Green Strategies for the Preparation of Enantiomeric 5–8-Membered Carbocyclic β-Amino Acid Derivatives through CALB-Catalyzed Hydrolysis

Abstract

Candida antarctica lipase B-catalyzed hydrolysis of carbocyclic 5–8-membered cis β-amino esters was carried out in green organic media, under solvent-free and ball-milling conditions. In accordance with the high enantioselectivity factor (E > 200) observed in organic media, the preparative-scale resolutions of β-amino esters were performed in tBuOMe at 65 °C. The unreacted β-amino ester enantiomers (1R,2S) and product β-amino acid enantiomers (1S,2R) were obtained with modest to excellent enantiomeric excess (ee) values (ees > 62% and eep > 96%) and in good chemical yields (>25%) in one or two steps. The enantiomers were easily separated by organic solvent/H2O extraction.

Scalable Synthesis of All Stereoisomers of 2-Aminocyclopentanecarboxylic Acid─A Toolbox for Peptide Foldamer Chemistry

“…Fülöp et al directly converted this lactam into a chiral amino acid by enzymatic hydrolysis . Later, the same research group developed enzymatic kinetic resolution for the amide and ester of cis -ACPC. , The crystallization-based resolution methods can be an attractive alternative to the enzymatic approach. For example, N -Cbz- and N -Boc-protected cis -ACPC were resolved with dehydroabiethylamine and ephedrine, respectively, while the ethyl ester of N -4-fluorobenzylated cis -ACPC was resolved with mandelic acid .…”

A Sustainable Green Enzymatic Method for Amide Bond Formation

“…In preliminary amidation experiments, the carboxylic acid and amine substrates (1:1 equiv) were dissolved in an organic solvent (1 mL) to provide a solution with a given concentration (46,92,460, or 920 mM). CALB (50 mg), molecular sieve (50 mg 3 Å size) to avoid the reversible hydrolysis reaction, and n-heptadecane (2 µL) as an internal standard were added to the above solution.…”

“…Several lipases have been reported to exhibit high catalytic activity and stability in organic solvents [39,40]. In particular, Candida antarctica lipase B (CALB; Novozyme 435) prefers anhydrous conditions and it has been widely applied in esterification and hydrolysis studies [41][42][43][44][45][46]. CALB could also catalyze amidation reactions [47][48][49][50][51][52] when the amine is used as a nucleophile in anhydrous organic media.…”