Cyclic Peptides from Linear Unprotected Peptide Precursors through Thiazolidine Formation

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Abstract

We describe a general method for the preparation of cyclic peptides by intramolecular thiazolidine formation from linear, unprotected peptide precursors. The precursors contain a protected 1,2-aminothiol from an N-terminal cysteine and a 1,2-amino alcohol or 1,2-diol as a masked aldehyde. Thiazolidine formation was effected by oxidation of the 1,2-amino alcohol or 1,2-diol by sodium periodate to give an aldehyde, followed by deprotection of the masked 1,2-aminothiol. The cyclization could be effected at concentrations as high as 20 mM and was free from any polymerized side products. Such high efficiency of macrocyclization may be attributed to the ring-chain” tautomerism of the open chain amino-aldehyde precursor that favors a macrocyclic thiazolidine ring. Thiazolidine formation was further exploited as a capture device to position the N and C termini covalently close together and then to allow a proximity-driven O to N acyl transfer through a novel tricyclic ring contraction to yield an all amide, end-to-end cyclic lactam. These macrocyclization methods have been applied to the synthesis of cyclic peptides containing 5 to 26 amino acids.

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