22. Carboxylic Acid Derivatives: NAS

Macrolide antibiotics all have large rings (macrocycle) in which

an ester makes the ring; a cyclic ester is termed a lactone.

One example is erythromycin A, first isolated from soil bacteria

in the 1950s. Over time, some pathogenic bacteria

have developed resistance to erythromycin by evolving

an enzymatic mechanism to cleave the macrocycle

at the ketone.

To counter this resistance, chemists modified the erythromycin

structure to replace the ketone with an amine that the bacteria

could not detoxify. This modified antibiotic, azithromycin,

trade name Zithromax®, is one of the most prescribed

drugs in the world for respiratory infections.

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(a) Identify the lactone group in each structure that merits the classification as macrolides.

(b) Two groups are circled. What type of functional group

are they? Explain.

When ethyl 4-hydroxybutyrate is heated in the presence of a trace of a basic catalyst (sodium acetate), one of the products is a lactone. Propose a mechanism for formation of this lactone.

Propose mechanisms for the following reactions.

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Show how you would add a Grignard reagent to an ester or a nitrile to synthesize

(b) heptan-4-ol.

Explain this curious result. What does this reaction tell you about the relative reactivity of esters and ketones?

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Macrolide antibiotics, including erythromycin and azithromycin (Zithromax®), contain a large ring lactone. One of the largest ever reported is Gargantulide A, the structure of which was determined by the research group of Prof. William Gerwick of the Scripps Institution of Oceanography (Organic Letters, 2015, 17, 1377–1380). Isolated from a Streptomyces bacterium, it kills pathogenic bacteria like MRSA and Clostridium difficile, but it proved too toxic to the test animals to continue further testing.

(a) Identify the lactone that makes this a macrolide structure.

(b) How many rings does this structure contain? How many atoms are in the largest ring?

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