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

Abstract

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.

Which Stereoinductor Is Better for Asymmetric Functionalization of α‐Amino Acids in a Nickel(II) Coordination Environment? Experimental and DFT Considerations

“…For binaphthyl complex II b , the differences between two diastereomers are less pronounced, but still mainly determined by the repulsive interactions between the phenylene ortho ‐proton and the phenyl ring (which are stronger in the R isomer). Any differences attributed to the through‐space interactions involving an auxiliary chiral moiety exhibiting axial chirality can barely be detected in the stereoisomers (no stereochemical contacts have been detected previously in the X‐ray data). The most “bulky” region in binaphthyl complex II b is the vicinity of the CH 2 group in the binaphthyl fragment.…”

“…The H atom of CH 2 is very close to the amide N atom. Because the position of H atoms cannot be reliably determined from the X‐ray data, this contact has not been detected previously . The calculated difference in energies for the S and R stereoisomers of II b gives a value of Δ E =1.5 kcal mol −1 , which is minimal among the compounds under consideration.…”

“…Later, this design was profoundly improved by introducing a new generation of tridentate ligands that possessed various elements of chirality (stereogenic center, stereogenic center in combination with axial chirality, etc. ) Chemical modification of the chiral ligand sphere by insertion of bulky electron‐donating or ‐withdrawing substituents was also tested to provide various stereoselectivity levels . To provide a rationale for variations in the stereoselectivity level, as well as for developing and molecular engineering of new chiral materials, elucidation of possible mechanisms that determine the relationship between the steric configuration of a molecule and its electronic structure will be helpful.…”

Recyclable and Stable α-Methylproline-Derived Chiral Ligands for the Chemical Dynamic Kinetic Resolution of free C,N-Unprotected α-Amino Acids

“…Several research groups have developed practical methods for the preparation of chiral unnatural α -amino acids and β -amino acids [34,35,36,37,38,39,40,41]. In particular, chiral ligands 1 , 2 , and 3 (Scheme 1) were successfully used for the preparation of structurally varied α -amino acids, respectively [42,43,44,45,46]. In 2015, our group realized chemical dynamic thermodynamic resolution and S / R interconversion of unprotected unnatural α -amino acids [43,44].…”

“…In particular, chiral ligands 1 , 2 , and 3 (Scheme 1) were successfully used for the preparation of structurally varied α -amino acids, respectively [42,43,44,45,46]. In 2015, our group realized chemical dynamic thermodynamic resolution and S / R interconversion of unprotected unnatural α -amino acids [43,44]. Unfortunately, ligand 1 has limited substrate generality and incomplete stereochemical outcome, and both of the chiral ligands 1 and 2 were synthesized bearing axially chiral 1,1’-binaphthyl moieties, which were rather expensive [43].…”