Erythromycin glycosidation

Cyclic carbonic esters were also prepared, for example, from the cardiac glycoside proscillaridine[257] (where besides CDI the benzyloxycarbonylimidazole was successfully used), ingenol, 2581 the macrolide antibiotic tylosine,[259] and an erythromycin A derivative.12601... 

Finally, macrocyclization is carried out via protection and deprotection sequences and cyclization of the activated ester 26, and this accomplishes the synthesis of 27 (Scheme 7-6), which, through deprotection and glycosidation, can be converted to erythromycin A, a compound containing a hopelessly complex array of chiral centers.4... 

The most impressive application of 2-thiopyridyl and 2-thiopyrimidinyl donors is in the area of antibiotics. Thus, Woodward et al. [481] successfully completed the total synthesis of erythromycin by using S Pyrm glycoside of D-desosamine and S Pyr-glycoside of L-cladinose as glycosyl donors to the subsequent glycosylation with erythronalide A. This methodology was also successfully used in the synthesis of oleandomycin [482,483], erythromycin A [484] and erythromycin B [485]. 

Cardiac depressant effects may occur when verapamil or diltiazem is combined with a (p-adrenoceptor antagonoist or a cardiac glycoside. Nifedipine and verapamil are metabolised by cytochrome P-450 3A4. Inhibitors of this enzyme, e.g. HIV-protease inhibitors, cimetidine, fluoxetine, ketoconazole, erythromycin, will increase plasma levels and the dose should be carefully monitored. Conversely, enzyme inducers, e.g. carbamazepine, rifampicin, phenytoin, will decrease their plasma concentrations. 

Chemistry of the glycoside linkage. Exceptionally fast and efficient formation of glycosides by remote activation, Carbohydr. Res. 80 07 (1980). (e) K. Wiesner, T. Y. R. Tsai, and H. Jiu, On cardioactive steroids. XVI. Stereoselective P-glycosylation of digitoxose the synthesis of digitoxin, Helv. Chim. Acta 60 300 (1985). (f) R. B. Woodward (and 48 collaborators), Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin, J. Am Chem. Soc. 103 3215 (1981). (g) P. G. M. Wuts and S. S. Bigelow, Total synthesis of oleandrose and the avermecin disaccharide, benzyl ot-L-oleandrosyl-ot-L-4-acetOxyoleandroside, J. Org. Chem. 43 3489 (1983). 

Erythromycin A 64 and spinosyns A and D 65a/65b are important macrolides produced by Saccharopolyspora erythraea and Sacch. spinosa, respectively. Compound 65a contains per-O-methylated L-rhamnose and D-forosamine attached O-glycosidically to the aglycone. Gene knockouts in respective strains as well as expression of various sugar cassettes (along with appropriate GT gene(s)) in Sacch. erythraea mutants led to production of many derivatives of 64 and 65a and tylosin [111-114],... 

The O-methyl group of L-cladinose (2) is also derived from L-methionine. The O-methylation step does not, however, take place at the level of the nucleotide-sugar, but it occurs when the substrate is erythromycin C, which contains L-mycarose and D-desosamine as glycosidic components9 (see Scheme la). The O-methylation of the L-mycarose moiety of erythromycin C by a partially purified enzyme from Streptomyces erythreus was described by Alpine and Corcoran.10,11 The reaction catalyzed is shown in Scheme la. 

S. Hanessian, C. Bacquet, and N. Lehong, Chemistry of the glycosidic linkage, exceptionally fast and efficient formation of glycosides by remote activation, Cabohydr. Res. S0 C17 (1980). R. B. Woodward, et al. Asymmetric total synthesis of erythromycin. 3. Total synthesis of erythromycin, J. Am. Chem. Soc. 103 3215 (1981). 

The C10-C13 segment 24 was prepared from D-ribose (35) (O Scheme 2). In this case, selective protection of the hydroxy groups was realized by isopropylidenation (from 35 to 36). One of the other procedures for conversion of cyclic monosaccharides to acyclic derivatives is nucleophilic addition to the anomeric position in free monosaccharides. Grignard reagent, MeMgl, was added to 36 to provide 37 as the sole product. The subsequent manipulation of 37 to the C10-C13 segment 24, which is not restricted in monosaccharides chemistry, is summarized in O Scheme 2. After the completion of the synthesis of erythronolide A (20), Toshima, Nakata, Tatsuta, Kinoshita, and coworkers achieved the total synthesis of erythromycin A (18) by their own glycosidation method [18,19]. 

Macrolide antibiotics are glycosides with a macrocyclic lactone aglycon, which is formed in the polyketide biosynthetic pathway [38,39]. The lactone ring is 12-, 14-, 16-, or 18-mem-bered. The polyoxo-macrolides such as the classical antibiotic erythromycin are produced by streptomyces microorganisms and form a clinically important group of polyketide antibiotics. Erythromycin (O Fig. 5) is the major component out of a mixture of macrolide antibiotics which is formed by Saccharopolyspora erythraea. It contains two deoxysugars attached to the aglycon, L-cladinose and D-desosamine. 

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