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Non-natural, tailor-made amino acids are of crucial importance to the synthesis of bioactive peptides and new chemical entities. Innovative methodology is always needed for the preparation of enant...

Unusual amino acids are of crucial importance to the synthesis of bioactive peptides and new chemical entities. Innovative methodology is always needed for the preparation of enantiomerically pure amino acids that does not rely on tedious resolution procedures. The proline-derived ligands (R)- and (S)-N-(2-benzoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl)pyrrolidine-2-carboxamide are outstanding, versatile, and recyclable reagents for the synthesis of tailor-made α- and β-amino acids. Here we report initial studies of the scale-up synthesis of the HCl salt of these reagents on the 100 g scale. The results demonstrate an increased efficiency and environmental friendliness of the bench-scale procedure and provides a firm foundation for the manufacture on multikilogram and larger scales.

Enantiomerically pure tailor-made amino acids are in extremely high demand in nearly every sector of the health-related industries. In particular, the rapidly growing number of amino-acid-based pharmaceuticals calls for the development of advanced synthetic approaches featuring practicality and commercial viability. Here we provide a brief summary of the development of axially chiral tridentate Hamari ligands and their application for general asymmetric synthesis of various structural types of amino acids. The methodological diversity includes: dynamic kinetic resolution and (S)-/(R)-interconversion of unprotected amino acids and homologation of nucleophilic glycine equivalents via alkyl halide alkylation reactions as well as multiple-step transformations allowing preparation of polyfunctional and cyclic derivatives. The practicality of these methods is critically discussed. We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21761132021) and IKERBASQUE, Basque Foundation for Science.

[formula: see text] The new crystalline phosphate reagent 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) mediates amide bond formation with a remarkable resistance to racemization. Comparative racemization studies were carried out and DEPBT proved to be superior to typical phosphonium and uronium coupling reagents. DEPBT is easily prepared and is exceedingly stable with a shelf life of months at room temperature. The advantageous properties of DEPBT render it a useful and unique addition to the arsenal of coupling reagents.

[formula: see text] The new crystalline phosphate reagent 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) mediates amide bond formation with a remarkable resistance to racemization. Comparative racemization studies were carried out and DEPBT proved to be superior to typical phosphonium and uronium coupling reagents. DEPBT is easily prepared and is exceedingly stable with a shelf life of months at room temperature. The advantageous properties of DEPBT render it a useful and unique addition to the arsenal of coupling reagents.

Unusual acid cleavage reactions are reported for derivatives containing acylated N-methyl-α-aminoisobutyryl (NMeAib) residues. The bond linking the NMeAib residue to the following amino acid is cleaved. Through X-ray diffraction studies of the NMeAib containing molecules, we have shown that the carbonyl oxygen atom of the preceding residue is in proximity to the carbonyl carbon of the NMeAib residue. Thus, it can act as an internal nucleophile leading to a cleavage reaction by way of an oxazolinium ion intermediate. Kinetic experiments for the cleavage reaction were carried out on a series of benzoyl dipeptide derivatives (p-X-C6H4C(O)-NMeAib-Phe-OMe) where X is varied from NO2 to Cl. The value of ρ = −1.335 for the Hammett linear free-energy relationship strongly supports the intermolecular oxazolinium intermediate proposed.