From determination of enantiopurity to the construction of complex molecules: The Horeau principle and its application in synthesis

In 1973, Horeau and co-workers reported a technique capable of upgrading the enantiopurity of a scalemic mixture (for example, [(R)-enantiomer]?>?[(S)-enantiomer]). This method involved coupling the compound of interest to a simple, bifunctional reagent in order to form a statistical mixture of (R,R)-, (S,S)-, and (R,S)-stereoisomers. Separation of the two diastereomers and cleavage of the incorporated coupling agent effectively removes the minor, (S)-enantiomer from the major, (R)-enantiomer; thereby increasing the enantiopurity of the starting compound. Since that time, this concept of removing a minor enantiomer through the statistical formation of diastereomeric compounds (the Horeau principle) has also been applied when sequential enantioselective reactions are performed on a substrate, when multiple enantioenriched fragments are coupled together, and for determining the enantiopurity of the initial scalemic mixture. Under the right circumstances, the Horeau principle can be deployed in an iterative fashion in order to access material with extremely high enantiopurity (>99.999% ee). This review provides comprehensive coverage of the underlying theory behind the Horeau principle and its application in organic synthesis.