O,N,N‘-Trialkylisoureas as Mild Activating Reagents for N-Acylsulfonamide Anchors

Abstract

[chemical reaction: see text]. Prior to detachment of compounds synthesized on sulfonamide based safety-catch linkers, the molecular anchor has to be activated. This is achieved by alkylation of the nitrogen atom of the N-acylsulfonamide using different established protocols. As an addition to the existing repertoire of activating reagents, we suggest the use of O,N,N'-trialkylisoureas. Besides the demonstration of the feasibility of these mild alkylating agents for this purpose, custom-tailored novel O,N,N'-trialkylisoureas prepared from electron-deficient alcohols are reported.

N-Acylsulfonamide Linker Activation by Pd-Catalyzed Allylation

“…The N -acylsulfonamide safety catch resin is especially valuable for the synthesis of peptide thioesters. − These species are critical components in the assembly of natural and nonnatural proteins using native-chemical ligation, expressed protein ligation, and Staudinger ligation . Peptide thioesters have been synthesized from the methylated alkylsulfonamide linker .…”

“…Accordingly, when cyanomethylation is used for linker activation, no thiophenol additive is required; the thioester is generated directly . The disadvantage of cyanomethylation is that the conditions are basic and side reactions can occur. , Moreover, N -acylsulfonamide cyanomethylation typically proceeds in lower yield than methylation. Thus, there remains a need for alternative methods for N -acylsulfonamide linker activation.…”

Isoureas: Versatile Alkylation Reagents in Organic Chemistry

“…The reaction can be carried out with polymer-bound sulfonamide. 10 (H) Phenol ether and thiophenolether can be prepared via the reaction of O-alkyl isoureas with phenol and thiophenol, respectively. 11,12 (I) O-alkyl isoureas were reported as allyl reagents in C-C bond formation reactions in the presence of a palladium catalyst.…”

4-Aminocyclopentane-1,3-diols as platforms for diversity: synthesis of a screening library

“…While the Oalkyl-isourea is easier to handle and cheaper, the reactivity of the N-acyl-N-alkylsulfonamides bearing a cyanomethyl residue is more pronounced. 18 All products were puried by medium pressure liquid chromatography (MPLC) on solid phase extraction (SEP) cartridges to remove particulates from the polymeric material because such impurities would be invisible in HPLC analyses but severely hamper biological evaluations. The subsequent analysis by HPLC revealed only two compounds with less than 80% purity and one compound with less than 85% purity.…”