Question

Following is the structural formula of the antihypertensive drug labetalol, a nonspecific \(\beta\)-adrenergic blocker with vasodilating activity. Members of this class have received enormous clinical attention because of their effectiveness in treating hypertension (high blood pressure), migraine headaches, glaucoma, ischemic heart disease, and certain cardiac arrhythmias. This retrosynthetic analysis involves disconnects to the \(\alpha\)-haloketone (B) and the amine (C). Each is in turn derived from a simpler, readily available precursor. (a) Given this retrosynthetic analysis, propose a synthesis for labetalol from salicylic acid and benzyl chloride. [Note: The conversion of salicylic acid to (E) involves a Friedel-Crafts acylation in which the phenolic - \(\mathrm{OH}\) must be protected by treatment with acetic anhydride to prevent the acylation of the \(-\mathrm{OH}\) group. The protecting group is later removed by treatment with \(\mathrm{KOH}\) followed by acidification.] (b) Labetalol has two chiral centers and, as produced in this synthesis, is a racemic mixture of the four possible stereoisomers. The active stereoisomer is dilevalol, which has the \(R, R\) configuration at its chiral centers. Draw a structural formula of dilevalol showing the configuration of each chiral center.

Short answer

Question: Propose a synthesis of the antihypertensive drug labetalol using salicylic acid and benzyl chloride as starting materials and draw the structural formula of active stereoisomer dilevalol. Answer: a) The synthesis of labetalol can be proposed as follows: 1. Formation of intermediate compound (E): Protect the phenolic OH group of salicylic acid by treating it with acetic anhydride to form compound (D). Next, perform a Friedel-Crafts acylation on compound (D) with benzoyl chloride, followed by treatment with KOH to remove the protecting group and acidification to obtain compound (E). 2. Preparation of α-haloketone precursor (B): React compound (E) with SOCl2 to replace the OH group with a Cl group forming compound (B), which is an α-haloketone precursor. 3. Preparation of amine precursor (C): Treat benzyl chloride with NaN3 to replace the Cl group with an N3 group, forming compound (F). Next, reduce compound (F) using LiAlH4 to convert the azide group to an amine, forming compound (C). 4. Synthesis of Labetalol: Finally, combine the precursor compounds (B) and (C) in a nucleophilic addition reaction, forming the labetalol molecule. b) To draw the structural formula of the active stereoisomer dilevalol: 1. Identify chiral centers: Labetalol has two chiral centers, and the active stereoisomer is dilevalol, which has the R,R configuration at the chiral centers. 2. Draw structural formula: Draw the structural formula of dilevalol with the R configuration at both chiral centers and properly label each chiral center with its configuration.

Step-by-step solution

1. Formation of intermediate compound (E)

First, protect the phenolic OH group of salicylic acid by treating it with acetic anhydride to form compound (D). Next, perform a Friedel-Crafts acylation on compound (D) with benzoyl chloride, followed by treatment with KOH to remove the protecting group and acidification to obtain compound (E).

2. Preparation of α-haloketone precursor (B)

React compound (E) with SOCl_2 to replace the OH group with a Cl group forming compound (B), which is an α-haloketone precursor.

3. Preparation of amine precursor (C)

Treat benzyl chloride with NaN_3 to replace the Cl group with an N_3 group, forming compound (F). Next, reduce compound (F) using LiAlH_4 to convert the azide group to an amine, forming compound (C).

4. Synthesis of Labetalol

Finally, combine the precursor compounds (B) and (C) in a nucleophilic addition reaction, forming the labetalol molecule. #b) Structural formula of dilevalol#

1. Identify chiral centers

Labetalol has two chiral centers, and the active stereoisomer is dilevalol, which has the R,R configuration at the chiral centers.

2. Draw structural formula

Draw the structural formula of dilevalol with the R configuration at both chiral centers and properly label each chiral center with its configuration.