Q65P Macrolide antibiotics all have l... [FREE SOLUTION]

Chapter 19: Q65P (page 1037)

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 1950鈥檚. 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庐, is one of the most prescribed drugs in the world for respiratory infections.
(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
(c) Identify the ketone in erythromycin targeted by bacteria as the site for detoxification.
(d) Identify the amine in azithromycin. What type of amine is it?
(e) From what you know about the reactivity of ketones and amines, why was an amine a good choice to be the 鈥渃hemical opposite of a ketone鈥�?

Short Answer

Expert verified

(b)

(e) A ketone is an electrophile, meaning that it will be attacked by a nucleophile. Presumably, bacteria used an enzyme with a nucleophile at its active site to detoxify erythromycin. In contrast, the amine in azithromycin is nucleophile and will be unaffected by another nucleophile, rendering the detoxifying enzyme useless.

Step by step solution

Step-1. Explanation of part (a):

A lactone is an ester in which the functional group of the ester has become part of a ring structure with carbon atoms. Examples of lactones are macrolides, kavalactones etc. Lactones are often used as flavors and fragrances.

Step-2. Explanation of part (b):

An acetal is a functional group in which carbon is attached by single bonds to ether oxygen and two carbons or hydrogens. Formation of acetal occurs when hydroxyl group of a hemiacetal becomes protonated and is lost as water. Both circled groups shown are acetals. One carbon bonded to two groups, one carbon and one hydrogen.

Acetal groups are squared out as shown

Step-3. Explanation of part (c) and (d):

Ketones are organic compounds which incorporate carbonyl functional group and the carbon atom of this group has remaining bonds that may be occupied by alkyl or aryl substituents. Tertiary amine is an amine in which the nitrogen atom is directly bonded to three carbons of any hybridization which cannot be carbonyl group carbons.

Depiction of ketonic and tertiary amine functional group in erythromycin and azithromycin respectively

Step-4. Explanation of part (e):

A ketone is an electrophile, meaning that it will be attacked by a nucleophile. Presumably, bacteria used an enzyme with a nucleophile at its active site to detoxify erythromycin. In contrast, the amine in azithromycin is nucleophile and will be unaffected by another nucleophile, rendering the detoxifying enzyme useless.