Diisopropyl Malonate as Acylating Agent in Kinetic Resolution of Chiral Amines with Lipase B from Candida antarctica

Abstract

Activity of diisopropyl malonate (2) as a novel acylating agent was investigated in kinetic resolution (KR) of various racemic amines [(±)-1a-d] catalyzed by lipase B from Candida antarctica. Diisopropyl malonate (2) proved to be effective acylating agent with four racemic amines [(±)-2-aminoheptane, (±)-1-methoxy-2-propylamine, (±)-1-phenylethylamine and (±)-4-phenylbutan-2-amine; (±)-1a-d, respectively] selected for this study. The lipase-catalyzed acylation of the amines (±)-1a-d with 2 proceeded with good conversions (44.9–52.1%) and provided the expected (R)-amides [(R)-3a-d] in moderate to excellent yields (51–98%) with high enantiomeric excess (ee(R)-3a-d 92.0–99.9%) after 4 h reaction time under mild reaction conditions in batch mode. The best conversion (50%) combined with high enantiomeric purity (ee(R)-2d > 99%ee) was achieved in the KR from racemic 2-aminoheptane (±)-1a. The four novel (R)-amides [(R)-3a-d] were isolated and properly characterized.

Stereoselective Synthesis of Novel (±)-trans-Dihydronarciclasine Analogues: Preparation of a Pivotal Intermediate Containing Two Methoxy Substituents

“…Prior to the conversion of the nitro group into the amino one by catalytic hydrogenation, the carbonyl group of (±)-17 was protected with ethylene glycol, in the presence of (COOH) in excel-lent yield (95%) over a 10% Pd/C catalyst (Selcat Q [34]), in methanol, at 80 °C and 12 bar. Subsequently, the N-acylation of compound (±)-19 by an activated ester [35] was carried out with methyl chloroformate in a biphasic solvent mixture (water and THF) to obtain (±)-7-(4',7'-dimethoxybenzo[d] [1,3]dioxol-5'-yl)-9-hydroxy-1,4-dioxaspiro [4.5]decan-8-yl)carbamic acid methyl ester [(±)-20] in very good yield (86%). The ketal protective group of (±)-20 was removed in acetone containing a catalytic amount of p-TsOH under reflux, but water elimination also took place to afford (±)-6-(4',7'-dimethoxybenzo[d] [1,3]dioxol-5'-yl)-4-oxocyclohex-2-en-1-yl)carbamic acid methyl ester [(±)-21] in excellent yield (97%).…”

Immobilization of Lipase B from Candida antarctica on Magnetic Nanoparticles Enhances Its Selectivity in Kinetic Resolutions of Chiral Amines with Several Acylating Agents

“…However, like every other free enzyme, it can have several limitations, such as instability, nonreusability, and sensitivity to several reactants, which immobilization can circumvent [6]. The immobilized forms of this versatile biocatalyst have been used for the KR of chiral alcohols [7][8][9][10], azolides [11], and amines [12][13][14][15][16][17].…”

“…In the lipase-catalyzed stereoselective N-acylations, a variety of acyl donors (or the so-called acylating agents) can be used. Nonactivated esters of acetic acid, such as ethyl acetate [20,21]; isopropyl acetate [22]; n-butyl acetate; or other fatty acids, like myristic acid [23]; as well as the so-called activated esters, such as alkyl 2-alkoxyacetates and alkyl 2-cyanoacetates, including isopropyl 2-methoxyacetate [24], diisopropyl malonate [14], isopropyl 2-cyanoacetate [15], or isopropyl 2-ethoxyacetate [16,17], have already been applied. In the activated esters, an electron-withdrawing group (such as an alkoxy, cyano, or halogen) at the β-position amplifying the partially positive nature of the ester carbonyl group enhances the reactivity of such esters as acylating agents.…”

“…Another advantage of malonates or cyanoacetates as acylating agents is the possibility of further molecule modifications, which is important in the pharmaceutical industry [14][15][16][17]. For example, from the product of Knoevenagel condensation of the enantiopure amide of (S)-1-phenylethan-1-amine and cyanoacetic acid, tyrphostins, which are inhibitors of protein tyrosine kinases that can be used as chemotherapeutic agents, can be synthesized [15].…”

“…Apart from the enhancement of catalytic properties, the reusability of the biocatalysts may also be improved [26]. Lipases immobilized in/on various carriers (or hybrid catalysts, involving metal and an enzyme) have been used in KRs or DKRs in order to obtain enantiopure amines such as mesoporous beads [15,17], phenyl-functionalized silica gel [15,16], macroporous acrylic resin [14,15], siliceous mesocellular foams (MCFs) [27,28], metal-organic frameworks (MOFs) [29], and hollow structure materials [30].…”