A macrolactonization approach to the total synthesis of the antimicrobial cyclic depsipeptide LI-F04a and diastereoisomeric analogues

Abstract

SummaryThe cyclic peptide core of the antifungal and antibiotic cyclic depsipeptide LI-F04a was synthesised by using a modified Yamaguchi macrolactonization approach. Alternative methods of macrolactonization (e.g., Corey–Nicolaou) resulted in significant epimerization of the C-terminal amino acid during the cyclization reaction. The D-stereochemistry of the alanine residue in the naturally occurring cyclic peptide may be required for the antifungal activity of this natural product.

The Pseudoproline Approach to Peptide Cyclization

“…4) were unsuccessful. [27] These examples illustrate that if the turn-inducer does not create a conformation in which the N-and C-termini of the peptide are in close proximity, then cyclization is not assisted by its incorporation, partly explaining the frequently observed sequence specificity of head-to-tail peptide cyclization reactions.…”

“…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.…”

Cyclic Lipodepsipeptides: A New Class of Antibacterial Agents in the Battle Against Resistant Bacteria

“…Total synthesis of fusaricidin A/LI-F04a (48; Figure 12; Table 7) was reported by Cochrane et al [133,134]. In this approach, a linear peptide sequence was assembled on a solid-support using Fmoc-chemistry, followed by peptide cleavage, in solution macrolactonization, and final attachment of 15-guanidino-3-hydroxyhexadecanoic acid.…”

“…In this approach, a linear peptide sequence was assembled on a solid-support using Fmoc-chemistry, followed by peptide cleavage, in solution macrolactonization, and final attachment of 15-guanidino-3-hydroxyhexadecanoic acid. Macrolactonization, a key step in this synthetic approach, was achieved by applying the Corey–Nicolaou, Boden–Keck or Yamaguchi lactonization procedures [134]. However, in all three cases analysis of the reaction, products revealed the mixtures of cyclic diastereoisomers, suggesting that the C-terminal D-Ala 6 underwent undesired epimerization during the macrolactonization reactions [134].…”