Novel 9a,11-bridged azalides: One-pot synthesis of N′-substituted 2-imino-1,3-oxazolidines condensed to an azalide aglycone

Biotic acts of antibiotics

“…On the other hand, there are continuous efforts to modify the existing macrolides to contain pathogens that are becoming resistant to older macrolides. Recent developments, for example, have been based on the use of azalide scaffold (Ištuk, 2011; Sugimoto et al, 2012), which was originally implemented in 9-dihydro-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A (azithromycin), the antibiotic with outstanding pharmacokinetic properties (Amsden, 2001; Mutak, 2007). …”

Novel Tandem Reaction for the Synthesis of N′‐Substituted 2‐Imino‐1,3‐oxazolidines from Vicinal (sec‐ or tert‐)Amino Alcohol of Desosamine

“…Therefore, NЈ-benzyl-thioureas attached to the 3Ј-position (7-9) were prepared on demethylated scaffolds 4-6 by reaction with benzyl isothiocyanate using a similar procedure to that described earlier for the formation of thioureas at the N-9a position. [7] Cyclization of the NЈ-benzylthiourea derivatives 7-9 by using 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) in chloroform readily afforded the desired 1,3-oxazolidine compounds 10-12 (Scheme 1).…”

“…When we had proved that the cyclization of 3Ј-thiourea derivatives could be easily achieved, the next step was to apply the sequential one-pot procedure [7] for the synthesis of 10-12 by using either EDC in solution or polymer-supported Mukaiyama reagent (N-methyl-2-chloropyridinium salt). The demethylated compounds 4-6 were treated with benzyl isothiocyanate and after 2 h EDC or the Mukaiyama reagent was added to the reaction mixture (Scheme 1).…”

“…The one-pot method using EDC afforded the desired NЈ-benzyl-2-imino-1,3-oxazolidine structures annulated to the desosamine ring (10)(11)(12) in comparable yields to the two-step procedure. Surprisingly, cyclization using the Mukaiyama reagent, either polymer-supported or in solution, proved faster and a better choice for the 9a,11 cyclization of azalides, [7] and in this case resulted in the formation of substantial amounts of side products 13-15 (Scheme 1).…”

“…This one-pot procedure involves the cyclization of a secondary amine at the 9a-position and the vicinal hydroxy group at C-11 via intermediate 9a-thiocarbamoyls to afford an NЈ-substituted 2-imino-1,3-oxazolidine moiety condensed to an azalide aglycon. [7] We envisioned that demethylation of the 3Ј-dimethylamino group of desosamine would provide another vicinal secondary amino alcohol unit suitable for the construction of an NЈ-substituted 2-imino-1,3oxazolidine moiety between the 2Ј-and 3Ј-positions of the desosamine ring of various macrolide scaffolds. However, steric hindrance around the desosamine ring is quite different in comparison to the 9a,11 part of the azalide aglycon in which the secondary amine is a part of the macrocyclic ring and thus the outcome of the reaction would be uncertain.…”