Trimethylsilyl triflate → (S)-1-[(2S,3R)-2-((S)-2-tert-Butoxycarbonylamino-3-methyl-butyrylamino)-3-(tert-butyl-diphenyl-silanyloxy)-butyryl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester

Participants

Reaction Steps

(S)-1-[(2S,3R)-2-tert-Butoxycarbonylamino-3-(tert-butyl-diphenyl-silanyloxy)-butyryl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (1.95 g, 2.79 mmol) was dissolved in dichloromethane (10 mL), under an atmosphere of nitrogen and cooled using an ice bath before adding trimethylsilyl trifluoromethanesulfonate (379 μL, 4.19 mmol). The reaction mixture was stirred for 1 h before adding N,N-diisopropylethylamine (1.95 mL, 11.2 mmol) and removing all volatiles. The residue was redissolved, along with (S)-2-tert-butoxycarbonylamino-3-methyl-butyric acid (728 mg, 3.35 mmol) in anhydrous acetonitrile (10 mL). The solution was cooled using an ice bath, before adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (1.49 g, 3.91 mmol) and N,N-diisopropylethylamine (1.95 mL, 11.2 mmol). The reaction mixture was allowed to slowly warm to room temperature and left to stir overnight. The solvent was evaporated and the remaining residue was purified by silica gel chromatography using a stepwise gradient of iso-hexanes/ethyl acetate 1:0 to 1:1 to afford the title compound (1.02 g, 46%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.03 (d, J=6.9 Hz, 6H), 1.12 (d, J=6.3 Hz, 3H), 1.49 (s, 9H), 1.21-1.25 (m, 1H), 1.74-1.94 (m, 2H), 2.12-2.24 (m, 1H), 2.66-2.86 (m, 2H), 3.48 (d, J=11.1 Hz, 1H), 4.06-4.29 (m, 4H), 4.76 (ABq, Δδ=0.24, JAB=11.8 Hz, 2H), 5.16 (d, J=9.3 Hz, 1H), 5.25 (d, J=9.0 Hz, 1H), 6.72 (d, J=8.7 Hz, 1H), 7.34-7.47 (m, 6H), 7.57-7.65 (m, 2H), 7.66-7.74 (m, 2H). LCMS (m/z) 801.2 [M+H], Tr=4.31 min.

Provenance & Evidence