Title : Combining Organocatalysis and Multicomponent reactions: A sequential synthesis of Sec-containing peptides and dehydropeptides
Abstract:
The efficient design, scalable synthesis of biologically relevant compounds with high structural similarity to natural products remains a challenge to chemical synthesis areas. Metal transition catalysts have been extensively employed for the synthesis of bioactive compounds.1 However, the combination of metal-free asymmetric methodologies like Organocatalysis with Isocyanide-based Multicomponent reactions (IMCRs) is a new trend to produce natural and natural-like compounds.2 The asymmetric aminocatalytic functionalization of aldehydes - via enamine mechanism - followed by IMCRs, provides a convergent and stereoselective way to obtain in one-pot manner different scaffolds (e.g., hydroquinolines, cyclopentenes, peptoids and depsipeptides).2 These compounds can be accessed with high economy atoms, good yields, excellent stereo and regioselectivity, and a high degree of scaffold diversity. The current work is directly related to the merging of Organocatalytic and IMCRs reactions to obtain novel natural-like enantioenriched selenocysteine N-alkylated peptides and also dehydropeptides under mild conditions. The synthetic protocol to the access of selenocysteine N-alkylated peptides comprises the organocatalytic asymmetric insertion of phenylselenium into aliphatic aldehyde moiety followed by the classic Ugi four-component reaction (Ugi-4CR) under mild conditions. After further optimization, selenocysteine compounds were obtained with up to 98:2 e.r., in good yield, as determined by chiral ultra-performance convergence chromatography (UPC2) analysis. We next study the oxidative-elimination of the phenylselenocysteine group to access some dehydropeptides containing ?Abu and ?Phe with high regioselectivity (Scheme 1). We demonstrated by 1D and 2D NMR spectroscopic analysis that Z alkene and cis-rotamer preferably formed for all synthesized compounds
