Ynamide Coupling Reagents: Origin and Advances

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Since the pioneering work of Curtius and Fischer, chemical peptide synthesis has witnessed a century's development and evolved into a routine technology. However, it is far from perfect. In particular, it is challenged by sustainable development because the state-of-theart of peptide synthesis heavily relies on legacy reagents and technologies developed before the establishment of green chemistry. Over the past three decades, a broad range of efforts have been made for greening peptide synthesis, among which peptide synthesis using unprotected amino acid represents an ideal and promising strategy because it does not require protection and deprotection steps. Unfortunately, C → N peptide synthesis employing unprotected amino acids has been plagued by undesired polymerization, while N → C inverse peptide synthesis with unprotected amino acids is retarded by severe racemization/epimerization owing to the iterative activation and aminolysis of high racemization/epimerization susceptible peptidyl acids. Consequently, there is an urgent need to develop innovative coupling reagents and strategies with novel mechanisms that can address the long-standing notorious racemization/ epimerization issue of peptide synthesis. This Account will describe our efforts in discovery of ynamide coupling reagents and their application in greening peptide synthesis.Over an eight-year journey, ynamide coupling reagents have evolved into a class of general coupling reagents for both amide and ester bond formation. In particular, the superiority of ynamide coupling reagents in suppressing racemization/epimerization enabled them to be effective for peptide fragment condensation, and head-to-tail cyclization, as well as precise incorporation of thioamide substitutions into peptide backbones. The first practical inverse peptide synthesis using unprotected amino acids was successfully accomplished by harnessing such features and taking advantage of a transient protection strategy. Ynamide coupling reagentmediated ester bond formation enabled efficient intermolecular esterification and macrolactonization with preservation of α-chirality and the configuration of the conjugated α,β-C−C double bond. To make ynamide coupling reagents readily available with reasonable cost and convenience, we have developed a scalable one-step synthetic method from cheap starting materials. Furthermore, a water-removable ynamide coupling reagent was developed, offering a column-free purification of the target coupling product. In addition, the recycle of ynamide coupling reagent was accomplished, thereby paving the way for their sustainable industrial application. As such, this Account presents the whole story of the origin, mechanistic insights, preparation, synthetic applications, and recycle of ynamide coupling reagents with a perspective that highlights their future impact on peptide synthesis.

Brønsted acid catalyzed Ficini [2 + 2] cycloaddition of ynamides with enones

“…5,6 However, its widespread application is precluded by the difficulties of synthesizing, handling, and storing highly reactive ynamines. Later, ynamides, which bear an electron-withdrawing substituent on the nitrogen atom, emerged as the superior synthetic alternatives, 7 and have been proven to be convenient substrates for the Ficini [2 + 2] cycloadditions (Scheme 1b). 8–10 In 2010, Hsung and coworkers reported their first realization of the ynamide-[2 + 2] cycloaddition under the catalysis of CuCl 2 and AgSbF 6 .…”