Tylosin aglycones

The western part 97 of tylosin aglycon (96), a 16-membered macrolide, has also been synthesized using this Kocienski metalate rearrangement [66]. Treatment of the lithiated dihydrofuran 99 with the stannyl cuprate [67] obtained from Bu3SnLi and CuCN, followed by Mel alkylation, exclusively gave the E vinyl stan-nane 100, in 80% yield. In the last stage, stannyl cupration [68] of the deprotected enyne diol 101 afforded the desired ( , E) stannyl diene 97 in 85% yield. 

The construction of the naturally derived narbomycin and tylosin-aglycones by Masamune and coworkers employ identical methodology for seco-acid formation. In each case, Peterson alkenadon of a functionalized aldehyde (not shown) and the silyl ketones (96 R = SiMes Scheme 36) or (99 Scheme 37) efficiently introduced the required ( )-a,3-unsaturation. Silyl ketone formation is accomplished in each case through cuprate acylation by an activated carboxylic acid derivative. Formation of an acid chloride was not possible in the sensitive tylosin-aglycone intermediate however, selective acylation of the silylcuprate proceeded at the pyridyl thiol ester moiety of (98) and not with the r-butyl thiol ester. In a related investigation, (97), an advanced intermediate for 6-deoxyerythronolide B, was obtained from (95) via addition of lithium diethylcuprate to the acid chloride (84% yield). In all the above cases, no addition was observed at the f-butyl thiol ester. 

Tylosin [46-49] (Fig. 6), produced by Streptomyces fradiae, was one of the first antibiotics for which a comprehensive set of blocked mutants was isolated. They were used to help define the biosynthetic pathway. Whereas erythromycin is a 14-membered macrolide, tylosin has a 16-membered lactone structure. The gene for the final step of biosynthesis was cloned by reverse genetics from the protein sequence of the enzyme [46], and specific segments of surrounding DNA were found to complement other classes of blocked mutants. The formation of tylosin aglycon, protylonolide, is involved in five polyketide synthases. 

Natural Products. 16-Membered macroHdes are divided into leucomycin- and tylosin-related groups, which differ in the substitution pattern of their aglycones. Multi-factor complexes are usually produced and some compounds have been isolated from culture broths of different organisms and then been given different names. 

The mycinamicin complex, also found as AR-5 complex, was isolated from culture broths of M. grixeorubida. These compounds contain a 2,3-double bond and a methyl group rather than a two-carbon substituent at 0-6 of the aglycone. A hydroxyl group is present at C-14 in mycinamicins II and V. X-ray crystallography established the stereochemistry and absolute configuration of the aglycone as identical to tylosin. 

As is the case for the leucomycin group, several aglycones exist in the tylosin group winch differ in the pattern of oxidation and substitution of the lactone. If the aglycone contains an aldehyde, cleavage of the aminosugar yields the hemiketal, such as tylonolide and rosaranolide. 

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],... 

Since tylosin is composed of tylonolide (macrolactone aglycone ring) and three attached sugars having several chemically reactive hydroxyl groups, it is... 

Diisopinocampheylborane is not an effective asymmetric hy-droborating agent for 2-substituted 1-alkenes. High selectivities have, however, been achieved where one of the substituents is very bulky. This aspect has been elegantly demonstrated by the synthesis of both enantiomers of a precursor of tylonolide, the aglycone of tylosin, which is one of the members of the polyoxomacrolide antibiotics. In both cases the isomeric ratio was at least 50 1 (eqs eq 8 and eq 9). ... 

The 16-membered macrolide antibiotics are generally divided into two principal families, the leucomycin-related family and the tylosin-related family, on the basis of the substitution pattern of their aglycones [13]. Generalized structures for these two types of aglycones are illustrated in... 

Figure 5.1. Comparative substitution pattern of aglycones for leucomycin-related (la) and tylosin-related (lb) 16-membered macrolides.

Tylosin (13) Figure 5.6) is the prototype of the second large division of 16-membered macrolides, based upon differences from the leucomycins in aglycone structure. Tylosin is an important veterinary antibiotic produced... 

Tylosin 33 from Streptomyces fradiae is a representative member of the large family of 16-membered macrolide antibiotics commonly utilised in veterinary medicine. The aglycone core, tylactone 34 is constructed from two acetate, five propionate and one butyrate units [68, 69]. The processive mechanism for its biosynthesis was demonstrated by the pioneering contributions of Hutchinson... 

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