Total Synthesis of the Bacterial Diisonitrile Chalkophore SF2768

Abstract

Chalkophores are bacterial natural products that chelate and transport extracellular copper. The diisonitrile natural product SF2768 was first isolated from a Streptomyces species as an antifungal antibiotic and has more recently been characterized as a bacterial chalkophore and potential virulence factor. Herein, we report a modular synthesis of SF2768 and related acyclic analogues, allowing assignment of syn-stereochemistry across the central lactol ring. The copper-binding properties of these diisonitriles have also been studied.

Figure 1.

Structures of diisonitrile natural products.

Figure 2.

Retrosynthesis of SF2768. The approach assumes the lactol is derived from l-lysine, by analogy to diisonitriles 3 and 4.

Figure 3.

Synthesis of NHS ester 5.

Figure 4.

Synthesis of SF2768. The epimer (2l,5R)-1 was also synthesized by the analogous route from (2l,5R)-8 (not shown). The (2l,5S) configuration was assigned by comparison to the ¹H-NMR and ¹³C-NMR spectra of the natural product.

Figure 5.

Selected regions of ¹H-NMR (left) and ¹³C-NMR spectra (right) of natural product SF2768 (top), synthetic syn-diastereomer (2l,5S)-1 (middle), and synthetic anti-diastereomer (2l,5R)-1 (bottom) in D₂O.

Figure 6.

(a) Formation of 2:1 complex of diisonitrile acetate 4 with Cu(I). (b) ¹H-NMR titration (DMSO-d₆) of diisonitrile acetate 4 with varying amounts of Cu(I).

Figure 7.

(a) UV-Vis titration of Cu(4)₂ (40 μM) by up to 100 equiv. BCS, indicating no formation of Cu(BCS)₂ (λ_max = 483 nm). (b) UV-Vis titration of Cu(BCS)₂ (40 μM) by diisonitrile acetate 4, indicating complete competition at 1 equiv.