Macrolides, antibiotics precursors

B) is in fact synthetic equivalent of (C)) which react readily with nucleophiles such as the malonate anion. This approach has been recommended for the synthesis of macrolide antibiotic precursors [5d]. 

The fungus Streptomyces erythreus is the source of a number of structurally related macrolide antibiotics that are collectively known as the erythromycins. The erythromycins occupy a prominent position in medicine by virtue of their useful antibacterial properties. Their use in therapy over the course of the last three decades has been widespread, and has resulted in the saving of many human lives. In this chapter, we address the landmark total synthesis of erythronolide B (1), the biosynthetic precursor of all the erythromycins, by E.J. Corey and his coworkers which was carried out at Harvard in the 1970s.1... 

Figure 10.9 NeuA catalyzed preparation of a synthetic precursor to the macrolide antibiotic amphotericin B.

Using FmA catalysis and protected 4-hydroxybutanal, compound (97) has been stereoselectively prepared as a synthetic equivalent to the C-3-C-9 fragment of (-F)-aspicillin, a lichen macrolactone (Figure 10.35) [160]. Similarly, FruA mediated stereoselective addition of (25) to a suitably crafted aldehyde precursor (98) served as the key step in the synthesis of the noncarbohydrate , skipped polyol C-9-C-16 chain fragment (99) of the macrolide antibiotic pentamycin [161,162]. 

Figure 10.35 Stereoselective generation of chiral precursors for the synthesis of the lichen macrolactone (+)-aspicillin and the macrolide antibiotic pentamycin using FruA catalysis.

A related method was applied in the course of synthesis of a precursor of a macrolide antibiotic, protomycinolide IV. The migrating group was an a-trimethylsilylalkenyl group.68 In this procedure, the DiBAlH first reduces the ketone and then, after rearrangement, reduces the aldehyde to a primary alcohol. 

The (R)-1-benzyloxy-4-penten-2-ol produced using enantiomerically-enriched starting material in this reaction is a useful precursor in the synthesis of the polyol section of the polyene macrolide antibiotic roflamycoin (Scheme 1). This molecule... 

A. F. Sviridov, A. Yu. Romanovich, and O. S. Chizhov, Synthetic studies in polyene macrolide antibiotics. 1. Synthesis of C1-C6 and C7-C12 fragments of amphothericin-B from carbohydrate precursors, Bioorg. Khim., (1987) 1665-1671. 

Thanks to the reliability of these conversions, compounds like 70-73 can all be regarded as products of a condensation between carbonyl components described in terms of an interaction between an electrophile and a nucleophile. Hence, an important recommendation in retrosynthetic analysis is to identify the presence of fragments identical to 70-73 (or easily derivable from them). Retrosynthetic cleavage of the respective C-C bond will then reveal the structures of possible carbonyl precursors. The retrosynthetic analysis of 74, a basic fragment of the complex macrolide antibiotic 6-deoxyerythronolide B, provides a good example of how workable this principle might be (Scheme 2.27). ... 

At least two unusual features characterize this biosynthesis. One is the origin of the methyl branches in the polyketide chain from the methyl group of methionine. This is in contrast to the biosynthesis of most macrolide antibiotics in which chain branches are formed by utilization of the appropriate homologs in place of acetate chain extension units, i.e., propionate units. The second unusual feature of this biosynthesis is the mode of incorporation of glycerol and particularly the fact that it is a specific precursor of the three-carbon polyketide chain starter unit [50 ]. 

Alkyl Grignard reagents as well as organolithium reagents add to 11b with equal facility. The utility of this process is exemplified in the total synthesis of protomycinolide IV (335), a biogenetic precursor of macrolide antibiotics of the mycinamicin family [111]. 

Candicidin production by Streptomyces griseus was inhibited by inorganic phosphate, which suppressed the biosynthesis of p-aminobenzoate, the starter unit for the synthesis of this 38-membered heptaene macrolide antibiotic [95]. P-aminobenzoic acid synthase (PABA synthase) catalyses the conversion of chorismic acid to PABA, which is a precursor to candicidin. 

Figure 11.17 (a) Chemical structures of macrolide antibiotics (note that erythromycin, ETM, was analyzed as its anhydro form shown, (ETM-H2O)), but tylosin (TLS) was analyzed as the intact protonated molecule. Spiromycin (SPM) was used as the internal standard, (b) Multiple reaction monitoring (MRM) chromatograms of macrolides, each spiked at a concentration of 300ng.L before extraction from 100 mL of influent wastewater from a water reclamation plant. The MRM transitions used for quantitation are shown in each case (the precursor ion for Spiromycin I was the (M+2H) + ion, the others were (M+H)+ ions), and the total ion current (TIC) chromatogram is simply the sum of the three MRM traces. Reproduced from Yang, Anal. Bioanal Chem. 385, 623 (2006), with permission from Springer Science and Business Media. 

The large 23-membered ting of the ascomycin family and the 31-membered ring of rapamycin are similar to many macrolide antibiotics. The biosynthetic precursors of the carbon backbone of macrolide antibiotics, which include compounds such as erythromycin and tylosin, have been shown to be acetate, propionate, and occasionally... 

Early studies demonstrated that oils and fatty acids stimulated the production of the polyene macrolide antibiotics fungichromin and filipin, but not amphotericin B or candicidin (89). The stimulation polyene antibiotic biosynthesis by oils might be a simple precursor effect. Catabolism of fatty acids results in a increased pool of acetyh QiA. which is subsequently used for polyene biosynthesis. 

Rose, ed.), pp. 239-291. Academic Press, London 1979 Martin, J.-F. Polyene macrolide antibiotics. In Secondary Products of Metabolism (A. H. Rose, ed.), pp. 355-387. Academic Press, London 1979 Shaw, G. J., Milne, G. W. A., Minghetti, A. Propionate precursors in the biosynthesis of dauno-mycin and adriamycin a nuclear magnetic resonance study. Phytochemistry 18, 178-179 (1979)... 

Thomas et al. [90] prepared two 17-membered macrocyclic tetraenes that are possible precursors of the natural product lankacidin C in this case, a trisubstituted vinyl iodide was involved, and the amount of Pdjdbaj required was relatively high (30%). Toshima et al. [91] reported a highly stereoselective total synthesis of the macrolide antibiotic concanamycin F again, intermolecular and intramolecular vinyl-vinyl couphngs were used. WhUe liCl was used as an additive in the former, it was replaced by DIPEA in the latter. In a recent pubUcation [49], Toshima et al. 

Vitamin E (a) L. F. Tietze, J. Gorlitzer, A. Schuffenhauer, M. HUbner, Eur. J. Org. Chem. 1999, 1075-1084. Enantioselective synthesis of the chromane moiety of vitamin E. (b) L. F. Tietze, J. Gorlitzer, Synlett 1997, 1049-1050. Preparation of enantiopure precursors for the vitamin E synthesis. A comparison of the asymmetric allylation of ketones and the sharpless bishydroxylation. (+)-Hydroxymyoporone (c) L. F. Tietze, C. Wegner, C. Wulff, Chem.-Eur. J. 1999, 5, 2885-2889. First total synthesis and determination of the absolute configuration of the stress factor (+)-hydroxymyoporone. 5,6-Dihydrocineromycin B (d) L. F. Tietze, L. Vblkel, Angew. Chem. Int. Ed. 2001, 40, 901-902. Total synthesis of the macrolide antibiotic 5,6-dihydrocineromycin B. 

The complex sixteen-membered-ring macrolide antibiotic tylosin (191) is extensively used today as a therapeutic agent and a nutrient. The molecule has been at the focus of a number of synthetic investigations. This year, Nicolaou and co-workers have described the elaboration of the three fragments (186), (187), and (188) for the synthesis of 0-mycinosyltylonolide (190) in their appropriate optically active forms, and all three were formed from carbohydrate precursors. Combination between (186) and (187) gave rise to an intermediate which, with (188), was then elaborated to the keto-phosphonate (189). The... 

A highly convergent synthesis of bafilomycin A, a macrolide antibiotic has been recently reported by Roush. A Suzuki cross-coupling reaction was performed between the functionalized alkenyl boronic acid 126 and the alkenyl iodide 127 generating appropriately protected macrocyclic precursor 128 in 65% yield (Scheme 3.67) [102]. 

Inverse type hetero-Diels-Alder reactions between p-acyloxy-a-phenylthio substituted a, p-unsaturated cabonyl compounds as 1-oxa-1,3-dienes, enol ethers, a-alkoxy acrylates, and styrenes, respectively, as hetero-dienophiles result in an efficient one step synthesis of highly functionalized 3,4-dihydro-2H-pyrans (hex-4-enopyranosides). These compounds are diastereospecifically transformed into deoxy and amino-deoxy sugars such as the antibiotic ramulosin, in pyridines having a variety of electron donating substituents, in the important 3-deoxy-2-gly-culosonates, in precursors for macrolide synthesis, and in C.-aryl-glucopyranosides. 

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