In Situ-Generated Glycinyl Chloroaminals for a One-Pot Synthesis of Non-proteinogenic α-Amino Esters

5 years ago

In Situ-Generated Glycinyl Chloroaminals for a One-Pot Synthesis of Non-proteinogenic α-Amino Esters

Stéphane P. Roche, Shyam S. Samanta

An acetyl chloride-mediated cascade transformation involving a primary carbamate, ethyl glyoxylate, and various types of nucleophiles is reported for the synthesis of orthogonally protected α-amino esters. These reactions proceeded rapidly to afford the pivotal α-chloroglycine intermediate in excellent yields, which can be directly functionalized in situ with various types of nucleophiles. A mild and unique AcOH(cat.)/AcCl system was found to promote an autocatalytic-like condensation and facilitate the multicomponent assembly of non-proteinogenic α-amino esters. To better understand this one-pot transformation and the orchestration of the components’ condensations, the investigation of a broader scope of nucleophiles and some kinetic studies are presented. Our findings suggest that the halogenation step toward the formation of α-chloroglycine is the rate-determining step likely proceeding through the formation of N-carbamoyl iminium. Also, the initial kinetic profiling for the nucleophilic substitution supports an S_N1-like (S_N2C+) mechanism in which nucleophiles add to the iminium–chloride tight ionic pair. These results lead ultimately to the design of a new protocol in which an achiral hydrogen bond donor thiourea catalyst was utilized to enhance the reaction scope and enable silylated nucleophiles to be efficiently exploited to synthesize novel non-proteinogenic α-amino esters.

Publisher URL: http://dx.doi.org/10.1021/acs.joc.7b01274

DOI: 10.1021/acs.joc.7b01274