The O-Acyl to N-Acyl salicylamide rearrangement Andrew Stachulski, Craig M. Robertson University of Liverpool, UK
We recently reported on the rearrangement of a prodrug amino-acid ester of a salicylaminothiazole derivative, which was stable as its HCl salt 1 but at pH>4 readily rearranged to a pseudotripeptide structure. 2 Hydrolysis, regenerating the parent amide, was a minor pathway. A similar rearrangement was reported in the 1950s by Brenner et al, 3 who claimed the synthesis of a number of di and tripeptides by this method. In our example, we believe the relatively high acidity of the NH proton facilitates the rearrangement, compared to standard peptide structures.
We have applied the synthesis and demonstrated the conversion of an O-acylated salicyl amino acid ester 1 to a salicyl dipeptide 2 , with complete retention of stereochemistry in the migrating unit. A plausible mechanism for this rearrangement will be presented, incorporating an intermediate of a type previously characterised, 4 together with a discussion of its possible application to broader peptide synthesis. References
1. 1. Eur. J. Med. Chem. , 2017, 126 , 154-159. 2. ACS Bio & Med Chem Au , 2023, Article ASAP. 3. Helv. Chim. Acta , 1957, 40 , 1497-1517. 4. Tetrahedron Lett ., 2010, 51 , 23-26.
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© The Author(s), 2023
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