A broadly useful acid-labile traceless azido linker for the solid-phase synthesis of NH-1,2,3-triazoles is presented. A variety of alkynes were efficiently immobilized on a range of polymeric supports by Cu(I)-mediated azide-alkyne cycloadditions. Supported triazoles showed excellent compatibility with subsequent peptide chemistry. Release of pure material (typically >95%) from the solid support was readily achieved by treatment with aqueous TFA.
N-Terminally modified α-thiourea peptides can selectively be synthesized on solid support under mild reaction conditions using N,N'-di-Boc-thiourea and Mukaiyama's reagent (2-chloro-1-methyl-pyridinium iodide). This N-terminal modification applies to the 20 proteinogenic amino acid residues on three commonly used resins for solid-phase synthesis. Complementary methods for the synthesis of α-guanidino peptides have also been developed. The thiourea products underwent quantitative reactions with α-halo ketones to form thiazoles in excellent purities and yields. When strategically installed between two alkene moieties, said thiazole core was conveniently embedded in peptide macrocycles via Ru-catalyzed ring-closing metathesis reactions. Various 15-17 membered macrocycles were easily accessible in all diastereomeric forms using this methodology. The developed "build/couple/pair" strategy is well suited for the generation of larger and stereochemically complete screening libraries of thiazole-containing peptide macrocycles.
An efficient reductive cyclization strategy was employed for the synthesis of N-substituted β,γ-dihydroxy-γ-lactams. A subsequent Petasislike reaction (PLR) through nucleophilic additions of boronic acids to intermediate N-acyliminium ions produced substituted γ-lactams. Overall, the application of this protocol provides β,γ-dihydroxy-γ-lactams and functionalized γ-lactams with potential interest for synthetic and bioorganic chemistry.
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