Asymmetric Metal‐Templated Route to Amino Acids with 3‐Spiropyrrolidine Oxindole Core via a 1,3‐Dipolar Addition of Azomethine Ylides to a Chiral Dehydroalanine Ni(II) Complex

Abstract

We herein developed a protocol for the asymmetric synthesis of artificial AAs featuring a 3‐spiropyrrolidine oxindole skeletal with continuous tetrasubstituted carbon stereocenters by a 1,3‐dipolar cycloaddition reaction of in situ generated azomethine ylides with a chiral dehydroalanine Ni(II) complex. A three‐component reaction of the Ni(II) complex with various isatins and AAs in green solvent (ethanol) provided series of diastereomeric complexes with high dr (>20:1) in 40–86% yields. The formation of different regioisomers in the case of sarcosine and proline was explained using quantum chemical calculation. The acidic decomposition of the obtained Ni(II) complexes led to the target unnatural complex AAs with a 3‐spiropyrrolidine oxindole core. The chiral auxiliary ligand was recovered after decomposition and reused for the synthesis of the starting dehydroalanine complex‐substrate.

Asymmetric Synthesis of Derivatives of Alanine via Michael Addition Reaction and their Biological Study

“…Starting with the publication of the Strecker reaction in the middle of the nineteenth century 9 up to date, a large number of new methods for the synthesis of nonprotein amino acids have been developed. 10 11 However, the main questions that accompany new methods for the development of nonprotein amino acids synthesis, to wit, the availability of starting substances, high chemical and asymmetric yields, and exclusion of racemization remain urgent and unsolved. An interesting approach is the reaction of addition of aryl radicals to dehydroalanine by the photocatalytic method.…”

Pd(II) Complexes of Chiral Proline-Derived Ligands: Application for Dynamic Thermodynamic Resolution of α-Amino Acids and Their Antibacterial Activities

“…Previously, Belokon’s group made early pioneering contributions to the asymmetric metal-templated synthesis of amino acids. − The groups of Saghyan, Larionov, and Magdesieva also fruitfully work in this field. − In recent years, our group has made considerable efforts and reported several efficient protocols to obtain N , C -unprotected α- and β-amino acids in an enantiopure form using metal complexes, including Ni­(II) complexes and Cu­(II) complexes. − However, the methods for Ni­(II) complexes required relatively high reaction temperatures or prolonged reaction time at room temperature, which led to low reaction efficiency . As for the resolution method via Cu­(II) complexes, the limitation is the inability to achieve configurational interconversion of α-amino acids and dynamic resolution of the racemic α-amino acids.…”

Sequential Heck Cross-Coupling and Hydrothiolation Reactions Taking Place in the Ligand Sphere of a Chiral Dehydroalanine Ni(II) Complex: Asymmetric Route to β-Aryl Substituted Cysteines

“…Given the importance in the enantiopure β-aryl-substituted cysteines, we herein report a general asymmetric route to these AAs via sequential Heck cross-coupling reaction taking place in the ligand sphere of a chiral Belokon’s dehydroalanine Ni­(II) complex ( S )-BPB-Ni-ΔAla 1 (the chiral auxiliary ( S )-BPB is ( S )-2- N -( N -benzylprolyl)­aminobenzophenone) and subsequent hydrothiolation of the obtained complex (Figure B). In this context, the functionalization and modification of the ligand sphere of a robust and bench-stable chiral Ni­(II) complex allowed us to obtain a broad range of natural and unnatural AAs in an enantioselective fashion; so, the present metal-templated approach has been proven as a simple and reliable tool for the large-scale production of enantiopure AAs on demand in academia and industry. − Although there is the precedence about the hydrothiolation of the Ni­(II) complex ( S )- 1 in literature, the synthesis of β-arylated analogues of 1 remains challenging. Furthermore, the Heck reaction with dehydroalanine derivatives is still limited to date …”

“…It is well-known that the acid-induced decomposition of corresponding Ni­(II) complexes with HCl gives α-AAs without erosion of enantiopurity (>97% ee ; see HPLC traces in the Supporting Information, Figures S29–S32). − The opposite enantiomers of cysteine derivatives ( S , R )- ent - 6a and ( S , R )- ent - 6b were also isolated in 82% and 85% yields, respectively (Scheme ). However, the decomposition of the complexes ( S , S , S )- 5f , 5i , 5g , and 5h will give the threo ( S , S )-form of cysteines, which synthesis, in fact, is also a challenging task .…”

“…However, the decomposition of the complexes ( S , S , S )- 5f , 5i , 5g , and 5h will give the threo ( S , S )-form of cysteines, which synthesis, in fact, is also a challenging task . Importantly, the chiral auxiliary was easily separated from the resulting reaction mixture by extraction or filtration in an enantiopure form as a hydrochloride salt (( S )-BPB·HCl) and can be reused for the synthesis of a new batch of the starting Ni­(II) complex 1 . − Besides, in the case of a large-scale synthesis, it is possible to recover the Ni­(II) ions as well …”