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

ABSTRACT: 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 ?-amino esters. These reactions proceeded rapidly to afford the pivotal ?-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 ?-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 ?-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 SN1-like (SN2C+) 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 ?-amino esters.

SUBMITTER: Samanta SS 

PROVIDER: S-EPMC5669263 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature