Exploring the Scope of Tandem Palladium and Isothiourea Relay Catalysis for the Synthesis of α-Amino Acid Derivatives

Abstract

The scope and limitations of a tandem N-allylation/[2,3]-rearrangement protocol are investigated through the incorporation of a variety of functional groups within an allylic phosphate precursor. This method uses readily accessible N,N-dimethylglycine aryl esters and functionalized allylic phosphates, forming quaternary ammonium salts in situ in the presence of a palladium catalyst. Subsequent enantioselective [2,3]-sigmatropic rearrangement, promoted by the chiral isothiourea tetramisole, generates α-amino acid derivatives with two contiguous stereocenters. The incorporation of electron-withdrawing ester and amide groups gave the best results, furnishing the desired products in moderate to good yields (29–70%), with low diastereocontrol (typically 60:40 dr) but high enantioselectivity (up to 90:10 er). These results indicate that substrate–catalyst interactions in the proposed transition state are sensitive to the substitution pattern of the substrates.

Understanding divergent substrate stereoselectivity in the isothiourea-catalysed conjugate addition of cyclic α-substituted β-ketoesters to α,β-unsaturated aryl esters

“…24 Initially demonstrated in the enantioselective conjugate addition of nitroalkanes, 19 it has since been exploited using heterocyclic pro-nucleophiles, 21,25 malonates, 26 benzophenone imines, 27 as well as co-operative Pd-isothiourea promoted cascade reactions. 28 Conjugate addition and lactonisation processes using acylbenzothiazole and benzoxazole pronucleophile derivatives with α,β-unsaturated para -nitrophenyl esters has also been investigated synthetically. 29 This study was complemented by a computational study by Wei and Ding who validated the postulated mechanism and outlined the key factors involved in stereoselective C–C bond-formation.…”