C(NC(C)C)(C)C.C([Li])CCC.[O:13]=[C:14]1[CH2:18][CH2:17][C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[O:15]1.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>C1COCC1>[O:13]=[C:14]1[CH:18]([CH2:36][C:35]2[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=2)[CH2:17][C:16]2([CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)[O:15]1A solution of diisopropyl amine (0.36 mL, 2.6 mmol) in 7.5 mL dry THF was cooled to −78° C. and n-butyllithium (1.5 mL, 1.6 M in hexane, 2.4 mmol) was added. The mixture was warmed to 0° C. for 15 min then recooled to −78° C. A solution of 2-oxo-8-(t-Butoxycarbonyl)-8-aza-1-oxaspiro[4.5]decane (510 mg, 2.0 mmol, from Step B) in 2 mL THF was added dropwise. After 30 min at −78° C. 4-fluorobenzyl bromide (0.32 mL, 2.6 mmol) was added and after 30 min the mixture was warmed to room temperature and quenched with sat'd ammonium chloride. The mixture was extracted with ethyl acetate and the organic portion was dried over sodium sulfate and concentrated. Flash chromatography (3/1 hexane/EtOAc) afforded 510 mg (70%) of the desired product. 1H NMR (400 MHz, CDCl3). δ 1.44 (s, 9H), 1.51-1.81 (5H), 2.03-2.19 (m, 1H), 2.76-2.81 (dd, 1H), 2.99-3.04 (m, 1H), 3.18-3.3 (m, 3H), 3.72-3.81 (m, 2H), 6.97-7.03 (m, 2H), 7.11-7.18 (m, 2H). The lactone was separated into its enantiomers by semiprep chiral HPLC (chiralpak AD, 9/1 hexane/IPA→8/1 hexane/IPA) to afford the two enantiomers (enantiomer A, 92% ee and enantiomer B, 73% ee). The two enantiomers were converted to the spiro tetrahydrofuran derivatives as described below for enantiomer B.
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