Regioselective Aldol Reactions Directed by Charge and Orbital Effects in Cyclic Germyl Dienolates: Synthesis of Three Distinct Regio‐ and Stereoisomers

Regioselective aldol reactions of dienolates represent a valuable method for the construction of complex molecular scaffolds; however, controlling the reaction site of the dienolate remains a significant challenge. This study presents a method for regioselectivity switching in the aldol reactions of cyclic Ge-dienolates, which are generated from the (4 + 1) cycloaddition of allenoates with Ge(II) salts. Through systematic tuning of the charge and orbital distributions of the Ge-dienolates and their aldehyde reaction partners, regio- and stereoselective access to three distinct aldol adducts (syn-α-, anti-α-, and anti-γ-adducts) is achieved. The aldol reaction of Ge-dienolates generally proceeds via an orbital-controlled pathway to afford the anti-γ-adduct through a cyclic transition state. Activation of the aldehyde with a Lewis acid shifts the reaction to a charge-controlled pathway, resulting in the syn-α-adduct via an acyclic transition state. Notably, coordination of a ligand or solvent to the Ge center of the cyclic Ge-dienolates increases electron density, thereby favoring a charge-controlled pathway, promoting selective α-addition to yield the anti-α-adduct through a distinct cyclic transition state. The synthetic utility of these types of adducts is further demonstrated via gold-catalyzed intramolecular C─H/C-Ge cross-coupling, which enables the efficient synthesis of various fused-ring systems.