The Horner–Wadsworth–Emmons reaction in the synthesis of macrocyclic peptides: the Trp-His-Gly-Arg derived macrocycle of moroidin

The Trp-His-Gly-Arg derived macrocycle 4 of moroidin 1 containing the unusual tryptophan C-2 histidine N-1 link has been synthesised in protected form. The key steps are displacement of a 2-chloroindole with a histidine derived nucleophile, a Horner–Wadsworth–Emmons reaction followed by asymmetric hydrogenation to establish the tryptophan side chain, and incorporation of the Gly-Arg dipeptide by peptide coupling.