Erythromycin derivatives reactions

These reactions liberate carbonyl fluonde and fluorotnmethylsilane and thus require no hydrolysis A fluorinated erythromycin derivative is obtained from fluorination of 3 O raycarosyl-8 9-anhydroerythronolideB 6,9 hemiacetal, an enol ether [iS] (equation 16)... 

Benzoxazoles have been prepared by intramolecular reaction of a phenolic —OH groiq) with a Beckmann intermediate (equation 30). A cyclic imidate was isolated in high yield from tosylation and in situ Beckmann reaction of the erythromycin-derived oxime (4[Pg.698]

Cholestatic hepatitis, which is associated primarily with erjdhromycin estolate, can be caused by all forms of erythromycin, including the base, estolate, ethylsuccinate, propionate, and stearate (39,41). Although it was originally speculated that a hypersensitivity reaction to the estolate ester rather than to the erjdhromycin itself was responsible for this adverse reaction (42), erythromycin does inhibit bile flow (43). Most probably the differences in hepatotoxicity between the various erythromycin derivatives are of a quantitative rather than a qualitative nature (44,45), perhaps because of better intestinal absorption of the estolate. Potentially severe but rare cholestatic liver injury occurs in perhaps up to 2-4% of... 

The reaction of 8-hydroxy acids with p-bromobenzenesulfonyl chloride in the presence of a tertiary amine gives /3-lactones (eq 5). Brosylate esters of oximes have been manipulated in the Beckmann rearrangement of erythromycin derivatives as an alternative to both 4-methylbenzenesulfonate esters and benzene-sulfonate esters. 

In some cases enzymes can increase the rate of reaction by up to lO times. Carnell and Roberts (1997) have briefly discussed the scope of biotransformations that are used to make pharmaceuticals like penicillins, cephalosporines, erythromycin, lovastatin, cyclosporin, etc., and for food additives like citric acid, L-glutamate, and L-lysine. A very successful transformation by Zeneca has been that of benzene reduction, with Pseudomonase Putida, to dihydrocatechol and catechol the dihydro derivative is used to produce (+/-) pinitol. Fluorobenzene has been converted to fluorodihydrocatechol, an intermediate for pharmaceuticals. The highly stereo selective Bayer-Villeger reaction has been carried out with genetically engineered S-cerevisvae. Hydrolases have allowed enantioselective, and in some cases regioselective, hydrolysis of racemic esters. 

Cholestatic hepatitis may occur when drug therapy lasts longer than 10 days or repeated courses are prescribed. The hepatitis is characterized by fever, enlarged and tender liver, hyperbilirubinemia, dark urine, eosinophilia, elevated serum bilirubin, and elevated transaminase levels. Hepatitis has been associated with the estolate salt of erythromycin but not with other formulations. Although the hepatitis usually occurs 10 to 20 days after the initiation of therapy, it can occur within hours in a patient who has had such a reaction in the past. The hepatitis is believed to be the result of both a hepatotoxic effect and a hypersensitivity reaction this latter effect is reversible on withdrawal of the drug. Erythromycin and derivatives induce hepatic microsomal enzymes and interfere with the actions of various drugs, including theophylline and carbamazepine. 

O Hara, K. Kanda,T. Kono, M. Structure of a phosphorylated derivative of oleandomycin, obtained by reaction of oleandomycin with an extract of an erythromycin-resistant strain of Escherichia coli. J. Antibiot., 41,823-827 (1988)... 

The O-methyl group of L-cladinose (2) is also derived from L-methionine. The O-methylation step does not, however, take place at the level of the nucleotide-sugar, but it occurs when the substrate is erythromycin C, which contains L-mycarose and D-desosamine as glycosidic components9 (see Scheme la). The O-methylation of the L-mycarose moiety of erythromycin C by a partially purified enzyme from Streptomyces erythreus was described by Alpine and Corcoran.10,11 The reaction catalyzed is shown in Scheme la. 

Aldol reaction of (5)-2-benzyloxypropanal with the lithium enolate of methyl 2-methoxypro-panoate gives a 7 2 1 mixture of /3-hydroxyesters. The major product has been converted into L-cladinose, a saccharide moiety of erythromycin A [332]. The isomeric methyl 3,6-dideoxy-3-C-methylhexofuranosides have been derived from (5)-2-benzyloxypropanal via homoaldol reactions in three steps. 

Spiramycin is a macrohde antibiotic. However, in contrast to other macrohde derivatives such as erythromycin salts, ototoxicity, neurosensorial disorders, and cardiac rhythm disorders do not appear to have been described after spiramycin. Reported adverse effects of spiramycin include G1 disorders, immune-allergic reactions, and liver injury (see also Figure 88). 

Another synthetic strategy for partially or completely inhibiting intramolecular cyclization of erythromycin to hemiketal (8) and spiroketal (9) is modification of the functional groups that participate in the cyclization reactions. These groups include the C-9 ketone, C-6 hydroxyl, and C-8 proton in addition to the 11,12-diol discussed above. These approaches have led to a variety of semi-synthetic derivatives of erythromycin, some of which have been recently approved by regulatory agencies or are in late stages of clinical trials [12-17],... 

A single diastereomer 93, however, results from addition of the lithium enolate 92 derived of t-butyl thiopropanoate to the chiral, enantiomerically pure aldehyde 91. The transformation is a key carbon-chain-elongation step in Woodward s synthesis of erythromycin A (Eq. (37)) [166]. Somewhat lower diastereoselectivity is observed in the aldol reaction between the lithium enolate 95 and the chiral aldehyde 94, a transformation used in a synthesis of maytansin (Eq. (38)). The diastereomeric adducts 96a and 96b result in a ratio of 90 10 [167]. 

The erythromycins are examples of polypropionates , natural products biosynthetically derived largely from propionic acid units via a series of condensation reactions. Many natural products, broadly called polyketides, share this biosynthetic origin. These compounds are decorated with multiple stere-ogenic centers, and acyclic diastereoselection problems that are much more complex than the terpenoid sidechain stereochemistry problem will surface with erythromycin, including the problem of asymmetric synthesis. 

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