Asymmetric catalytic sulfoxidation by a novel V^IV₈ cluster catalyst in the presence of serum albumin: a simple and green oxidation system

Abstract

A novel V^IV₈ cluster formulated as [V₈O₁₂(OH)₄(CH₃O)₄(DAC)₄]·7CH₃OH (1) (DAC = 1,2-diaminocyclohexane) has been constructed successfully. Enantioselective oxidation of a series of alkyl aryl sulfides catalyzed by 1 is tested in an aqueous medium in the presence of serum albumin. The catalytic procedure is found to be simple and environmentally friendly. The influences of the parameters such as concentration of catalyst and oxidant, pH, and reaction time on the thioanisole as models are investigated. Under optimum conditions, 1 exhibits high conversion (up to 99%), excellent chemoselectivity (≥90% in all cases) and moderate enantioselectivity (up to 75% ee). After binding with serum albumin, the catalytic activity of 1 is promoted. The bovine serum albumin (BSA) and pig serum albumin (PSA) molecules have a more positive effect on the catalytic activity.

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Introduction

Polyoxometalates (POMs) stimulate many current research activities in broad fields of science, such as catalysis,^1–7 materials,⁸ medicine,⁹ magnetism,^10–13 and photochemistry.^14,15 This can be attributed to their favorable chemical and physical properties, such as redox potentials,^16–18 acidities,² solubility in various media,¹⁹ and impressive sensitivity to light and electricity.²⁰ Notably, their thermal,⁸ hydrolytic,²¹ and oxidative redox stabilities²² make them competitive candidates to rival organometallic complexes and enzymes for deployment in organic oxidation processes.^23–25

The use of POMs for carrying out asymmetric catalysis²⁶ remains a major challenge because most POM anions possess high symmetry.¹⁸ To date, much effort has been devoted to exploring the preparation of chiral POM-based systems,¹⁸ as well as the enantioselectivity achievable with enantiopure POMs for asymmetric transformations.^27–30 Nevertheless, there are still many shortcomings, such as low efficiency,²⁷ instability,³¹ use of toxic organic solvents,²⁸ rapid racemization in solution,³¹ and complicated synthetic steps to obtain POMs with chiral structures.

Serum albumins (SAs) are the major soluble protein constituents of the circulatory system and have many physiological functions.³² They are generally robust, abundant, readily accessible, inexpensive, and easy to handle.^33,34 In addition, SAs have the unique property of specific binding sites for hydrophobic organic molecules,³⁵ and as additives presenting a chiral environment³⁶ may be capable of inducing enantioselectivity. For example, Manfred T. Reetz and Ning Jiao carried out Diels–Alder reactions in water with phthalocyanine–Cu^II complexes in the presence of SAs, which afforded the products with up to 98% ee.³⁷ In situ generated dioxiranes have been used to oxidize a series of prochiral sulfides to the corresponding sulfoxides with up to 89% ee in the presence of bovine serum albumin (BSA) as a chiral auxiliary.³⁸ However, to the best of our knowledge, few studies have demonstrated the catalysis systems based on POMs with SAs as chiral additives for obtaining enantiomerically pure products.

Chiral sulfoxides and their derivatives are an important class of compounds that are extensively used as chiral synthetic intermediates and auxiliaries for the preparation of biologically active molecules, both in academia and in industry.³⁹ Furthermore, compounds with sulfur chirality play a crucial role in many biochemical processes⁴⁰ and are widely exploited in the pharmaceutical industry.⁴¹ The selective oxidation of organic sulfides to sulfoxides without any over-oxidation to sulfones,^42–44 as well as devising environmentally benign catalytic oxidations, are still key challenges in the synthesis of enantiopure sulfoxides.

Herein, we report a new V^IV₈ cluster formulated as [V₈O₁₂(OH)₄(CH₃O)₄(DAC)₄]·7CH₃OH (1) (DAC = 1,2-diaminocyclohexane) with a novel distorted shuriken-like topology containing two V₄ butterfly subunits arranged vertically. This cluster has been used as a homogeneous catalyst for asymmetric sulfoxidation reactions in water in the presence of SAs (Scheme 1). Satisfactory chemoselectivities (>90%) for sulfoxides were obtained in the presence of different SAs. Compared to related chiral POM systems,^31,45,46 this system has the advantages of inexpensive chiral ligands, green reaction media, and extremely simple working procedures. Consequently, this V^IV₈ cluster in conjunction with SAs represents a promising type of POM catalytic system for diverse asymmetric reactions, making it potentially useful in chemical and biological synthesis.

Scheme 1 Oxidation of sulfides catalyzed by 1 in the presence of SA.

Experimental section

Materials

All reagents and solvents for synthesis and analysis were commercially available. Bovine serum albumin (BSA) was provided by Sigma-Aldrich, human serum albumin (HSA), porcine serum albumin (PSA), rabbit serum albumin (RSA) and sheep serum albumin (SSA) were obtained from Zhejiang, China. All the sulfides were purchased from Energy Chemical.

Physical measurements

UV-Vis spectra were recorded on a Cary 100 UV-visible spectrophotometer. The FT-IR spectra were recorded on a Perkin-Elmer Spectrum One FT-IR spectrophotometer with a germanium attenuated total reflection (ATR) accessory, a DTGS KBr detector and a KBr beam splitter ratio. Elemental analyses for C, H and N were carried out on a model 2400 II, Perkin-Elmer elemental analyzer. ESI-MS (electrospray ionization mass spectrum) spectra were recorded on a Bruker HCT Electrospray Ionization Mass Spectrometer. HPLC experiments were carried out using UV2302II/P2302II high performance liquid chromatograph. ¹H and ¹³C NMR spectra were recorded on a Bruker NMR.

Syntheses of complex 1

[V₈O₁₂(OH)₄(CH₃O)₄(DAC)₄]·7CH₃OH (1). A mixture containing 1,2-diaminocyclohexane (57 mg, 0.5 mmol), V₂O₅ (91 mg, 0.5 mmol), methanol (10 mL), water (5 mL) and triethylamine (0.5 mL) was sealed in a Teflon-lined stainless steel vessel (25 mL), which was heated at 120 °C for 3 days and then cooled to room temperature at a rate of 10 °C per hour. Black block crystals of 1 were obtained and picked out, washed with ethanol and dried in air. Yield: 37% (based on V(IV)). Anal. calc. for C₃₅H₉₆N₈O₂₇V₈: C, 28.62; H, 6.59; N, 7.63. Found: C, 28.57; H, 6.64; N, 7.69. IR (KBr, cm⁻¹): 3748 w, 3425 s, 3296 s, 3244 s, 3142 m, 2936 s, 2863 m, 2820 w, 1642 s, 1602 m, 1451 m, 1399 w, 1384 w, 1359 w, 1304 w, 1236 w, 1202 w, 1132 m, 1040 s, 944 s, 754 s, 652 s, 563 m, 541 w, 508 w, 449 w, 422 w.

X-ray crystallographic determination

All reflection data were collected on an Agilent Supernova diffractometer (Mo, λ = 0.71073 Å) at room temperature. A semiempirical absorption correction by using the SADABS program was applied, and the raw data frame integration was performed with SAINT.⁴⁷ The crystal structures were solved by the direct method using the program SHELXS-97 (ref. 48) and refined by the full-matrix least-squares method on F² for all non-hydrogen atoms using SHELXL-97 (ref. 49) with anisotropic thermal parameters. All hydrogen atoms were located in calculated positions and refined isotropically, except the hydrogen atoms of water molecules were fixed in a difference Fourier map and refined isotropically. The details of the crystal data were summarized in Table 1, and selected bond lengths and angles for compounds 1 are listed in Table S1.†

Table 1 Crystal data and structure refinement for 1

Complex	1
Empirical formula	C35H96N8O27V8
Formula weight (M)	1468.72
Crystal system	Triclinic
Space group	P1̄
a (Å)	14.1442 (11)
b (Å)	14.9100 (11)
c (Å)	16.0774 (13)
α (°)	117.151 (8)
β (°)	92.303 (6)
γ (°)	91.772 (6)
V/(Å ^3)	3009.9 (4)
Z	2
Dc (g cm^−3)	1.621
F(000)	1524
θ range for data collection (°)	3.4–26.4
Reflections collected/unique	25 154/12 271 [R(int) = 0.032]
Goodness-of-fit on F^2	1.046
Final R indices [I > 2σ(I)]	R1 = 0.0604, ωR2 = 0.1433
R indices (all data)	R1 = 0.0753, ωR2 = 0.1554

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Characterization of 1 in the absence of SA

A 33.3 μM solution of the 1 in 0.05 M phosphate-buffered saline (PBS), pH 7.45, was prepared by mixing 100 μL of a 1 × 10⁻³ M solution of the 1 and 2900 μL of 0.05 M PBS, pH 7.45. In parallel, a 33.3 μM solution of SA-1 in 0.05 M PBS, pH 7.45, was obtained by mixing 100 μL of a 1 × 10⁻³ M solution of 1 and 100 μL of a 1 × 10⁻³ M solution of SA (1.0 equiv.) in 2800 μL of 0.05 M PBS, pH 7.45. The UV/Vis spectra of these solutions were then recorded between 250 and 500 nm.

General procedure for oxidation of sulfides

The SA (2.7 μmol, 176 mg) was mixed for 10 min at room temperature with 1 (2.7 μmol, 0.4 mg) through a simple mechanical stirring in 2 mL 50 mM PB (phosphate buffer) solution. 0.27 mmol sulfide was added to the reaction mixture and the stirring was continued for 5 hours. The oxidant (1.5 equiv.) was then added to the solution in one portion and the reaction mixture stirred for another 10 h at room temperature. Then, the solution was quenched with sodium sulfite solution and extracted with dichloromethane (2 mL × 5). Finally, the combined organic solutions were dried over by anhydrous sodium sulfate, filtered, and evaporated under vacuum. The same procedure was followed with complex 1 alone or without 1. A sample of the crude reaction mixture re-dissolved in a minimum amount of isopropanol before being analyzed by HPLC with Chiralcel OB-H (4.6Φ mm × 250 mm) column (Daicel Chemical Industries, Tokyo) at room temperature. Further purification was achieved by chromatography on silica gel then was taken for the NMR analysis. The enantiomeric excess (ee) and chemoselectivity were calculated using the formulas: ee% = [peak area (S − R)/(S + R)] × 100%; chemoselectivity% = [peak area SO/(SO + SO₂)] × 100%, SO = sulfoxide, SO₂ = sulfone. Conversions were based on sulfide substrate; yields were referred to isolated product after column chromatography and were based on substrate; the absolute configurations of the sulfoxides were assigned by comparison of HPLC elution orders reported in the literature.^50,51

XRPD results

To confirm whether the crystal structures are truly representative of the bulk materials, X-ray powder diffraction (XRPD) experiments had also been carried out for 1. The XRPD experimental and computer-simulated patterns of the corresponding complexes are shown in Fig. S2.† Although the experimental patterns have a few unindexed diffraction lines and some are slightly broadened in comparison with those simulated from the single crystal models, it can still be considered favorably that the bulk synthesized materials and the as-grown crystals are homogeneous for 1.

Results and discussion

Description of the crystal structures

[V₈O₁₂(OH)₄(CH₃O)₄(DAC)₄]·7CH₃OH (1). X-ray structural analysis shows that compound 1 crystallizes in space group of P1̄ (Table 1). The asymmetric unit contains a [V₈O₁₂(OH)₄(CH₃O)₄(DAC)₄] unit (Fig. 1e) as well as seven lattice methanol molecules. And the [V₈O₁₂(OH)₄(CH₃O)₄(DAC)₄] unit consists of eight V(IV) ions, four 1,2-diaminocyclohexane ligands, four μ₂-OH⁻ anions, four μ₂-CH₃O⁻ anions, four μ₃-O²⁻ anions, four μ₂-O²⁻ anions, and eight terminal O²⁻ anions (Fig. 1e and f). Four external V(IV) ions (V1, V2, V5 and V8) of the V₈ octamer are six-coordinate with a distorted octahedral [VN₂O₄] geometry formed by the coordination of four O atoms (one terminal O²⁻ anion, one μ₂-OH⁻ anion, one μ₃-O²⁻ anion, and one μ₂-CH₃O⁻ anion), and two N atoms from a DAC ligand. The distorted quartet cone coordination sphere of the internal V₄ is [VO₅], in which two μ₃-O²⁻ anions, one μ₂-OH⁻ anion and one μ₂-CH₃O⁻ anion lie in the equatorial plane and one terminal O²⁻ anion locate in the axial position. The arrangement of eight vanadium atoms supported by four μ₂-OH⁻ anions, four μ₂-CH₃O⁻ anions, and four μ₃-O²⁻ anions displays a distorted shuriken topology which can be described as consisting of five edge-sharing distorted V₄ tetrahedron (Fig. 1b) with the adjacent V⋯V distance range of 2.9012 (4)–3.1951 (5) Å. To the best of our knowledge, very rare of metallic skeletons with this topology have been observed in the polynuclear metal complexes.^52–54

Fig. 1 (a) The simple structural anatomy of the V₈ unit; (b) the V₈ skeleton with shuriken topology which can be described as consisting of five edge-sharing distorted V₄ tetrahedron; (c) the two V₄ butterfly subunits with vertical arrangement; (d) the arrangement of eight vanadium atoms supported by four μ₂-OH⁻ anions, four μ₂-CH₃O⁻ anions, and four μ₃-O²⁻ anions, and the distribution of the eight terminal O²⁻ anions; (e) a view of the V₈ cluster; (f) the V₈ cluster with polyhedron mode; (g) the space-filling plot of the V₈ cluster, and it's the size.

From another perspective, 1 could also view as an unusual linked-butterfly structure (Fig. 1a and c). In the V₄ butterfly subunit, the four V centers are connected by two μ₃-O²⁻ anions and two μ₂-CH₃O⁻ anions (Fig. 1d). Different with the Mn₈ octamers with linked-butterfly structure reported by Christou et al.,^55,56 the two V₄ butterfly subunits which are connect each other by four μ₂-OH⁻ anions (Fig. S1d†) arrange vertically.

ESI-MS solution analysis

Mass spectroscopy is a powerful tool for probing the properties of inorganic clusters in solution as well as investigating the supramolecular self-assemblies of inorganic coordination architectures, as reported by Cronin and co-workers.^57–59 In our work, the electrospray mass spectrometric experiment of 1 was taken to explore their solution stability in water.

The ESI mass spectrum of 1 is shown in Fig. 2. The main ion peak observed at a weight of 1246 which is isotopically resolved and agree with the theoretical distributions (see Fig. 1, inset) results from obtaining a proton of the [V₈O₁₂(OH)₄(CH₃O)₄(DAC)₄] unit to form [V₈O₁₂(OH)₄(CH₃O)₄(DAC)₄ + H]⁺. These results support the opinion that the V^IV₈ cluster of 1 remains stable in solution.^60–62

Fig. 2 The ESI mass spectrum of 1 in the scale of m/z = 400–3000; insert: the black spectra is the experimentally collected for low resolution, and the red spectra is the predicted isotopic envelopes.

Binding of complex 1 with the serum albumin

UV/Vis spectra (Fig. 3) of 33.3 μM solutions of the 1 were recorded in 50 mM PBS buffer, pH 7.45, in the absence and presence of equimolar SAs (BSA, HSA, RSA, PSA, SSA) in order to examine the extremely simple noncovalent binding.³⁸ Comparing the spectrum of the 1 with those recorded in the presence of SAs (Fig. 3), it can be seen that PSA and BSA caused bathochromic shifts of 10 nm (from 254 to 264 nm) and 6 nm (from 254 to 260 nm), respectively, accompanied by strong increases in intensity. It is thus clear that stronger association complexes of the 1 were formed with PSA and BSA. On the contrary, in the presence of SSA, the spectrum of the 1 was largely unchanged, suggesting weaker binding.³⁷

Fig. 3 UV/Vis spectra of 1 (33.3 μM) in the absence and presence of SAs (33.3 μM).

Asymmetric sulfoxidation

Taking the aspect of green chemistry into account, a preliminary investigation on the oxidation of methyl phenyl sulfide (PhSMe) catalyzed by 1 was carried out in the presence of BSA (1 : BSA molar ratio 1 : 1) employing the environmentally benign oxidant H₂O₂ (ref. 64) (1.5 equiv.) (PhSMe and BSA were chosen for these preliminary studies as a well-known model substrate⁶³ and serum albumin, respectively). Control reactions without 1 or BSA were performed under the same conditions. As shown in Fig. 4, the best result was obtained for 1 in the presence of BSA. Satisfactory yield (93%) and chemoselectivity (98%) were obtained, albeit only with 10% ee. To rule out possible catalysis by BSA alone, the reaction was repeated in the absence of 1. Under otherwise identical conditions, inferior catalytic activity (30% yield and 87% chemoselectivity) was observed. A control experiment without BSA afforded the sulfoxide with 52% chemoselectivity in 51% yield, but the major product was essentially racemic (ee < 1%). Thus, comparison of the results of these reactions clearly demonstrates that the catalysis was mainly due to complex 1, and that the enantiomeric excess was determined by the protein.^65–67

Fig. 4 Controlled experiments for oxidation of PhSMe at room temperature for 10 h.

Disappointingly, unsatisfactory enantioselectivity was obtained with H₂O₂. Therefore, sulfoxidation reactions were evaluated with other oxidants. Among these oxidants, sodium hypochlorite (NaClO) and sodium periodate (NaIO₄) gave lower yields and product selectivities, and the ee values obtained were only 15% and 3%, respectively (Fig. 5). However, tert-butyl hydroperoxide (TBHP) effectively oxidized PhSMe affording a yield (92%) comparable to that with H₂O₂, but with somewhat higher selectivity (97%) and ee (20%). Interestingly, the opposite major enantiomer was produced (R-configured sulfoxide with H₂O₂; S-configured sulfoxide with TBHP). Thus, the nature of the oxidizing agent determines the enantiomeric excess of the reaction product in some cases.

Fig. 5 Screening of oxidants for oxidation of PhSMe catalyzed by 1 in PB (pH 5.1) at room temperature after 10 h. The mol ratios of oxidant : PhSMe : BSA : 1 (2.7 μmol) were 150 : 100 : 1 : 1.

The reaction conditions for the oxidation of PhSMe were further optimized by studying four different parameters, namely the catalyst concentration, the oxidant concentration, reaction time, and pH. Our results showed that the sulfoxide yield and selectivity were strongly affected by the catalyst concentration (Fig. 6). PhSMe was obtained in excellent yield with high selectivity and the maximum enantioselectivity using 0.5 mol% 1 within 10 h. At higher catalyst concentration, the yield and selectivity of the sulfoxide were much lower and the enantioselectivity decreased to 9%.

Fig. 6 Effect of the concentration of 1 on the oxidation of PMS using TBHP in PB (pH 5.1) at room temperature after 10 h. The mol ratios of TBHP : PhSMe (2.7 μmol) were 150 : 100.

The effects of the TBHP concentration on the catalytic activity and enantioselectivity were studied by employing various TBHP/PhSMe molar ratios in the presence of 0.5 mol% 1 (Table 2). Increase of this ratio significantly increased the conversion and sulfoxide yield, which were maximized at 1.5 equiv. of TBHP. It is noteworthy that at a TBHP : PhSMe molar ratio of 2.5 : 1 (entry 4), significant decreases in both selectivity (78%) and yield (76%) were observed. Compared with the results at a 2 : 1 molar ratio, the conversion was almost the same and the ee was slightly higher. These experimental results clearly indicated that the reaction occurred with over-oxidation,^68,69 that is, a kinetic resolution process^70–72 was operative in the presence of excess oxidant.

Table 2 Effect of varying TBHP amount on oxidation of PhSMe catalyzed by 1^a

Entry	TBHP (mmol)	Conversion (%)	Yield (%)	Chemoelectivity (%)	ee (%)
a All reactions were carried out in PB buffer (2 mL, pH 5.1) at room temperature for 10 h. The mol ratios of PhSMe : BSA : 1 (1.35 μmol) were 100 : 0.5 : 0.5.
1	0.27	73	69	95	31
2	0.41	98	97	99	35
3	0.54	96	93	97	34
4	0.689	97	76	78	38

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Next, complex 1 was used to catalyze the oxidation of PhSMe in the presence of BSA under the above optimized reaction conditions over a period of 22 h. From the reaction time profile of the oxidation of PhSMe (Fig. 7), it can be seen that the conversion increased steadily up to 8 h and attained a maximum value of 99%. Notably, chemoselectivity (98–99%) and enantioselectivity (35–36%) remained nearly constant throughout the course of the reaction, confirming that the obtained enantioselectivity was completely induced during the sulfide oxidation process and was not due to a concomitant kinetic resolution.⁷³

Fig. 7 Effect of the reaction time on the oxidation of PhSMe using TBHP in PB (pH 5.1) at room temperature. The mol ratios of TBHP : PhSMe : BSA : 1 (1.35 μmol) were 150 : 100 : 0.5 : 0.5.

Under the above optimized reaction conditions, the oxidation of PhSMe was performed at different pH values (Fig. 8). The oxidation of PhSMe in PBS (pH 4.7) gave a significantly higher enantioselectivity (up to 57% ee) compared to the other reactions (3–33% ee), albeit with a lower yield. Increasing or decreasing the pH from 4.7 significantly reduced the conversion, yield, and, enantioselectivity, possibly because complex 1 became less stable.⁷⁴

Fig. 8 Effect of pH values on the oxidation of PhSMe using TBHP at room temperature after 8 h. The mol ratios of TBHP : PhSMe : BSA: 1 (1.35 μmol) were 150 : 100 : 0.5 : 0.5.

We then tested the catalytic activity of complex 1 in the presence of BSA and other commercially available serum albumins, HSA, PSA, RSA, and SSA, in reactions of a series of alkyl aryl sulfoxides (1–10). The results, which are summarized in Table 3, showed that chemoselectivity was almost unaffected by the albumin source or the substrate (>90% sulfoxide selectivity in each case). However, in terms of conversion and yield, PSA, RSA, and SSA led to poor results, whereas BSA and HSA performed relatively well (typically >90% conversion/yield). Furthermore, the albumin source had a highly significant effect on the ee values, with those for all of the substrates averaging 45.1%, 24.3%, 42%, 7.8%, and 3.8% for 1 in the presence of BSA, HSA, PSA, RSA, and SSA, respectively. The experimental results and spectral studies discussed above clearly indicate that the enantioselectivity was associated with the binding strength between 1 and SA. The high enantioselectivities induced by the PSA-1 and BSA-1 systems indicate that 1 was strongly anchored to the protein. However, in the cases of HSA, RSA, and SSA, this effect was very small, leading to lower ee values (typically <10% ee with SSA), implying weaker binding. Thus, it seems that increasing the interaction of the metal complex with the protein leads to better enantioselectivities.⁷⁵ Compared with the other proteins, RSA provided the opposite major enantiomer in many cases. For example, opposite results in terms of the configuration were obtained for 2-Cl-, 3-Cl- and 4-Cl-phenyl methyl sulfide (substrates 2, 3 and 5) with RSA; 3-Br-phenyl methyl sulfide (substrate 4) with PSA; vinyl phenyl sulfoxide (substrate 9) with SSA.

Table 3 Effects of albumin source, and substrate on asymmetric oxidation of aryl alkyl sulfides^a (conversions of ≥90%, chemoselectivities of ≥90% and enantiomeric excesses (ee) of ≥50% are emphasized)

Substrate	Complex 1: conversion (%), chemoselectivity (%), yield (%), ee (%) (configuration)
	BSA	HSA	PSA	RSA	SSA
a Reactions were performed in 2 mL PB pH 4.7 at room temperature for 8 h. The ratios of TBHP: substrate: SA: 1 (2.7 μmol) were 150 : 100 : 0.5 : 0.5.
	71, 99, 70, 77, R	90, 98, 88, 35, R	75, 99, 74, 41, R	77, 99, 76, 5, R	82, 99, 81, 2, R
	99, 100, 99, 23, R	90, 100, 90, 3, R	95, 95, 90, 36, R	95, 95, 90, 6, S	88, 92, 81, 1, R
	98, 97, 95, 19, R	95, 96, 91, 3, R	90, 98, 88, 23, R	90, 98, 88, 2, S	95, 92, 87, 1, R
	98, 98, 96, 75, R	94, 97, 91, 56, R	92, 97, 89, 62, S	92, 96, 88, 10, R	91, 98, 89, 9, R
	97, 98, 95, 41, R	96, 98, 94, 2, R	95, 99, 94, 60, R	95, 100, 95, 9, S	95, 97, 92, 3, R
	95, 100, 95, 57, R	94, 100, 94, 21, R	94, 100, 94, 46, R	94, 94, 88, 4, R	97, 98, 95, 13, R
	99, 98, 97, 58, R	99, 98, 97, 34, R	99, 98, 97, 50, R	95, 98, 93, 3, R	99, 100, 99, 3, R
	99, 98, 97, 64, R	99, 98, 97, 67, R	95, 98, 93, 68, R	89, 98, 87, 2, R	96, 98, 94, 4, R
	91, 100, 91, 26, S	97, 95, 92, 18, S	95, 90, 85, 25, S	95, 91, 86, 29, S	87, 97, 85, 1, R
	98, 96, 94, 11, S	94, 98, 92, 4, S	90, 96, 86, 9, R	95, 99, 94, 8, R	71, 99, 76, 1, R

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Irrespective of electron-withdrawing and/or electron-donating groups and their position on the aromatic ring (entries 2–8), good conversions (88–99%) and yields (81–99%) were obtained. Nevertheless, the data suggested that electron-donating groups had a more pronounced effect on the enantioselectivity of the product. The average ee values obtained for electron-deficient 4-Cl- and 4-Br-phenyl methyl sulfides (substrates 5 and 6) were 23% and 28%, respectively. In comparison, electron-rich 4-Me-phenyl methyl sulfide and 4-OMe-phenyl sulfide (substrates 7 and 8) gave average ee values of 30% and 41%, respectively. Sulfoxidations of sterically bulky substrates, such as vinyl phenyl sulfoxide and methyl benzyl sulfoxide (substrates 9 and 10), were successfully achieved with high chemoselectivities. However, lower enantioselectivities were observed in the oxidation of these sterically bulky substrates to the corresponding sulfoxides, possibly due to the increased steric demand.⁷⁶ Significantly, the oxidation-sensitive C=C double bond was not sacrificed under the mild oxidation conditions, producing the requisite sulfoxide in high yield (>85%). Notably, the results indicate that the steric effect had a stronger influence on the configuration. For example, except for vinyl phenyl sulfoxide and methyl benzyl sulfoxide, the products were obtained in the R form in the presence of BSA or HSA. In particular, for vinyl phenyl sulfoxide, the opposite configuration was obtained compared to the reactions of other sulfides in the presence of the same SA (except SSA). The mechanistic details of this reaction are still under investigation.

Conclusions

In conclusion, a novel V^IV₈ cluster has been successfully constructed based on 1,2-diaminocyclohexane. Using this V^IV₈ cluster as a homogeneous catalyst, we have devised an efficient biomimetic procedure for the oxidation of sulfides to sulfoxides in the presence of serum albumin in water at room temperature. This methodology is simple and environmentally friendly. Its simplicity lies in the preparation of the catalyst from easily available starting materials as well as a facile sulfoxidation procedure by physical stirring at room temperature. In addition to the above-mentioned advantages, the use of eco-friendly reaction media and inexpensive chiral additives make it cost-effective, environmentally benign, and thus compatible with the goals of green sustainable chemistry.

Acknowledgements

We gratefully acknowledge the National Nature Science Foundation of China (No. 21361003, 21461003 and 21101035), the Guangxi Natural Science Foundation (2014GXNSFBA118056), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, the Talent's Small Highland project of Guangxi Medicinal Industry (1201), New Century Ten, Hundred, Thousand Talents Project in Guangxi, IRT 1225 and the Foundation of Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Education of China (CMEMR2011-20, CMEMR2013-A05).

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1439891. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra08153c

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