A Pd-H/Isothiourea Cooperative Catalysis Approach to anti-Aldol Motifs: Enantioselective α-Alkylation of Esters with Oxyallenes

The biological and therapeutic significance of natural products is a powerful impetus for the development of efficient methods to facilitate their construction. Accordingly, and reflecting the prevalence of beta-oxy-carbonyl motifs, a sophisticated arsenal of aldol-based strategies has evolved that is contingent on the generation of single enolate isomers. Since this has the potential to compromise efficiency in reagent-based paradigms, direct catalysis-based solutions would be enabling. To complement the array of substrate-based strategies, and regulate enolate geometry at the catalyst level, a direct catalytic alkylation of esters with oxyallenes has been developed. Synergizing metal hydride reactivity with Lewis base catalysis has resulted in a broad reaction scope with useful levels of stereocontrol (up to >99 % ee). Facile derivatization of these ambiphilic linchpins is demonstrated, providing access to high-value vicinal stereocenter-containing motifs, including 1,2-amino alcohols.

Automated summary

The biological and therapeutic significance of natural products drives the development of efficient methods for their synthesis. A strategy based on aldol condensation has been developed, which involves direct catalytic alkylation of esters with oxyallenes to regulate the enolate geometry. This strategy shows a broad reaction scope and high levels of stereocontrol.