Carboxylic acid derivatives synthesis antibiotics

Largely stimulated by the synthesis of 3-lactam antibiotics, there have been widespread investigations into the stereochemical aspects of imine condensations, mainly involving reactions of enolates of carboxylic acid derivatives or silyl ketene acetals. In analogy to the aldol condensation, stereoselectivity of imine condensations will be discussed in terms of two types in this chapter (i) simple dia-stereoselectivity or syn-anti selectivity, when the two reactants are each prochiral (equation 12) and (ii) diastereofacial selectivity, when a new chiral center is formed in the presence of a pre-existing chiral center in one of the reactants (e.g. equation 13). The term asymmetric induction may be used synonymously with diastereofacial selectivity when one of the chiral reactants is optically active. For a more explicit explanation of these terms, see Heathcock s review on the aldol condensation. ... 

In a similar vein, Davis and co-workers have found the p-toluenesulf nyl group to be useful for such purposes. Aziridine-2-carboxylic acid derivatives 138 are prepared in high diastereomeric purity by a Darzens-type reaction of the lithium enolate of methyl bromoacetate (137) with enantiopure sulfrnimines (e.g., 136) [94JOC3243]. These compounds have been employed as intermediates in the asymmetric synthesis of the antibiotic (+)-thiamphenicol (139) [94TL7525]. 

Our interest in the polyoxin group of antibiotics [50] was focused on the nature of polyoximic acid [51], a deceptively simple azetidine carboxylic acid derivative which had eluded the efforts of synthetic chemists [52] since the original publication of the structure. Only recently was a synthesis reported for /rnatural product based on low field NMR stupes [51]. A total synthesis of this acid in our laboratory [54,55], and comparison of NMR spectra with a sample kindly provided by Professor Isono showed that they were different. The sample of the naturally-derived amino acid was suitable for X-ray analysis (even after 20 years of isolation and storage ), and it proved to be ci5-polyoximic acid [54]. A new synthesis of this isomer was undertaken and confirmed its structural as well as stereochemical identity (Scheme 9) [55]. TTie stereochemical revision of polyoximic acid could... 

An interesting preparation of alkyl carboxylates in high yield (Table 3.14) from the sodium salt of the carboxylic acids under mild phase-transfer catalytic conditions involves their reaction with alkyl chlorosulphate [50] and has been used with success in the preparation of alkyl esters derived from p-lactam antibiotics. The procedure is also excellent for the production of chloromethyl esters, particularly where the carboxylic acids will not withstand the classical Lewis acid-catalysed procedure using an acid chloride and formaldehyde, or where the use of iodochloromethane [51] results in the formation of the bis(acyloxy)methane. The procedure has been applied with some success to the synthesis of chloromethyl A-protected a-amino carboxylates [52],... 

The synthesis of the carbapenam-3-carboxylic acid 36 <03JA15746> as well as a study on carbapenem biosynthesis have been documented <03JA8486>. The cephalosporin derivative 37 has been prepared and its use as a novel fluorogenic substrate for imaging P-lactamase gene expression demonstrated <03JA11146>. The nucleus of the carbacephem antibiotic loracarbef has been synthesized in a highly efficient and enantioselective fashion from 25,3iS-2-amino-3-hydroxy-6-heptenoic acid, which was derived from enzyme-catalyzed... 

A stereoselective synthesis of 6-amino acid derivatives by an aldol-type condensation of tin(II) carboxylic thioester enolates with imines has been reported (Scheme 90) the method was used to synthesize an intermediate of the carbapenem antibiotic... 

The known 7-e carboxylic acid 506, obtained by the condensation of acrylic acid with furan, was used as a substrate for synthesis of validamine, (510) a component of validamycin antibiotics. The treatment of 506 with hydrogen peroxide in formic acid gave the tricyclic compound 507, which after reduction and hydrolysis afforded cyclitol. Treatment of 508 with 2,2-dimethoxy-propane in the presence of an acid gave a mixture of diisopropylidene derivatives in which compound 509 was predominant. Introduction of an amino group, by way of a tosyl ester and azide displacement, followed by hydrogenation and hydrolysis, completed the synthesis of DL-val-... 

Several 3-C-branched D-allofuranosyl (7) and 3-C-D-psicopyranosyl (8) derivatives have been obtained from l,2 5,6-di-0-isopropylidene-a-r>-ribo-hexofuranose-3-ulose and l,2 4,5-di-0-isopropylidene-P-D-erythro-2-hexulopyranos-3-ulose respectively by treatment with lithium dianions of the respective carboxylic acids. Synthesis of 3-C-methyl-rhamnose has been reported in connection with the total synthesis of eviminomicin 13,3B4-1, an orthosomicin class antibiotic (see also Section 2 and Chapter 4). ... 

A microwave assisted Comforth rearrangement of oxazole-4-carboxamides 106 efficiently afforded 5-aminooxazole-4-carboxylates 107. This procedure was applied to the formal synthesis of a natural antibiotic derived from pseudomonic acid <06TL4698>. 

Analogous to the use of chiral enoates (see previous section), a, -unsaturated carboxylic amides, prepared from chiral amines, may be utilized in asymmetric 1,4-additions. When Grignard reagents are added to unsaturated amides (21), derived from (-)-ephedrine (20),25 highly optically active fi-sub-stituted alkanoic acids (22 R and R = alkyl or phenyl) are obtained in a variety of cases, after hydrolysis of the initially formed adducts (Scheme 7). This method was used for the synthesis of the antibiotic (-) malyngolide and its stereoisomers.26 Recrystallization of the intermediate (saturated) amide was necess-... 

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