Total synthesis and mechanism of action of the antibiotic armeniaspirol A

Emerging antimicrobial resistance urges the discovery of antibiotics with unexplored, resistance-breaking mechanisms. Armeniaspirols represent a novel class of antibiotics with a unique spiro[4.4]non-8-ene scaffold and potent activities against Gram-positive pathogens. We report a concise total synthesis of (±) armeniaspirol A in six steps with a yield of 20.3% that includes the formation of the spirocycle through a copper-catalyzed radical cross-coupling reaction. In mechanistic biological experiments, armeniaspirol A exerted potent membrane depolarization, accounting for the pH-dependent antibiotic activity. Armeniaspirol A also disrupted the membrane potential and decreased oxygen consumption in mitochondria. In planar lipid bilayers and in unilamellar vesicles, armeniaspirol A transported protons across membranes in a protein-independent manner, demonstrating that armeniaspirol A acted as a protonophore. We provide evidence that this mechanism might account for the antibiotic activity of multiple chloropyrrole-containing natural products isolated from various origins that share a 4-acylphenol moiety coupled to chloropyrrole as a joint pharmacophore. We additionally describe an efflux-mediated mechanism of resistance against armeniaspirols.

The antibiotic armeniaspirol A depolarized bacterial and mammalian cell membranes through a protonophore activity, that accounts for its potent antibiotic effects. A total synthesis of (±) armeniaspirol A was achieved in six steps.     

Dramatically Enhanced Fluorescence of Heteroaromatic Chromophores upon Insertion as Spacers into Oligo(triacetylene)s

In continuation of a previous study on the modulation of π‐electron conjugation of oligo(triacetylene)s by insertion of central hetero‐spacer fragments between two (E)‐hex‐3‐ene‐1,5‐diyne ((E)‐1,2‐diethynylethene, DEE) moieties (Fig. 1), a new series of trimeric hybrid oligomers ( 14 – 18 and 22 – 24 , Fig. 2) were prepared (Schemes 1–3). Spacers used were both electron‐deficient (quinoxaline‐based heterocycles, pyridazine) and electron‐rich (2,2′‐bithiophene, 9,9‐dioctyl‐9H‐fluorene) chromophores. With 19–21 (Scheme 4), a series of transition metal complexes was synthesized as potential precursors for nanoscale scaffolding based on both covalent acetylenic coupling and supramolecular assembly. The UV/VIS spectra (Fig. 3) revealed that the majority of spacers provided hetero‐trimers featuring extended π‐electron delocalization. The new hybrid chromophores show a dramatically enhanced fluorescence compared with the DEE dimer 13 and homo‐trimer 12 (Fig. 5). This increase in emission intensity appears as a general feature of these systems: even if the spacer molecule is non‐fluorescent, the corresponding hetero‐trimer may show a strong emission (Table 2). The redox properties of the new hybrid chromophores were determined by cyclic voltammetry (CV) and rotating‐disk voltammetry (RDV) (Table 3 and Fig. 5). In each case, the first one‐electron reduction step in the hetero‐trimers appeared anodically shifted compared with DEE dimer 13 and homo‐trimer 12 . With larger spacer chromophore extending into two dimensions (as in 14 – 18 , Fig. 2), the anodic shift (by 240–490 mV, Table 3) seems to originate from inductive effects of the two strongly electron‐accepting DEE substituents rather than from extended π‐electron conjugation along the oligomeric backbone, as had previously been observed for DEE‐substituted porphyrins.     

Synthesis of Amphiphilic Fullerene Derivatives and Their Incorporation in Langmuir and Langmuir‐Blodgett Films

Various amphiphilic fullerene derivatives were prepared by functionalization of [5,6]fullerene‐C₆₀‐I_h (C₆₀) with malonate or bis‐malonate derivatives obtained by esterification of the malonic acid mono‐esters 5 – 7 . Cyclopropafullerene 10 was obtained by protection of the carboxylic acid function of 6 as a tert‐butyl ester, followed by Bingel addition to C₆₀ and a deprotection step (Scheme 2). The preparation of 10 was also attempted directly from the malonic acid mono‐ester 6 under Bingel conditions. Surprisingly, the corresponding 3′‐iodo‐3′H‐cyclopropa[1,9][5,6]fullerene‐C₆₀‐I_h‐3′‐carboxylate 11 was formed instead of 10 (Scheme 3). The general character of this new reaction was confirmed by the preparation of 15 and 16 from the malonic acid mono‐esters 13 and 14 , respectively (Scheme 4). All the other amphiphilic fullerene derivatives were prepared by taking advantage of the versatile regioselective reaction developed by Diederich and co‐workers which led to macrocyclic bis‐adducts of C₆₀ by a cyclization reaction at the C‐sphere with bis‐malonate derivatives in a double Bingel cyclopropanation. The bis‐adducts 37 – 39 with a carboxylic acid polar head group and four pendant long alkyl chains of different length were prepared from diol 22 and acids 5 – 7 , respectively (Scheme 9). In addition, the amphiphilic fullerene derivatives 45, 46, 49, 54 , and 55 bearing different polar head groups and compound 19 with no polar head group were synthesized (Schemes 11–13, 15, and 5, resp.). The ability of all these compounds to form Langmuir monolayers at the air‐water interface was investigated in a systematic study. The films at the water surface were characterized by their surface pressure vs. molecular area isotherms, compression and expansion cycles, and Brewster‐angle microscopy. The spreading behavior of compound 10 was not good, the two long alkyl chains in 10 being insufficient to prevent aggregation resulting from the strong fullerene‐fullerene interactions. While no films could be obtained from compound 19 with no polar head group, all the corresponding amphiphilic fullerene bis‐adducts showed good spreading characteristics and reversible behavior upon successive compression/expansion cycles. The encapsulation of the fullerene in a cyclic addend surrounded by four long alkyl chains is, therefore, an efficient strategy to prevent the irreversible aggregation resulting from strong fullerene‐fullerene interactions usually observed for amphiphilic C₆₀ derivatives at the air‐water interface. The balance of hydrophobicity to hydrophilicity was modulated by changing the length of the surrounding alkyl chains or the nature of the polar head group. The best results in terms of film formation and stability were obtained with the compounds having the largest polar head group, i.e. 45 and 46 , and dodecyl chains. Finally, the Langmuir films obtained from the amphiphilic fullerene bis‐adducts were transferred onto solid substrates, yielding high‐quality Langmuir‐Blodgett films.     

The triclinic polymorph of di­bromo[(–)‐sparteine‐κ2N,N′]­zinc(II)

The title compound, [ZnBr₂(C₁₅H₂₆N₂)], when synthesized starting from Zn⁰, is obtained in two polymorphic forms, one belonging to space group P2₁2₁2₁ and one to P1. The present contribution deals with the triclinic phase, which is isostructural with the orthorhombic form but presents a larger metal–metal intermolecular separation; the Zn⃛Zn distance is 7.4715 (6) Å for the triclinic polymorph as opposed to 6.534 Å for the orthorhombic polymorph.