In Situ-Generated Glycinyl Chloroaminals for a One-Pot Synthesis of Non-proteinogenic α-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 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 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 α-amino esters.

Enantioselective Synthesis of α-Allyl Amino Esters via Hydrogen-Bond-Donor Catalysis

“…Inspired by this precedent, we envisioned a new approach involving nucleophilic allylation of α-halo amino esters catalyzed by chiral hydrogen-bond-donor catalysts (Scheme C). This strategy benefits from the ready accessibility of N- carbamoyl α-chloro amino esters as α-imino ester equivalents. , The products resulting from the proposed nucleophilic allylation protocol would possess readily cleavable carbamate protecting groups, facilitating further manipulations . Herein, we report the highly enantioselective and diastereoselective synthesis of α-allyl amino esters via anion-abstraction catalyzed addition of allylsilane and allylstannane nucleophiles to N -carbamoyl-α-chloro amino esters.…”

The Appropriate Acyclic Precursors to Build Biologically Active 5-acylamino-1,3-thiazoles

“…It emerged that the target compounds 13 and 14 could be accessed by a Hatzsch-like reaction between an α-chloroglycinate 17, and either a thioamide (18) or a thiourea (19) as depicted in scheme 9. The α-chloroglycinates 17 are available starting with a Ben-Ishai addition of a primary amide 15 to ethyl glyoxylate to obtain the corresponding alcohol compound, followed by reaction of the resultant 16 with SOCl2 [47][48][49][50]. These molecules are perfectly isolable and fairly stable on storage at −20 •C with exclusion of moisture (two weeks at least) [51][52][53][54][55], even though the halogen atom is quite labile.…”

Catalyst-Free Synthesis of Polysubstituted 5-Acylamino-1,3-Thiazoles via Hantzsch Cyclization of α-Chloroglycinates

“…It appeared that the target compounds 4 – 5 could be accessed by a Hatzsch-like reaction between an α-chloroglycinate, 8 , and a thioamide, 9 , or thiourea, 11 (Scheme 2). Compounds 8 are readily available starting with a Ben-Ishai addition of a primary amide, 6 , to, e.g., ethyl glyoxylate, followed by reaction of the resultant 7 with SOCl 2 [39,40,41,42]. They are perfectly isolable and fairly stable on storage at −20 °C with exclusion of moisture (two weeks at least) [43,44,45,46,47], even though the halogen atom is quite labile.…”