Chloramphenicol synthesis

The promising results of triazolium salt catalysis inspired our research group to synthesize a variety of chiral triazolium salts for the asymmetric benzoin condensation (Enders et al. 1996b Enders and Breuer 1999 Teles et al. 1999). Extensive investigations have shown that the enantiomeric excesses and catalytic activities are highly dependent on the substitution pattern of the triazolium system. The most active catalyst (S, S)-97, which is readily available from an intermediate of the industrial chloramphenicol synthesis, provided benzoin (857) in its (R)-configuration with 75% ee and a good yield of 66%. Remarkably, only... 

Liu, Z.-S., Fang, Z.-L., Combination of flow injection with capillary electrophoresis. Part 2. Chiral separation of intermediate enantiomers in chloramphenicol synthesis. Anal. Chim. Acta 1997, 353(2-3), 199-205. 

The group of early proteins also evidently include certain repressors formed by the phage to inhibit RNA and DNA synthesis in the cells of the infected bacteria themselves. If synthesis of only the early proteins is inhibited without inhibition of synthesis of phage RNA (by chloramphenicol), synthesis of ribosomal and soluble RNA in the host cells continues even after infection, but synthesis of bacterial DNA and of messenger RNA is inhibited in this case also (Okamoto et al., 1962 Nomura, Okamoto,and Asano, 1962 Nomura, Matsubara, et al., 1962). Different forms of RNA... 

Lack of Repression of the Shildmic Acid Pathway.—It is well established that a control mechanism on the shikimic acid pathway is by repression of enzymes early in the pathway by the end products, e.g. by phenylalanine. Cases where this type of control appear to have broken down have now been reported. Lowe and Westlake, in studying the biosynthesis of the phenolic antibiotic chloramphenicol in Streptomyces sp. 3022a, examined several enzymes of the pathway, notably chorismate mutase and anthranilate synthetase, but could find no evidence that end-product control on chloramphenicol synthesis was operating in this organism. Similarly, Chu and Widholm fed phenylalanine and tyrosine to a range of tissue cultures of higher plants, but were not able to observe any evidence of feedback control on chorismate mutase levels. 

Legator, M., and D. Gottlieb The dynamics of chloramphenicol synthesis. Antibiotics Chemotherapy 3, 809 (1953). 

Dichloroacetic acid is used in the synthesis of chloramphenicol [56-75-7] and aHantoin [97-59-6]. Dichloroacetic acid has vimcidal and fungicidal activity. It was found to be active against several staphylococci (36). The oral toxicity is low the LD q in rats is 4.48 g/kg. It can, however, cause caustic bums of the skin and eyes and the vapors are very irritating and injurious (28). 

In pharmaceutical appHcations, the selectivity of sodium borohydride is ideally suited for conversion of high value iatermediates, such as steroids (qv), ia multistep syntheses. It is used ia the manufacture of a broad spectmm of products such as analgesics, antiarthritics, antibiotics (qv), prostaglandins (qv), and central nervous system suppressants. Typical examples of commercial aldehyde reductions are found ia the manufacture of vitamin A (29) (see Vitamins) and dihydrostreptomycia (30). An acyl azide is reduced ia the synthesis of the antibiotic chloramphenicol (31) and a carbon—carbon double bond is reduced ia an iatermediate ia the manufacture of the analgesic Talwia (32). 

Chloramphenicol may be prepared by fermentation or by chemical synthesis. The fermentation route to chloramphenicol is described in U.S. Patents 2,4B3,B71 and 2,4B3,B92. To quote from U.S. Patent 2,4B3,B92 The cultivation of Streptomyces venezuelae may be carried out in a number of different ways. For example, the microorganism may be cultivated under aerobic conditions on the surface of the medium, or it may be cultivated beneath the surface of the medium, i.e., in the submerged condition, if oxygen is simultaneously supplied. 

This is by far the most versatile route to the synthesis of ester-substituted aziridines, especially as the benzhydryl group can easily be cleaved by hydrogenolysis. Wulff has applied this methodology to a short asymmetric synthesis of the antibiotic (-)-chloramphenicol in four steps from p-nitrobenzaldehyde (Scheme 1.34) [61]. In this case it was found that treatment of the aziridine 111 with excess dichloroacetic acid gave the hydroxy acetamide directly, so no separate deprotection step was required. 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

Ribosomal Protein Synthesis Inhibitors. Figure 5 Nucleotides at the binding sites of chloramphenicol, erythromycin and clindamycin at the peptidyl transferase center. The nucleotides that are within 4.4 A of the antibiotics chloramphenicol, erythromycin and clindamycin in 50S-antibiotic complexes are indicated with the letters C, E, and L, respectively, on the secondary structure of the peptidyl transferase loop region of 23S rRNA (the sequence shown is that of E. coll). The sites of drug resistance in one or more peptidyl transferase antibiotics due to base changes (solid circles) and lack of modification (solid square) are indicated. Nucleotides that display altered chemical reactivity in the presence of one or more peptidyl transferase antibiotics are boxed. 

Chloramphenicol (Chloromycetin) interferes witii or inhibits protein synthesis, a process necessary for the growth and multiplication of microorganisms. This is a potentially dangerous drug (see below), and therefore its use is limited to serious infections when less potentially dangerous drugp are ineffective or contraindicated. 

A famous example of the use of nitro compounds in synthesis was the original synthesis of the antibiotic chloramphenicol (8), which is still used to treat tropical diseases. This synthesis also confirmed the structure of chloramphenicol and established that the (-)-thrco compound was the biologically active stereoisomer. 

What could be the signal for the induction of the cold shock proteins It has been observed that shifting E. coli cells from 37 to 5 °C results in an accumulation of 70S monosomes with a concomitant decrease in the number of polysomes [129]. Further, it has been shown that a cold shock response is induced when ribosomal function is inhibited, e.g. by cold-sensitive ribosomal mutations [121] or by certain antibiotics such as chloramphenicol [94]. These data indicate that the physiological signal for the induction of the cold shock response is inhibition of translation caused by the abrupt shift to lower temperature. Then, the cold shock proteins RbfA, CsdA and IF2 associate with the 70S ribosomes to convert the cold-sensitive nontranslatable ribosomes into cold-resistant translatable ribosomes. This in turn results in an increase in cellular protein synthesis and growth of the cells. 

Synthesis. Chloramphenicol is now usually produced by a synthetie process. 

Bacterial ribosome function Aminoglycosides Tetracyclines Chloramphenicol Macrolides, azalides Fusidic acid Mupirocin Distort SOS ribosomal subunit Block SOS ribosomal subunit Inhibits peptidyl transferase Block translocation Inhibits elongation factor Inhibits isoleucyl-tRNA synthesis No action on 40S subunit Excluded by mammalian cells No action on mammalian equivalent No action on mammalian equivalent Excluded by mammalian cells No action on mammalian equivalent... 

Of the fonr possible optical isomers of chloramphenicol, only the o-threo form is active. This antibiotic selectively inhibits protein synthesis in bacterial ribosomes by binding to the 50S subunit in the region of the A site involving the 23 S rRNA. The normal binding of the aminoacyl-tRNA in the A site is affected by chloramphenicol in such a... 

Feedback inhibition of amino acid transporters by amino acids synthesized by the cells might be responsible for the well known fact that blocking protein synthesis by cycloheximide in Saccharomyces cerevisiae inhibits the uptake of most amino acids [56]. Indeed, under these conditions, endogenous amino acids continue to accumulate. This situation, which precludes studying amino acid transport in yeast in the presence of inhibitors of protein synthesis, is very different from that observed in bacteria, where amino acid uptake is commonly measured in the presence of chloramphenicol in order to isolate the uptake process from further metabolism of accumulated substances. In yeast, when nitrogen starvation rather than cycloheximide is used to block protein synthesis, this leads to very high uptake activity. This fact supports the feedback inhibition interpretation of the observed cycloheximide effect. 

An important feature of the antibiotic chloramphenicol (9) is the presence of the dichloroacetamide function. Inclusion of this amide in a simpler molecule, teclozan (15), leads to a compound with antiamebic activity. Whether this is cause and effect or fortuitous is unclear. The synthesis begins with alkylation of the alkoxide derived from ethanolamine (10) with ethyl iodide to give the aminoether (11). Reaction of a,a -dibromo-p-xylene (12) with 2-nitropropane in the presence of base leads to dialdehyde (13). The reaction probably proceeds by O-alkylation on the nitropropyl anion... 

To establish whether rifaximin, like the other members of the rifamycin family [36, 58], specifically inhibits bacterial RNA synthesis the effect of this antibiotic as well as that of rifampicin and chloramphenicol on RNA (via 3H-uridine incorporation), DNA (via 3H-thymidine incorporation) and protein (via 35S-methionine incorporation) synthesis was studied in growing cultures of Escherichia coli [59], While chloramphenicol reduced protein synthesis, both rifaximin and rifampicin inhibited RNA synthesis in a concentration-dependent fashion. In contrast, none of them affected 3H-thymidine incorporation into DNA. These data suggest that rifaximin, like rifampicin, inhibits RNA synthesis by binding the (3 subunit of the bacterial DNA-dependent RNA polymerase [60],... 

Protein synthesis inhibitors Chloramphenicol Tetracyclines Macrolides Lincosamides Aminoglycosides... 

The answer is b. (Hardman, p 1131.) Chloramphenicol inhibits protein synthesis in bacteria and, to a lesser extent, in eukaryotic cells. The drug binds reversibly to the. 505 ribosomal subunit and prevents attachment of aminoacybtransfer RNA (tRNA) to its binding site. The amino acid substrate is unavailable for peptidyl transferase and peptide bond formation. 

Certain antibiotics (for example, chloramphenicol) inhibit mitochondrial protein synthesis, but not cytoplasmic protein synthesis, because mitochondrial ribosomes are similar to prokaryotic ribosomes. 

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