Reaction Steps
Racemic rel-(3aR,5R)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C18) (20 g, 0.12 mol) was separated into its enantiomers using supercritical fluid chromatography (Column: ChiralPAK® AS-H, 5 μm; Eluent: 9:1 carbon dioxide/methanol). The first-eluting enantiomer provided (3aS,5S)-5-cyclopropyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C75) as a pale yellow solid. The indicated absolute stereochemistry was assigned to compound C75 on the basis of the biological activity of this compound's final targets, which proved to have very poor activity (see Examples 17-18, Table 3); the final targets of its enantiomer C76 (below) proved active (see Examples 9-16, Table 3). Yield: 8.97 g, 0.053 mol, 44%. GCMS m/z 167 [M+]. 1H NMR (400 MHz, CDCl3) δ 4.69 (d, J=13.5 Hz, 1H), 4.57 (ddd, J=10.2, 7.9, 0.7 Hz, 1H), 4.14 (dt, J=13.4, 1.0 Hz, 1H), 3.77 (dd, J=11.8, 7.7 Hz, 1H), 3.39 (qd, J=11.1, 6.7, 1H), 2.81 (ddd, J=10.3, 8.7, 1.4 Hz, 1H), 2.28 (ddd, J=13.1, 6.5, 1.6 Hz, 1H), 1.64 (ddd, J=12.8, 11.4, 11.3 Hz, 1H), 0.86-0.95 (m, 1H), 0.49-0.61 (m, 2H), 0.36-0.42 (m, 1H), 0.19-0.25 (m, 1H).
