Hiroki Moriwaki

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases; Part 1: alkyl halide alkylations

Alkylations of chiral or achiral Ni(II) complexes of glycine Schiff bases constitute a landmark in the development of practical methodology for asymmetric synthesis of α-amino acids. Straightforward, easy preparation as well as high reactivity of these Ni(II) complexes render them ready available and inexpensive glycine equivalents for preparing a wide variety of α-amino acids, in particular on a relatively large scale. In the case of Ni(II) complexes containing benzylproline moiety as a chiral auxiliary, their alkylation proceeds with high thermodynamically controlled diastereoselectivity. Similar type of Ni(II) complexes derived from alanine can also be used for alkylation providing convenient access to quaternary, α,α-disubstituted α-amino acids. Achiral type of Ni(II) complexes can be prepared from picolinic acid or via recently developed modular approach using simple secondary or primary amines. These Ni(II) complexes can be easily mono/bis-alkylated under homogeneous or phase-transfer catalysis conditions. Origin of diastereo-/enantioselectivity in the alkylations reactions, aspects of practicality, generality and limitations of this methodology is critically discussed.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: Aldol, Mannich addition reactions, deracemization and (S) to (R) interconversion of α-amino acids

Abstract This review provides a comprehensive treatment of literature data dealing with asymmetric synthesis of α-amino-β-hydroxy and α,β-diamino acids via homologation of chiral Ni(II) complexes of glycine Schiff bases using aldol and Mannich-type reactions. These reactions proceed with synthetically useful chemical yields and thermodynamically controlled stereoselectivity and allow direct introduction of two stereogenic centers in a single operation with predictable stereochemical outcome. Furthermore, new application of Ni(II) complexes of α-amino acids Schiff bases for deracemization of racemic α-amino acids and (S) to (R) interconversion providing additional synthetic opportunities for preparation of enantiomerically pure α-amino acids, is also reviewed. Origin of observed diastereo-/enantioselectivity in the aldol, Mannich-type and deracemization reactions, generality and limitations of these methodologies are critically discussed.

Chemical Dynamic Kinetic Resolution and S/R Interconversion of Unprotected α-Amino Acids†

Reported herein is the first purely chemical method for the dynamic kinetic resolution (DKR) of unprotected racemic α-amino acids (α-AAs), a method which can rival the economic efficiency of the enzymatic reactions. The DKR reaction principle can be readily applied for S/R interconversions of α-AAs, the methodological versatility of which is unmatched by biocatalytic approaches. The presented process features a virtually complete stereochemical outcome, fully recyclable source of chirality, and operationally simple and convenient reaction conditions, thus allowing its ready scalability. A quite unique and novel mode of the thermodynamic control over the stereochemical outcome, including an exciting interplay between axial, helical, and central elements of chirality is proposed.

Recyclable Ligands for the Non‐Enzymatic Dynamic Kinetic Resolution of Challenging α‐Amino Acids

Structurally simple and inexpensive chiral tridentate ligands were employed for substantially advancing the purely chemical dynamic kinetic resolution (DKR) of unprotected racemic tailor-made α-amino acids (TM-α-AAs), enabling the first DKR of TM-α-AAs bearing tertiary alkyl chains as well as multiple unprotected functional groups. Owing to the operationally convenient conditions, virtually complete stereoselectivity, and full recyclability of the source of chirality, this method should find wide applications for the preparation of TM-α-AAs, especially on large scale.

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

Unnatural (R)-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 (R)-α-AAs via (S)-to-(R)-interconversion of natural and tailor-made (S)-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.

Advanced asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by alkylation/cyclization of newly designed axially chiral Ni(II) complex of glycine Schiff base

Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is in extremely high demand due to the pharmaceutical importance of this tailor-made, sterically constrained α-amino acid. Here we report the development of an advanced procedure for preparation of the target amino acid via two-step SN2 and SN2′ alkylation of novel axially chiral nucleophilic glycine equivalent. Excellent yields and diastereoselectivity coupled with reliable and easy scalability render this method of immediate use for practical synthesis of (1R,2S)-vinyl-ACCA.

Asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid by sequential SN2–SN2′ dialkylation of (R)-N-(benzyl)proline-derived glycine Schiff base Ni(II) complex

This work describes a new process for the asymmetric synthesis of (1R,2S)-1-amino-2-vinylcyclopropanecarboxylic acid of high pharmaceutical importance. The sequence of the reactions includes PTC alkylation (SN2), homogeneous SN2′ cyclization followed by disassembly of the resultant Ni(II) complex. All reactions are conducted under operationally convenient conditions and suitably scaled up to 6 g of the starting Ni(II) complex.

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

Described here is an advanced, general method for purely chemical dynamic thermodynamic resolution and S/R 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.

Synthesis and stereochemical assignments of diastereomeric Ni(II) complexes of glycine Schiff base with (R)-2-(N-{2-[N-alkyl-N-(1-phenylethyl)amino]acetyl}amino)benzophenone; a case of configurationally stable stereogenic nitrogen

Summary A family of chiral ligands derived from α-phenylethylamine and 2-aminobenzophenone were prepared by alkylation of the nitrogen atom. Upon reaction with glycine and a Ni(II) salt, these ligands were transformed into diastereomeric complexes, as a result of the configurational stability of the stereogenic nitrogen atom. Different diastereomeric ratios were observed depending on the substituent R introduced in the starting ligand, and stereochemical assignments were based on X-ray analysis, along with NMR studies and optical rotation measurements.

Inexpensive chemical method for preparation of enantiomerically pure phenylalanine

Abstract Here, we report the most inexpensive procedure for chemical synthesis of enantiomerically pure phenylalanine. As a source of chirality, we use the ultimately inexpensive chiral auxiliary, 1-(phenyl)ethylamine, incorporated into the specially designed ligands which form the corresponding intermediate Ni(II) complexes with racemic phenylalanine. Diastereomerically pure Ni(II) complexes, containing either (S)- or (R)-phenylalanine, were disassembled to produce enantiomerically pure target amino acid, along with recycling the chiral ligand. All reactions were conducted under operationally convenient conditions, featuring high yields and thus underscoring attractive cost structure of this method.