Practical, Modular Synthesis of Macrolid Antibiotics

This post-doctoral research proposal consists of two aims. First, the development of a modular, concise and scalable total synthesis of the azalide azithromycin 1 (Zithromax ) and second the design of improved macrolide antibiotics thereof. Azithromycin 1, the first azalide antibiotic on the market has gained widespread application in human therapy and is one of the most prestigious and active members of macrolide antibiotics. Azalides, semi-synthetic derivatives of erythromycin show superior pharmacokinetics compared to the first generation drugs, particularly with regard to acid stability and bio-availability. However, the need for more efficient antibiotics due to the rapid emergence of bacterial resistance over the last decades has increased. The total syntheses of 1 and its modifications represent a synthetic challenge due to several reasons. The highly complex molecular framework and the aim to develop a scalable synthesis, which could even be implemented into industrial processes demands a very convergent, efficient and precise approach. Total synthesis is by far more flexible than semi-synthesis and capable of providing rapid access to specifically improved derivatives. The selective incorporation of fluorine, almost impossible for semi-synthesis should improve the binding interactions, the metabolic stability and the bio-availability of 1. Assembling of fragments is done in a highly convergent and modular way, hence allowing the selective synthesis of derivatives. The preparation of the key fragments and the accomplishment of the total synthesis should be secured by alternative backup routes. For the synthesis of the western and the eastern subunit two and for the connection of these fragments three, slightly modified strategies are presented. The key steps consist of Myers` recently developed methodology to build up the tertiary hydroxyl function, Ireland-Claisen rearrangement for the construction of the eastern moiety, Sharpless aminohydroxylation, Evans` aldol reaction to generate the south- eastern domain and macrocyclization via macroalkylation, Mitsunobu reaction or reductive macroamination. The incorporation of Myers` protocol will disclose its power in total synthesis for the first time. The proposed total synthesis is characterized by a shortest number of synthetic steps, highest flexibility as well as modularity and benefits from cheap, commercially available starting materials. Additionally, structure activity relationships (SAR) studies will expedite the development of new antibiotic drugs.