Glycine → L-Phenylalanine, methyl ester

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Reaction Steps

Peptide bond formation was also easily accomplished using the silylative activation of N-protected α-amino thiol acids (FIG. 5). The peptidic thiol acids were generated from the corresponding 9-fluorenylmethyl thiol esters by the method of Crich et al., Org. Lett. 2007, 9, 4423-4426, hereby incorporated by reference in entirety, and used without further purification. As shown in FIG. 5, Gly, Met, Phe, Glu, and Pro thiol acid residues reacted smoothly to give the corresponding dipeptides (entries 1-9). It is noteworthy that sterically hindered α-amino thiol acids like Val (entries 10 and 11) and even 2-aminoisobutyric thiol acid (entry 12) are effectively coupled using this method, although longer reaction times were required to achieve acceptable yields. The amino acids, Phe, Tyr, Val, Ala, Gly, Met, Trp and Pro were all equally effective as N-terminal coupling partners (entries 1-15). The formation of Cbz-Gly-L-Tyr-OMe indicates that phenolic residues do not interfere with the coupling reaction (entry 2). Cbz-Gly-L-Phe-OMe, which is formed as a single dipeptide in 78% yield from Cbz-Gly-SH and L-Phe-OMe under the general coupling conditions (entry 1), is generated in almost an identical isolated yield (71%) when an equimolar amount of Cbz-L-Arg-OH is added to the reaction mixture. This simple experiment confirms the compatibility of this method with both carboxylic acid and guanidine functionalities.

Provenance & Evidence