Catalytic Asymmetric Dihydroxylation of Olefins Using a Recoverable and Reusable Ligand

A free bis-cinchona alkaloid derivative ligand was prepared by a simple synthetic manipulation. With ligand/olefin mole ratio of 1%, the asymmetric dihydroxylation reactions of six olefins proceeded smoothly to give the chiral vicinal diols in high chemical yields and optical yields. The ligand itself could be recovered quantitatively by a simple operation and reused five times without loss of enantioselectivity.


INTRODUCTION
The osmium-catalyzed asymmetric dihydroxylation (AD) of olefins provides one of the most elegant methods for the preparation of chiral vicinal diols, the key intermediates in pharmaceutical and chemical synthesis. 1 However, the high cost of osmium and ligands has restricted its use in industry. Many efforts were made to address this issue in the past decade. The ligand immobilized on an insoluble polymer was synthesized in order to recover the expensive ligand and a small amount of OsO 4 . But, low catalytic activity and enantioselectivity were reported. This is because the restrictions of the polymer matrix resulted in limited mobility and accessibility to the active sites and thus obstructed the ligand-accelerated catalysis in the AD reaction. [2][3][4] To take advantage of homogeneous catalysis with respect to the easy separation of a ligand bound to the solid phase, cinchona alkaloidtype ligands were attached to a soluble polymer, polyethylene glycol monomethyl ether. [5][6][7][8][9] However, complicated synthetic manipulations were required for the prepara-tion of PEG-bound ligand. Moreover, for all of the reported PEG-bound cinchona alkaloid-derived ligands, the required mole ratio of ligand with respect to olefin in the AD reactions was as high as 10-25 %, much higher than the corresponding ratio for the extensively used free ligands 1,4-bis(9-O-dihydroquinidinyl)phthalazine [(DHQD) 2 -PHAL] and 1,4-bis(9-O-dihydroquininyl)phthalazine [(DHQ) 2 PHAL]. 10 In 2002, a recoverable and reusable free ligand was reported originally by our group. 11 This free ligand showed high catalytic activity and enantioselectivity with a low ligand/olefin mole ratio (5 %). Herein, we introduce another free ligand for the AD reaction ( Figure 1). This ligand can be also circularly used but is more efficient. With this ligand, the AD reaction of six olefins gave high chemical yields and optical yields. Furthermore, the ligand was recovered and reused in the AD reaction of ethyl trans-cinnamate for 5 runs without any loss of catalytic activity and enantioselectivity.
When ligand 1 was used to catalyze the AD reaction of olefins (Scheme 2), it was completely soluble in the reaction solvent in favor of homogeneous catalysis. Six olefins were converted into the corresponding diols in excellent yields and ees during 24 hours at room temperature. Especially, the AD reactions of ethyl trans-cinnamate and isopropyl trans-cinnamate were totally completed within 6-10 h by TLC examination. Both reactions consumed less time compared to other olefins. Evidently, ligand 1 has a special catalytic ability for dihydroxylation of trans-cinnamate. It may be because the AD reactions can be effected by the asymmetry of ligand 1. The reaction results for the selected olefins are presented in Table I.
To evaluate the recyclability of ligand 1 in the AD reaction, ethyl trans-cinnamate was employed as the substrate. After the reaction, ligand 1 was extracted with CH 2 Cl 2 and precipitated by addition of diethyl ether. 92-96 % of the ligand was recovered by simple filtration. Pure diol can be obtained by washing the crude product with n-hexane. The results are presented in Table II.

CONCLUSIONS
In conclusion, we have demonstrated that ligand 1 was not only obtained easily but also showed powerful catalytic ability. This recoverable and reusable bis-cinchona alkaloid derivative effectively catalyzed the AD reactions of six olefins to give the corresponding chiral diols in excellent yields and ees. Without significant loss of enantioselectivity, repetitive use of the ligand was also possible by addition of a small amount of OsO 4 after each run.

EXPERIMENTAL
General 1 H NMR and 13 C NMR spectra were recorded on a Bruker AV-400 spectrometer with CDCl 3 as solvents. MS was performed on a Bruker APEX2. High performance liquid chromatography (HPLC) was performed by Agilent 1100 interfaced to a HP 71 series computer workstation with Daicel Chiralcel OD-H, OJ-H and OB-H chiral columns. Optical rotations were obtained on a Perkin-Elmer 343 polarimeter. (QN) 2 PHAL (2) was prepared according to published methods. 12 All other solvents and chemicals were obtained from commercial sources and were used without further purification unless otherwise stated.

Procedure for the Preparation of Intermediate 3
A 100 mL three-necked round-bottom flask was charged with 2 (3.  13

Procedure for the Preparation of Ligand (1)
Intermediate 3 (1.7 g, 20 mmol), NMO (0.7 g, 6 mmol), THF (20 mL), t-BuOH (8 mL) and a solution of OsO 4 in toluene (0.24 mL, 0.094 mmol) were added to a flask. The reaction mixture was stirred for 12 h at room temperature. NaSO 3 (6 g) was added and stirred for another 2 h. The mixture was subsequently filtered. The filtrate was dried over anhydrous MgSO 4 and concentrated under vacuum. The residue was then purified by flash column chromatography (eluent MeOH-CH 2 Cl 2 1:5) to afford a white solid (1)  Typical Procedure for Asymmetric Dihydroxylation K 3 Fe(CN) 6 (1.96 g, 6.0 mmol), K 2 CO 3 (0.82 g, 6.0 mmol) were dissolved in t-BuOH-H 2 O (20 mL, y = 1:1) at room temperature, followed by addition of OsO 4 in toluene (26 mL, 0.01 mmol) and ligand 1 (0.92 g, 0.10 mmol). Then, olefin (2.0 mmol) was added into the mixture. For trans-1,2-disubstituted olefins, CH 3 SO 2 NH 2 (0.19 g, 2.0 mmol) was needed. The mixture was then stirred vigorously at 25°C for 24 h. When the reaction was over (monitored by TLC), Na 2 SO 3 (2.5 g) was added into the solution and stirred for 45 min. CH 2 Cl 2 (20 mL) was subsequently added to the reaction mixture, followed by separation of the organic layer. The aqueous phase was further extracted with CH 2 Cl 2 (10 mL × 3) (When CH 3 SO 2 NH 2 was used, the combined organic layers had to be washed with NaOH (2 mol /L). The combined organic layers were then dried over anhydrous MgSO 4 and evaporated to dryness under reduced pressure. The residue was dissolved in CH 2 Cl 2 (5 mL) and dry Et 2 O (30 mL) was slowly added to the solution under vigorous stirring. The obtained precipitate was collected by filtration, washed with cool Et 2 O and dried under vacuum. The filtrate was evaporated to give the crude product, which was washed by nhexane to afford pure diol.
With ethyl trans-cinnamate as substrate, similar workup was repeated four times using the recovered ligand. Each time, 30 % of the initial amount of OsO 4 was added to regenerate the reaction.