Enantioselective Electrophilic Amination of α‐Cyanothioacetates with Azodicarboxylates Catalyzed by an Axially Chiral Guanidine Base

Abstract

An enantioselective electrophilic amination of a-substituted cyanothioacetates with azodicarboxylate is demonstrated using an axially chiral guanidine as a chiral Brønsted base catalyst. The corresponding product, having a quaternary stereogenic center at the a-carbon atom, is formed in excellent enantioselectivity.Keywords: amination; amino acids; asymmetric catalysis; organocatalysis; quaternary stereocenters a-Amino acids having a quaternary stereogenic center at the a-position are attractive compounds owing to their potent biological activities as non-proteinogenic analogues of natural a-amino acids and their increasing importance as constituents for preparing conformationally restricted peptides.[1] Catalysis of the enantioselective electrophilic amination of a,adisubstituted carbonyl compounds using azodicarboxylates has emerged as an efficient strategy to address the challenging issue of constructing a nitrogen-substituted quaternary stereogenic center at the a-position of a carbonyl compound. [2][3][4] Recently, several excellent enantioselective catalytic reactions for electrophilic amination of a-substituted b-keto esters and their analogues have been developed using chiral metal-based catalysts [3] or organocatalysts. [2,4] Among these, the enantioselective amination of a-substituted a-cyanoacetates is a powerful method to construct a densely functionalized quaternary stereogenic center, and hence is a substantial step toward the enantioselective synthesis of a-amino acid derivatives having a quaternary a-carbon atom. [3d,4a,c,d,f,g,5] However, the methods are applicable to a-cyanoacetates with an aromatic group at the a-position. General approaches to the highly enantioselective amination of alkyl-substituted a-cyanoacetates have not been established to date, [4a,c,6] despite the potential for further elaboration of the corresponding amination products.Recently, we successfully developed the novel axially chiral guanidines 1 [4e,7] as highly efficient Brønsted base catalysts for promotion of enantioselective transformations.[4e,7-9] Specifically, we reported on the enantioselective electrophilic amination of unsymmetrical 1,3-dicarbonyl compounds with di-tert-butyl azodicarboxylate catalyzed by a chiral guanidine catalyst (1a), which afforded excellent enantioselectivity and catalytic efficiency for cyclic b-keto esters; however, for the acyclic b-keto esters, the enantioselectivities were highly dependent on the alkyl substituent at the a-position of the keto ester.[4e] In this context, we aimed to develop the enantioselective electrophilic amination of a-alkyl-substituted a-cyanoacetate derivatives 2 with azodicarboxylate 3. Herein, we report that the guanidine catalyst 1 exhibited excellent performance for the amination of a-cyanothioacetates 2 having a variety of primary alkyl substituents at the a-position, giving the products 4 in excellent enantioselectivity and chemical yield (Scheme 1).Our investigation began by using thioacetate 2 as a substrate in the present electrophilic amin...

Recent Advances in Chiral Guanidine‐Catalyzed Enantioselective Reactions

“…[45c] In order to expand the scope, they further attempted enantioselective electrophilic aminationo fa-substituted a-cyanothioacetates with azodicarboxylate. [46] As eries of a-cyanothioacetates and a-cyanoacetates, including primary alkyl, secondary alkyl, and aromatic substituents, was appliedt ot he amination (Scheme 27). Excellent enantioselectivities were achieved for varioussubstituents.…”

Asymmetric Synthesis of Quaternary α‐Amino Acids and Their Phosphonate Analogues

“…[78] Axially chiral guanidinium catalyst C56 promoted the aamination of a-cyanothioacetates with tert-butyl azodicarboxylate (188), affording a-aminated adducts 193 in good to excellent yields and enantioselectivities in most cases (Scheme 63). [79] Reduction of the thioacetate, acid hydrolysis of the cyano group and tert-butyl carbamate group, followed by reductive N À N bond cleavage and Boc protection of the resulting free amine provided quaternary a-aminoester 194 in moderate overall yield (Scheme 63).…”

Organic Chemistry: Krische and Terada Awarded / Materials Science: Prize for Whitesides

“…In 2001 he took up a position at Tohoku University. He recently reported in Advanced Synthesis & Catalysis on the enantioselective amination of α‐cyanothioacetates with azodicarboxylates2a and in Angewandte Chemie on the activation of hemiaminal ethers by chiral Brønsted acids 2b …”