Ionophoric macrolides

The frequent occurrence of /Thydroxy carbonyl moiety in a variety of natural products (such as macrolide or ionophore antibiotics or other acetogenics) has stimulated the development of stereocontrolled synthetic methods for these compounds. Indeed, the most successful methods have involved aldol reactions.13... 

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

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). 

Polyether antibiotics contain tetrahydrofuran rings. In monensin 11, three tetrahydrofuran rings are linearly connected. The molecule contains 17 asymmetric centres. Stereoselective syntheses for monensin have been elaborated [18]. In nonactin 12, the rings are interconnected in an a,a -orientation via ester groupings. Nonactin is therefore classed as a macrolide antibiotic. Polyethers of the type 11/12 are capable of facilitating ion transport across biological membranes they are, therefore, also known as ionophores. 

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. 

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. 

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. 

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