Macrolide antibiotics, 16-membered chemical modifications

The 16-membered macrolide antibiotics are generally classified into two large groups, namely, the leucomycin-related family and the tylosin-related family, on the basis of the substitution patterns of their aglycons (Fig. 28) [187]. Interestingly, the leucomycin series, such as leucomycin, josamycin, midecamycin, and spiramycin, have been used clinically for humans, while the tylosin series has been utilized in veterinary medicine. In this section, we describe recent studies on the chemical modification of 16-membered macrolides and their structure-activity relationships. 

One of the most pleasant aspects of total synthesis involves the observation of serendipitous and often unexpected chemical reactions. Indeed the annals of synthesis have reported innumerable examples of such events. Sometimes failed reactions or astute observations of reactivity have resulted in the formulation of rules (e.g. Woodward-Hoffmann, Baldwin, etc.). We recount here a recent serendipitous reaction experienced during our studies on the total synthesis and chemical modification of bafilomycin Ai [56], an unusual 16-membered macrolide antibiotic [57]. In an attempt to obtain a branched derivative, we explored the reaction of 7-keto bafilomycin A2-TMS ether with methyl copper. We were intrigued by the formation of an isomeric product without the inclusion of a C-methyl group. When the same reaction was applied to 7,21-di-TMS bafilomycin A2, a new product was formed in high yield. Deprotection of the silyl group led to a crystalline product which proved to be the 18-membered isomer as evidenced by single-crystal X-ray diffraction analysis [58] (Scheme 10). 

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