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, 20 (22), 6472-4

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

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

Hong Zhao et al. Bioorg Med Chem Lett.

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.

Figures

Figure 1
Figure 1
Structures of Thiamine Diphosphate and 3-Deazathiamine Diphosphate.
Figure 2
Figure 2
Inhibition curves for deazaTh and deazaThDP. Experiments were performed in phosphate buffer pH 7.4 at 37°C. DeazaTh (closed circles) was varied from 30 to 600 µM and deazaThDP (open circles) was varied from 1 to 200 µM. Symbols represent data and the solid curve represents the fit to ν = ν0/[1+(I/IC50)nH].
Scheme 1
Scheme 1
Retrosynthetic Analysis Profile of 3-DeazaThDP.
Scheme 2
Scheme 2
Synthesis of 3-Deazathiaminea aReagents and conditions: (a) Zn powder, AcOH, reflux overnight. (b) n-BuLi, 1.0eq, ethylene oxide, BF3-Et2O, −78°C to 0°C, 3 h. (c) n-BuLi, 2.0eq, DMF, −78°C to rt, 3 h. (d) β-anilinopropionitrile, NaOMe/MeOH, DMSO, 40°C, 2 h. (e) acetamidine hydrochloride, NaOEt/EtOH, reflux, 48 h.
Scheme 3
Scheme 3
NOE and Exhaustive Lithiation of 5

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