Erythromycins fluorination

Erythromycins are macrolide antibiotics produced by bacterial fermentation. Fluoiination of erythromycin has been studied as a strategy to insure better stability in acidic medium and/or to achieve better bioavailability. An erythromycin, fluorinated at C-8, flurithromycin, was launched several years ago. Its preparation involves an electrophilic fluorination, with CF3OF [119] or with an N-F reagent A/-fluorobenzenesulfonimide (NFSI) [120], of the 8,9-anhydroerythromy-cin-6,9-hemiacetal or of the erythronolide A (Fig. 44). 

Flurithromycin is an erythromycin fluorinated at C-8, which was launched several years ago (cf. Chapter 8). Its preparation involves an electrophilic fluorination with or with an N— F reagent (NFSI) of 8,9-anhydroerythromycin-6,9-hemiacetal or of erythronolide A. Glycosylations have also been performed by fermentation (Figure 4.57). ... 

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)... 

Several 2-fluoroerythromycin derivatives have also been prepared by means of electrophilic fluorination with Selectfluor of the enolate of the )S-ketoester fragment (Fig. 45) [121]. Fluorination is stereoselective and leads to the a-fluo-rine compound [122]. Two derivatives of 2-fluoroerythromycin are in clinical development HMR-3562 and HMR-3787). These compounds are promising agents for the treatment of respiratory pathogens resistant to erythromycin A (Fig. 45) [123]. 

Recently, a novel fluorinated erythromycin (16-fluoroerythromycin A) has been produced by Saccharopolyspora erythraea, using an m-fluorobutyrate as precursor for the biosynthesis (Fig. 46) [124]. 

R.J.M. Goss, H. Hong, A novel fluorinated erythromycin antibiotic, Chem. Comm. (2005) 3983-3985. 

Flurithromycin (120), a fluorinated erythromycin macrolide, has been isolated from a mutant strain of Streptomyces erythraeus. It shows antibacterial activity against Streptococcus pneumoniae (MIC 0.0015-... 

Most cases of Legionella pneumonia show improvement within 12-48 hours of starting antibiotic therapy. The antibiotic of choice has been erythromycin, sometimes paired with a second antibiotic, rifampin. Tetracycline, alone or with rifampin, is also used to treat Legionnaires disease, but has had more mixed success in comparison to erythromycin. Other antibiotics that have been used successfully to combat Legionella include doxycycline, clarithromycin, fluorinated quinolones, and trim ethoprim/sulfamethoxazole. 

Other approaches to inhibiting intramolecular cydizations of erythromycin have also proven successful. From a series of O-alkyl derivatives of erythromycin, darithromycin (6-O-methylerythromycin) (37) was sdected for clinical devdopment (146,147). Another approach replaced the C-8 proton of erythromycin with fluorine, which was accomplished by both chemical and bioconversion methods to yidd flurithromycin (38) (148). 

Another successful approach for blocking the intramolecular decomposition illustrated in Fig. 2 involved inhibition of the dehydration step leading to the anhydrohemiketal by replacement of the C-8 proton of erythromycin with fluorine. Preparation of flurithromycin (8-fluoroerythromycin, see Fig. 4) has been achieved by both chemical and biochemical methods. Addition of 8(S)-8-fluoroerythronolide A to a mutant strain of Streptomyces erythreus blocked in biosynthesis of its endogenous lactone (erythronolide) yielded the desired fluorinated erythromycin [40]. This technique of mutasynthesis has been further employed for the production of other fluorinated derivatives of erythromycin [40, 41]. Fluorination of different 8,9-anhydro-6,9-hemiketal derivatives of erythromycin by chemical means with reagents such as trifluoromethyl hypo-fluorite or perchloryl fluoride (with subsequent reduction of the N-oxide) has also been reported [42, 43]. 

Solithromycin (CEM-101, Figure 44.8) is a ketolide antibiotic undergoing clinical development for the treatment of community-acquired pneumonia. It is another example of semi-synthetic antimicrobial agents derived from erythromycin, which was designed to overcome erythromycin resistance in Streptococcus pneumoniae. The synthesis of solithromycin involves the introduction of the fluorine atom on the (3-keto ester moiety with Selectfluor in the presence of potassium tert-butoxide in tetrahydrofuran (THF). Solithromycin shows the greatest potency and widest spectrum of activity against respiratory tract... 

---