Use of triphenylmethyl (trityl) amino protecting group in the synthesis of ketomethylene analogues of peptides

The Grignard reagents of 2‐(2‐bromoethyl)‐1,3‐dioxane and 2‐(2‐bromoethyl)‐1,3‐dioxolane readily reacted with the 2‐thiopyridyl ester of N‐triphenylmethyl‐l‐leucine to give the ketone adducts 2‐[3‐oxo‐4(S)‐(triphenylmethyl) amino‐6‐methylheptyl]‐1,3‐dioxane (8a) and 2‐[3‐oxo‐4(S)‐(triphenylmethyl) amino‐6‐methylheptyl]‐1,3‐dioxolane (8b) in near quantitative yield. When 1 equiv. of the Grignard reagent of 2‐(2‐bromoethyl)‐1,3 dioxane was used, the desired ketone adduct 8a was formed slowly but quantitatively. In contrast, when 2 equiv. of the Grignard reagent were used, the formation of ketone 8a was instantaneous. The triphenylmethyl protecting group was easily removed from 8a using dilute acid to give the amino ketone 2‐[3‐oxo‐4(S)‐amino‐6‐methylheptyl]‐1,3‐dioxane oxalate salt (9). This material served as a useful intermediate in the synthesis of the ketomethylene analogues of the peptides, Z‐Pro‐Leu‐Gly‐OH and Leu‐Gly‐Val‐Phe‐OCH₃.