Candida antarctica Lipase B in a Chemoenzymatic Route to Cyclic α‐Quaternary α‐Amino Acid Enantiomers

Abstract

Kinetic resolution of three cyclic quaternary ethyl 1‐amino‐2,3‐dihydro‐1H‐indene‐1‐carboxylates and both 1‐ and 2‐amino‐1,2,3,4‐tetrahydronaphthalene analogues have been studied. Interesterification with butyl butanoate and Candida antarctica lipase B accomplished the task. The enantiomers of all 1‐amino analogues reacted with excellent enantioselectivity (enantiomeric ratio er greater than 200), whereas the 2‐amino analogue was not enantioselective (er = 4). Amino acid enantiomers were finally obtained as their respective hydrochlorides with almost maximum theoretical yields. For the first time, a lipase enzyme was effectively used in the kinetic resolution of cyclic α‐quaternary α‐amino esters.

Kilogram-Scale Preparation of the Amino Alcohol Fragment of Selgantolimod by Enzymatic Resolution of an α,α-Disubstituted Amino Ester

“…A Strecker reaction of 2-hexanone followed by treatment with benzoyl chloride gave N -benzoyl amino nitrile 5 , and participation of the benzoyl group facilitated hydrolysis of the nitrile to carboxylic acid 6 and conversion to ethyl ester 7 . Substrate 7 was subjected to a preliminary screen of commercially available hydrolase enzymes under select conditions based on a survey of the literature. , The leading result was obtained with Alcalase, a readily available liquid formulation of subtilisin protease that has been applied to the resolution of aminocyclopropane carboxylates on kilogram scale. , Efforts to optimize the conditions for Alcalase-mediated resolution of substrate 7 achieved only 8% conversion to the carboxylic acid product ( S )- 6 after 63 h (Scheme b). Chiral LC analysis revealed ( S )- 6 formed with 84% ee .…”

Recent Advances in the Synthesis of Hydantoins: The State of the Art of a Valuable Scaffold

“…328 In turn, these hydantoins can be hydrolyzed into the corresponding amino acids with resolution of the enantiomers, notably by lipase catalysis. 329 This strategy afforded potent group II mGluR agonists, 330,331 phosphotyrosyl mimetics to induce a specific conformation in peptides, 332 or cage-like amino acids that, once incorporated into drugs, would improve its transport through lipophilic membranes. 333 8.1.2.…”

“…The resolution can be performed by column chromatography, 487,511 selective recrystallization of diastereoisomeric derivatives, 331,512 formation of complexes, 251,513,514 or by an enzymatic pathway. 329,515…”

“…In the same manner as the preparation of 5- and 5,5-disubstituted hydantoins, the synthesis of 5,5-spirohydantoins mainly relies on the use of the Bucherer–Bergs reaction, in classical conditions or using microwave technology. ,− This method enabled unusual and constrained hydantoin structures to be accessed such as camphor, anthracene, and naphthalene-derived hydantoins . In turn, these hydantoins can be hydrolyzed into the corresponding amino acids with resolution of the enantiomers, notably by lipase catalysis . This strategy afforded potent group II mGluR agonists, , phosphotyrosyl mimetics to induce a specific conformation in peptides, or cage-like amino acids that, once incorporated into drugs, would improve its transport through lipophilic membranes …”

“…In the case of constrained structures, the Bucherer–Bergs reaction afforded the corresponding hydantoins with a favored isomer that enabled then to recover one major isomer of the desired amino acid. , In any case, the mixture of isomers needed to be separated. The resolution can be performed by column chromatography, , selective recrystallization of diastereoisomeric derivatives, , formation of complexes, ,, or by an enzymatic pathway. , …”