A Platform for the Discovery of New Macrolide Antibiotics
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CitationZhang, Ziyang. 2016. A Platform for the Discovery of New Macrolide Antibiotics. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractThe macrolide class of antibiotics has been widely used to treat bacterial infections for over 65 years. To date, all practical routes to clinically used macrolide antibiotics have relied on the chemical modification of the fermentation product erythromycin, a process referred to as semisynthesis. As bacterial resistance to semisynthetic macrolides emerges, a new approach to the discovery of structurally novel antibiotic candidates is urgently required.
This dissertation presents a general and practical strategy for the synthesis of macrolide antibiotics based on the convergent assembly of simple building blocks. Implementation of this strategy has led to the synthesis of novel macrolide antibiotic candidates in as few as 10 longest linear steps (from building blocks). The synthesis features a thermal macrocyclization reaction that proves generally successful for the construction of several macrolide scaffolds. In the past four years, my coworkers and I have prepared more than 350 fully synthetic macrolides with substantial structural diversity by adaptation of the synthetic route, variation of the building blocks, or a synergic combination of both. Preliminary antimicrobial testing against a panel of Gram-positive and Gram-negative strains reveals that many of the fully synthetic macrolides exhibit promising activities, and several of them are efficacious against pathogens resistant to currently used macrolide antibiotics.
Also described in this dissertation are chemical methods developed specifically for the practical synthesis of two key building blocks. The 3-amino sugar desosamine, a common constituent of many macrolide antibiotics, is synthesized in four steps from methyl vinyl ketone. The key step of the synthesis involves a new method developed for the single-step construction of 3-nitro sugars by the coupling of γ-nitro alcohols and glyoxal. This method has been applied to the preparation of an array of 3-amino sugars analogous to desosamine, which have been incorporated to provide novel macrolides with modified glycosidic residues. The synthesis of silyl enol ether 72 is enabled by an efficient directed Claisen reaction. The reaction of the lithium enolate of a tert-butyl ester and a phenyl ester in the presence of lithium hexamethyldisilazide affords a tert-butyl β-keto ester in high yield. Two subsequent steps transform this product to silyl enol ether 72.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:33493421
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