Reaction Steps
di-tert-Butyl {(4aS,5R,7aS)-7a-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl}imidodicarbonate (0.1 g, 0.17 mmol) was dissolved in dry methanol (1 mL) and dry toluene (1 mL). To the solution was added 2-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyrazine (mixture of isomers) (0.054 g, 0.15 mmol), palladium-triphenylphosphine (1:4) (0.020 g, 0.02 mmol) and Na2CO3 (0.33 mL, 1M solution in water) and the reaction was stirred at reflux in a sealed tube overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM and the layers separated. The aqueous layer was extracted with DCM (×2) and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (0-15% MeOH in DCM). The product, (4aS,5R,7aS)-7a-{2-fluoro-5-[2-(pyrazin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-5-yl]phenyl}-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine was dissolved in EtOH (5 mL) and CHCl (2 mL) and the reaction was stirred at reflux overnight to remove the SEM protecting group. The reaction mixture was concentrated in vacuo and loaded onto a SCX ion exchange cartridge washing with MeOH followed by 2N NH3 in MeOH. The basic fraction was concentrated in vacuo. The residue was purified by column chromatography (gradient 0-15% MeOH in EtOAc) to afford the title compound (15 mg, yellow film). 1H NMR (400 MHz, MeOH-d4) δ ppm: 9.32 (s, 1 H), 8.65 (t, J=1.0 Hz, 1 H), 8.54 (d, J=2.5 Hz, 1 H), 7.73-8.01 (m, 2 H), 7.58 (br. s., 1 H), 7.17 (dd, J=12.1, 8.6 Hz, 1 H), 4.63 (d, J=9.1 Hz, 1 H), 4.30-4.40 (m, 1 H), 3.82 (dd, J=8.6, 2.3 Hz, 1 H), 3.16 (dd, J=13.5, 3.9 Hz, 1 H), 2.88 (dd, J=13.4, 4.0 Hz, 1 H), 2.61 (dt, J=8.3, 4.1 Hz, 1 H), 1.34 (d, J=6.1 Hz, 3 H).
