Chemoselective substitutions in the C10-methyl group of erythromycin A ketolides is reported. The C10-methyl group in the clarithromycin derived substrate 10,11-anhydro-O ⁶-methyl-descladinosylerythromycin was activated by conversion into an allyl acetate and thereafter to the corresponding allylic cyanide. Both the allylic acetate and the cyanide reacted with carbonyldiimidazole and ammonia to afford a C11,C12-cyclic carbamate with concurrent elimination of the allylic function to yield a methylene α,β-unsaturated ketone. Conjugate addition with amines resulted in stereoselective C-N bond formation between the terminal methylene carbon and the amino nitrogen. Carbylation in the methylene group was effected under Stille conditions for cross-coupling with Pd-catalysis. With anion stabilized nucleophiles, such as a sodium salt of a malonate, stereoselectivity was observed in the formation of the 10-substituent. Stereoselective cycloaddition with trimethylsilyldiazomethane afforded a spirane where the C10 carbon of the macrolide skeleton had become a quaternary spirocarbon. Antibacterial in vitro data for a selected group of compounds against strains of respiratory pathogens S. pneumoniae and S. aureus are reported. Most of the compounds tested showed improved activities over CLA as a reference compound against efflux resistant S. pneumoniae as well as against efflux and inducibly resistant strains of S. aureus.

中文翻译：

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在未反应的C10-甲基上化学修饰的克拉霉素缩酮的合成

据报道，在红霉素A酮醇化物的C10-甲基中有化学选择性取代。克拉霉素衍生的底物10,11-anhydro-O ^6中的C10-甲基通过转化成乙酸烯丙酯，然后转化成相应的烯丙基氰化物，活化了-甲基-癸二糖基红霉素。乙酸烯丙基酯和氰化物都与羰基二咪唑和氨反应，得到C11，C12-环状氨基甲酸酯，同时消除了烯丙基官能团，得到亚甲基α，β-不饱和酮。与胺的共轭加成导致在末端亚甲基碳和氨基氮之间形成立体选择性CN键。在Stille条件下进行亚甲基的羰基化以与Pd催化交叉偶联。用阴离子稳定的亲核试剂，如丙二酸酯的钠盐，在形成10位取代基时观察到立体选择性。与三甲基甲硅烷基重氮甲烷的立体选择性环加成反应生成了一个螺环烷，其中大环内酯骨架的C10碳已成为季螺碳。报道了针对呼吸道病原体肺炎链球菌和金黄色葡萄球菌菌株的一组选定化合物的体外抗菌数据。作为参考化合物，大多数测试化合物显示出比CLA更高的活性，可抵抗耐药的肺炎链球菌以及耐药的金黄色葡萄球菌的耐药菌株。