Stereoselective Synthesis of 1-Substituted Homotropanones, including Natural Alkaloid (-)-Adaline

The stereocontrolled synthesis of 1-substituted homotropanones, using chiral N-tert-butanesulfinyl imines as reaction intermediates, is described. The reaction of organolithium and Grignard reagents with hydroxy Weinreb amides, chemoselective N-tert-butanesulfinyl aldimine formation from keto aldehydes, decarboxylative Mannich reaction with beta-keto acids of these aldimines, and organocatalyzed L-proline intramolecular Mannich cyclization are key steps of this methodology. The utility of the method was demonstrated with a synthesis of the natural product (-)-adaline, and its enantiomer, (+)-adaline.

Automated summary

The stereocontrolled synthesis of 1-substituted homotropanones was achieved using chiral N-tert-butanesulfinyl imines as intermediates. Key steps in this methodology include the reaction of organolithium and Grignard reagents with hydroxy Weinreb amides, chemoselective N-tert-butanesulfinyl aldimine formation from keto aldehydes, decarboxylative Mannich reaction with beta-keto acids of these aldimines, and organocatalyzed L-proline intramolecular Mannich cyclization. The utility of the method was demonstrated with the synthesis of (-)-adaline and its enantiomer (+)-adaline.