Question

Question:One step in the synthesis of sitagliptin (Problem 17.14, a drug used to treat type 2 diabetes) involves reaction of the mixed anhydride A with B to form C. Draw a stepwise mechanism for this reaction.

Short answer

Answer

Step 1:

Step 2:

Step 3:

Step 4:

Step-by-step solution

Determination of enolate source

The reaction is an example of carbonyl condensation reactions. All carbonyl condensation reactions proceed via the formation of enolate from any one of the carbonyl systems.

Out of A and B, B is the carbonyl system that forms an enolate, as shown below:

Formation of enolate

Nucleophilic attack

Once the enolate is formed, it acts as a nucleophile and attacks at the electrophilic carbon of the other carbonyl system, as shown below:

Attack of nucleophile

Elimination of the leaving group

The ester group acts as a leaving group in this step

Elimination of leaving group

Tautomerization 

The product formed in the previous step tautomerizes to form the more stable compound as shown below. The stability of the compound is because of the intramolecular hydrogen bonding of the alcohol group with the adjacent carbonyl group.

Tautomerism