Reaction Steps
A flame-dried 250-mL round-bottomed flask was charged with urea 2 (2.38 g, 12.28 mmol, 1.0 equiv), cinchonidine (7) (0.72 g, 2.46 mmol, 0.2 equiv), and CH2Cl2 (65 mL). The resulting suspension was cooled to −78° C. and a cold solution of imine 3 (5.1 g, 19.24 mmol, 1.5 equiv) in CH2Cl2 (35 mL) was added via cannula transfer. The reaction was warmed to −65° C. and stirred until complete consumption of urea 2 was indicated by TLC analysis, typically 14-36 h (scale-dependent). The crude reaction was filtered through a short silica plug and rinsed with EtOAc (300 mL). The filtrate was concentrated in vacuo to give a pale yellow foam with a 84:16 enantiomeric ratio. Crystalline racemic product was isolated via trituration with 60:40 (v/v) hexanes:EtOAc (300 mL). The analytically-pure white solid was removed by filtration (1.33 g, 24%) and the filtrate was concentrated in vacuo to give a yellow oil. The crude oil was purified by flash chromatography (60:40 to 50:50 hexanes:EtOAc) affording diketone 4 as a pale yellow foam (3.87 g, 70%, 97:3 er). The enantiomeric ratio (er) was determined by SFC analysis (Chiralcel, OD, 9.0% MeOH, 1.5 mL/min, 150 bar, 210 nm; tR-minor 12.8 min, tR-major 14.7 min). Analytical data: [α]D19 +16.5 (c=1.00, CHCl3); mp (racemate) 130-134° C.; 1H NMR (600 MHz, CDCl3): δ 7.37-7.21 (m, 10H), 7.07 (br d, J=6.0 Hz, 1H), 6.59 (d, J=16.2 Hz, 1H), 6.50 (s, 1H), 5.96 (dd, J=16.2 Hz, 7.2, 1H), 5.40 (t, J=7.2 Hz, 1H), 5.14 (d, J=12.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 2.97 (s, 6H), 2.28 (s, 3H), 2.14 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 200.9, 200.4, 157.6, 156.7, 136.9, 136.5, 133.2, 128.7, 128.6, 128.2, 128.2, 128.1, 126.9, 124.6, 81.7, 67.0, 57.2, 36.8, 26.2, 25.4; LRMS (ESI+) Calcd. For C25H29N3O5+Na, 474.20. Found, 474.22. IR (thin film, cm−1) 3418, 2243, 1702, 1635, 1507, 1371, 1249, 1066, 912, 693; TLC (60:40 Hexanes:EtOAc): Rf=0.20.
