Hexamethylenetetramine → methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylate

Participants

Reaction Steps

A solution of (S)-methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)-4,5-dihydrooxazole-4-carboxylate (1.62 g, 5.14 mmol) in anhydrous dichloromethane (15 mL+15 mL+6 mL washing) was added via a glass Pasteur pipette to a stirred suspension of copper(II) bromide (4.60 g, 20.61 mmol), hexamethylenetetramine (2.89 g, 20.61 mmol) and DBU (3.11 ml, 20.61 mmol) in anhydrous dichloromethane (20 mL). The thick suspension was stirred at room temperature for 1.5 hours-HPLC analysis (at 220 nm) indicated complete consumption of starting material and desired product formation. The reaction was partitioned between dichloromethane (20 mL) and a mixture of 10% NH4OH solution and saturated aqueous ammonium chloride solution (1:1, 30 mL). The aqueous phase was extracted with dichloromethane (3×25 mL). The combined organic phase was then washed with 10% NH4OH solution and saturated aqueous ammonium chloride solution (1:1, 30 mL), and a mixture of 1N HCl:brine (1:1, 30 mL). The organic layer was then dried (MgSO4) and evaporated in vacuo to give the crude product which was purified by column chromatography using ethyl acetate-hexane as eluent to give methyl 2-((2R,3R)-2-((tert-butoxycarbonyl)amino)pentan-3-yl)oxazole-4-carboxylate (711 mg, 2.28 mmol, 44.2% yield) as an oil. 1H NMR (400 MHz, CCl3D) δ 8.20 (s, 1H), 5.00 (d, J=9.0 Hz, 1H), 4.17-3.99 (m, 1H), 3.92 (s, 3H), 2.94 (dt, J=9.6, 5.4 Hz, 1H), 1.95-1.70 (m, 2H), 1.42 (s, 9H), 1.10 (d, J=6.8 Hz, 3H), 0.88 (t, J=7.4 Hz, 3H). LC/MS: M+H+313.08, ret. time=0.93 min. Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Temperature: 50° C.; Gradient: 0-100% B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.11 mL/min.

Provenance & Evidence