Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Jan 7;59(2):890-895.
doi: 10.1002/anie.201911886. Epub 2019 Nov 27.

Cobalt(III)-Catalyzed C-H Amidation of Dehydroalanine for the Site-Selective Structural Diversification of Thiostrepton

Ryan J Scamp  1 , Edward deRamon  1 , Eric K Paulson  1 , Scott J Miller  1 , Jonathan A Ellman  1
Affiliations

Cobalt(III)-Catalyzed C-H Amidation of Dehydroalanine for the Site-Selective Structural Diversification of Thiostrepton

Ryan J Scamp et al. Angew Chem Int Ed Engl. .

Abstract

Thiostrepton is a potent antibiotic against a broad range of Gram-positive bacteria, but its medical applications have been limited by its poor aqueous solubility. In this work, the first C(sp2 )-H amidation of dehydroalanine (Dha) residues was applied to the site selective modification of thiostrepton to prepare a variety of derivatives. Unlike all prior methods for the modification of thiostrepton, the alkene framework of the Dha residue is preserved and with complete selectivity for the Z-stereoisomer. Additionally, an aldehyde group was introduced by C-H amidation, enabling oxime ligation for the installation of an even greater range of functionality. The thiostrepton derivatives generally maintain antimicrobial activity, and importantly, eight of the derivatives displayed improved aqueous solubility (up to 28-fold), thereby addressing a key shortcoming of this antibiotic. The exceptional functional group compatibility and site selectivity of CoIII -catalyzed C(sp2 )-H Dha amidation suggests that this approach could be generalized to other natural products and biopolymers containing Dha residues.

Keywords: C−H activation; antibiotics; chemoselectivity; cobalt; natural products.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Thiostrepton 1 and applicability of Dha residues as scaffolds for analog synthesis.
Figure 2.
Figure 2.
Optimization of reaction conditions for thiostrepton C─H amidation. (a) Reaction scheme and generated regioisomers. (b) Conditions screened for C─H amidation. (c) Crude UPLC chromatogram for optimized conditions (entry 8).
Scheme 1.
Scheme 1.
Scope of thiostrepton C─H amidation.
Scheme 2.
Scheme 2.
Oxime synthesis from a C─H amidation-condensation sequence.
See this image and copyright information in PMC

References

    1. Bagley MC, Dale JW, Merritt EA, Xiong X, Chem. Rev 2005, 105, 685–714. - PubMed
    2. Just-Baringo X, Alberico F, Álvarez M, Mar. Drugs 2014, 12, 317–351. - PMC - PubMed
    1. For leading references on biosynthetic methods to access thiostrepton derivatives, see:Wang X, Lin Z, Bai X, Tao J, Liu W, Org. Chem. Front 2019, 6, 1194–1199.
    1. Shugrue CR, Miller SJ, Chem. Rev 2017, 117, 11894–11951. - PMC - PubMed
    1. For leading references on the total synthesis of thiostrepton, see: Nicolaou KC, Angew. Chem., Int. Ed 2012, 51, 12414–12436. - PMC - PubMed
    1. For leading references on the chemical functionalization of Dha residues, see: (a) Bogart JW, Bowers AA, Org. Biomol. Chem 2019, 17, 3653–3669. - PMC - PubMed
    2. Dadová J, Galan SRG, Davis BG, Curr. Opin. Chem. Biol 2018, 46, 71–81. - PubMed
    3. Cox CL, Tietz JI, Sokolowski K, Melby JO, Doroghazi JR, Mitchell DA, ACS Chem. Biol 2014, 9, 2014–2022. - PMC - PubMed
    4. Naidu BN, Li W, Sorenson ME, Connolly TP, Wichtowski JA, Zhang Y, Kim OK, Matiskella JD, Lam KS, Bronson JJ, Ueda Y, Tetrahedron Lett. 2004, 45, 1059–1063. - PubMed
    5. (e) Zhu Y, van der Donk W, Org. Lett 2001, 38, 1189–1192. - PubMed

Publication types