Lipase-Catalyzed Strategies for the Preparation of Enantiomeric THIQ and THβC Derivatives: Green Aspects

This report reviews the most important lipase-catalyzed strategies for the preparation of pharmaceutically and chemically important tetrahydroisoquinoline and tetrahydro-β-carboline enantiomers through O-acylation of the primary hydroxy group, N-acylation of the secondary amino group, and COOEt hydrolysis of the corresponding racemic compounds with simple molecular structure, which have been reported during the last decade. A brief introduction describes the importance and synthesis of tetrahydroisoquinoline and tetrahydro-β-carboline derivatives, and it formulates the objectives of this compilation. The strategies are presented in chronological order, classified according to function of the reaction type, as kinetic and dynamic kinetic resolutions, in the main text. These reactions result in the desired products with excellent ee values. The pharmacological importance of the products together with their synthesis is given in the main text. The enzymatic hydrolysis of the hydrochloride salts as racemates of the starting amino carboxylic esters furnished the desired enantiomeric amino carboxylic acids quantitatively. The enzymatic reactions, performed in tBuOMe or H2O as usable solvents, and the transformations carried out in a continuous-flow system, indicate clear advantages, including atom economy, reproducibility, safer solvents, short reaction time, rapid heating and compression vs. shaker reactions. These features are highlighted in the main text.

Lipases (triacylglycerol hydrolases E.C. 3.1.1.3) are versatile enzymes, widely used for various kinds of biocatalyzed reactions, performed in both aqueous and nonaqueous media.They can catalyze chemical transformations with high catalytic efficiency and specificity as chemo-, regio-, and enantio-selectivities.Lipase-catalyzed enantioselective acylation of alcohols and amines together with the hydrolysis of esters and amides are among the most utilized biocatalytic methods for the preparation of enantiomerically pure alcohols, esters, amines, amides, and acids.The reason is that lipases are highly active and robust enzymes with broad substrate specificities.
From a green chemistry perspective, the best solvent for reactions is no solvent [24][25][26][27][28].The solvent-free reactions are not always achievable and the selection of another more efficient solvent becomes critical.Water has increasing popularity, because it is inexpensive, nontoxic, nonflammable, and safe for use.In addition, to ensure high activity and selectivity, water allows easy product isolation by filtration.
Green solvents play a crucial role in lipase-catalyzed reactions, offering numerous advantages over traditional solvents in terms of environmental sustainability, safety, and efficiency [29][30][31][32][33][34][35].Lipase-catalyzed reactions are widely employed in various industries, including the production of pharmaceuticals, food, and biofuels, due to their ability to produce enantiopure compounds and minimize unwanted side reactions.The choice of solvent significantly influences the overall performance of the enzymatic reaction, and the use of green solvents has emerged as a preferred option for several reasons.First, green solvents are available from renewable resources, making them inherently more sustainable compared to conventional solvents obtained from petroleum-based sources.This is in accordance with the growing global emphasis on reducing the carbon footprint and moving toward ecofriendly practices in chemical processes.Furthermore, green solvents are nontoxic and biodegradable, minimizing environmental hazards and reducing health risks for both workers and consumers.Their low toxicity is also beneficial for the stability and activity of enzymes during catalysis leading to enhanced reaction rates and product yields.Moreover, the use of green solvents promotes improved enzymatic selectivity.They typically have lower polarity, which can reduce nonspecific interactions between the enzyme and the substrate, resulting in higher enantioselectivity and regioselectivity.This is particularly important in the synthesis of pharmaceutical intermediates and fine chemicals, where chirality is of utmost significance.Green solvents also contribute to overcome mass transfer limitations.They possess lower viscosities compared to conventional solvents, facilitating better diffusion of substrates to the active site of the enzyme and faster product release.These properties can lead to shorter reactions and increased productivity.Furthermore, green solvents are often compatible with a wide range of substrates and enzyme types.Their ecofriendly nature, reduced toxicity, improved selectivity, and enhanced mass transfer properties make them invaluable tools for sustainable and efficient enzymatic processes.Although there are some greener organic solvents, for example, cyclopentyl methyl ether (CPME), a promising ecofriendly solvent without any handling difficulties, and tBuOMe, which is one of the most widely used solvents for lipase-catalyzed transformations.Note, however, that according to the green solvent selection guide [36], there are some unfavorable issues and substitution is advisable.
The majority of lipase-catalyzed reactions have been performed as batch reactions.However, enzymatic continuous-flow processes, because of their numerous advantages, have gained significant attention in recent years as promising alternatives to traditional batch reactions [37][38][39][40][41][42].For example, continuous flow systems allow controlled flow of reactants, ensuring a constant supply of substrates to the enzyme, which improves the overall reaction efficiency, leading to higher productivity and increased yield of the desired products.Enzyme-catalyzed reactions in continuous flow can be finely tuned by adjusting residence times, temperature, and enzyme concentration, enabling better selectivity in product formation, minimizing unwanted byproducts, and reducing the need for downstream purification steps.Continuous-flow reactors can handle hazardous materials more safely than traditional batch reactors.The smaller reaction volumes in continuous flow reduce the risk of accidental spills and exposure to toxic or reactive substances, enhancing overall operator safety.The continuous flow of reactants ensures that they spend less time in the reactor, leading to shorter reaction times.This is of particular significance when working with unstable substrates or sensitive enzymes that may degrade over prolonged exposure.Enzymatic continuous-flow processes are readily scalable, making it easier to transition from laboratory-scale to industrial-scale production.Additionally, continuous-flow setups can be easily integrated into automated systems, allowing precise control and reproducibility.
Although lipase-catalyzed kinetic resolution (KR) methods have been developed for the enantioselective acylation in a large number of primary and especially secondary alcohols or the hydrolysis of their corresponding esters, the first chemoenzymatic method for the preparation of optically active alcohols and esters possessing the 1,2,3,4-tetrahydroquinoline (THQ) moiety was published only recently [43].The enantioselective transesterification (E values > 328) of racemic 1,2,3,4-THQ-propan-2-ols was performed with vinyl acetate (VA) in the presence of immobilized Candida antarctica lipase B (CALB) or Burkholderia cepacia lipase (BCL) or engineered acyltransferase variants from Mycobacterium smegmatis (MsAcT).These reactions furnished (S)-alcohols and the corresponding (R)-acetates with excellent optical purities (ee > 99%).
The aim of this compilation is to present the most important lipase-catalyzed routes devised for the preparation of pharmaceutically and chemically important THIQ and THβC enantiomers (simple molecular structures) with the appropriate absolute configuration of the asymmetric center (Scheme 1) over the last decade.The transformations through O-acylation (I), N-acylation (II), and COOEt hydrolysis (III) of the corresponding racemates (Scheme 1) are classified as KR (a maximum yield of 50% enantiopure product is obtainable from asymmetric acylation, hydrolysis, etc.) and DKR (this theoretically allows 100% conversion), and they are discussed in chronological order.The reactions, performed under environmentally benign green conditions, are highlighted in the main text.

Enzymatic Strategies for the Synthesis of THIQ and THβC Enantiomers 2.1. KR through O-Acylation
Successful lipase-catalyzed methods for the asymmetric O-acylation of the primary hydroxy group of several 1,2,3,4-THIQ and 1,2,3,4-THβC racemates were developed.Efficient enzymatic resolution processes of racemates, bearing a stereogenic center separated from the functional group by a larger nonchiral moiety, were also developed.In general, good yields accompanied by high enantioselectivities were obtained, thus underlining the potential of enzymes to recognize and transform enantiomers of racemates with 'remote' stereogenic centers in an enantioselective manner.The reactions were performed in an organic solvent either in a continuous-flow system or as a batch reaction.

KR through O-acylation
Successful lipase-catalyzed methods for the asymmetric O-acylation of the primary hydroxy group of several 1,2,3,4-THIQ and 1,2,3,4-THβC racemates were developed.Efficient enzymatic resolution processes of racemates, bearing a stereogenic center separated from the functional group by a larger nonchiral moiety, were also developed.In general, good yields accompanied by high enantioselectivities were obtained, thus underlining the potential of enzymes to recognize and transform enantiomers of racemates with 'remote' stereogenic centers in an enantioselective manner.The reactions were performed in an organic solvent either in a continuous-flow system or as a batch reaction.

KR through N-Acylation
A number of racemic cyclic secondary amines bearing a stereogenic center such as 1-substituted 1,2,3,4-THIQs and 1,2,3,4-THβCs were resolved successfully through N-acylation/alkoxycarbonylation.In general, good yields accompanied by high enantioselectivities were obtained.The reactions were performed in an organic solvent either in a continuous-flow system or as a batch reaction.

KR through N-acylation
A number of racemic cyclic secondary amines bearing a stereogenic center such as 1substituted 1,2,3,4-THIQs and 1,2,3,4-THβCs were resolved successfully through N-acylation/alkoxycarbonylation.In general, good yields accompanied by high enantioselectivities were obtained.The reactions were performed in an organic solvent either in a continuous-flow system or as a batch reaction.

Conclusions and Outlook
This compilation presents the most important lipase-catalyzed strategies reported over the last decade for the preparation of pharmaceutically and chemically important THIQ and THβC enantiomers, with simple molecular structure through O-acylation of the primary hydroxy group (with remote stereocenter), N-acylation of the secondary amino group, and COOEt hydrolysis of the corresponding racemic amino alcohols and amino CEs.
The strategies are classified as KR and DKR and presented in chronological order.The reactions resulted in the formation of the desired products with excellent ee values and good chemical yields isolated either by column chromatography or by organic solvent-H 2 O extraction.The pharmacological importance of the products together with their synthesis is given in the main text.
The lipase-catalyzed reactions performed in the usable tBuOMe and green H 2 O as vents and those carried out in a continuous-flow system, with clear advantages including atom economy, reproducibility, safer solvents, short reaction time, rapid heating and compression vs. shaker reactions, are highlighted in the main text and summarized in Table 3.
Because of the growing demand for biologically active enantiomeric compounds in pharmaceutical chemistry (e.g., derivatives containing the THIQ or THβC moiety), it is predicted that a large number of new green chemoenzymatic strategies (e.g., flow biocatalysis) will be devised for the preparation of such enantiomers.

Table 3 .
Green aspects of enzymatic strategies.Reactions in tBuOMe and aqueous NH 4 OAc buffer; reactions in continuous-flow system. *