Diphenylphosphinic Chloride

Experimental procedure: N-Benzyloxycarbonylvaline (30.15 g, 0.12 mol) is dissolved in dichloromethane (200 mL) and cooled to 0 °C at which temperature NMM (13.2 mL, 0.12 mol) and a solution of DppCl (28.38 g, 0.12 mol) in dichloromethane (200 mL) are added in quick succession. After an activation period of 15 min a precooled solution of alanine phenyl ester tosylate (33.74 g, 0.1 mol) in dry, distilled DMF (80 mL) is added immediately followed by NMM (11 mL, 0.1 mol) and the mixture is stirred for 30 min. Removal of the reaction solvent left a pale yellow oil which is partitioned between ethyl acetate and water. The organic phase is washed with saturated NaHCO₃ (5 times), 5% citric acid (3 times), water (2 times), saturated NaHCO₃ (2 times), water (2 times) and brine (2 times) before drying over anhydrous magnesium sulfate. Evaporation of solvent under reduced pressure from the final dried solution afforded a white powder which is crystallized from ethyl acetate with light petroleum to give 1 (38.73 g, 81%).

Introduction of the diphenylphosphinyl (Dpp) group: To a vigorously stirred suspension of the amine hydrochloride (0.2 mol) in dichloromethane (500 mL) at 0 °C are added NMM (43.5 mL, 0.4 mol) and DppCl (47.4 g, 0.2 mol) in dichloromethane (90 mL) in such a way as to maintain the temperature of the reaction mixture at 0 °C. The reactants are then stirred for 2 h during which time the temperature rises to ca. 15 °C. Removal of the reaction solvent left a pale yellow oil which is partitioned between ethyl acetate and water. The organic phase is washed with saturated NaHCO₃ (5 times), 5% citric acid (3 times), water (2 times), saturated NaHCO₃ (2 times), water (2 times) and brine (2 times) before drying over anhydrous magnesium sulfate. Following evaporation of the solution, the desired product is crystallized from the residue with appropriate crystallization solvent to afford the protected amine.
Cleavage of the Dpp group: A 1.5 mol/L solution of HCl in methanol (3.5 mL, 5.3 mmol) is added to DppTrp-Met-Asp(OtBu)-PheNH₂ (750 mg, 0.9 mmol) and the mixture is stirred. After 90 min white crystals begin to precipitate out of solution and 1 h later optimum cleavage is considered to have occurred. The reaction mixture is poured into vigorously stirred cold, anhydrous diethyl ether (200 mL) and after stirring for a further 1 h at low temperature. HCl·H₂NTrp-Met-Asp(OtBu)-PheNH₂ (470 mg, 78%) is filtered off, washed with cold diethyl ether, and dried.