Erythromycin cyclic 11,12-carbonate

Antibiotics. — Erythromycin cyclic carbonate,daunomycin butanol complex,hedamycin (see Chapter 18), and olgose (a major degradation product of the oligosaccharide antibiotic everninomicin... 

Cyclic carbonic esters were also prepared, for example, from the cardiac glycoside proscillaridine[257] (where besides CDI the benzyloxycarbonylimidazole was successfully used), ingenol, 2581 the macrolide antibiotic tylosine,[259] and an erythromycin A derivative.12601... 

Macro ides - Clinical trials are underway for erythromycin A, 11,12-cyclic carbonate,72 which is said to be more active than erythromycin A. Josa-mycin was tolerated better than erythromycin in fasting patients, while plasma concentrations, half lives, and elimination constants were equivalent.73 Josamycin was less active than rosamicin or erythromycin A against aerobic cocci while clindamycin was more active than all three against anaerobes.714,75... 

Morimoto, S., Misawa, Y., Kondoh, H., Watanabe, Y, and Omura, S. (1990). Chemical modification of erythromycins. V. Synthesis and antibacterial activity of 4"-0-methyl derivatives of erythromycin A 11,12-cyclic carbonate. J. Antibiot. 43,566-569. 

Typical procedure. 2 -Acetyl-4"-O-benzyloxycarbonyl-G-O-methyl-erythromycin A 11,12-carbonate 920 [660] A solution of diol 919 (0.51 g, 0.55 mmol) in THF (10 mL) at —35 °C was treated with sodium bis(trimethylsilyl)amide in THF (0.7 mL of a 0.84 M solution 0.6 mmol). After 10 min, a solution of CDI (0.33 g, 2.0 mmol) in THF (5 mL) was added. The reaction mixture was allowed to warm to room temperature and kept at this temperature for 15 min. It was then cooled to 0-5 °C (ice/ water bath) and 0.5 m NaH2P04 solution was added. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The residue was purified by flash chromatography eluting with acetonitrile/dichloromethane/concentrated ammonium hydroxide (1 1 0.01) to afford 370 mg (70%) of carbonate 920 mp 248-250 °C IR (CDCI3) Vmax = 1800 cm (cyclic carbonate C=0). 

Erythronolide B, the biosynthetic progenitor of the erythromycin antibiotics, was synthesized for the first time, using as a key step a new method for macrolactone ring closure (double activation) which had been devised specifically for this problem. Retrosynthetic simplification included the clearance of the stereocenters at carbons 10 and 11 and the disconnection of the 9,10-bond, leading to precursors A and B. Cyclic stereocontrol and especially the Baeyer-Villiger and halolactonization transforms played a major role in the retrosynthetic simplification of B which was synthesized starting from 2,4,6-trimethylphenol. 

The 11,12-carbonate of erythromycin (32) is an older cyclic ester which had greater stability and antibiotic activity by diminishing formation of intramolecular enol ether (27) (136,137). A later analogue, the 11-IV- 12-0-cyclic carbamate of... 

In erythromycin-11,12-carbonate (11), the cyclic ester locks the structure of the ring predominantly into the 6,9-hemiketal, with only a minor amount of the 9-keto form present [36, 77-79]. As a consequence, the facile dehydration of the 6,9-hemiketal to the 8,9-anhydro derivative (8) is inhibited. The increased stability results in better potency, pharmacokinetics, and tissue penetration than erythromycin [80, 81]. However, concerns about potential hepatotoxicity have prevented its wider usage [71, 82, 83]. 

The cyclic 11,12-carbonate of erythromycin represents a previously recognized method for stabilization of erythromycin by maintaining an equilibrium between the 6-hydroxy-9-keto and 6,9-hemiketal forms [44]. A new direction within this approach was recently reported with a series of cyclic 11,12-carbamate derivatives of erythromycin and clarithromycin (see Fig. 5), prepared by a general sequence of 10,11-dehydration, 12-0-carbamoylation, and intramolecular cyclization [45, 46]. Other structural modifications within this part of the erythromycin molecule include 10,11-anhydroerythromycin, previously synthesized from the cyclic 11,12-carbonate [47],... 

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