Cladinose, erythromycin

Erythromycin A R =OH, R2= L-Cladinose Erythromycin B RH, R2=L-Cladinose Erythromycin C Fig. 85. Formation of erythromycins... 

Erythromycins. Erythromycin A (14, R = OH, R = CH3, R" = H), the most widely used macroHde antibiotic, was the principal product found in culture broths of Streptomjces eTythreus (39), now reclassified as Saccharopoljspora eythraea (40). It contains a highly substituted aglycone, erythronoHde A, (16, R = R = OH) to which desosamine (1, R = OH, R = H) and cladinose (8, R = CH ) are attached (41). The complete stereochemistry of erythromycin A was estabUshed by x-ray analysis of its hydroiodide dihydrate (42) total synthesis of erythromycin A was a landmark achievement (43), a task previously considered hopeless (44). 

Branched-chain sugars are found in nature, eg, cladinose, ie, 2,6-dideoxy-3-C-meth5l-3-0-methyl-L- 7 (9hexose [3758-45-0] a component of erythromycin. 

Erythromycin is a macrolide antibiotic consisting of the aglycone, erythronolide A the aminosugar, desosamine and the neutral sugar, cladinose. 

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]. 

The general structure of erythromycin is shown with the macrolide ring and the sugars desosamine and cladinose. It is poorly soluble in water (0.1%) but dissolves readily in organic solvents. Solutions are fairly stable at 4°C but lose activity rapidly at 20°C and at acid pH. Erythromycins are usually dispensed as various esters and salts. 

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. 

Aldol reaction of (5)-2-benzyloxypropanal with the lithium enolate of methyl 2-methoxy-propanoate gives a 7 2 1 mixture of (3-hydroxyesters (Scheme 13.70). After protection of the alcohol moiety, the isomeric mixture is reduced with LiAlH4 and the resulting primary alcohols separated by chromatography on silica gel. Oxidation of the major alcohol 223 (isolated in 40% yield) into an aldehyde is followed by Wittig methylenation. This provides 224. Hydroboration of 224 gives a primary alcohol that is oxidized (Swem) into aldehyde 225. Hydrogenation yields L-cladinose, a saccharide moiety of erythromycin A [127]. 

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. 

Note The erythromycin molecule was synthesized by the Harvard chemist Robert Woodward. The synthesis was almost completed at the time of his death in 1979, and was finished by his associates in 1981. It is an extremely complex structure containing a lactone ring of 14 members with 10 asymmetric centers it also has two specialized sugar molecules, L-cladinose and D-desosamine. The reported molecular configuration is ... 

For example, the cladinose ring seems to make hydrophobic contacts with 30S. Nevertheless, there are also regions of erythromycin that make only minor contributions to binding, such as the region encompassed by C7-C11. 

The cladinose ring seems to be an essential determinant for the induction of the inducible form of MLSg resistance, an observation that prompted the investigation of analogs in which the cladinose was removed or replaced by other moieties. Numerous 3-O-acyl derivatives of erythromycin were synthesized and observed to be active antibiotics (11 l)Someof those antibiotics remained active against MLSs-resistant Staphylococcusawrews and ef-... 

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