Synthesis of 3-acyltetramates by side chain manipulation and their antibacterial activity

Abstract

An efficient approach for the introduction of 3-acyl side chain groups onto a core tetramate system, which are suitable for further manipulation by nucleophilic displacement or Horner-Wadsworth-Emmons coupling, provides access to a diverse library of substituted tetramates related to two distinct classes of natural products, equisetin and pramanicin. Assessment against S. aureus and E. coli indicated that some compounds exhibit significant antibacterial activity, providing unusual leads for further optimisation in the drug discovery process.

Chemoselective Formation and Reaction of Densely Functionalised Bicyclic Tetramic Acids and Their Biological Activity

“…In conclusion, a fully chemoselective Grignard displacement of Weinreb amides 7a – c has enabled the preparation of tetramic acids substituted with a range of side chain acyl groups; this alternative strategy to the classical acylation approach, offers a solution to the recently highlighted difficulty of the introduction of unsaturated side chains in such systems, and neatly complements the work of Schobert which has demonstrated the suitability of Lacey‐Dieckman cyclisation in highly sensitive substrates . Some of these analogues had potent and selective activity against Gram‐positive bacteria, and one is a first‐in‐class proteasome inhibitor.…”

“…in MeCN resulted in quantitative recovery of starting material. This lack of reactivity of the acylated products towards hydrolysis could be due to the presence of the exocyclic enol moiety, which stabilises the lactam by hydrogen bonding . This hypothesis was supported by the successful deprotection of Weinreb amide 7a (Scheme A), which has a free lactam carbonyl.…”

“…We recently reported the preparation of acyltetramates from 4a using the corresponding carboxylic acid and stoichiometric amounts of DCC‐DMAP, which proceeded via O ‐acylation followed by rearrangement to C ‐acylated products 6a , but which was found to be limited in substrate scope, and not suitable for vinylic substrates in particular . In order to enable the introduction of a wider range of functionalities to the tetramate core, we decided to prepare Weinreb amides 7a – c , for the introduction of the desired acyl group at C (6) by Grignard reaction.…”

Bioinspired Synthesis of (−)‐PF‐1018

“…In the final stage of our synthesis, 23 was oxidized to an unstable aldehyde, which was condensed with tetramic acid phosphonate 25 . This gave (−)‐PF‐1018 as an inseparable 3.5:1 mixture of Z and E isomers with respect to the C19=C2′ double bond.…”

“…Acetylation and conversion into the Weinreb amide gave 24 . A subsequent Dieckmann condensation then afforded an unstable pyrrolizidine dione, which was coupled with diethyl phosphonoacetic acid to afford the tetramic acid phosphonate 25 . This building block was also condensed with octanal to afford the recently isolated anionic lipid pyreudione C …”