((3As,5r,6s,6as)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone → (3-(4-(benzyloxy)benzyl)-4-methylphenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone

Participants

Reaction Steps

To a solution of 2-(4-(benzyloxy)benzyl)-4-bromo-1-methylbenzene (34, 2.71 g, 7.4 mmol) in THF (37 mL) under nitrogen at −78° C. was slowly added n-butyllithium (3.3 mL of 2.5 M solution in hexanes, 8.1 mmol), and the reaction was stirred for 30 min. Meanwhile, to a solution of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)(morpholino)methanone (2.02 g, 7.4 mmol) in THF (37 mL) under nitrogen at 0° C. was added tert-butylmagnesium chloride (8.1 mL of 1 M solution in THF, 8.1 mmol). The reaction was stirred for 20 min, then added slowly by cannula to the aryl lithium solution at −78° C. The reaction was allowed to gradually warm to room temperature over 3 hours, then quenched with saturated aqueous NH4Cl, diluted with EtOAc, washed with H2O and brine (with back extraction), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient 0-50% EtOAc/hexanes) to give 2.44 g (70% yield) of the product 35 as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86 (dd, J=7.8, 1.8 Hz, 1 H), 7.75-7.80 (m, 1 H), 7.27-7.49 (m, 6 H), 7.04 (d, J=8.6 Hz, 2 H), 6.86-6.96 (m, 2 H), 6.09 (d, J=3.5 Hz, 1 H), 5.32 (d, J=2.8 Hz, 1 H), 5.04 (s, 2 H), 4.60 (d, J=3.5 Hz, 1H), 4.53-4.58 (m, 1 H), 3.98 (s, 2 H), 3.03 (d, J=4.3 Hz, 1 H), 2.31 (s, 3 H), 1.56 (s, 3 H), 1.36 (s, 3 H); MS (ES+) [M+H]+=475.

Provenance & Evidence