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Elsevier, Bioorganic and Medicinal Chemistry Letters, 22(20), p. 6472-6474, 2010

DOI: 10.1016/j.bmcl.2010.09.053

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A Protecting Group-Free Synthesis of Deazathiamine: A Step Toward Inhibitor Design

Journal article published in 2010 by Hong Zhao, Luiz Pedro S. de Carvalho, Carl Nathan, Ouathek Ouerfelli ORCID
This paper is available in a repository.
This paper is available in a repository.

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Abstract

The discovery of 3-deazathiamine diphosphate (deazaThDP) as a potent inhibitor analog of the cofactor thiamine diphosphate (ThDP) has highlighted the need for an efficient and scalable synthesis of deazaThDP. Such a method would facilitate development of analogs with the ability to inhibit individual ThDP-dependent enzymes selectively. Toward the goal of developing selective inhibitors of the mycobacterial enzyme 2-hydroxy-3-oxoadipate synthase (HOAS), we report an improved synthesis of deazaThDP without use of protecting groups. Tribromo-3-methylthiophene served as a versatile starting material whose selective functionalization permitted access to deazaThDP in five steps, with potential to make other analogs accessible in substantial amounts.