Diisobutylaluminum hydride → Benzyl N,N-bis(tert-butoxycarbonyl)-5-oxo-D-norvalinate

Participants

Reaction Steps

To a stirred solution of 1-benzyl 5-methyl N,N-bis(tert-butoxycarbonyl)-D-glutamate from Step A (48.2 g, 106.8 mmol) in Et2O (400 mL), at −78° C., was added DIBAL (1.0 M in toluene, 133 mL, 133 mmol) slowly so as not to let the internal temperature exceed −65° C. After 15 min, an additional portion of DIBAL (20 mL, 20 mmol) was added. After stirring for a further 20 min, H2O (300 mL) was added and the reaction was warmed to ambient temperature and stirred for 30 min. This mixture was diluted with Et2O and H2O, the layers separated and the aqueous phase extracted with more Et2O. The combined organic extracts were washed with saturated aqueous sodium potassium tartrate (2×), then brine, then dried over MgSO4, filtered and concentrated in vacuo to give benzyl N,N-bis(tert-butoxycarbonyl)-5-oxo-D-norvalinate. This material was dissolved in toluene (310 mL) and nitromethane (57.1 mL, 1.05 mol) and 1,1,3,3-tetramethylguanidine (1.3 mL, 10.5 mmol) were added at 0° C. After stirring for 30 min the nitroaldol reaction was complete, and methanesulfonyl chloride (12.2 mL, 158 mmol) was added, followed by triethylamine (22.0 mL, 158 mmol) at 0° C. and the reaction mixture was allowed to warm to ambient temperature. After 1 h, additional methanesulfonyl chloride (3 mL, 39 mmol) and triethylamine (5.5 mL, 39 mmol) were added. The mixture was stirred for an additional 30 min, then diluted with Et2O and aqueous NaHCO3. The phases were separated and the aqueous layer was extracted further with Et2O. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—95:5 to 50:50, to give the title compound. MS: m/z=487 (M+Na).

Provenance & Evidence