Question

In the following asymmetric transformation, the key aldol reaction involves the attack of 

• A. $Si$ face of enolate on the $Re$ face of aldehyde
• B. $Si$ face of enolate on the $Si$ face of aldehyde
• C. $Re$ face of enolate on the $Re$ face of aldehyde
• D. $Re$ face of enolate on the $Si$ face of aldehyde

Hint:

Asymmetric aldol reactions are highly stereoselective. The facial selectivity of the enolate and the aldehyde is governed by the chiral auxiliary through a well-defined transition state geometry (often Zimmerman-Traxler). Carefully consider the steric interactions in the transition state to predict the major diastereomer formed and hence deduce the faces involved in the attack. Drawing out a possible transition state can be very helpful.

Answer 1

The Correct Option is D

The reaction shown is an asymmetric aldol reaction using a chiral auxiliary derived from proline. The stereochemistry of the newly formed chiral centers in the aldol product is determined by the chiral auxiliary and the facial selectivity of the enolate and aldehyde.

Step 1: Enolate Formation

• The chiral auxiliary directs the formation of a specific enolate geometry upon treatment with n-Bu₂BOTf and i-Pr₂NEt.
• The boron enolate formed is known to have a defined geometry (usually Z).
• The stereochemistry of the enolate is crucial for predicting the stereochemical outcome of the aldol reaction.
• The methyl group on the chiral auxiliary shields one face of the enolate, leading to preferential attack from the less hindered face.
• Considering the typical stereochemical outcome with this type of auxiliary (which often leads to syn-aldol products), and analyzing the spatial arrangement of the substituents on the enolate, the more accessible face for attack, leading to the observed product stereochemistry, is the Re face.

Step 2: Aldol Addition to Benzaldehyde (PhCHO)

• Benzaldehyde (PhCHO) is prochiral, having a Re and a Si face.
• The chiral boron enolate attacks one of these faces preferentially, leading to the stereoselective formation of the new chiral center in the aldol product.
• The chiral auxiliary controls the stereochemistry through a cyclic Zimmerman–Traxler transition state.
• To achieve the specific stereochemistry observed in the product, the phenyl group of the aldehyde and the methyl group of the enolate prefer to be anti to each other in the transition state to minimize steric interactions.
• Analyzing the stereochemistry of the product, the relative configuration of the newly formed hydroxyl-bearing carbon and the carbon bearing the methyl group (which originated from the aldehyde) is syn.
• This suggests that the Re face of the enolate attacks the Si face of the benzaldehyde, minimizing steric hindrance and producing the observed diastereomer.

Step 3: Oxidative Cleavage of the Chiral Auxiliary

The final step releases the chiral aldol product with the stereochemistry established in the previous step, preserving the relative and absolute configuration defined by the selective facial attack in the Zimmerman–Traxler transition state.