Catalysis of Organic..

Augustine, Tanielyan, Marin and Alvez 467succinimid solution at such a rate that the internal temperature remained below 20°C.After the addition was completed the mixture was sonicated for an additional onehour. To this solution (suspension) was added dropwise over a period of one hourwith stirring a solution of 27.84g (0.18 mole) of phenacyl chloride (2)in 120 mL ofDMF. After addition the reaction mixture was stirred overnight during which timethe initial red solution changed color to orange. Water (2.5 L) was added dropwiseto the stirred suspension and the pale yellow precipitate was filtered and dried in avacuum oven at 45°C/3-4 mm Hg to give 30 g of the crude succinimido ketone (79%yield). This material was recrystallized twice from ethanol (700 mL) to produce awhite solid which after drying in a vacuum oven at 40°C gave 20 g (67%) of thesuccinimido ketone, 6, of sufficient purity for the hydrogenation step.Catalyst preparation: Five milligrams (0.02 mmol Ru) of {[RuCl 2 (benzene)] 2 } and14 mg of CTH-(R)-3,5-xylylphanephos (0.02 mmol) were placed in a 50 mL Schlenkflask. After completely replacing all of the air with argon, 2 mL of DMF was addedto the flask via cannula and the mixture heated to 100°C for 10 min with stirring togive a reddish brown solution. After cooling to ambient, 4 mg S,S-DPEN (0.19mmol) dissolved in 2 mL of degassed DMF was added and the mixture stirred for3 hours. The DMF was removed under 1 mm Hg pressure at 25°C and then at 50°Cto give a light yellow solid containing 20 μmole Ru. This was dissolved in 10 mL ofdegassed methanol to give a stock catalyst solution containing 2 μmol Ru/mL. Thissolution was kept in a completely de-aerated air tight septum sealed flask until use.A second stock methanol solution containing 0.25 mmol / mL of potassiumt-butoxide was prepared using 700 mg (6.25 mmol) of potassium t-butoxidedissolved in 25 mL of degassed methanol. This was also kept in a deaerated air tightseptum sealed flask until use.Asymmetric hydrogenation: The succinimido ketone, 6, (4.34 g, 20 mmole) wasplaced in a 250 mL jacked glass reactor vessel (13) and the air in the reactorcompletely replaced by argon using fill-release cycles. Degassed methanol (250 mL)was added to the reactor via cannula and the mixture stirred at 30°C to dissolve theketone. Four milliliters of the catalyst solution (8 μmol Ru) and 12 mL of theK-O-tBu solution (3 mmole) were injected into the reactor using gas tight syringes.The argon in the reactor was replaced with hydrogen (fill/release cycles) and thereactor pressurized to 60 psig with hydrogen. The reaction mixture was stirred at1000 rpm overnight at 30°C with the hydrogen uptake recorded as describedpreviously (13). The reaction mixture was passed through a short alumina columnand the solvent removed to give the (S) succinimido alcohol, 7, with an ee of 99% at100% conversion.Amino alcohol, 1: The succinimido alcohol, 7, (1.74g) was dissolved in 60 mL of95% ethanol and 36 mL of 20% aqueous sodium hydroxide added to the solution.The solution was the refluxed for 18 hours and cooled to ambient which resulted inthe separation of two layers. The top, organic, layer was separated and evaporated todryness to give a solid material which was refluxed with 30 mL of MTBE and 10 mLof methylene chloride for 30-40 minutes to extract the amino alcohol from the solidsodium succinate. After cooling to ambient the solid was removed by filtrationthrough a Celite pad and the filtrate decolored by stirring with Norit. Filtration gave