Question

Following is a retrosynthetic analysis for propoxyphene, the hydrochloride salt of which is Darvon. The naphthalenesulfonic acid salt of propoxyphene is Darvon- \(N\). The configuration of the carbon in Darvon bearing the hydroxyl group is \(S\), and the configuration of the other stereocenter is \(R\). Its enantiomer has no analgesic properties, but it is used as a cough suppressant. (a) Propose a synthesis for propoxyphene from 1-phenyl-1-propanone and any other necessary reagents. (b) Is propoxyphene chiral? If so, which of the possible stereoisomers are formed in this synthesis?

Short answer

Question: Perform a retrosynthetic analysis for propoxyphene, propose a synthesis starting from 1-phenyl-1-propanone, and determine whether propoxyphene is chiral and which stereoisomers are formed. Answer: Propoxyphene is a chiral molecule with two stereocenters. A possible synthesis starts with 1-phenyl-1-propanone reacting with a Grignard reagent, such as 2-bromopropyl phenyl ether. Due to the lack of stereocontrol during the Grignard reaction, a mixture containing four stereoisomers (\(R,R\), \(R,S\), \(S,R\), and \(S,S\)) is formed. The desired stereoisomer is \((R,S)\) in this synthesis.

Step-by-step solution

Understand propoxyphene's structure

To answer this question, we need to know the structure of propoxyphene. Propoxyphene is an analgesic drug with the following chemical structure: C₁₇H₂₁NO₂. It is a tertiary amine with an aromatic ring, a hydroxyl group, and an ether linkage. Its configuration is \(R\) for the stereocenter attached to the naphthalene ring and \(S\) for the stereocenter attached to the hydroxyl group.

Propose a synthesis from 1-phenyl-1-propanone

We are asked to propose a synthesis for propoxyphene from 1-phenyl-1-propanone and any other necessary reagents. The retrosynthetic analysis suggests that we can take advantage of the Grignard reaction to synthesize propoxyphene. 1-phenyl-1-propanone (C₉H₁₀O) can be converted to propoxyphene by reacting it with a Grignard reagent, such as 2-bromopropyl phenyl ether (C₉H₁₁Br). The Grignard reagent should be first formed by treating the 2-bromopropyl phenyl ether with magnesium in anhydrous ether, yielding the magnesium salt of the Grignard reagent (C₉H₁₁MgBr): C₉H₁₁Br + Mg -> C₉H₁₁MgBr Then, reacting the 1-phenyl-1-propanone with the Grignard reagent would form the propoxyphene: C₉H₁₀O + C₉H₁₁MgBr -> C₁₇H₂₁O₂MgBr Finally, we need to hydrolyze the ester group to obtain the final propoxyphene molecule: C₁₇H₂₁O₂MgBr + H₂O -> C₁₇H₂₁NO₂ + Mg(OH)Br

Determine if propoxyphene is chiral and identify stereoisomers

Propoxyphene is chiral since it has two stereocenters, each containing 4 different groups. The synthesis described above generates a mixture of four stereoisomers: \((R,R)\), \((R,S)\), \((S,R)\), and \((S,S)\) due to the lack of stereocontrol during the Grignard reaction. The desired stereoisomer is \((R,S)\) in this synthesis.