methyl (2S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of L-proline methyl ester.HCl (8.04 g, 43 mmol) in CH2Cl2 (86.0 ml) at 0° C. was added NEt3 (12.0 mL, 86 mmol), followed by chloroacetyl chloride (1.1 equiv, 3.72 g, 47 mmol) dropwise via syringe. The reaction mixture was allowed to warm to room temperature with stirring. After 16 h, the mixture was diluted with sat. aqueous NaHCO3 and the organic layer was removed. The aqueous portion was extracted with CH2Cl2 (25 mL). The combined organic layers were washed with brine (25 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford N-chloroacetyl-L-proline methyl ester as a light brown oil (7.85 g, 38 mmol). A portion of the resulting oil (5.25 g, 26 mmol) was dissolved in butanone (51 mL) at RT and NaN3 (3.67 g, 51 mmol) was added in one portion. The reaction vessel was fitted with a reflux condenser and the heterogenous mixture was heated at 80° C. for 20 h. The resulting mixture was cooled to room temperature, filtered and concentrated in vacuo to afford N-azidoacetyl-L-proline methyl ester as a light red oil (5.37 g, 25 mmol). A portion of the oil (1.97 g, 9 mmol) was dissolved in anhydrous PhMe (38 mL) and PPh3 (2.55 g, 10 mmol) was added in one portion. After gas evolution steadied, the reaction mixture was heated at 90° C. for 20 h. The reaction mixture was concentrated in vacuo and triturated with a 1:1 mixture of Et2O/hexanes in order to remove the desired diketopiperazine product from the bulk of phosphine oxide byproduct. The trituration solution was concentrated and the resulting residue was purified by flash column chromatography on silica gel (elution: 1% MeOH to 10% MeOH in 1:1 EtOAc/PhMe+1% NEt3). The resulting diketopiperazine lactim ether product, (S)-1-methoxy-6,7,8,8a-tetrahydropyrrolo[1,2-a]pyrazin-4(3H)-one (13), (1.43 g, 8 mmol, 80% yield, 3 steps) was obtained as a light yellow oil: TLC (60% EtOAc in hexane), Rf: 0.20 (CAM); [α]D25=+102 (c 2.07, CH2Cl2); IR (film): 2951, 2984, 2889, 2360, 2107, 1685, 1457, 1322, 1263, 1022, 751, 673, 625, 573 cm−1; 1H NMR (400 MHz, CDCl3) 4.21 (dd, J=9.5 Hz, 1.6 Hz, 1H), 4.11 (d, J=4.9 Hz, 1H) 4.03 (m, 1H), 3.68 (s, 3H), 3.65 (m, 1H) 3.47 (m, 1H), 2.25 (m, 1H), 2.03 (m, 1H), 1.83 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 166.4, 161.8, 56.5, 53.3, 52.3, 44.2, 29.3, 22.2; Exact mass calcd for C8H12N2O2 [M+Na+], 191.0791. Found 191.0790. the organic layer was removed The aqueous portion was extracted with CH2Cl2 (25 mL) The combined organic layers were washed with brine (25 mL) dried (Na2SO4) filtered concentrated in vacuo