Ynamide-Mediated Peptide Bond Formation: Mechanistic Study and Synthetic Applications.

Ynamides, a class of novel coupling reagents for peptide synthesis, facilitated peptide bond formation in a one-pot, two-step manner with α-acyloxyenamide active esters of amino acids as stable intermediates. Ynamide-mediated peptide synthesis proceeded by a reaction mechanism that is completely different from that of conventional coupling reagents and exhibited superiority in addressing the issue of racemization/epimerization during peptide bond formation. Herein, we present a systematic mechanistic analysis, including kinetics and Brønsted-type structure-reactivity studies and density functional theory calculations, providing unprecedented mechanistic insight into ynamide-mediated peptide bond formation. Based on these mechanistic studies, significant improvements were made, and the applicability of ynamide-mediated peptide bond formation was successfully expanded to peptide fragment condensation, head-to-tail cyclization and solid-phase peptide synthesis.

Palladium-Catalyzed Hiyama Coupling of Benzylic Ammonium Salts via C-N Bond Cleavage.

The first palladium-catalyzed Hiyama cross-coupling of arylsilanes with benzyltrimethylammonium salts is reported. The reaction proceeds smoothly to facilitate C(sp2)-C(sp3) bond formation via cleavage of the C-N bond and provides a useful approach to various diarylmethanes with a broad substrate scope and excellent functional group tolerance in good to excellent yields.

Palladium-Catalyzed Coupling of Terminal Alkynes with Benzyl Ammonium Salts.

A highly efficient palladium-catalyzed Sonogashira coupling of benzylic ammonium salts with terminal alkynes is developed. This strategy provides a facile access to a series of internal alkyne derivatives in moderate to excellent yields via C-N bond cleavage and C(sp3)-C(sp) bond formation. The broad substrate scope and high functional group tolerance make this reaction attractive for organic synthesis.

Ynamide-Mediated Thiopeptide Synthesis.

Exploration of the full potential of thioamide substitution as a tool in the chemical biology of peptides and proteins has been hampered by insufficient synthetic strategies for the site-specific introduction of a thioamide bond into a peptide backbone. A novel ynamide-mediated two-step strategy for thiopeptide bond formation with readily available monothiocarboxylic acids as thioacyl donors is described. The α-thioacyloxyenamide intermediates formed from the ynamides and monothiocarboxylic acids can be purified, characterized, and stored. The balance between their activity and stability enables them to act as effective thioacylating reagents to afford thiopeptide bonds under mild reaction conditions. Amino acid functional groups such as OH, CONH2 , and indole NH groups need not be protected during thiopeptide synthesis. The modular nature of this strategy enables the site-specific incorporation of a thioamide bond into peptide backbones in both solution and the solid phase.

Ynamides as Racemization-Free Coupling Reagents for Amide and Peptide Synthesis.

A highly efficient, two-step, one-pot synthetic strategy for amides and peptides was developed by employing ynamides as novel coupling reagents under extremely mild reaction conditions. The ynamides not only are effective for simple amide and dipeptide synthesis but can also be used for peptide segment condensation. Importantly, no racemization was detected during the activation of chiral carboxylic acids. Excellent amidation selectivity toward amino groups in the presence of -OH, -SH, -CONH2, ArNH2, and the NH of indole was observed, making the protection of these functional groups unnecessary in amide and peptide synthesis.