Compound 6ba

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InChIKey VTMYPMPMVJPAFL-GXTWGEPZSA-N

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

To a flame-dried, 10-mL, single-necked Schlenk flask fitted with a magnetic stir bar, argon inlet and a septum were added 21 mg of 7 (0.025 mmol, 0.025 equiv), 102 µL of benzaldehyde (1.00 mmol) and 5.0 mL anhydrous CH₂Cl₂ (0.2 M in aldehyde). The solution was stirred, cooled to -78 °C (internal) with a dry ice/acetone bath and then 175 µL of N,N-diisopropylethylamine (1.00 mmol, 1.0 equiv) and 130 µL of SiCl₄ (1.1 mmol, 1.1 equiv) were added via syringe to the reaction vessel. The resulting solution was stirred for 5 min at -78 °C and then 0.84 mL of a 1.43 M solution of silyl ketene imine 4b (1.2 mmol, 1.2 equiv) in dichloromethane was added dropwise via syringe over 3 min. The yellow reaction mixture was allowed to stir for an additional 2 h at -78 °C before 0.65 mL of a 2:1:1 mixture of Et₃N/CH₂Cl₂/MeOH was added via syringe. The quenched solution was stirred for 5 min at -78 °C and then was transferred to a 50-mL Erlenmeyer flask containing a stirred, sat. aq. solution of NaHCO₃ (10 mL) and KF (10 mL). The biphasic mixture was stirred vigorously for 1 h at rt and then was filtered through a pad of packed Celite (ca. 7 g) in a 60-mL, coarse, glass-sintered Büchner funnel. The filter cake was washed with 10 mL of CH₂Cl₂ and 10 mL of H₂O and then the filtrate was transferred to a 125-mL separatory funnel where the organic layer was isolated. The aquaeos layer was extracted with CH₂Cl₂ (2 x 20 mL) and the resulting organic extracts were combined, washed with brine (1 x 25 mL), and dried over MgSO₄ (ca. 3 g). The solution was filtered and concentrated in vacuo (40 °C, 30 mm Hg) to give a yellow oil. The crude residue was purified by column chromatography (25 g SiO₂ gel, Ø 20 mm column, hexanes/EtOAc gradient (11:1, 120 mL to 9:1, 300 mL)) to afford 195 mg of 6ba (84%) as a viscous, yellow oil after drying in vacuo for 12 h (Abderhalden, 40 °C, 0.3 mm Hg). The diastereomeric ratio was determined to be 96:4 by ¹H NMR (500 MHz) analysis of the crude product. mp: 63–65 °C; ¹H NMR: (500 MHz, CDCl₃) 7.50 (d, J=7.7 Hz, 2 H, HC(5)), 7.41 – 7.33 (m, 3 H, HC(6, 7)), 4.57 (s, 1 H, HC(3)), 3.33 (s, 1 H, OH), 1.50 (s, 3 H, H₃C(8)), 1.46 (s, 9 H, H₃C(10)); ¹³C NMR: (125 MHz, CDCl₃) 136.2 (C(4)), 128.8 (C(7)), 128.2 (C(5, 6)), 128.0 (C(5, 6)), 120.3 (C(1), 80.2 (C(3)), 79.0 (C(2)), 74.7 (C(9)), 29.9 (C(10)), 24.0 (C(8)); IR: (KBr Pellet) 3505 (s), 3070 (m), 2985 (s), 2936 (m), 2886 (s), 1497 (m), 1455 (s), 1368 (s), 1318 (s), 1225 (s), 1198 (s), 1125 (s), 1089 (s), 1060 (s), 1028 (m), 972 (s), 871 (m), 818 (m), 772 (m), 740 (s); MS: (ESI) 256.1 (63.9, M+Na⁺), 240.1 (18.3), 207.1 (8.3), 152.1 (13.6), 151.1 (100.0), 133.0 (97.6), 105.1 (50.3) HRMS: calcd for C₁₄H₁₉NO₂Na⁺: 256.1308, found: 256.1310; TLC: 0.15 (hexane/EtOAc, 9:1) [CAM]; Opt. Rot.: [α]_D²⁴ –12.7 (c=2.13, EtOH); SFC: see 3,5-DNB-derivative (-)-16, page S64; Analysis: C₁₄H₁₉NO₂ (233.306) Calcd: C, 72.07; H, 8.21; N, 6.00% Found: C, 71.94; H, 8.37; N, 6.05%.