Compound 1a

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Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

The peptide NH-Pro-Gly-Leu-Gly-Phe-CO₂H (24.5 mg, 0.05 mmol, 1 eq) was dissolved in a mixture of 1:1 dichloroethane:acetonitrile (1 mL). Propionaldehyde (5.4 μL, 0.075 mmol, 1.5 eq) and (N-isocyanimino)triphenylphosphorane (15.1 mg, 0.05 mmol, 1 eq) were added to the reaction mixture. After cyclization and reverse phase purification the pure fractions were pooled and lyophilized to afford 14mg of the title compound major diastereomer 1a (50% yield) and 5 mg of the minor diastereomer 1b (18 % yield) for a total 68% overall yield. Major (S,S)- 1a: HR-MS (ESI) calculated for C₂₈H₄₀N₇O₅[M+H]⁺: 554.3085 found: 554.3086. HPLC method: low-resolution mass spectra (ESI) were collected on an HPLC paired to a single-quad mass spectrometer. Compounds were resolved on an Agilent Poroshell 120 EC-C₁₈, 2.7 µm, 4.6 x 50 mm² column at room temperature with a flow of 1 mL/min. The gradient consisted of elutents A (0.1% formic acid in double distilled water) and B (0.1% formic acid in HPLC-grade acetonitrile). Absorbance was monitored at λ=214 nm. The gradient method started at 5% of B for the first 1.0 minutes, followed by a linear gradient from 5% to 95% B in 15 minutes. The column was then washed with 95% B for 1.0 minutes and re-equilibrated at 5% B for 2 minutes. Retention time 7.85 min