Prelog's Rule

In 1953, Prelog extended Cram's concept of reactive conformations to chiral esters of α-ketoesters (pyruvates), establishing Prelog's Rule. This rule predicts the stereochemical outcome of Grignard additions to chiral pyruvates, specifically those formed using chiral alcohols.

Applications and Rationale:

Prelog's Rule has been valuable in the asymmetric synthesis of α-hydroxyacids and in determining the configurations of secondary and tertiary alcohols. The rule is based on the preferred anti arrangement of the two α-carbonyl groups, minimizing dipole-dipole repulsion. The lone pairs on the ether oxygen, often described as "rabbit ears," position the keto-carbonyl between them. This alignment brings the bonds shown in red (in Figure 1.2.9) into the same plane as the keto-carbonyl.

Stereochemical Prediction:

Similar to Cram's Rule, Prelog's Rule predicts that the Grignard reagent will attack from the side of the smallest substituent (S) on the chiral alcohol portion of the ester.

Limitations:

It's important to note that the asymmetric induction observed with Prelog's Rule can sometimes be poor. This is attributed to the significant distance between the reaction center (the carbonyl) and the chiral center that induces the asymmetry.