Erythromycin carbamate

The 11,12-carbonate of erythromycin (32) is an older cycHc ester which had greater stabdity and antibiotic activity by diminishing formation of intramolecular enol ether (27) (136,137). A later analogue, the ll-A/-12-0-cychc carbamate of... 

The hydroxy groups in natural products like, for example, the macrolide antibiotics erythromycin, 1"1 and desmycosin, 2001 2011 as well as the 3-(hydroxymethyl)-2- or 3-cephems 2021 and derivatives of the amino sugar garamin 2031 have been converted into the carbamate function with CDI and amines. In the case of aminoglycoside antibiotics of the sisomicin series, thiocarbamates or dithiocarbamates have been prepared from alcohols or thiols using ImCSIm and amines.12041... 

Chloroethyl chloroformate, EtOAc, 7 eq. 50°C, 5 h followed by treatment with methanol which removes the carbamate by solvolysis. This method was used to cleave the IV-methyl from erythromycin B and in the synthesis of a series of Strychnos alkaloids. ... 

Modification of C6-OH of the aglycone is not only possible, it is preferable. Methylation I of this hydroxyl group yields an antibiotic (cla-I rithromycin) with superior pharmacokinetics I (82). Numerous 6-0-aryl derivatives yielded I agents with superior antibiotic activity for I erythromycin, ketolide, and 11,12-carbamate derivatives (106, 116). The authors of this I study speculated that the newly introduced... 

Macrolides such as erythromycin bind 50S by occupying one large pocket formed by nucleotides within the central loop of domain V and then branch out into other neighboring pockets by way of external sugar groups or, in the case of the ketolides, by extensions from either the 11,12-carbamate or the C6-OH. With the possible exception of the 11,12-carbamate and C6-OH extensions, interactions with these satellite pockets are essentially in-... 

Baker, W. R., Fernandes, P. B., Bopp, B., Marsh, K., Nellans, H., Clark, J., Herrin, T., and Hannick, S. (1987). Synthesis and biological activity of erythromycin A 11,12-cyclic carbamates. Presented at 27th Intersci. Conf. Antimicrob. Agents Chemother (Oct. 4-7, New York). Abstr. No. 221. 

ABT-773, 1 l-amino-3-O-descladinosyl-l l-deoxy-3-oxo-6-0-(3"-quinolyl-2 -propenyl) erythromycin A 11,12-cyclic carbamate, is a novel ketolide antimicrobial being developed for clinical use. ABT-773 has demonstrated in vitro activity against community-acquired respiratory pathogens including penicillin/ erythromycin sensitive and resistant strains of S. pneumoniae. Due to its in vitro activity against resistant pathogens, ABT-773 may represent another therapeutic option for community-acquired pneumonia and other respiratory infections [106]. To date, published pharmacokinetic information about clinical trials is not available. The following preclinical results could be used to assist in the prediction of potential in vivo human pharmacokinetic profiles with ABT-773. 

The cyclic 11,12-carbonate of erythromycin represents a previously recognized method for stabilization of erythromycin by maintaining an equilibrium between the 6-hydroxy-9-keto and 6,9-hemiketal forms [44]. A new direction within this approach was recently reported with a series of cyclic 11,12-carbamate derivatives of erythromycin and clarithromycin (see Fig. 5), prepared by a general sequence of 10,11-dehydration, 12-0-carbamoylation, and intramolecular cyclization [45, 46]. Other structural modifications within this part of the erythromycin molecule include 10,11-anhydroerythromycin, previously synthesized from the cyclic 11,12-carbonate [47],... 

The Sonogashira reaction can also be applied in quinoline halogens, attaching alkynes the quinoline ring. This method has been employed as an easy way to connect the quinoline pharmacophore tmit in interesting biological molecules as in the derivatization of 2-fluoro-6-0-propargyl-11,12-carbamate ketolide of erythromycin. ... 

In principle, all that remained to do to reach erythronolide (2) was to deprotect the Ci3 hydroxyl group of 62, conduct the macrolactonization, remove the acetonides, and carry out an oxidation state adjustment at C9. Of course this was easier said than done. The macrolactonization turned out to be very difficult. The Woodward group degraded Erythromycin A (1) to 17 thiopy-ridyl ester substrates, only three of which underwent lactonization under the Corey-Nicolaou conditions. Two of these derivatives gave low yields, but 63 cyclized to 64 in good yield. This effort established that (1) the 5-configuration was essential at C9 and (2) the C3-C5 and C9-C11 diol units had to be protected as cyclic acetals. Based on this information, carbamate-acetal 65 was eventually prepared Ifom the natural product and found to cyclize to 66 in 70% yield. Thus, to complete a total synthesis, it was necessary to convert w-acetorude 62 to 65, and move 66 forward to erythromycin A (1). 

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