Asymmetric synthesis by combining photoredox with organocatalysis

Abstract

With the rise of metal-mediated reactions, numerous enantioselective oxidation, reduction, and Lewis acid-catalyzed processes have been reported over the last 50 years. Curiously, few articles using organic molecules as asymmetric catalysts appear in the literature until 2000, with the impressive work of MacMillan and List (2021 Chemistry Nobel Prize). The increasing interest of the research community towards visible light-driven processes, have made photoredox catalysis merge with asymmetric organocatalysis to become one of the most important frontiers of academic research in organic synthesis. The combination of two catalysts working in tandem fashion for a single reaction is called dual catalysis. This technique opens new paths of non-toxic, sustainable reactions that enable the synthesis of a wide range of organic molecules and the formation of C-C and C-Het bonds; such as the reaction of α-alkylation of aldehydes with ethyl diazoacetates, which uses a porphyrin derivative (TPP-S4-H2) as a photocatalyst and a proline derivative as an organocatalyst. In this context, the enantioselectivity of two new L-prolineamide derivatives is tested with different aldehydes in the mentioned reaction. The results obtained with one of them (the N-neopentyl prolineamide 4) are outstanding in terms of enantioselectivity, and the stereochemical outcome of the reaction (unambiguously ascertained by chemical correlation with a known compound) can be rationalized by a simple mechanistic model in terms of both steric hindrance and hydrogen bond-directing effects.