Amide assembly through Ag(I) promoted reaction of thioamides bearing self cleaving auxiliaries

© 2018 Dr. Biana IslandSynthesis of amide bonds is an important issue in organic chemistry but is often overlooked as a contemporary challenge. Existing methods are reaching their limits and new chemical approaches are being developed. The Ag(I) promoted coupling reaction of thioamides with protected amino acids, recently reported in our group, leads to imide formation without epimerisation. This approach was shown to be general for various N-protected amino acids and peptides, including preparation of the pentapeptide thymopentin. However, hydrolysis of the imide is not always regioselective and occasionally results in undesired bond cleavage, leading us to investigate alternative solutions. Thioamides bearing a pendant nucleophile have been investigated as a general method for directed self cleavage of the imide. Amino acid derived o hydroxyphenacetyl thioamides have been applied to the Ag(I) promoted coupling reaction with various N-protected amino acids in good to excellent yields. Self immolative cleavage results in extrusion of benzofuranone to generate the desired amide bond. Application of this method to synthesise peptide based proteasome inhibitors was exemplified by the synthesis of epoxomicin natural product analogue and bortezomib analogue