The total synthesis of cyclic hexapeptide dichotomin A from linear peptide precursors containing penicillamine-derived pseudoproline residues is reported. The incorporation of a pseudoproline residue led to a faster reaction and higher head-to-tail cyclization yields in comparison to linear precursors containing the native valine residue. However, deprotection of the pseudoproline resulted in significant amounts of a by-product in which a threonine side chain had undergone dehydration, resulting in a low overall yield of the natural product.
Pasireotide is a multi-receptor ligand somatostatin analogue approved for medical treatment of Cushing’s disease and acromegaly. The liquid-phase total synthesis of pasireotide-a 18-membered cyclic hexapeptide-was achieved by the 3 + 2 + 1 strategy, and the Pro1-Phe6 peptide bond was selected as the final cyclization position. Two key fragments were simply synthesized using N,O-bis(trimethylsilyl)acetamide/N-hydroxysuccinimide ester (BSA/NHS) as coupling agents, and processes of the two key fragments were simple without any chromatographic purification. The current synthesis method is easily scalable and produces the target peptide with an overall yield of 15%.
A Practical and Total Synthesis of Pasireotide: Synthesis of Cyclic Hexapeptide via a Three-Component Condensation
