4-Methylmorpholine → (R)-tert-Butyl 3-methyl-2-(3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoate

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Reaction Steps

Sodium triacetoxyborohydride (603 mg, 2.85 mmol) and D-valine-tert-butyl ester HCl salt (597 mg, 2.85 mmol) were combined in DCM (15 mL). The reaction mixture was stirred for 20 min at room temperature and then cooled to 0° C. 4-Formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (700 mg, 2.03 mmol) was added, and the solution was stirred for 1 h. The solution was concentrated in vacuo to give a white foam, which was re-dissolved in THF (40 mL). HATU (1.16 g, 3.05 mmol) and N-methylmorpholine (339 μL, 3.05 mmol) were added, and the reaction mixture was stirred at 52° C. for 2 h. Additional HATU (580 mg, 1.53 mmol) and N-methylmorpholine (170 μL, 1.53 mmol) were added, and the reaction mixture was stirred for an additional 2 h at 52° C. The solution was subsequently cooled, diluted with EtOAc, and washed with brine. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (1:2:2 EtOAc/Hexanes/DCM) gave the title compound as a yellow oil, which solidified upon sitting (840 mg, 85%). 1H NMR (500 MHz, CDCl3) δ 0.86 (d, J=7.0 Hz, 3H), 1.08 (d, J=7.0 Hz, 3H), 1.42 (s, 9H), 2.25-2.34 (m, 1H), 2.35 (s, 3H), 4.77-5.14 (m, 3H), 7.05 (d, J=5.0 Hz, 1H), 7.28 (d, J=7.5 Hz, 2H), 8.05-8.10 (m, 3H), 8.45 (d, J=5.0 Hz, 1H). [M+H] calc'd for C25H29N3O5S, 484; found, 484.

Provenance & Evidence