Macrolides methods

Total syntheses have been reported by E.J. Corey (1978B, 1979). We outline only the stereoselective synthesis of a protected fragment (A) which contains carbon atoms 1—9. This fragment was combined with fragment (B) by a Grignard reaction and cyclized by one of the methods typical for macrolide formation (see p. 146). 

This method is based on the generation of the tetraalkylammonium salt of pyrrolidorle, which acts as a base. The method is compatible with a large variety of carboxylic acids and alkylating agents. The method is effective for the preparation of macrolides. 

Use of DMF as a solvent for the oxidation of l-o1efins has been reported by Clement and Selwitz. The method requires only a catalytic amount of PdCl2 and gives satisfactory yields under mild conditions. A small amount of olefin migration product is the only noticeable contaminant in the cases reported. The procedure can be applied satisfactorily to various 1-olefins with other functional groups. This useful synthetic method for the preparation of methyl ketones has been applied extensively in the syntheses of natural products such as steroids,macrolides, dihydrojasmone, and muscone. " A comprehensive review article on the palladium-catalyzed oxidation of olefins has... 

Polymer-supported esters are widely used in solid-phase peptide synthesis, and extensive information on this specialized protection is reported annually. Some activated esters that have been used as macrolide precursors and some that have been used in peptide synthesis are also described in this chapter the many activated esters that are used in peptide synthesis are discussed elsewhere. A useful list, with references, of many protected amino acids (e.g., -NH2, COOH, and side-chain-protected compounds) has been compiled/ Some general methods for the preparation of esters are provided at the beginning of this chapter conditions that are unique to a protective group are described with that group/ Some esters that have been used as protective groups are included in Reactivity Chart 6. 

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. 

Entries 5 to 8 are synthetic applications in more complex molecules. Entries 5 and 6 illustrate the diphenylphosphoroyl azide method. Entry 7 was used in the late stages of the synthesis of an antitumor macrolide, zampanolide, to introduce the amino group. The ultimate target molecule in Entry 8 is himandrine, one of several polycyclic alkaloids isolated from an ancient plant species. 

The Prelog-Djerassi lactone (abbreviated here as P-D lactone) was originally isolated as a degradation product during structural investigations of antibiotics. Its open-chain equivalent 3 is typical of the methyl-branched carbon chains that occur frequently in macrolide and polyether antibiotics. The compound serves as a test case for the development of methods of control of stereochemistry in such polymethylated structures. There have been more than 20 different syntheses of P-D lactone.24 We focus here on some of those that provide enantiomerically pure product, as they illustrate several of the methods for enantioselective synthesis.25... 

Macrolides and Related Compounds.- Phosphorus-based methods have... 

Acyclic stereocontrol has been a striking concern in modern organic chemistry, and a number of useful methods have been developed for stereoregulated synthesis of conformationally nonrigid complex molecules such as macrolide and polyether antibiotics. Special attention has therefore been paid to the aldol reaction because it constitutes one of the fundamental bond constructions in biosynthesis. 

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... 

This method of cyclization has been used successfully for synthesis of four 11-membered dilactone pyrrolizidine alkaloids,2 but it does not appear to be useful for cyclization to simple macrolides. 

In connection with the synthetic work directed towards the total synthesis of polyene macrolide antibiotics -such as amphotericin B (i)- Sharpless and Masamune [1] on one hand, and Nicolaou and Uenishi on the other [2], have developed alternative methods for the enantioselective synthesis of 1,3-diols and, in general, 1, 3, 5...(2n + 1) polyols. One of these methods is based on the Sharpless asymmetric epoxidation of allylic alcohols [3] and regioselective reductive ring opening of epoxides by metal hydrides, such as Red-Al and DIBAL. The second method uses available monosaccharides from the "chiral pool" [4], such as D-glucose. 

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. ... 

Advent of ring-closing olefin metathesis reaction has influenced the synthetic strategy of pheromones very much. For example, the racemate of a macrolide pheromone such as (5Z,13S)-5-tetradecen-13-olide (29) (aggregation pheromone of the flat grain beetle, Cryptolestes pusillus) could readily be synthesized as shown in Scheme 42 [67]. Unfortunately, ( )-29 prepared by this method was a mixture of c/s, trans-isomers (Z/E=69 31). (S)-5-Hexadecanolide (27) was also synthesized by means of ring-closing olefin metathesis as shown in Scheme 43 [68]. 

The application of chromatographic methods to analyze the residues of macrolide antibiotics has been very limited. Moats (85) listed four TLC and one HPLC method for tylosin and one TLC method for erythromycin. In a comparison of the HPLC and microbiological methods for incurred residues in swine, the HPLC method was more sensitive and usually gave higher results (86). 

A General Method for the Preparation of 9-, 10-, and 11-Membered Unsaturated Macrolides Synthesis of 8-Prop1onyl-E-5-nonenol1de... 

New methods for the synthesis of 2,4-disubstitued oxazoles are summarized in a recent review. 2-Alkyl-1,3-oxazoles bearing alkyl, aryl, or acyl substitution at C4 are common substructures in natural products. Examples include macrolides such as rhizoxin (4), hennoxazole A (5), and phorboxazole A (6), ° as well as many cyclic peptides that incorporate an oxazole subunit presumably derived from serine. ... 

The effectiveness of this method has been demonstrated in a convergent asymmetric synthesis of (2S,4f ,65, 8R)-l,2,4,6,8,10-decanehexol (overall yield 27%), a degradation product of the polyene macrolide lienomycin52. Starting from methyl (,S )-3,4-dihydroxybu-tanoate, the key intermediate (4S, 6>S )-2,2-dimethyl-6-phenyllhio-4-triisopropylsiloxymethyl-1,3-dioxane was obtained51. 

Erythromycin A, a widely used, macrolide, antibiotic substance, was crystallized as the hydriodide dihydrate. It would be expected that the iodine atom would be used as the heavy atom in solving the structure, and, indeed, the authors tried the heavy-atom method first.68 Unfortunately, the iodine atom lies on a crystallographic mirror-plane, and so this method failed. Because erythromycin con-... 

Available methods for the synthesis of macrolides involve the cyclization of long-chain bifunctional precursors,3 depolymerization processes,4 ring-enlargement reactions,5 and special methods... 

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