Oleandomycin synthesis

Tatsuta s oleandomycin synthesis is based on the construction of the aglycone by coupling of the C1-C7 (131) and Cg-Ci3 (136) segments, which are derived from L-rhamnose and (S)-( + )-methyl 3-hydroxy-2-methylpropionate, respectively, and on the stereo- and regioselective introduction of the two sugar moieties. Methods for selective esterification and for the synthesis of 2-deoxy-a-glycosides were developed in the course of the synthesis. 

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]. 

Cyclization via intramolecular olefination of complex phosphonates remains the most important method of synthesis for complex natural macrocycles. Examples include syntheses of 20-membered macrolide antibiotic, aglycones of venturicidins A and B,108 oleandomycin (a 14-membered macrolide antibiotic), 109 the 19-membered macrocyclic antibiotic, anti-tumour agent (-t-)-hitachimycin,ll0 and the macrocyclic lactones (183).1H Cyclization of the phosphonate (184) under Masamune-Roush conditions has been used to synthesize the 28-membered macrolactam myxovirescin B.112... 

Tatsuta, K, Kobayashi, Y, Gunji, H, Masuda, H, Synthesis of oleandomycin through the intact aglycone, oleandolide. Tetrahedron Lett., 29, 3975-3978, 1988. 

More than 500 different representatives of the macrolide antibiotics are known, most of which are biologically active against Gram-positive bacteria, displaying a relatively low toxicity. Clinically used are erythromycin, oleandomycin, carbomycin and leucomycin (O Fig. 5). They act as inhibitors of the bacterial protein biosynthesis by binding to the 50S-ribosomal subunit. The synthesis of the two clinically important 16-membered ring macrolide antibiotics leucomycin A3 and carbomycin B could be started from D-glucose, which was chosen because it contained three of the required stereocenters [40]. 

Chloramphenicol is a bacteriostatic agent that binds to the 508 ribosomal subunit and inhibits the transpeptidation in protein synthesis. While this agent is not widely used to treat staphylococcal infection, resistance to chloramphenicol is due to inactivation of the antibiotic by chloramphenicol acetyltransferase enzyme (CA7). Macrolides, such as erythromycin and oleandomycin lincosamides, such as lincomycin and clindamycin and streptogramin antibiotics also have a bacteriostatic effect on Staphylococcus spp. by binding to their 508 ribosomal subunit, arresting protein synthesis, but resistance to these antibiotics is also prevalent. Rifampin has also been used to treat staphylococcal infections, but when used alone, resistant strains quickly arise. 

Total syntheses of the following antibiotics and/or their aglycones are dealt with methymycin, erythromycin, pikromycin, oleandomycin, ingramycin (albo-cycline), carbomycin B, leucomycin A3 (josamycin), tylosin, mycinamicins, rosaramicin, A26771B and elaiophylin (azalomycin B). Since the total synthesis of the macrolide-like immunosuppressant FK-506 has been recently reported, it is also reviewed here. Today, erythromycin A, oleandomycin, leucomycin A3 (josamycin), tylosin and mycinamicin II are clinically important antibiotics. 

The macrolide antibiotics are a group of compounds which have as a nucleus a ma-crocyclic lactone ring to which one or more sugars are attached. These sugars are essential for the antibiotic activity. Only three of the macrolides, i.e., erythromycin, oleandomycin, and spiramycin are used in human clinical practice, while a fourth, tylosin, is used in veterinary medicine and as a food preservative in industrial canning. These are all weakly alkaline and only slightly soluble in water. Erythromycin is the most active antibiotic of this group (Fig. 7). All of them are able to inhibit bacterial protein synthesis and are characterized by their bacteriostatic qualities. The antibacterial spectrum is similar to that of benzylpenicillin. 

MaerolldM, macrolide antibiotics a group of antibiotics from various strains of Streptomyces, all with the same complex macrocyclic structure. M. inhibit protein synthesis by blocking transpeptidation, and translocation on the 50S ribosomal subunit (similar to Chloramphenicol, see). Examples of M. are erythromycin (Fig.), spiramycin, oleandomycin, carbo-mycin, angolamycin, leucomycin, picromycin. Almost all M. are used therapeutically as broad spectrum antibiotics. 

The chiral pool refers to readily available optically active natural products, some of which are commercially used in quantities of 10 -10 tonnes per year [5], Among them, the most inexpensive compounds are a-amino acids, like monosodium L-glutamate, or carbohydrates, like dextrose or sorbitol. The success of the second method depends on the availability of particular catalysts. One rather special example, how efficient stereoselective synthesis can work, is the syn-selective aldol reaction followed by a stereoselective alkene hydroboration and ketone reduction (Figure 1.8) which were used by Paterson et aJ. [26] to synthesize intermediates for the antibiotic oleandomycin. According to Paterson et al., four new stereocenters are formed in only two synthetic steps [9]. For the purpose of separating racemic mixtures... 

These antibiotics (erythromycin, spiramycin, carbomycin, oleandomycin) are very effective in inhibiting protein synthesis. They are called macrolides because they contain a large lactone ring (Fig. 5). 

Paterson s synthesis of oleandolide, the aglycon of the macrolide antibiotic oleandomycin, relied on an analogous use of macrocyclic stereocontrol for the introduction of an epoxide late in the route (Equation 5) [20]. The reaction between ketone 48 and trimethylsulfonium ylide thus furnished epoxide 49 in 83 % yield and dr >97 3. 

The sequential use of Panek s allyl silane reagents 137 and 138 provides convenient, rapid access to complex propionate subunits. The total synthesis of oleandolide (151), the aglycone of the macrolide antibiotic oleandomycin, demonstrates the tactical advantages of using these reagents (Scheme 5.25) [103]. Four sequential diastereoselective allylation reactions provided products 144, 147, 148, and 150 with excellent stereocontrol (dr s 20 1). 

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