Synthetic Studies Toward the Skyllamycins: Total Synthesis and Generation of Simplified Analogues

Herein, we report our synthetic studies toward the skyllamycins, a highly modified class of nonribosomal peptide natural products which contain a number of interesting structural features, including the extremely rare α-OH-glycine residue. Before embarking on the synthesis of the natural products, we prepared four structurally simpler analogues. Access to both the analogues and the natural products first required the synthesis of a number of nonproteinogenic amino acids, including three β-OH amino acids that were accessed from the convenient chiral precursor Garner’s aldehyde. Following the preparation of the suitably protected nonproteinogenic amino acids, the skyllamycin analogues were assembled using a solid-phase synthetic route followed by a final stage solution-phase cyclization reaction. To access the natural products (skyllamycins A–C) the synthetic route used for the analogues was modified. Specifically, linear peptide precursors containing a C-terminal amide were synthesized via solid-phase peptide synthesis. After cleavage from the resin the N-terminal serine residue was oxidatively cleaved to a glyoxyamide moiety. The target natural products, skyllamycins A–C, were successfully prepared via a final step cyclization with concomitant formation of the unusual α-OH-glycine residue. Purification and spectroscopic comparison to the authentic isolated material confirmed the identity of the synthetic natural products.AR

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis.

Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues were also shown to be nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis

Total Synthesis of Natural Products with Antimicrobial Activity

Natural products are an essential source of many modern medicines. Examples of important natural products include the antibiotic penicillin and the antimalarial quinine. One significant class of bioactive natural products are non-ribosomal peptides (NRPs) and two prototypical members of this class are the extremely important antibiotics, penicillin and vancomycin. Currently, bacterial resistance to antibiotics is one of the most pressing global health issues. The need for new antibiotics with novel mechanisms of action is paramount. This thesis describes the total synthesis of the recently isolated antimicrobial NRPs teixobactin and skyllamycins A-C. Chapter two of this thesis describes the first total synthesis of teixobactin, a novel cyclic NRP antibiotic isolated in 2015. This was carried out via a solid-phase peptide synthesis (SPPS) strategy with a late stage cyclisation reaction. The synthetic natural product possessed potent activity against a number of clinically relevant Gram-positive bacterial pathogens. Chapters three and four describe investigations towards the total synthesis of skyllamycins A-C, a family of structurally complex cyclic NRPs. These natural products inhibit the growth of bacterial biofilms, a mechanism by which bacteria evade antibiotics. The most unusual feature of these natural products is the presence of an α-OH-glycine (Gly) moiety, which to date has only been found in one other linear peptide natural product. Chapter three details the synthesis of the non-proteinogenic amino acids present in the natural products and their incorporation into the synthesis of four skyllamycin analogues that omit the unusual α-OH-Gly residue. These analogues were analysed for their biofilm growth inhibition activity. Chapter four describes the completion of the first total synthesis of skyllamycins A-C. This was achieved through a SPPS strategy followed by a late stage cyclisation and concomitant formation of the unusual α-OH-Gly residue in one step

Total Synthesis of Fellutamide B and Deoxy-Fellutamides B, C, and D

The total syntheses of the marine-derived lipopeptide natural product fellutamide B and deoxy-fellutamides B, C, and D are reported. These compounds were accessed through a novel solid-phase synthetic strategy using Weinreb amide-derived resin. As part of the synthesis, a new enantioselective route to (3R)-hydroxy lauric acid was developed utilizing a Brown allylation reaction followed by an oxidative cleavage-oxidation sequence as the key steps. The activity of these natural products, and natural product analogues was also assessed against Mycobacterium tuberculosis in vitro

Synthesis of β-Thiol Phenylalanine for Applications in One-Pot Ligation- Desulfurization Chemistry

The efficient synthesis of a β-thiol phenylalanine derivative is described starting from Garner’s aldehyde. The utility of this amino acid in peptide ligation–desulfurization chemistry is described, including the trifluoroethanethiol (TFET)-promoted one-pot assembly of the 62 residue peptide hormone augurin

Total Synthesis of Fellutamide B and Deoxy-Fellutamides B, C, and D

The total syntheses of the marine-derived lipopeptide natural product fellutamide B and deoxy-fellutamides B, C, and D are reported. These compounds were accessed through a novel solid-phase synthetic strategy using Weinreb amide-derived resin. As part of the synthesis, a new enantioselective route to (3R)-hydroxy lauric acid was developed utilizing a Brown allylation reaction followed by an oxidative cleavage-oxidation sequence as the key steps. The activity of these natural products, and natural product analogues was also assessed against Mycobacterium tuberculosis in vitro

Total Synthesis of Skyllamycins

The skyllamycins are a family of highly functionalized non‐ribosomal cyclic depsipeptide natural products which contain the extremely rare α‐OH‐glycine functionality. Herein the first total synthesis of skyllamycins A–C is reported, together with the biofilm inhibitory activity of the natural products. Linear peptide precursors for each natural product were prepared through an efficient solid‐phase route incorporating a number of synthetic modified amino acids. A novel macrocyclization step between a C‐terminal amide and an N‐terminal glyoxylamide moiety served as a key transformation to install the unique α‐OH‐glycine unit and generate the natural products in the final step of the synthesis

Dissecting the binding interactions of teixobactin with the bacterial cell wall precursor lipid II

The prevalence of life‐threatening, drug‐resistant microbial infections has challenged researchers to consider alternatives to currently available antibiotics. Teixobactin is a recently discovered “resistance‐proof” antimicrobial peptide that targets the bacterial cell wall precursor lipid II. In doing so, teixobactin exhibits potent antimicrobial activity against a wide range of Gram‐positive organisms. Herein we demonstrate that teixobactin and several structural analogues are capable of binding lipid II from both Gram‐positive and Gram‐negative bacteria. Furthermore, we show that when combined with known outer membrane‐disrupting peptides, teixobactin is active against Gram‐negative organisms.</p

Total Synthesis of Teixobactin

The first total synthesis of the cyclic depsipeptide natural product teixobactin is described. Synthesis was achieved by solid-phase peptide synthesis, incorporating the unusual l-<i>allo</i>-enduracididine as a suitably protected synthetic cassette and employing a key on-resin esterification and solution-phase macrolactamization. The synthetic natural product was shown to possess potent antibacterial activity against a range of Gram-positive pathogenic bacteria, including a virulent strain of <i>Mycobacterium tuberculosis</i> and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)