Ynamines derived from various amines were examined as coupling agents for peptide synthesis soon after the use of alkoxyacetylenes; 53 however, epimerization was encountered likely due to the alkaline nature of the reagents. To overcome the issue of racemization and provide an electron deficient acetylene for effective carboxylate activation, the Zhao laboratory has explored N-methylynetoluenesulfonamide (74) and N-methylynemethylsulfonamide (75) as ynamides in peptide synthesis (Scheme 9). Sulfonyl ynamides 74 and 75 are stable and have been employed in N-to C-direction peptide synthesis in solution and on solid phase with high yields and minimal epimerization. Mechanistic studies supported by X-ray analysis of the adduct from pivalic acid and toluenesulfonyl ynamide 74 have indicated that the ester carboxylate bond of the α-acyloxyenamide is elongated relative to those of vinyl and aryl ester counterparts. The rate-limiting step in the aminolysis reaction was deduced to be formation Twenty-one amino acid peptide 85 was prepared by N-C-SPPS using methansulfonyl ynamide 78 (Scheme 10). Onto Rink amide MBHA AM resin, Boc-Glu-OFm was anchored by way of the side chain and converted to carboxylic acid 80 with 20% piperidine in DMF.