Synthesis of Enantiopure Isosteres of Amino Acids Containing a Quaternary Stereocenter: Experimental and Computational Evaluation of a Novel Class of Atropisomers

Abstract

Electrophilic amination of diastereomeric 4‐methoxycarbonyl pyrrolidin‐2‐ones allowed to prepare both diastereomers of an amino acid bearing a quaternary chiral center, a key intermediate to antibiotic 8‐methoxyquinolone carboxylic acid. Within this synthesis, novel atropisomers, exceedingly stable at room temperature, were isolated and characterized, which were subsequently converted into the desired products by a novel reductive N–N bond cleavage reaction.

A nonneglectable stereochemical factor in drug development: Atropisomerism

“…41 With the increasing attention on atropisomerism, research on various aspects of the asymmetric synthesis, resolution, and biological evaluation of atropisomers is substantially increasing. 4,30,[42][43][44][45][46][47][48][49][50] Herein, we focus on the biological activities and pharmacokinetic and toxicity properties of various atropisomers and highlight the role of atropisomerism in drug design.…”

Synthesis of Atropisomeric Hydrazides by One‐Pot Sequential Enantio‐ and Diastereoselective Catalysis

“…Zhao and Yang realized a similar approach, reporting an interesting example of an enantiodivergent Paal–Knorr reaction [8] . Recently, Rinaldi isolated a stable atropisomeric hydrazide as an intermediate for the preparation of isosteres of amino acids and conformationally restricted γ‐lactams [9] …”

Stereochemistry and Recent Applications of Axially Chiral Organic Molecules

“…N‐N stereogenic axes are uncommon and scarce literature is present. Rinaldi and co‐workers have recently synthetized novel atropisomers with hindered rotation around a N‐N bond, in a synthetic procedure to obtain α‐amino acids containing a quaternary stereogenic centre (compound 38 in Scheme ) . In this strategy the alkylation on one nitrogen atom of one hydrazidic moiety hinders the rotation of the N‐N bond, thus driving the four substituents in a perpendicular conformation, with total loss of conjugation between the two nitrogen atoms.…”