c) Synthesis of 1,1-dimethylethyl (3S)-3-(aminomethyl)-1-pyrrolidine carboxylate
1,1-Dimethylethyl (3R)-3-cyano-1-pyrrolidine carboxylate (73.9 mmol) was dissolved in ethanol (100 mL) in a Parr bottle. Raney Nickel (73.9 mmol; about 2 scoops of aqueous Raney Nickel) was added under nitrogen protection. After sufficiently displacing the air in the reaction system with nitrogen, the reaction mixture was placed on a Parr shaker at 60 psi hydrogen pressure overnight. Upon completion of the reaction, the reaction mixture was filtered through diatomaceous earth under nitrogen protection and the filter cake was washed with a small amount of ethanol. Subsequently, the filter cake was immediately treated with water. The ethanol filtrate was concentrated under reduced pressure to give the title product as a clear oil (71.9 mmol, 97% yield). The enantiomeric ratio of the product was determined to be 95:5 (i.e. >90% ee).
The product was analyzed by chiral HPLC (Daicel Chiralpak AD-H column, 4.6 x 150 mm; mobile phase: heptane:ethanol:isopropylamine=85:10:0.1; flow rate: 1.0 mL/min; UV detection wavelength: 215 nm), and the retention of 1,1-dimethylethyl (3R)-3-(aminomethyl)-1-pyrrolidinecarboxylate time was 4.4 min, and the retention time of 1,1-dimethylethyl (3S)-3-(aminomethyl)-1-pyrrolidine carboxylate was 4.8 min.
1H NMR (400 MHz, CDCl3) δ ppm: 1.47 (s, 9H), 1.54-1.73 (m, 1H), 1.91-2.13 (m, 1H), 2.28-2.52 (m, 1H), 2.78-2.93 (m, 1H), 2.95-3.16 (m, 1H), 3.24-3.67 (m, 5H) .
