N-(TERT-BUTOXYCARBONYL)-D-PROLINAL

Clear colorless to yellow liquid

1 49A. tert-Butyl (2R)-2-formylyrrolidine-1 -carboxylateDess-Martin periodinane (15.9 g, 37.4 mmol) was added in portions over 5 minutes toa stirred solution of tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine- 1 -carboxylate (5.0 g, 24.9 mmol) in DCM (75 mL) under a nitrogen atmosphere. The resulting suspensionwas stirred for one hour then filtered through a pad of celite washing with DCM (100 mL). The filtrate was evaporated under reduced pressure to leave a residue which was purified by column chromatography on neutral silica gel using 12percent EtOAc/hexanes as the eluent to give the title compound (4.4 g, 89percent).DMSO (0.698 g, 8.94 mmcl) was added dropwise to a solution of oxalyl chloride (0.566 g, 2.93mmol) in anhydrous DCM (12 mL) at -78C under nitrogen. The reaction mixture was stirred at - 78CC under nitrogen for 15 mm then a solution of (2R)-(+)-1-Boc-2-pyrrolidmnemethanol (0.600 g, 2.98 mmol) in anhydrous DCM (4 mL) was added dropwise. The reaction mixture was stirredat -7&C under nitrogen for 15 mm then Et3N (1.06 g, 11 .92 mmcl) was added and the reaction mixture was stirred at DC under nitrogen for 1 h. The reaction mixture was quenched with sat. NaHCO3 (aq) (20 mL) and extracted with DCM (2 x 20 mL), the organic layers were combined and dried by passing through a Biotage Phase Separator Cartridge and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil log 4O-63im, 60A, l2mL per mm, gradient 0percent 104percent MeOH I DCM]) to give tert-butyl(2R)-2-formylpyrrolidine-1-carboxylate (0.435 g, 73percent).Weigh 100g BOC-D-prolinol into a 2L four-neck reaction flask, add 1.5L of dichloromethane, stir at room temperature After dissolution, add 15.5g of sodium bromide, 2.5g of TEMPO, and cool down to -10 °C.Start to add a sodium hypochlorite solution with a pH of 8 to 9 and maintain the temperature at -5 to -10 °C. TLC tracking (developing agent ethyl acetate: petroleum ether = 1:1), after the reaction of the raw materials was completed, stop adding sodium hypochlorite solution (about 500 ml), stratify at rest, leave the organic layer, and use 1percent sulfuric acid solution respectively.800ml, 5percent sodium thiosulfate solution 800ml and saturated saline 800ml each wash once, The organic layer was dried over anhydrous magnesium sulfate. Filtration and evaporation to give BOC-D-prolinal 95 g.Step B: (2R) -N-Boc-Prolinecarboxyaldehyde To a solution of (2R)-N-Boc-Proline thioester, prepared in Step A, (15.0 g, 6.5 mmol) in acetone was added triethylsilane (5.39 g, 46.3 mmol) and Pd/C (100 mg) at 0°C. When the bubbling was not generated any more, the reaction mixture was warmed to rt and stirred for 30 min. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc/Hex = 1/2) to give the title compound (1.43 g, 93.2percent). MS [M+H] = 200 (M+1)To a solution of oxalyl chloride (6.39 mL, 75 mmol) in DCM (200 mL) at -78 00 under nitrogen, was added DMSO (10.66 mL, 150 mmol) dropwise, the reaction mixture was stirred at -78 00 for 15 mins. (Teit-butoxycarbonyl)-D-proline (10.0 g, 46.4 mmol) in DCM (50 mL) was added dropwise to the reaction mixture at -78 00 over 1 h and thenthe reaction mixture was stirred at -78 00 for 15 mins. Et3N (28 mL, 200 mmol) was added dropwise to the reaction mixture at -78 00 the reaction mixture was warmed to 0 00 and stirred for 1 h under nitrogen. The reaction mixture was quenched with saturated NaHCO3 (aq) (200 mL), combined aqueous layers washed with DCM (100 mL), the organic layers were combined, dried (Na2SO4) and solvents were removed invacuo to give crude teit-butyl (2R)-2-formylpyrrolidine-1-carboxylate (11.1 g, 100percent) asa colourless oil. Used directly without further purificationTo a solution of compound 1 (10.00 g, 38.71 mmol) in THF (100.00 mL) was added LiA1H4 (1.76 g, 46.45 mmol) at -10 -0 C. The mixture was stirred at -10 -0 C for 1 hr. TLC showed compound 1 was consumed and new spot was detected. The mixture was quenched by addition MgSO4 (aq., 3.5 mL) at -10 -0 C, then diluted with ethyl acetate (100 mL), filtered and concentrated under reduced pressure to give a crude. Compound 2 (7.50 g, crude) was used into the next step without further purification. TLC (Petroleum ether: Ethyl acetate = 3: 1) Rf =0.51.LiHMDS (12.8mL, 1M, 12.8mmol, 1.5eq) was added dropwise to the compound 3 (3.0g, 8.54mmol, 1.0eq) at -78 C.In THF (30mL) solution, the reaction solution was reacted at -78 C for 1h, and raised to 0 C for 1h.Then, a THF solution of compound 4 (2.5 g, 12.8 mmol, 1.5 eq) was added dropwise to the system at 0 C, and the reaction was carried out at 0 C for 1 h, and the temperature was raised to room temperature overnight.The reaction solution was quenched with a saturated NH4Cl solution, added with EA, and washed with saturated brine.It was dried over anhydrous sodium sulfate and spin-dried (PE / EA / DCM = 10/1/1 4/1/1) to obtain compound 5 (2.0 g, 59%).TLC: PE / EA = 4/1, 254 nm, Rf (compound 3) = 0.2, Rf (compound 5) = 0.7.

peptide synthesis

Molecular Weight:199.25
XLogP3:1.2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:199.12084340
Monoisotopic Mass:199.12084340
Topological Polar Surface Area:46.6
Heavy Atom Count:14
Complexity:232
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes