of phosphate in this current method is in excess over
tungstate, we speculated that the Ishii–Venturello catalyst,
[PO4{WO(O2)2}4]3À, is not the active catalyst in this method.
When we replaced the Ag2WO4/NaH2PO4 with H3PW12O40
(Kegginꢀs reagent) as in Ishiiꢀs procedure, the reaction
provided sulfoxides in 40% yield and 30% ee.
Ligand coordination or substitution has been previously
shown to be an important factor that can influence the
catalytic activities of peroxotungstates. Under the current
experimental conditions, monomeric and oligomeric dihydr-
oxide species i (Figure 2) should exist and in the presence of
phosphate additive, form substituted phosphate species ii–
calcd. 1014 1001
expt. 1042 1014
940
943
840, 802
872, 825
713
711
643asym, 564sym
631asym, 564sym
Supporting Information, Figures S18–S23, for details). This
same peak was found only in the computed spectra of P2W
(713 cmÀ1). A more thorough analysis of the P2W structures
revealed that intramolecular hydrogen bond interaction
between the two phosphate ligands is important for this
peak; absence of such interaction will shift the vibrational
frequency towards 800 cmÀ1. We thus proposed that the active
anion of this enantioselective sulfoxidation is diphosphato-
bisperoxotungstate, [{PO2(OH)2}2{WO(O2)2}]2À
.
Preliminary computational studies of the complete BG1-
P2W structure using ONIOM method (Supporting Informa-
tion, Figures S24–S31) revealed a stable ion-pair interaction,
where P2W is buried in the chiral cavity of BG1 (Figure 4).
This configuration results in only one of the peroxo-oxygen
Figure 2. Four possible peroxotungstate species.
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Acknowledgements
We gratefully acknowledge the financial support by grants
from NTU (M4080946.110 and M4011372.110) and a scholar-
ship (to X.Y.). A.M.P.M. and H.H. accomplished the compu-
tational work.
Keywords: asymmetric sulfoxidation · bisguanidinium ·
ion-pair catalysis · lansoprazole · Raman spectroscopy
How to cite: Angew. Chem. Int. Ed. 2016, 55, 7101–7105
Angew. Chem. 2016, 128, 7217–7221
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In summary, we report the first enantioselective tungstate-
catalyzed oxidation reaction. High enantioselectivities were
achieved for a variety of drug-like heterocyclic sulfides under
mild conditions with H2O2, a cheap and environmentally
friendly oxidant. Synthetic utility was demonstrated through
the preparation of (S)-Lansoprazole, a commercial proton-
pump inhibitor. The active ion-pair catalyst was identified to
be bisguanidinium diphosphatobisperoxotungstate using
Raman spectroscopy and computational studies.
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Received: February 14, 2016
Revised: March 24, 2016
Published online: May 6, 2016
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