Abstract
Rifamycins are an extremely important class of antibacterial agents whose action results from the inhibition of DNA-dependent RNA synthesis. A special arrangement of unsubstituted hydroxy groups at C21 and C23, with oxygen atoms at C1 and C8 is essential for activity. Moreover, it is known that the antibacterial action of rifamycin is lost if either of the two former hydroxy groups undergo substitution and are no longer free to act in enzyme inhibition. In the present work, we describe the successful use of an Alder-Ene reaction between Rifamycin O, 1 and diethyl azodicarboxylate, yielding 2, which was a targeted introduction of a relatively bulky group close to C21 to protect its hydroxy group. Many related azo diesters were found to react analogously, giving one predominant product in each case. To determine unambiguously the stereochemistry of the Alder-Ene addition process, a crystalline zwitterionic derivative 3 of the diethyl azodicarboxylate adduct 2 was prepared by reductive amination at its spirocyclic centre C4. The adduct, as a mono chloroform solvate, crystallized in the non-centrosymmetric Sohnke orthorhombic space group, P212121. The unique conformation and absolute stereochemistry of 3 revealed through X-ray crystal structure analysis is described.
Highlights
The rifamycins constitute an important class of ansamycin antibiotic active against mycobacteria and other bacterial pathogens, exhibiting antiviral properties
New synthetic access to modified ansamycins is important for combatting mutant New synthetic access to modified ansamycins is important for combatting mutant strains of bacterial pathogens
We have shown that whilst pure Rifamycin O is totally strains of bacterial pathogens
Summary
The rifamycins constitute an important class of ansamycin antibiotic active against mycobacteria and other bacterial pathogens, exhibiting antiviral properties. These molecules are comprised of a substituted naphthalene or naphthoquinone core spanned by a seventeen-membered aliphatic ansa bridge. The important bridging ansa moiety has not been so intensively studied, though recent highlights are the excellent antibacterial activity found for. 24-desmethylrifampicin [2]; and the synthesis of C25 carbamate derivatives which are resistant to ADP-ribosyl transferases [3]. The present work was directed at the introduction of a bulky group close to the hydroxy group on C21 of Rifamycin O, 1, Scheme 1, to inhibit transferase deactivation [4,5]. Attempts to carry out a Diels–Alder reaction with dimethyl acetylenedicarboxylate, hoping to exploit the cisoid diene arrangement of 1, torsion angle
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