Acid-Induced Wagner−Meerwein Rearrangements of Lupeol, Betulin, and Betulinic Acid and Synthesis of Allobetulin-Type Triterpenoids

Abstract

Acid-induced skeletal rearrangements represent an inherent reactivity of lupane-type pentacyclic triterpenoids. This work provides a comprehensive review of these transformations, occurring through sequential Wagner−Meerwein-type 1,2-suprafacial shifts that provoke (undesired) scaffold hopping. Thermodynamic factors, stability of the carbocationic intermediates, and structural features governing the chemical events are discussed. Significant emphasis is devoted to the mechanistic effect imposed by the nucleophilic moieties emplaced at position C28. In fact, while the rearrangements of the unfunctionalized lupeol are frequently associated with divergent degradative pathways, betulin and betulinic acid and related terpenesfeaturing oxygen-centered nucleophilic moietiesexhibit a distinct mechanistic deviance that enables the selective assembly of allobetulin-type triterpenoids. Furthermore, this study offers a comprehensive collection of the experimental protocols established thus far for the preparation of allobetulin and its derivatives, categorized by reagents and reaction conditions employed, and describes additional non-canonical synthetic approaches and alternative one-pot procedures that enable further structural decorations. Finally, applications of this chemistry to C28 functional derivatives are discussed and illustrated, evidencing the feasibility of accessing new libraries of rare semisynthetic allobetulins for pharmacological optimization.