Effect of the Substituent and Amino Group Position on the Lipase‐Catalyzed Resolution of γ‐Amino Esters: A Molecular Docking Study Shedding Light on Candida antarctica lipase B Enantioselectivity

• Published in: European Journal of Organic Chemistry
• Main Authors: Ortega‐Rojas, Marina A., Castillo, Edmundo, Razo‐Hernández, Rodrigo Said, Pastor, Nina, Juaristi, Eusebio, Escalante, Jaime
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2021
• Subjects: Antarc*; Antarctica
• Online Access: http://dx.doi.org/10.1002/ejoc.202100712; https://onlinelibrary.wiley.com/doi/pdf/10.1002/ejoc.202100712; https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ejoc.202100712

Abstract The kinetic resolution of N ‐ tert ‐butoxycarbonyl γ‐amino methyl esters bearing different stereocenters at alpha (γ 2 ), beta (γ 3 ), or gamma (γ 4 ) positions was carried out by enantioselective hydrolysis with Candida antarctica lipase B (CaLB) in 2‐methyl‐2‐butanol solvent. The results show that the process is significantly less enantioselective for the γ 2 ‐amino methyl ester ( E =2.5), the γ 3 ‐amino methyl ester ( E =7.6), and the γ 4 ‐amino methyl ester ( E =8.3) when compared with the kinetic resolution of analogous N ‐protected β 3 ‐amino esters ( E >80). Based on these results, molecular docking studies were carried out, through which particular regions in the CaLB catalytic cavity were analyzed. The steric exclusion region composed of Ile189 and Val190 residues, together with the amino bonding region that induces a hydrogen bond with the Asp134 residue, appear to be responsible for the high selectivity in the resolution of carboxylic acid derivatives with beta stereocenters. This interaction is well preserved for β‐amino esters as substrates. By contrast, γ‐amino esters exhibit greater conformational diversity, so the effectiveness of the interaction is reduced, which apparently is responsible for the loss of enantioselectivity in the resolution process.