Synthesis of Pyrazolines via Enantioselective 1,3-Dipolar Cycloadditions

1,3-dipolar cycloaddition - chiral relay - magnesium - cp-Indabox ligand - diazoesters - pyrazolines

Significance

Cycloadditions are among the best ways to rapidly create complexity in heterocycle synthesis. Readily available diazoesters 2 can now be used in enantioselective dipolar cycloadditions with activated alkenes 1. Previous methods were limited either to diazomethane derivatives, or did not tolerate β-substitution on the alkene (R² in 1). The method was applied to a rapid total synthesis of (-)-manzacidin A (6), where the stereochemistry of the quaternary tert-alkyl amino stereocenter was fully controlled in the key step.

Comment

The method relies on pyramidalization of the cyclic hydrazine to act as chiral relay to obtain the pyrazoline cycloadducts 4 in excellent enantioselectivity. An intriguing observation was made by the authors who point out that, in multiple instances, the reaction gives better enantioselectivity at higher temperatures. Although no explanation is given, it is still fortunate as some substrates needed higher temperatures to achieve reasonable yields.