Cholesterol → Cholesterol TREN methylphosphonamidate

Participants

Reaction Steps

Refering to FIG. 6, 4-Dimethylaminopyridine (DMAP) (0.31 g, 2.5 mmol) was added to a solution of methylphosphonic dichloride (0.332 g, 2.5 mmol, 31P NMR s, 43.93 ppm) stirring at room temperature under positive pressure argon gas. The resulting clear, colorless solution was cooled to −70° C. and a solution of cholesterol (0.97 g, 2.5 mmol) in anhydrous dichloromethane (20 ml) was added via syringe with vigorous stirring over a period of one hour. The reaction mixture was allowed to warm to room temperature and was maintained for 18 hours at which time 31P NMR analysis of a small aliquot of the reaction mixture indicated complete reaction (d, 39.08 ppm). Crude (13) was treated with additional DMAP (0.31 g, 2.5 mmol) and the reaction mixture cooled to −70° C. while stirring under positive pressure argon. Tris(2-aminoethyl)amine (TREN) (0.37 ml, 2.5 mmol) in anhydrous dichloromethane (20 ml) was added dropwise via syringe over a period of two hours. The reaction mixture was warmed to room temperature and stirred for an additional 18 hours (reaction complete by 31P NMR). Direct loading onto flash silica followed by a gradient of 10 to 20% MeOH/dichloromethane with 1 to 4% NH4OH gave 0.442 g of (18) as a white foam: (yield, 28% over two steps), 31P NMR (d, 32.57 ppm), mass spec. calcd=592.89. Found=593.49.

Provenance & Evidence