Recent Advances in Asymmetric Synthesis of Pyrrolidine-Based Organocatalysts and Their Application: A 15-Year Update

Abstract

In 1971, chemists from Hoffmann-La Roche and Schering AG independently discovered a new asymmetric intramolecular aldol reaction catalyzed by the natural amino acid proline, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction. These remarkable results remained forgotten until List and Barbas reported in 2000 that L-proline was also able to catalyze intermolecular aldol reactions with non-negligible enantioselectivities. In the same year, MacMillan reported on asymmetric Diels-Alder cycloadditions which were efficiently catalyzed by imidazolidinones deriving from natural amino acids. These two seminal reports marked the birth of modern asymmetric organocatalysis. A further important breakthrough in this field happened in 2005, when Jørgensen and Hayashi independently proposed the use of diarylprolinol silyl ethers for the asymmetric functionalization of aldehydes. During the last 20 years, asymmetric organocatalysis has emerged as a very powerful tool for the facile construction of complex molecular architectures. Along the way, a deeper knowledge of organocatalytic reaction mechanisms has been acquired, allowing for the fine-tuning of the structures of privileged catalysts or proposing completely new molecular entities that are able to efficiently catalyze these transformations. This review highlights the most recent advances in the asymmetric synthesis of organocatalysts deriving from or related to proline, starting from 2008.