Macrolides and Ionophores

The macrolide and ionophore group of antibiotics consist of long, usually polyoxygenated, carbon chains derived by canbination 

Three possible mechanisms can be postulated for formation of the oxygen-bearing centres in the macrolides and ionophores (a) retention or direct reduction of the keto group in the growing -ketoacyl chain (b) reduction followed by dehydration and stereospecific rehydration of the resulting enone or (c) multistep reduction to a fully saturated deoxygenated chain followed by aerobic oxidation. A number of studies have shown path (a) to be the predominant one. 

H labels from [1- C, H ]acetate are incorporated into the propionate-and butyrate-derived methyls but oddly the apparent 

Incorporation of C-labelled precursors established the biosynthetic origins of all the carbons of monensin (91), an 

D-Valine, rather than the L-isomer, is the immediate precursor of 

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Total synthesis of macrolide and ionophore antibiotics containing fragments of tetronic acid 92YZ358. 

Desulfurization of 522d with Raney nickel followed by debenzylation and acetonide formation gives 526 [165] in good yield. Both 525 and 526 are useful building blocks for the construction of macrolides and ionophores. 

Mandelic acid and its derivatives are utilized as convenient precursors for the introduction of a chiral center, and they possess the extra advantage of bearing a useful functional group. Many mandelic acid derivatives also act as chiral auxiliaries for the induction of a chiral center in stereoselective transformations. Numerous natural products, such as macrolides and ionophore antibiotics, possess a carbon framework that may be viewed synthetically as arising from a sequence of highly stereo- and enantioselective aldol condensations. Boron enolates, chiral auxiliaries derived from mandelic acids 1 or 2, provide remarkably high aldol stereoselectivity. 

In an aldol reaction, the enolate of one compound reacts with the electrophilic carbonyl carbon of the other carbonyl compound. A problem can arise when the other regioisomeric enolate can form easily or when the electrophilic carbonyl compound is enolizable. In addition, the product is enolizable and the wrong carbonyl compound could act as the electrophile therefore a mixture of products or predominantly the undesired product may result. An added complication arises when more than one chiral centre is present in the product and therefore two diastereomeric products can be formed. The course of the reaction between unlike components must be directed so that only the product required is obtained, or at least is formed predominantly. In addition, the stereochemical course of the reaction must be controlled. These difficulties have been overcome as a result of intensive study of the aldol reaction, spurred on by the presence of the (3-hydroxycarbonyl functional group in the structures of many naturally occurring compounds such as the macrolides and ionophores. 

Natural product synthesis, can lead to the discovery of new reactions by chance, by open-eyed serendipity, or by design. Our total synthesis of ionomycin (Scheme 6) [45] led us in fact to consider a design-based approach for the construction of deoxypropionate, and propionate subunits which are the natural building blocks for a large number of macrolide and ionophore-type antibiotics [46]. 

Diastereoselective aldol reactions have been extensively utilized in the synthesis of complex natural products, including macrolides [4] and ionophores [5]. In this context, iterative approaches are often exploited to append propionate units one at a time. This approach leads to double stereodifferentiation [6] in tvhich the reactant pairs can be either matched or mismatched . The chirality of the t vo reactants reinforce each other if they are matched. As a result, the diastereoselectivity is often higher than vould... 

Various examples of use of alkenyltin/vinyl iodide couplings in natural-product synthesis have been provided Evans and Black [33] have obtained the macrolide insecticide (+)-A83 453A [(+)-lepicidin A] (Scheme 4-7), Burke et al. the ionophore antibiotic X-14547A [34] (Scheme 4-8), Kende et al. [35] lankacidin C (Scheme 4-9), while Han and Wiemer [36] have used the combination alkenyltin/vinyl triflate in the total synthesis of (+)-jatrophone. 

Penicillin, the first natural antibiotic produced by genus Penicillium, discovered in 1928 by Fleming, as well as sulfonamides, the first chemotherapeutic agents discovered in the 1930s, lead a long list of currently known antibiotics. Besides 3-lactams (penicillins and cephalosporines) and sulfonamides, the list includes aminoglycosides, macrolides, tetracyclines, quinolones, peptides, polyether ionophores, ri-famycins, linkosamides, coumarins, nitrofurans, nitro heterocytes, chloramphenicol, and others. 

Development of diastereoselective and enantioselective aldol reactions has had a profound impact on the synthesis of two important classes of natural products—the macrolide antibiotics and the poly ether ionophores. The aldehyde and the enolate involved in aldol reactions can be chiral, but we shall discuss only the case of chiral enolates. 

Moreover, myopathic Syrian hamsters given a calcium-deficient diet exhibit fewer lesions in skeletal and cardiac muscle (17). Conversely, facilitation of calcium uptake with ionophores or membrane-active toxins such as lysophospholipids or macrolide antibiotics accelerate necrosis of isolated skeletal muscle (19) and rat hepatocytes in culture (10). 

A 2008 paper has described for the first time a dilute and shoot strategy for the simultaneous extraction of wide variety of residues and contaminants (pesticides, myco-toxins, plant toxins, and veterinary drugs) from different foods (meat, milk, honey, and eggs) and feed matrices. Several antimicrobial classes were included (sulfonamides, quinolones, P-lactams, macrolides, ionophores, tetracyclines, and nitroimidazoles) in the analytical method. Sample extraction was performed with water/acetonitrile or acetone/1% formic acid, but instead of dilution of the extracts before analysis by UPLC-MS/MS, small extract volumes (typically 5 til) were injected to minimize matrix effects. Despite the absence of clean-up steps and the inherent complexity of the different sample matrices, adequate recoveries were obtained for the majority of the ana-lyte/matrix combinations (typical values for antimicrobials were in the range of 70-120%). In addition, the use of UPLC allows high-speed analysis, since all analytes eluted within 9 min. 

Notation-. A = aminoglycosides AMP = amphenicols fj-L = P-lactams d-SPE, dispersive SPE FQ = fluoroquinolones IP = ionophores L = lincosamides M = macrolides NMZ = nitroimidazoles P = penicillins PLE = pressurized liquid extraction Q = quinolones S = sulfonamides T = tetracyclines TMP = trimethoprim. This table is adapted from QuEChERS = quick, easy, cheap, effective, rugged, and safe ... 

Heller DN, Nochetto CB, Development of multiclass methods for drug residues in eggs Silica SPE cleanup and LC-MS/MS analysis of ionophore and macrolide residues, J. Agric. Food Chem. 2004 52(23) 6848-6856. 

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