(3S,4S)-1-Benzylpyrrolidine-3,4-diol

off-white to light brown powder or needles

Under nitrogen, cooled to LiAlH4 0 after (61.2g, 1.6mol) in tetrahydrofuran (3.6L) was slowly added a solution of Intermediate ((3R, 4R) -4) (132.7g, 0.6mol). The reaction mixture was refluxed for 12h, cooled to room temperature, ethyl acetate was added dropwise in an ice-water bath (144mL). Distilled water was added dropwise with vigorous stirring followed (61.2mL), 5percent NaOH (61.2mL) and distilled water (183.6mL). Filter cake was washed with hot tetrahydrofuran (2 × 1.2L) and washed. The combined filtrate and washings were concentrated under reduced pressure, the residue was separated and purified by silica gel column to give a pale yellow oil which was recrystallized from ethyl acetate as a white solid intermediate ((3S, 4S) -5) 82.3g, yield 71.0percent.Under a nitrogen atmosphere, intermediate ((3R, 4R)-4) (132.7 g, 0.6 mol) was slowly added to a solution ofLiAlH4 (61.2 g, 1.6 mol) in tetrahydrofuran (3.6 L) which was cooled to 0°C. The reaction mixture was refluxed for 12 h, and cooled to room temperature. Ethyl acetate (144 mL) was added dropwise to the reaction mixture in a cold waterbath. Distilled water (61.2 mL), 5percent NaOH (61.2 mL) and distilled water (183.6 mL) were sequentially added dropwiseunder vigorous stirring. The mixture was filtered, and the filter cake was washed with hot tetrahydrofuran (231.2 L). Thefiltrate and wash solution were combined and concentrated under reduced pressure. The residue was separated on asilica gel column to obtain a light yellow oil, which was then recrystallized with ethyl acetate to obtain intermediate((3S, 4S)-5) as a white solid (82.3 g, yield: 71.0percent).MASS (ESI+) m/z = 194 (M+H)+.1 H NMR (400 MHz, DSO-d6): 2.30 (dd, 2H), 2.74 (dd, 2H), 3.46 (d, 1H), 3.57 (d, 1H), 3.84 (m, 2H), 4.84 (br s, 2H), 7.20-7.35 (m, 5H).Lithium aluminum tetrahydrate (5 g, 132 mmol)Was dissolved in anhydrous tetrahydrofuran (100 ml)A solution of (3R, 4R) -1-benzyl-3, 4-dihydroxy-2, 5-pyrrolidinedione (10 g, 45 mmol) in dry tetrahydrofuran was added at -5 ° C. After completion of the dropwise addition, The reaction was allowed to proceed to 95 ° C for 12 hours, Cooled to room temperature, 6.8 g of water was added dropwise to the reaction system, and the floc was present. Then, 6.8 g of 20percent NaoH solution and 20.4 g of water were added. Filtered and purified under reduced pressure and purified by silica gel column chromatography (dichloromethane: methanol = 50: 1)To give 6 g of (3S, 4S) -1-benzyl-3, 4-pyrrolidine diol (pale yellow solid in 69percent yield).The (3R, 4R)-l-benzyl-3, 4-dihydroxypyrrolidine-2, 5-dione (0.98 g, 4.4 mmol) To a stirred solution of boron trifluoride ethyl etherate (23 mL, 0.16 mol) in DME (120 mL) were added SLnHK-01-2a (10 g, 0.04 mol) and sodium borohydride (6.2 g, 0.16 mol) at 0° C. The mixture was stirred at 70° C. for 2 h. Then 6 N HCl (62.5 mL) was added slowly at 70° C., stirred for 15 min. Sodium fluoride (28 g) was added and the mixture was heated at reflux temperature for 30 min. The mixture was cooled to room temperature, 20percent aq. NaOH (53 mL) was added and the resulting mixture was filtered. The organic phase was isolated, evaporated to dryness and obtained residue was partitioned between water and diethyl ether. The water phase was extracted with diethyl ether (2x100 mL). The combined organic phases were dried over MgSOTo a mixture of (3R, 4R)-1-benzyl-3, 4-dihydroxypyrrolidine-2, 5-dione (44 g, 199 mmol, 1.0 eq) and THF (176 mL) at 20° C. (vessel jacket temperature) was added borane-tetrahydrofuran complex (1.0 mol/L) in THF (800 mL, 800 mmol, 1.0 mol/L, 4.0 eq) at a rate to maintain the temperature between 20° C. and 25° C. Over 1 hr, the jacket temperature was ramped to 60° C. and then held for 1 hr. Upon completion, the reaction was cooled to 30° C. and quenched by the slow dropwise addition of MeOH (97 mL, 12 eq) to the mixture at a rate to control off gassing. The reaction mixture was then heated to reflux and concentrated to a low stir volume. The reaction solvent THF was then replaced by a constant volume displacement with MeOH (total of 1.5 L). Once the THF content had been reduced to less than 1 wt percent, MeOH was replaced by a constant volume displacement with EtOAc (total of 1.5 L) to reduce the MeOH content to less than 1 wt percent. The total volume of EtOAc was then readjusted to about 250 mL (6 vol) and then cooled to 5° C. to crystallize the product. The desired product was isolated by filtration, washed with cold EtOAc (88 mL) and dried to give title compound (27.0 g, 140 mmol, 70percent). A second crop of product was isolated by concentration of the combined filtrate and cake wash to half volume, which was then cooled to 5° C., filtered and washed with cold EtOAc (50 mL) to afford additional title compound (4.5 g, 23 mmol, 12percent). General procedure: Borane in THF (1.0 M) (17.19 mL, 180.99 mmol) was added drop-wise to a solution of 2a (10.0 g, 45.24 mmol) in THF (200 mL) at RT, after completion of addition, reaction mixture was slowly heated to 70 °C for 3 h. The reaction mixture was cooled to 0 °C, quenched with methanol (50 mL) by the drop-wise addition, slowly warmed to RT, stirred for 1 h. (Note: intensive gas evolution is occurred). The reaction mixture was concentrated in vacuo, crude was purified on a silica gel column using a linear gradient of ethyl acetate in Pet-ether yielding 7.73 g (88.5percent) of yellowish crystals of compound 3a.

Molecular Weight:193.24
XLogP3:0.3
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:193.110278721
Monoisotopic Mass:193.110278721
Topological Polar Surface Area:43.7
Heavy Atom Count:14
Complexity:170
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes