Neutral iridium catalysts with chiral phosphine-carboxy ligands for asymmetric hydrogenation of unsaturated carboxylic acids

The new neutral iridium catalyst with chiral spiro phosphine-carboxy ligand exhibited exceptionally high enantioselectivity in the hydrogenation of 3-alkyl-3-methylenepropionic acids.


Preparation and Analytical Data of Iridium Complexes with Chiral Spiro Phosphine-Carboxy Ligands (S)-2d
Typical procedure: (S)-1d (112 mg, 0.250 mmol), [Ir(COD)Cl]2 (84 mg, 0.125 mmol) and Na2CO3 (13 mg, 0.125 mmol) were mixed in CH2Cl2 (2 mL) in a Schlenk tube under argon atmosphere. The resulting suspension was heated to 40 o C till that the TLC analysis showed no free ligand existed. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue was purified by a flash column chromatography on silica gel with petroleum ether/ethyl acedate (PE/EA = 1:1, v/v) to offer (S)-2d (133 mg, yield: 71%) as an orange-yellow solid, mp: 190-191 o C.

Asymmetric Hydrogenation and Analytical Data of Products
General procedure of hydrogention A hydrogenation tube was charged with a stir bar, -alkyl--unsaturated acids 5 (0.5 mmol), catalyst (S)-2d (3.7 mg, 0.005 mmol), Cs2CO3 (82 mg, 0.25 mmol) in an argon-filled glovebox. Then 2 mL n BuOH was injected into the hydrogenation tube by a syringe with stirring. The hydrogenation tube was put into an autoclave. The argon in the autoclave was replaced with hydrogen for 3 times, and was finally charged with hydrogen to 3 atm. The reaction mixture was stirred at 65 o C for specified time before releasing the hydrogen.
After releasing hydrogen, the reaction mixture was added with 20 mg NaOH and concentrated under reduced pressure. The mixture was added 25 mL water and washed with Et2O. The aqueous layer was acidified with conc. HCl, and extracted with Et2O. The organic layer was dried with anhydrous Na2SO4. The conversion of substrate was determined by 1 H NMR analysis. The crude product was purified by a flash chromatography on silica gel column to give pure product 6. The acid 6 (0.

4-Ethyl-3-methylhexanoic acid (6e)
Yield   11 Yield    20 A solution of acid 6a (72 mg, 0.50 mmol) in 1 mL of anhydrous THF was added to a stirred suspension of LiAlH4 (38 mg, 1.0 mmol) in 1 mL of anhydrous THF at 0 °C. The reaction mixture was warmed to room temperature, and stirred for 2 h. After cooling to 0 °C, 1 mL of water and 1 mL of aq. NaOH (10% solution) were added with stirring. The organic layer was separated, and the aqueous layer was extracted with Et2O. The combined organic layer was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by a flash column chromatography on silica gel with PE/EA (4:1) to offer 9 (61 mg, 94%) as a colorless oil.  20 Tosyl chloride (70 mg, 0.38 mmol) was added to a solution of alcohol 9 (50 mg, 0.35 mmol) in 1 mL of anhydrous pyridine at 0 °C and the mixture was stirred for 16 h at the same temperature. The mixture was added 20 mL of Et2O and washed successively with brine, saturated solution of CuSO4 and NaHCO3, and brine. The organic phase was dried with Na2SO4, and concentrated to give tosylate 10. The product was used in the next step without further purification.

(S)-3-Methylheptyl 4-methylbenzenesulfonate (10)
(S)-14-Methyloctadec-1-ene 20 A solution of tosylate 10 in 3 mL of anhydrous THF was added dropwise to a stirred solution of the Grignard reagent (0.38 mmol) at 0 o C. A solution of Li2CuCl4 (0.2 N, 0.10 mL) in anhydrous THF was added. The reaction mixture was stirred at -70 °C for 1 h, at -10 °C for 2 h, and at 25 °C for 2 h, poured into a cooled saturated solution of NH4Cl, and extracted with Et2O. The combined extract was washed successively with saturated solution of NaHCO3 and brine, dried with Na2SO4, and concentrated under reduced pressure. The residue was purified by a flash column chromatography on silica gel with PE to offer (S)-14-methyloctadec-1-ene (62 mg, 67% for two steps) as a colorless oil.

X-ray Diffraction Analysis of (S)-2d
The fine yellow crystals of (S)-2d suitable for the X-ray diffraction analyses grow slowly on the interface of a solution of (S)-2d (30 mg) in dichloromethane (0.5 mL) and n-hexane (1.5 mL). Absolute structure parameter 0.010 (7) Largest diff. peak and hole 2.781 and -1.354 e.Å -3