Direct Catalytic N-Alkylation of α-Amino Acid Esters and Amides Using Alcohols with High Retention of Stereochemistry

The direct functionalization of naturally abundant chiral scaffolds such as alpha-amino acid esters or amides with widely abundant alcohols, without any racemization, is a demanding transformation that is of central importance for the synthesis of bio-active compounds. Herein a robust and general method was developed for the direct N-alkylation of alpha-amino acid esters and amides with alcohols. This powerful ruthenium-catalyzed methodology is atom-economic, base-free, and allowed for excellent retention of stereochemical integrity. The use of diphenylphosphate as additive was crucial for significantly enhancing reactivity and product selectivity. Notably, the only by-product was water and both substrates could be potentially derived from renewable resources.

Automated summary

The direct N-alkylation of alpha-amino acid esters and amides with alcohols is achieved through a robust and general ruthenium-catalyzed method, allowing for excellent retention of stereochemical integrity. The use of diphenylphosphate as additive is crucial for enhancing reactivity and selectivity, with water being the only by-product and both substrates potentially derived from renewable resources.