Bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pair-catalyzed enantioselective sulfoxidation

Catalytic use of peroxomolybdate for asymmetric transformations has attracted increasing attention due to its catalytic properties and application in catalysis. Herein, we report chiral bisguanidinium dinuclear oxodiperoxomolybdosulfate [BG]2+[(μ-SO4)Mo2O2(μ-O2)2(O2)2]2− ion pair, as a catalyst for enantioselective sulfoxidation using aqueous H2O2 as the terminal oxidant. The ion pair catalyst is isolatable, stable and useful for the oxidation of a range of dialkyl sulfides. The practical utility was illustrated using a gram-scale synthesis of armodafinil, a commercial drug, with the catalyst generated in situ from 0.25 mol% of bisguanidinium and 2.5 mol% of Na2MoO4·2H2O. Structural characterization of this ion pair catalyst has been successfully achieved using single-crystal X-ray crystallography.

M etalloenzymes containing molybdenum, responsible for nitrogen and sulfur metabolism [1][2][3][4] , continue to fuel interest in the exploration of novel molybdenum complexes with catalytic activities. Various neutral coordination complexes of Mo(VI) containing chiral organic ligands have been synthesized and studied extensively for enantioselective reactions [5][6][7][8][9][10][11] . In particular, one interesting example of highly enantioselective sulfoxidation of alkyl aryl sulfides was demonstrated using a complex derived from MoO 2 (acac) 2 and chiral bis-hydroxamic acids 12 . In contrast to their neutral counterparts, there have been no successful attempts to utilize peroxomolybdate 13 for asymmetric reactions, even though many of these species have been comprehensively characterized.
It is well known that peroxomolybdates are formed on the treatment of molybdate salts with aqueous H 2 O 2 oxidant 14,15 . Monomeric, oligomeric and polymeric peroxomolybdate species could be generated under similar conditions (Fig. 1) 14 . The addition of different organic ligands can further increase the structural and functional diversity of peroxomolybdate complexes [16][17][18] . Other ligands such as silanol 19 , phosphate 20 , arsenate 21 and sulfate [22][23][24][25] have been used to bridge molybdates to construct dinuclear or trinuclear peroxomolybdate complexes. Peroxomolybdates species have been shown to be excellent catalysts for the oxidation of numerous substrates, including alkenes, alcohols 26 and sulfides. The complexity of peroxomolybdates is thus recognized to be a challenging obstacle for elaborating them into highly enantioselective catalysts.

Results
Catalytic application of molybdate in sulfoxidation. At the onset of this work, we realized that we were unable to approach enantiopure 2-sulfinyl esters through enantioselective alkylation of sulfenate anion, as the reaction was incompatible with a-halogenated carboxylates ( Supplementary Fig. 1) 29 . We were attracted to the low cost and easy accessibility of molybdate salts and thus we attempted to investigate the direct sulfoxidation of 2-sulfanyl acetate, by utilizing a catalytic amount of molybdate salts and aqueous H 2 O 2 as terminal oxidant. Methyl 2-(benzhydrylsulfanyl)acetate 2a was chosen as the model substrate (Table 1), since 2-sulfinyl acetate 3a could be easily transformed to armodafinil, a commercial drug used for the treatment of narcolepsy and shift work sleep disorder [46][47][48] .
When the reaction was performed in the presence of 1 mol% of (S,S)-1a, 5 mol% of (NH 4 ) 6 Mo 7 O 24 Á 4H 2 O and 1.05 equiv. 35% aqueous H 2 O 2 , poor yield and no enantioselectivity were observed (Table 1, entry 1). With the addition of acetic acid 49 , the enantioselectivity was slightly improved, albeit with low yield (entries 2 and 3). Using trifluoroacetic acid as additive, a marked enhancement of the reactivity was achieved, but with negligible enantioselectivity (entry 4). With the addition of sodium or potassium hydrogen sulfate, we observed significant improvement of yield, as well as enantioselectivity (entries 5 and 6) 50,51 . Switching to other additives, such as dihydrogen phosphate or hydrogen phosphate led to poor results (entries 7 and 8). Further investigation of reaction parameters (entries 9-14), such as the source of molybdate, solvent and stoichiometry of KHSO 4 , led to the enhancement of reactivity, as well as enantioselectivity (entry 14, 93% ee; Supplementary Table 1  temperature to 0°C and using just 1 mol% of (S,S)-1a together with 2.5 mol% Na 2 MoO 4 Á 2H 2 O in i Pr 2 O, affording 2-sulfinyl acetate 3a in 99% yield with 94% ee (entry 15). The absolute configuration of 3a was confirmed to be S through comparison with the reported data 46 .
Substrate scope of various sulfides using (S,S)-1a. The reaction scope was examined using a series of substrates with a relatively low reactivity, in which the electron density of sulfur is reduced, due to strong electron-withdrawing groups like ester, ketone and nitrile ( Table 2). The reactions performed efficiently and were generally completed within 1 h. For benzyl 2-sulfanylacetates with different substituents on the aromatic ring, dialkyl sulfoxides 3b-3i were obtained in high yields and excellent enantioselectivities. Sulfoxide 3j bearing 2-thienyl was obtained in high yield and good enantioselectivity without oxidation at the thiophene. With a slight variation of reaction conditions, using 0.25 equivalent of KHSO 4 and 2.5 mol% of K 2 MoO 4 , various aromatic 2-sulfanylacetates were efficiently converted to alkyl aryl sulfoxides 3k-3q in high yields with good enantioselectivities. For the oxidation of sulfide-bearing para-OMe substituent, leading to sulfoxide 3l, slight over-oxidation to sulfone was observed. For a less reactive substrate 2r, the reaction was conducted at room temperature using 1.5 equiv. H 2 O 2 , affording sulfoxide 3r with good enantioselectivity. With less favourable substrates such as tert-butyl substituted 2-sulfanyl acetate 2s, low enantioselective induction was observed ( Table 2, 3s).
To further explore the scope, a diverse range of substrates bearing different functional groups were examined ( Table 2, 3t-3y). 3-Sulfinyl propanoate 3t was produced with excellent enantioselectivity. Sulfoxides 3u-3y bearing amide, ketone, acrylate, nitrile and aldehyde moieties were furnished with good to excellent enantioselectivities. The absolute configurations of 3f and 3o were confirmed to be R and S, respectively, using single-crystal X-ray diffraction; thus, absolute configurations of sulfoxides 3 were assigned by analogy to either 3f or 3o.
Identification and characterization of ion pair (R,R)-1b. We attempted to identify the reactive catalytic species by mimicking the reaction conditions in the absence of sulfide substrate (Fig. 4). After a simple workup procedure, (R,R)-1b was isolated and a single crystal suitable for X-ray diffraction was grown by vapour diffusion of Et 2 O into a dimethylformamide (DMF) solution of (R,R)-1b. The structure of (R,R)-1b was fully characterized using X-ray analysis (Fig. 2b), 95 Mo nuclear magnetic resonance (NMR) (Fig. 5b) and fourier transform-infrared spectroscopy (FT-IR) ( Supplementary Fig. 2).
The achiral anionic metallic species [(m-SO 4 )Mo 2 O 2 (m-O 2 ) 2 (O 2 ) 2 ] 2 À is revealed by X-ray crystallography to be embedded within the chiral cavity formed by two side arms of the chiral bisguanidinium dication (Fig. 2b). The coordination geometry surrounding the Mo was clearly elucidated (Fig. 5a). The SO 4 2 À ligand plays a crucial role in constructing the dimeric symmetric structure. Each Mo centre comprises one bridging peroxo ligand, one side-on peroxo group and a terminal oxo ligand, with the sulfate group acting as a bipodal ligand to the two Mo atoms. Each Mo atom is 7-coordinated with oxygen atoms in a pentagonal bipyramidal arrangement. The two associated pentagonal bipyramids share one edge  95 Mo NMR spectrum of (R,R)-1b was also obtained in DMF-d 7 at 22°C, using 2 M Na 2 MoO 4 Á 2H 2 O solution in D 2 O as an external reference (assigned to 0 p.p.m.). The chemical shift at À 199.3 p.p.m. is characteristic of oxodiperoxomolybdate species (Fig. 5b) 52 .
We found that (R,R)-1b (1.0 equiv.), prepared using the method in Fig. 4, can be used directly as the oxidant for  (Fig. 6a,  equation 1). This result indicates that (R,R)-1b is the actual oxidizing specie providing high enantiodiscrimination. Utilizing 0.25 equiv. (R,R)-1b led to the formation of ent-3a in 50% yield in 24 h with 31% ee (Fig. 6a, equation 2     the sulfides 53 . The second oxygen transfer is slower and less enantioselective than the first. As expected, (R,R)-1b can be used catalytically in the presence of H 2 O 2 , providing sulfoxide ent-3a in 95% yield with 91% ee at a loading of 1 mol% (Fig. 6b,  equation 3). This result is comparable to the reaction, in which this active catalyst is prepared in situ from (R,R)-1a (Fig. 3). The catalyst can be recycled from the reaction (Fig. 6b, equation 3) and used for a second round of reaction, but an additional amount of 0.5 equiv. of KHSO 4 must be added to restore the reactivity and enantioselectivity (Fig. 6b, equation 4).
Computational studies of (R,R)-1b using the ONIOM method revealed that a more stable ion-pairing arrangement, with the distance between the anionic cluster and the cationic bisguanidinium noticeably reduced compared with that in the crystal structure (Fig. 7). As a result of this rearrangement, approach of the substrate to most of the peroxo-oxygen atoms is obstructed by bisguanidinium and sulphate groups. Only one of side-on peroxo-oxygen atoms (marked as O 14 in Fig. 7) remains accessible for reaction. This is consistent with the experimentally observed high enantioselectivity, since restricted access to secondary reaction sites will result in a reaction with higher selectivity.
Reaction selectivity was evaluated using 50 mol% tetrabutylammonium hydrogen sulfate ( n Bu 4 NHSO 4 ) as an achiral ion-pairing reagent (Fig. 8). A high level of enantiocontrol can still be achieved, which indicates ion pairing interaction between chiral bisguanidinium and dinuclear oxodiperoxomolybdosulfate anion [(m-SO 4 )Mo 2 O 2 (m-O 2 ) 2 (O 2 ) 2 ] 2 À accelerates the reaction rate significantly over tetrabutylammonium, promoting the reaction through the desired asymmetric pathway. The stereoinduction observed in the current methodology may be ascribed to ion pairing interaction and other non-covalent interactions  between dicationic bisguanidinium, oxodiperoxomolybdosulfate anion, as well as the substrates in the stereoselectivity determining transition state ( Supplementary Fig. 5) 33,54 .

Discussion
In the present study, we have described the first catalytic use of peroxomolybdate for enantioselective sulfoxidation; a series of enantioenriched dialkyl sulfoxides and alkyl aryl sulfoxides have been obtained using inexpensive molybdates and aqueous H 2 O 2 through a simple experimental protocol. The practical value of current methodology was demonstrated using a gram-scale synthesis of armodafinil, a commercial drug, with a low loading (0.25 mol%) of bisguanidinium. The 'active' catalyst is isolatable, stable and has been identified to be bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pair [BG] 2 þ [(m-SO 4 )Mo 2 O 2 (m-O 2 ) 2 (O 2 ) 2 ] 2 À . Its structure is also unambiguously confirmed by X-ray analysis. Preparation of ion pair (R,R)-1b. To the solution of Na 2 MoO 4 Á 2H 2 O (24.1 mg, 0.1 mmol) dissolved in 1 M H 2 SO 4 (1 ml), 35% H 2 O 2 (345 ml, 4.0 mmol) was added dropwise to give a yellow solution at room temperature. Then the above solution was added dropwise to a solution of (R,R)-1a (56.4 mg, 0.04 mmol) in Et 2 O (2 ml). After vigorously stirring for 15 min, a pale yellow precipitate was formed in the Et 2 O layer. After further stirring for 2 h and removal of Et 2 O by evaporation, 4 ml deionized water was added and the resulting heterogeneous mixture was submitted to ultrasound for 1 min. Then the pale yellow solid was filtered off and washed with deionized water (40 ml). After drying over concentrated H 2 SO 4 under vacuum at room temperature, (R,R)-1b was obtained as a pale yellow powder (65.5 mg, 91% yield) and its structure was characterized and determined by X-ray single-crystal diffraction. Increase of the amount of Na 2 MoO 4 Á 2H 2 O to 0.1 equivalent or replacement of 1 M H 2 SO 4 with 0.5 equivalent of solid KHSO 4 all led to the formation of identical complex (R,R)-1b, which is confirmed by X-ray diffraction analysis.

Methods
General procedure for synthesis of sulfoxides 3. A 10 ml round-bottom flask (RBF) was charged with a solution of sulfide 2 (0.2 mmol) and bisguanidinium phase-transfer catalyst (S,S)-1a (2.8 mg, 0.002 mmol) in i Pr 2 O (4 ml). Then Na 2 MoO 4 Á 2H 2 O (1.2 mg, 0.005 mmol) and KHSO 4 (13.6 mg, 0.1 mmol) were added. The reaction mixture was stirred for 5 min in an ice bath, and then aqueous 35% H 2 O 2 (18.1 ml, 0.21 mmol) was added in one portion. The resulting mixture was stirred vigorously at 0°C and monitored by thin-layer chromatography until 2 was completely consumed. Purification using silica gel column chromatography (CH 2 Cl 2 /EtOAc ¼ 2:1) afforded the desired sulfoxide 3. Minor changes in the amount of KHSO 4 and choice of molybdate salt (K 2 MoO 4 ) and solvent ( n Bu 2 O) were conducted for some substrates to achieve slightly better enantioselectivity.
Data availability. CCDC 1456987-1456990 contain 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. The data that support the findings of this study are available from the corresponding authors on request.