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

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Abstract
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 equivalent 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. This material served as a useful intermediate in the synthesis of the ketomethylene analogs of the peptides, Z-Pro-Leu-Gly-Oh [Z = benzyloxycarbonyl] and Leu-Gly-Val-Phe-OCH3.