(2R,5S)-2-Trichloromethyl-3-oxa-1-azabicyclo[3.3.0]octan-4-one

Uses

An useful precursors of enantiomeric pure C- and N-protected α-alkylproline.

Synthesis

At room temperature, 22 mL (225 mmol, 2.5 eq.) of trichloroacetaldehyde was added dropwise to a 45 mL suspension of acetonitrile containing 10.470 g (90.94 mmol, 1.0 eq.) of L-proline. The reaction mixture was stirred continuously for 19.5 hours at room temperature. Upon completion of the reaction, the solvent was removed by distillation under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and filtered to remove insoluble material. The filtrate was concentrated and the dissolution-filtration-concentration process was repeated three times to finally obtain 18.141 g (74.20 mmol, 82% yield) of the target compound 3-(trichloromethyl)tetrahydro-1H,3H-pyrrolo[1,2-C]oxazol-1-one (103) as a white solid. Molecular formula: C7H8Cl3NO2, molecular weight: 244.50 g-mol1. Specific optical rotation: [α]20D = +34.3° (c = 0.970, benzene). Melting point: 109.6 °C. 1H NMR (400 MHz, CDCl3): δ 1.78-1.64 (m, 1H, H-4'), 1.96-1.85 (m, 1H, H-4), 2.13-2.02 (m, 1H, H-3'), 2.26-2.13 (m, 1H, H-3), 3.15-3.06 (m, 1H, H -5'), 3.39 (ddd, J = 10.9, 7.8, 6.0 Hz, 1H, H-5), 4.09 (dd, J = 8.9, 4.6 Hz, 1H, H-2), 5.14 (s, 1H, H-7).13C NMR (100 MHz, CDCl3): δ 25.32 (t, C-4), 29.91 (t, C-3) 57.87 (t, C-5), 62.38 (t, C-2), 100.62 (s, C-8), 103.60 (d, C-7), 175.43 (s, C-6).IR (FT-ATR, cm1): 2958 (m), 2920 (w), 2893 (w), 2866 (w), 1784 (s), 1725 (m ), 1449(w), 1373(w), 1359(w), 1322(m), 1283(m), 1270(m), 1243(m), 1174(s), 1107(s), 1083(m), 1043(w), 1001(s), 958(s), 913(w), 898(m), 838(s), 813( s), 790(s), 744(s).

References

[1] Tetrahedron Asymmetry, 2002, vol. 13, # 20, p. 2229 - 2234
[2] Synlett, 2007, # 18, p. 2882 - 2884
[3] Patent: US2015/18269, 2015, A1. Location in patent: Paragraph 0110-0117
[4] Chemistry - A European Journal, 2015, vol. 21, # 23, p. 8464 - 8470
[5] Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 837 - 841