Asymmetric Synthesis of Chiral Heterocyclic Amino Acids via the Alkylation of the Ni(II) Complex of Glycine and Alkyl Halides

An investigation into the reactivity profile of alkyl halides has led to the development of a new method for the asymmetric synthesis of chiral heterocyclic amino acids. This protocol involves the asymmetric alkylation of the Ni­(II) complex of glycine to form an intermediate, which then decomposes to form a series of valuable chiral amino acids in high yields and with excellent diastereoselectivity. The chiral amino acids underwent a smooth intramolecular cyclization process to afford the valuable chiral heterocyclic amino acids in high yields and enantioselectivities. This result paves the way for the development of a new synthetic method for chiral heterocyclic amino acids

Ruthenium-Catalyzed Redox-Neutral [4 + 1] Annulation of Benzamides and Propargyl Alcohols via C–H Bond Activation

Internal alkynes have been used widely in transition-metal-catalyzed cycloaddition reactions, in which they generally serve as two-carbon reaction partners. Herein, we report ruthenium­(II)-catalyzed redox-neutral [4 + 1] annulation of benzamides and propargyl alcohols, in which propargyl alcohols act as one-carbon units. This synthetic utility of propargyl alcohols led to a series of potentially bioactive N-substituted quaternary isoindolinones with moderate to high yields under mild conditions. Without the requirement for an external metal oxidant, this title transformation is compatible with various functional groups, which further underscores its synthetic utility and versatile applicability. In addition, preliminary mechanism experiments have been conducted and a plausible mechanism is proposed

Chemical Resolution of <i>C</i>,<i>N</i>‑Unprotected α‑Substituted β‑Amino Acids Using Stable and Recyclable Proline-Derived Chiral Ligands

We report the first purely chemical method for the resolution of <i>C</i>,<i>N</i>-unprotected racemic α-substituted β-amino acids (β²-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic β²-AAs along with Ni­(II) could form a pair of Ni­(II) complex diastereoisomers with a desirable diastereoselectivity (dr up to 91:9). Enantiomerically pure <i>C</i>,<i>N</i>-unprotected β²-AAs could be obtained by simple hydrolysis of an isolated favored Ni­(II) complex. The method featured unique versatility compared with enzymatic approaches and characterized by its broad synthetic generality, good stereochemical outcome, and mild reaction conditions, thus making it a powerful supplement in the field of chemical resolution of β²-AAs

Enantioselective Synthesis of 2‑Substitued-Tetrahydroisoquinolin-1-yl Glycine Derivatives via Oxidative Cross-Dehydrogenative Coupling of Tertiary Amines and Chiral Nickel(II) Glycinate

The asymmetric synthesis of 2-substituted-tetrahydroisoquinolin-1-yl glycines was achieved by an oxidative cross-dehydrogenative coupling (CDC) reaction. This method for activation of the α-C-H bonds of amines with chiral nickel­(II) glycinate using <i>o</i>-chloranil as the sole oxidant afforded highly diastereoselective coupling adducts. The decomposition of coupling adducts readily afforded 2-substituted-tetrahydroisoquinolin-1-yl glycine derivatives

Enantioselective Synthesis of 2‑Substitued-Tetrahydroisoquinolin-1-yl Glycine Derivatives via Oxidative Cross-Dehydrogenative Coupling of Tertiary Amines and Chiral Nickel(II) Glycinate

The asymmetric synthesis of 2-substituted-tetrahydroisoquinolin-1-yl glycines was achieved by an oxidative cross-dehydrogenative coupling (CDC) reaction. This method for activation of the α-C-H bonds of amines with chiral nickel­(II) glycinate using <i>o</i>-chloranil as the sole oxidant afforded highly diastereoselective coupling adducts. The decomposition of coupling adducts readily afforded 2-substituted-tetrahydroisoquinolin-1-yl glycine derivatives

Enantioselective Synthesis of 2‑Substitued-Tetrahydroisoquinolin-1-yl Glycine Derivatives via Oxidative Cross-Dehydrogenative Coupling of Tertiary Amines and Chiral Nickel(II) Glycinate

The asymmetric synthesis of 2-substituted-tetrahydroisoquinolin-1-yl glycines was achieved by an oxidative cross-dehydrogenative coupling (CDC) reaction. This method for activation of the α-C-H bonds of amines with chiral nickel­(II) glycinate using <i>o</i>-chloranil as the sole oxidant afforded highly diastereoselective coupling adducts. The decomposition of coupling adducts readily afforded 2-substituted-tetrahydroisoquinolin-1-yl glycine derivatives

Chemical Resolution of <i>C</i>,<i>N</i>‑Unprotected α‑Substituted β‑Amino Acids Using Stable and Recyclable Proline-Derived Chiral Ligands

We report the first purely chemical method for the resolution of <i>C</i>,<i>N</i>-unprotected racemic α-substituted β-amino acids (β²-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic β²-AAs along with Ni­(II) could form a pair of Ni­(II) complex diastereoisomers with a desirable diastereoselectivity (dr up to 91:9). Enantiomerically pure <i>C</i>,<i>N</i>-unprotected β²-AAs could be obtained by simple hydrolysis of an isolated favored Ni­(II) complex. The method featured unique versatility compared with enzymatic approaches and characterized by its broad synthetic generality, good stereochemical outcome, and mild reaction conditions, thus making it a powerful supplement in the field of chemical resolution of β²-AAs

Chemical Resolution of <i>C</i>,<i>N</i>‑Unprotected α‑Substituted β‑Amino Acids Using Stable and Recyclable Proline-Derived Chiral Ligands

We report the first purely chemical method for the resolution of <i>C</i>,<i>N</i>-unprotected racemic α-substituted β-amino acids (β²-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic β²-AAs along with Ni­(II) could form a pair of Ni­(II) complex diastereoisomers with a desirable diastereoselectivity (dr up to 91:9). Enantiomerically pure <i>C</i>,<i>N</i>-unprotected β²-AAs could be obtained by simple hydrolysis of an isolated favored Ni­(II) complex. The method featured unique versatility compared with enzymatic approaches and characterized by its broad synthetic generality, good stereochemical outcome, and mild reaction conditions, thus making it a powerful supplement in the field of chemical resolution of β²-AAs

Chemical Dynamic Thermodynamic Resolution and <i>S</i>/<i>R</i> Interconversion of Unprotected Unnatural Tailor-made α‑Amino Acids

Described here is an advanced, general method for purely chemical dynamic thermodynamic resolution and <i>S</i>/<i>R</i> interconversion of unprotected tailor-made α-amino acids (α-AAs) through intermediate formation of the corresponding nickel­(II)-chelated Schiff bases. The method features virtually complete stereochemical outcome, broad substrate generality (35 examples), and operationally convenient conditions allowing for large-scale preparation of the target α-AAs in enantiomerically pure form. Furthermore, the new type of nonracemizable axially chiral ligands can be quantitatively recycled and reused, rendering the whole process economically and synthetically attractive

Purely Chemical Approach for Preparation of d‑α-Amino Acids via (<i>S</i>)‑to‑(<i>R</i>)‑Interconversion of Unprotected Tailor-Made α‑Amino Acids

Unnatural (<i>R</i>)-α-amino acids (α-AAs) are in growing demand in the biomedical research and pharmaceutical industries. In this work, we present development of a purely chemical approach for preparation of (<i>R</i>)-α-AAs via (<i>S</i>)-to-(<i>R</i>)-interconversion of natural and tailor-made (<i>S</i>)-α-AAs. The method can be used on free, unprotected α-AAs and features a remarkable structural generality including substrates bearing tertiary alkyl chains and reactive functional groups. These attractive characteristics, combined with simplicity of reaction conditions and virtually complete stereochemical outcome, constitute a true methodological advance in this area, rivaling previously reported chemical and biocatalytic approaches