Diversity-Oriented Syntheses by Combining CuAAC and Stereoselective INCIC Reactions with Peptides

Abstract

Cascade reactions proceeding through peptide-derived N-carbamoyl iminium ions are reported. Two new reactions of N-carbamoyl iminium ions are described, including a stereoselective double cyclization generating N,N'-aminals and an acid-promoted auto-oxidation. Mechanistic investigations revealed that the N,N'-aminal formation is reversible under strongly acidic conditions. Both of these new reactions proved to be completely orthogonal to subsequent CuAAC chemistry. The reactions were performed in solution and on solid support. The robustness and high stereoselectivity of the methodology holds great promise for applications in parallel diversity-oriented synthesis and in combinatorial synthesis for drug screening.

Keywords: Pictet-Spengler; click chemistry; conformational analysis; diversity oriented synthesis; peptide heterocycles.