A comparison of pseudoproline substitution effects on cyclisation yield in the total syntheses of segetalins B and G

Abstract

The total syntheses of the naturally occurring cyclic pentapeptides, segetalins B and G, using a traceless pseudoproline‐mediated cyclization reaction is reported. The incorporation of a cysteine‐derived gem‐dimethyl pseudoproline [Cys(ΨMe,MePro)] residue in the linear precursors to induce a cisoid amide bond prior to the head‐to‐tail cyclization resulted in improved cyclization yields in both cases. Cysteine‐derived pseudoproline residues lacking the gem‐dimethyl substituents [Cys(ΨH,HPro)] were not as effective at inducing cisoid conformations of the amide bonds and resulted in lower cyclization yields with a concomitant increase in the formation of cyclodimers. The Cys(ΨMe,MePro) containing cyclic peptides were subject to deprotection and desulfurization to give the alanine containing natural products in high overall yields. In contrast, deprotection of cyclic peptides containing Cys(ΨH,HPro) residues upon treatment with trifluoroacetic acid removed other side chain‐protecting groups but left the Cys(ΨH,HPro) residues intact.

The Pseudoproline Approach to Peptide Cyclization

“…5). [30] Neither of these cyclic peptides contains a Ser, Thr or Cys residue, but both contain at least one Ala. Replacement of Ala by a CysC Me,Me pro residue in the linear peptide precursor led to high cyclization yields for both sequences and eliminated the formation of cyclodimers in the cyclization reaction.…”

“…Recently developed approaches to the head-to-tail cyclization of a native peptide sequence include the use of native chemical ligation, [12] a-ketoacid-hydroxylamine amide ligation, [13] traceless Staudinger ligation, [14] Ugi peptide ligation, [15] auxiliary-based ring contraction approaches, [16] and the use of traceless turn-inducers. [9,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Traceless Turn-Inducers to Facilitate Peptide Cyclization…”

“…Subsequently, a variety of removable turn-inducers have been employed for peptide cyclization, including 2,4-dimethoxybenzyl (Dmb) protecting groups, [17] 2-hydroxy-6-nitrobenzyl substituents, [18] dehydrophenylalanine, [19] and pseudoprolines. [20][21][22][23][24][25][26][27][28][29][30][31] A related approach, which uses a removable tether to bring the N-and C-termini of a cyclic peptide into close proximity has also been reported. [33] The present account will focus on the use of pseudoprolines as traceless turn-inducers to facilitate the headto-tail cyclization of peptides.…”