Total Synthesis and Assignment of the Side Chain Stereochemistry of LI-F04a: An Antimicrobial Cyclic Depsipeptide

Abstract

The total synthesis of the potent antifungal and antibiotic cyclic depsipeptide LI-F04a and its side chain epimer was accomplished using macrolactonization to assemble the cyclic peptide core, followed by attachment of the 15-guanidino-3-hydroxypentadecanoyl (GHPD) side chain. The side chain was assembled by Yamaguchi-Hirao alkylation of both enantiomers of a chiral epoxide to provide a pair of enantiomeric side chains. The attachment of both these chains to the cyclic peptide allowed the absolute configuration of the side chain hydroxyl group in LI-F04a to be assigned as (R).

Cyclic Lipodepsipeptides in Novel Antimicrobial Drug Discovery

“…49 The (R)-configuration of fatty acid for LI-F04a 13 was determined just recently upon total synthesis of both fatty acid enantiomers and their comparison with the natural LI-F04a. 50 However, it is not yet known whether this stereochemistry is conserved within the family. All isolated antimicrobials showed high activity against a variety of fungi and Gram-positive bacteria, whereas no activity was observed against Gram-negative bacteria.…”

“…LI-Fs/fusaricidins did not, however, show activity against Gram-negative bacteria. 47,48 Low acute toxicity in mice have been reported for LI-F03, LI-F04, LI-F05, LI-F07, and LI-F08 (LD 50 150−200 mg/kg). 46 LI-Fs/fusaricidins' mode of action is still unknown.…”

“…Total synthesis of this natural product was reported in 2010 by Cochrane et al 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. 50 Both enantiomers of this fatty acid were assembled by Yamaguchi-Hiaro alkylation of corresponding chiral epoxide precursors. By comparison of the optical rotations of both synthetic fusaricidin A (LI-F04a) analogs with the natural product, it was determined that the natural product has fatty acid with (R)-absolute configuration.…”

Total Synthesis of the Marine-Derived Cyclic Depsipeptide Alternaramide

“…Alternaramide 1 can be obtained via either a macrolactonization or a macrolactamization event on the precursor linear peptides 5 and 6, respectively. While there are examples of the use macrolactonization in the synthesis of depsipeptides, [13][14][15][16] such a cyclisation performed on 5 may be problematic. However, due to the short synthetic sequence to give the precursor 5 we thought this would be a viable route to explore, alongside the macrolactamization approach.…”

“…Supporting Information for this article includes the 1 H and 13 C NMR spectra of synthetic alternaramide (-)-1 and crystallographic data for (-)-1.…”