Macrolide analysis

In the last fifteen years macrolides have been the major target molecules for complex stereoselective total syntheses. This choice has been made independently by R.B. Woodward and E.J. Corey in Harvard, and has been followed by many famous fellow Americans, e.g., G. Stork, K.C. Nicolaou, S. Masamune, C.H. Heathcock, and S.L. Schreiber, to name only a few. There is also no other class of compounds which is so suitable for retrosynthetic analysis and for the application of modem synthetic reactions, such as Sharpless epoxidation, Noyori hydrogenation, and stereoselective alkylation and aldol reactions. We have chosen a classical synthesis by E.J. Corey and two recent syntheses by A.R. Chamberlin and S.L. Schreiber as examples. 

Configurational assignment of polyene macrolide antibiotics using the [ C]ace-tonide analysis 98ACR9. 

Scheme 43 Structure and retrosynthetic analysis of the salicylate macrolides salicylihalamide A (215a) and B (215b) by various groups [103]...

In the synthesis of a macrolide 17A, known as latrunculin A, the intermediate 17B was assembled from components 17C, 17D, and 17E in a one-pot tandem process. By a retrosynthetic analysis, show how the synthesis could occur and identify a sequence of reactions and corresponding reagents. 

P2j Z = 2 D = 1.17 R = 0.080 for 3,888 intensities. This is aconfigu-rational analysis of the macrolide antibiotic 23672RP from Streptomyces chryeus. All three sugar residues are pyranoid the conformation of the a-ketose is CX, with Q = 56 pm, 0 = 9° that of the / -D-mycinose (6-deoxy-2,3-di-0-methyl-D-allose) is 4Clt with Q = 59 pm, 0 = 6° and that of the / -L-mycarose (2,6-dideoxy-3-C-methyl-L-riho-hexose) is 1C4, with Q = 53 pm, 0= 177°. The O-5-C-l-O-l-C glycosidic torsion-angles are —71, —87, —83°. The atomic coordinates reported in the paper refer to the opposite enantiomer. 

Borisova, S., Zhao, L., Melancon, C.E. et al. (2004) Characterization of the glycosyltransferase activity of desVII analysis of and implications for the biosynthesis of macrolide antibiotics. Journal of the American Chemical... 

Four macrolides, 11-undecanolide (12-membered,UDL) [85,86], 12-dodeca-nolide (13-membered,DDL) [86,87], 15-pentadecanolide (16-membered, PDL) [85,86,88,89], and 16-hexadecanolide (17-membered, HDL) [90], were subjected to the lipase-catalyzed polymerization. For the polymerization of DDL, lipases CC, PC, PF, and PPL showed the high catalytic activity and the activity order in the bulk polymerization was as follows lipase PC > lipase PF > lipase CC> PPL. These enzymes were also active for the polymerization of other macrolides. NMR analysis showed that the terminal structure of the polymer was of carboxylic acid at one end and of alcohol at the other terminal. 

Synthesis of the macrolide 6-deoxyerythronolide B 28 is one of the successful demonstrations of double asymmetric induction applied to the construction of complicated natural products.5 Retro synthetic analysis (Scheme 7-7) shows that 28 can be obtained from thio-seco acid 29, which consists of seven propionate building blocks. This is a typical aldol product in which a boron reagent... 

The 13C NMR spectrum of 64, an amide of 63, showed sixty-two carbon signals of which partial assignments, shown in Table 16, were made based upon distortionless enhancement by polarization transfer(DEPT), H-13C correlation experiments and literature data describing 13C NMR analysis of polyene macrolides. 

Erythromycin, a macrolide antibiotic, lacks a significant chromophore. Detection sensitivity was enhanced by using a wavelength of 200 nm and selecting an injection solvent of lower conductivity than the BGE. In order to facilitate the separation of erythromycin and its related substances, 35% (v/v) ethanol was incorporated into a 150 mM phosphate buffer pH 7.5. Resolution of all of the compounds was achieved in approximately 45 min. The method was employed as an assay method for erythromycin and for impurity determination. Peptide antibiotics, such as colistin and polymyxin, are mixtures of many closely related compounds. A validated CZE method for impurity analysis of polymyxin B was described, employing 130 mM triethanolamine-phosphate buffer at pH 2.5 to reduce the adsorption of analyte onto the capillary wall. Methyl-/l-cyclodextrin (M-/1-CD) and 2-propanol were found to be necessary for selectivity enhancement. Using similar buffer additives, the same group developed and validated a method for colistin analysis. ... 

The structure of the toxins was elucidated by NMR and approved by X-ray diffraction analysis (Fig. 7). The two compounds were found to contain a new class of 16- and l4-membered macrolides attached via 6-membered lactol to the rare 2-thiazolidinone moiety. Both toxins are... 

For the analysis of macrolide and lincosamide residues in liquid foods such as milk, a pretreatment step for fat removal carried out by centrifugation (133-135) is usually required. Semisolid food samples such as muscle, kidney, and liver require often more intensive sample pretreatment including a mincing and/or a homogenization step for breaking up tissue. 

For efficient extraction of macrolide and lincosamide residues from edible animal products, bound residues should be rendered soluble, most if not all of the proteins should be removed, and high recoveries for all analytes should be provided. Since tliese antibiotics do not strongly bind to proteins, many effective extraction methods have been reported. Sample extraction/deproteinization is usually accomplished by vortexing liquid samples or homogenizing semisolid samples with acetonitrile (136—139), acidified (136,140-142) orbasified acetonitrile (143), methanol (14, 144, 145), acidified (145-147) or basified methanol (148), chloroform (149-151), or dichloromethane under alkaline conditions (152). However, for extraction of sedecamycin, a neutral macrolide antibiotic, from swine tissues, use of ethyl acetate at acidic conditions has been suggested (153), while for lincomycin analysis in fish tissues, acidic buffer extraction followed by sodium tungstate deproteinization has been proposed (154). 

In liquid chromatographic analysis of macrolides and lincosamides, most popular is the ultraviolet detector (Table 29.4). Tylosin, tilmicosin, spiramycin, sedecamycin, and josamycin exhibit relatively strong ultraviolet absorption, but erythromycin, lincomycin, pirlimycin, and oleandomycin show extremely weak absorption in the ultraviolet region. Hence, detection at 200-210 nm has been reported for the determination of lincomycin (146). However, a combination of poor sensitivity and interference from coextractives necessitated extensive cleanup and concentration of the extract. Precolumn derivatization of pirlimycin with 9-fluorenylmethyl chloroformate has also been described to impart a chromophore for ultraviolet detection at 264 nm (140). 

Electrochemical detection is better suited to the analysis of erythromycin and lincomycin. This method of detection has been applied for the determination of erythromycin A (139) and lincomycin (154) residues in salmon tissues. Liquid chromatography coupled with mass spectrometry is particularly suitable for confirmatory analysis of the nonvolatile macrolides and lincosamides. Typical applications of this technique are through thermospray mass spectrometry, which has been used to monitor pirlimycin in bovine milk and liver (141,142), and chemical ionization, which has been applied for identification of tilmicosin (151) in bovine muscle, and for identification of spiramycin, tylosin, tilmicosin, erythromycin, and josamycin residues in the same tissue (150). 

Yang, S. and K.H. Carlson. 2004. Solid-phase extraction-high-performance liquid chromatography-ion trap mass spectrometry for analysis of trace concentrations of macrolide antibiotics in natural and waste water matrices. J. Chromatogr. A 1038 141-155. 

At the start of the analysis when you have done no more than recognise the FGs and note special features (such as rings) or easy disconnections, note also the number of chiral centres and their relationship to each other. The Prelog-Djerassi lactone 1 is an important intermediate in the synthesis of macrolide antibiotics.1 It has a six-membered lactone ring and a separate carboxylic acid. More to the point, it has four chiral centres la. Three (1-3) are adjacent and one (5) separate. We might say that the three adjacent centres should be easy to control because they are next to each other but that we might have trouble with C-5. Another way to look at it is to say that the three round the six-membered ring (2, 3 and 5) should be easy to control, as the... 

Presence (+) or absence (—) of acyltransferase activity for 16-membered macrolide antibiotics. b Presence (+) or absence (—) of hybridizing band(s) in Southern blot analysis using acyA or acyBl as a probe. " Weakly hybridizing bands were detected. 

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