Lipase‐Catalyzed Synthesis of Substituted Phenylacetamides: Hammett Analysis and Computational Study of the Enzymatic Aminolysis

Abstract

A series of hydroxy‐, methoxy‐, and nitrophenylacetamides was synthesized by enzyme catalysis. The 28 new products were obtained through a lipase‐catalyzed two‐step reaction in very good to excellent yield. In the case of nitro derivatives, a one‐pot, two‐step methodology allowed the desired products to be obtained in high yields. The influence of various reaction parameters in the lipase‐catalyzed reactions, such as enzyme source, nucleophile (alcohol or amine)/substrate ratio, enzyme/substrate ratio, solvent and temperature were studied. It was observed that nitro‐substituted phenylacetates were more reactive in the aminolysis reaction than phenylacetates substituted with a hydroxyl group. To study this substituent effect, a Hammett analysis and the determination of the ρ parameter were carried out. Moreover, a computational study was applied to the most representative systems, performing an exploration of the potential energy surface for the catalyzed and noncatalyzed aminolysis reaction for nitro‐ and hydroxyphenylacetates. Both analysis showed that the presence of a strongly electron‐attracting group favors the activity of the enzyme, in complete agreement with the experimental results of the enzymatic catalysis.

Recent advances on sources and industrial applications of lipases

“…Some of the noteworthy pharmaceutical applications include peptide syntheses that contain usual and unusual amino acids produced by porcine pancreatic lipase and C. cylindracea lipase . Other examples are the synthesis of β‐amino acid esters, which are the chief components in many drugs, the synthesis of drugs such as milnacipran that help in clinical treatment of fibromyalgia, and the synthesis of potential anti‐malarial drugs as well as hormone receptors . The widespread usage of this reaction in the pharma domain is due to its potential in effective kinetic resolution of molecules .…”

“…Other examples are the synthesis of β‐amino acid esters, which are the chief components in many drugs, the synthesis of drugs such as milnacipran that help in clinical treatment of fibromyalgia, and the synthesis of potential anti‐malarial drugs as well as hormone receptors . The widespread usage of this reaction in the pharma domain is due to its potential in effective kinetic resolution of molecules . Other application domains of lipase‐catalyzed aminolysis include cosmetics, and agrochemical products …”

“…204 The widespread usage of this reaction in the pharma domain is due to its potential in effective kinetic resolution of molecules. 203 Other application domains of lipase-catalyzed aminolysis include cosmetics, and agrochemical products. 205…”

Bile acids: Lipase-catalyzed synthesis of new hyodeoxycholic acid derivatives

“…[21][22][23][24][25]. In our laboratory several studies have been accomplished on the use of lipases, obtaining a wide variety of biologically active compounds, many of them new [26][27][28][29][30][31][32][33][34][35].…”

Optimization of the Lipase-Catalyzed Selective Amidation of Phenylglycinol

“…Among the enzymes, lipase (EC 3.1.1.3) was often applied for the esterification and amidation reactions (Kirchner et al, 1985;Martinek and Semenov, 2002;Vicente, 2002;Slotema et al, 2003;Tan, 2010). Due to the excellent regio-selectivity, high efficiency and environment amity, many works about lipase, especially commercial lipase Novozym 435, synthesizing high value-added amide products, applied for drug intermediates and cosmetic materials have been reported (Levinson et al, 2005;Martínková et al, 2008;Baum et al, 2011;Schwab et al, 2013;Stavila et al, 2013;Liñares et al, 2014). Among all the researches, amino alcohols have two active hydrogen groups, the amidation reaction on which have been well studied (Syrén et al, 2012;Wang et al, 2015).…”