This article provides a review of the paramount lipase-catalyzed strategies employed in the preparation of (2R,3S)-3-amino-2-hydroxy-3-phenylpropionic acid, several of its derivatives, and precursor 2-azetidinones through β-lactam ring opening, OAc hydrolysis, COOEt hydrolysis, O-acylation, and sequential kinetic resolution through a two-step cascade reaction. It involves OAc hydrolysis followed by β-lactam ring opening and β-lactam ring opening followed by hydroxymethyl group degradation of the corresponding racemic compounds, reported over the last 15 years. A brief introduction describes the pharmaceutical and chemical importance of the Taxol molecule as well as various synthetic methods involving its side chain and it delineates the key objectives of this mini-review. The strategies are classified on the basis of reaction types and are presented in chronological order, discussing kinetic and sequential kinetic resolutions in the main text. These reactions yield the intended products, exhibiting excellent enantiomeric excess values.

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.

A sustainable enzymatic strategy for the preparation of amides by using Candida antarctica lipase B as the biocatalyst and cyclopentyl methyl ether as a green and safe solvent was devised. The method is simple and efficient and it produces amides with excellent conversions and yields without the need for intensive purification steps. The scope of the reaction was extended to the preparation of 28 diverse amides using four different free carboxylic acids and seven primary and secondary amines, including cyclic amines. This enzymatic methodology has the potential to become a green and industrially reliable process for direct amide synthesis.

The most relevant lipase-catalyzed strategies for the synthesis of pharmaceutically important cyclic and acyclic α-, β- and γ-amino carboxylic acid enantiomers through hydrolysis of the corresponding amino carboxylic esters and lactams, over the last decade are overviewed. A brief Introduction part deals with the importance and synthesis of enantiomeric amino acids, and formulates the objectives of the actual work. The strategies are presented in the Main Text, in chronological order, classified as kinetic, dynamic kinetic and sequential kinetic resolution. Mechanistic information of the enzymatic transformations is also available at the end of this overview. The pharmacological importance of the enantiomeric amino acids is given next to their synthesis, in the Main Text, and it is also illustrated in the Conclusions and Outlook sections.

The enantioseparation of five fluorinated beta-phenylalanine analogs together with the nonfluorinated alpha- and beta-phenylalanines has been investigated utilizing chiral stationary phases. The employed chiral selectors include macrocyclic antibiotics, such as vancomycin, teicoplanin, and teicoplanin aglycone, isopropyl carbamate functionalized cyclofructan-6, and Cinchona alkaloid-based tert.-butyl carbamate quinine, all covalently bonded to 2.7 mu m superficially porous silica particles. The applied conditions included reversed-phase and polar-ionic modes where the vancomycin-, and the cyclofructan-6-based core-shell particles proved to offer suitable efficiency. Under reversed-phase conditions typical hydrophobic chromatographic behavior was observed, especially in the H2O/MeOH system. The improved selectivity with increasing MeOH content observed in polar ionic mode suggests that H-bonding may not play a major role in the chiral recognition. The stoichiometric displacement model was probed to gather information on the ionic interactions. The ion-exchange process was found to affect retention, but it has no essential contribution to chiral recognition. Without paying special attention to the optimization of the system volume of the UHPLC instrument plate heights varying in the range of 10-50 mu m were obtained. In all cases, retention and selectivity decreased with increasing temperature, and enthalpy-driven enantiorecognition was observed. Elution sequences were determined in all cases.

The enantioselective separation of newly synthesized fluorine-substituted β-phenylalanines has been performed utilizing Cinchona alkaloid-based ion-exchanger chiral stationary phases. Experiments were designed to study the effect of eluent composition, counterion content, and temperature on the chromatographic properties in a systematic manner. Mobile phase systems containing methanol or mixtures of methanol and acetonitrile together with acid and base additives ensured highly efficient enantioseparations. Zwitterionic phases [Chiralpak ZWIX (+) and ZWIX(-)] were found to provide superior performance compared to that by the anion-exchangers (Chiralpak QN-AX and QD-AX). A detailed thermodynamic characterization was also performed by employing van't Hoff analysis. Using typical liquid chromatographic experimental conditions, no marked effect of the flow rate could be observed on the calculated thermodynamic parameters. In contrast, a clear tendency has been revealed about the effect of the eluent composition on the thermodynamics for the zwitterionic phases.

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.

In this study, we present results obtained on the enantioseparation of some cationic compounds of pharmaceutical relevance, namely tetrahydro-ß-carboline and 1,2,3,4-tetrahydroisoquinoline analogs. In high-performance liquid chromatography, chiral stationary phases (CSPs) based on strong cation exchanger were employed using mixtures of methanol and acetonitrile or tetrahydrofuran as mobile phase systems with organic salt additives.Through the variation of the applied chromatographic conditions, the focus has been placed on the study of retention and enantioselectivity characteristics as well as elution order. Retention behavior of the studied analytes could be described by the stoichiometric displacement model related to the counter-ion effect of ammonium salts as mobile phase additives. For the thermodynamic characterization parameters, such as changes in standard enthalpy Δ(ΔH°), entropy Δ(ΔS°), and free energy Δ(ΔG°), were calculated on the basis of van't Hoff plots derived from the ln α vs. 1/T curves. In all cases, enthalpy-driven enantioseparations were observed with a slight, but consistent dependence of the calculated thermodynamic parameters on the eluent composition. Elution sequences of the studied compounds were determined in all cases. They were found to be opposite on the enantiomeric stationary phases and they were not affected by either the temperature or the eluent composition.

AbstractStructural diversity-oriented synthesis of some azaheterocyclic β-amino acid derivatives has been accomplished by selective functionalization of readily available cyclodienes. The stereocontrolled synthetic concept was based on the oxidative ring cleavage of unsaturated cyclic β-amino acids derived from cycloalkadiene, followed by ring closing with double reductive amination, which furnished some conformationally restricted β-amino acid derivatives with a piperidine or azepane core.

Enantiomers of cationic compounds of pharmaceutical relevance, namely tetrahydro-ß-carboline and 1,2,3,4-tetrahydroisoquinoline analogs, were separated by high-performance liquid chromatography. Separations were performed on Cinchona-alkaloid-based zwitterionic ion exchanger type chiral stationary phases applied as cation exchangers using mixtures of methanol and acetonitrile or tetrahydrofuran as bulk solvent components containing triethylammonium acetate or ammonium acetate as organic salt additives. On the zwitterionic ZWIX(+) and ZWIX(-) columns investigated, retention and enantioseparation of the studied basic analytes were influenced by the nature and concentration of the organic components of the mobile phase. The effect of organic salt additives on the retention behavior of the studied analytes can be described by the stoichiometric displacement model related to the counterion concentration. Investigations on the structure-retention relationships were performed applying different mobile phase systems for the two types of cationic analytes. For the thermodynamic characterization, parameters such as changes in standard enthalpy (Δ(ΔH°)), entropy (Δ(ΔS°)), and free energy (Δ(ΔG°)) were calculated on the basis of van't Hoff plots derived from the ln α versus 1/T curves. In most cases, enthalpy-driven enantioseparations were observed, with a consistent dependence of the calculated thermodynamic parameters on the mobile phase composition. Elution sequences of the studied compounds were determined in all cases.

An efficient and novel enzymatic method has been developed for the synthesis of β-fluorophenyl-substituted β-amino acid enantiomers through lipase PSIM (Burkholderia cepasia) catalyzed hydrolysis of racemic β-amino carboxylic ester hydrochloride salts 3a–e in iPr2O at 45 °C in the presence of Et3N and H2O. Adequate analytical methods were developed for the enantio-separation of racemic β-amino carboxylic ester hydrochlorides 3a–e and β-amino acids 2a–e. Preparative-scale resolutions furnished unreacted amino esters (R)-4a–e and product amino acids (S)-5a–e with excellent ee values (≥99%) and good chemical yields (>48%).

An efficient synthetic approach for the construction of fluorine‐containing piperidine γ‐amino acid derivatives has been developed. The synthetic concept was based on oxidative ring opening of an unsaturated bicyclic γ‐lactam (Vince‐lactam) through its ring C=C bond, followed by double reductive amination of the diformyl intermediate performed with various fluoroalkylamines. The method has been extended towards the access of alkylated and perfluoroalkylated substances and for γ‐lactam derivatives. The transformations proceeded with stereocontrol: the configuration of the stereocenters in the products were predetermined by the configuration of the chiral centers of the starting γ‐lactam. The method could be extended for the access to enantiopure piperidine γ‐amino esters.

The Front Cover shows the sunset over lake Balaton, Hungary in the background of some novel fluorine-containing piperidine derivatives. Despite of the fact that fluorinated organic compounds are practically absent in the nature, an increasing number of drugs introduced to the market are containing fluorine. Functionalized fluorine-containing azaheterocycles have been synthetized with stereocontrol across oxidative ring opening followed by ring closing with double reductive amination. More information can be found in the Full Paper by L. Kiss et al.

In the frame of substrate engineering, the steric effect of different N-protecting groups on the enantioselectivity and reaction rate of CAL-B-catalysed (S)-selective O-acylation of N-protected 1hydroxym-ethyl-tetrahydro-beta-carbolines was investigated. Excellent enantioselectivities (E > 200) were observed when the acylation of N-Boc [(+/-)-l](,) N-Cbz [(+/-)-3), and N-Fmoc-protected [+/--4] substrates was performed with the use of CAL-B and acetic anhydride in toluene at 60 degrees C. The resolution of N-acetylprotected substrate +/--2 showed excellent E (>200) after 30 min, but as the reaction progressed, E started decreasing after 2 days, because of and N -> O and O -> N acly migrations. Preparative resolutions of +/--3 and +/- 4 resulted in unreacted amino alcohols (R)-3 and (R)-4 and esters (S)-7a and (S)-8a with good enantiomeric excesses (>= 88%) and high yields (>= 44%). (C) 2018 Elsevier Ltd. All rights reserved.

In the present work the effects of N-methylation and N-amidination of ampholytic cyclic beta-amino acids on their retention and enantioseparation characteristics on Cinchona alkaloid- and sulfonic acid-based zwitterionic chiral selectors, namely Chiralpak ZWIX(+)(TM) and ZWIX(-)(TM) columns are described. In a polar-ionic mobile phase, a double ion-pairing interaction mechanism takes place between the charged sites of the chiral analytes (the selectands) and the chiral selector moieties. As a support to correlate the chromatographic results with the structural details of the analytes, pK(a) values and van der Waals volumes of the substituted amino groups were calculated. In order to ensure better understanding of the mechanistic details of the chromatographic system the composition of the bulk solvent, the role of acid base additives, the concentration of the counter-ions, temperature and the structures of the ampholytic analytes have been investigated. Applying N-Fmoc protection, the ampholytic character of the analytes diminished, leading to a marked loss of retention, In the temperature range studied (5-40 degrees C) thermodynamic parameters, such as the difference in the standard enthalpy change Delta(Delta H degrees), entropy Delta(Delta S) and Gibbs energy Delta(Delta G degrees) were calculated from linear van't Hoff plots derived from the In a vs. 1/T curves. The values of the thermodynamic parameters depended on the structures of the chiral selectors applied and the analytes studied. (C) 2017 Elsevier B.V. All rights reserved.

In the frame of substrate specificity, CAL-B-catalysed asymmetric N-alkoxycarbonylations of 1-substituted tetrahydro-beta-carbolines (Me, Et, Pr, iPr) have been studied. High enantioselectivities (>200) were observed, when alkoxycarbonylation of racemic compounds (+/-)-1,35,7 were performed in DIPE in the presence of phenyl allyl carbonate and Et3N at 60 degrees C using ultrasound shaking method. The reaction time increased considerably with increasing substituent size on C1; however, the isopropyl-substituted compound proved to be too bulky for the optimum activity of CAL-B. The (R)-carbamate enantiomers were hydrolysed using Pd-2(dba)(3 center dot)CHCI3 and the enantiomers of the free amines were obtained with excellent ee (>99%). (C) 2018 Published by Elsevier Ltd.

Heterogeneously catalyzed racemization reactions of the secondary amines (S)-1-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroi-soquinoline (salsolidine) and (S)-1-methyl-1,2,3,4-tetrahydro-beta-carboline were investigated using Pd, Pt, and Ir on carbon or Al2O3 supports. A comparison of kinetics and deactivation on selected platinum and iridium catalysts was performed. Furthermore, the relative stabilities of (S)-salsolidine and the corresponding imine on Pt(111) and Ir(111) surfaces were analyzed by density functional theory calculations. The racemization was faster on platinum and took place without detectable byproduct formation. Iridium, however, proved reusable and, in contrast to the platinum catalyst, deactivation at low catalyst concentration was not observed. Also, the physisorption of (S)-salsolidine and the imine was stronger on platinum than on iridium.

Efficient enzymatic resolutions are reported for the preparation of new eight-membered ring-fused enantiomeric β-amino acids [(1R,2S)-9 and (1S,2R)-9] and β-lactams [(1S,8R)-3, (1R,8S)-3 (1S,8R)-4 and (1R,8S)-7], through asymmetric acylation of (±)-4 (E > 100) or enantioselective hydrolysis (E > 200) of the corresponding inactivated (±)-3 or activated (±)-4 β-lactams, catalyzed by PSIM or CAL-B in an organic solvent. CAL-B-catalyzed ring cleavage of (±)-6 (E > 200) resulted in the unreacted (1S,8R)-6, potential intermediate for the synthesis of enantiomeric anatoxin-a. The best strategies, in view of E, reaction rate and product yields, which underline the importance of substrate engineering, are highlighted.

Lipase-catalyzed enzymatic resolution of several new, exotic and variously substituted rac -(5-phenylfuran-2-yl)-β-alanine ethyl esters was investigated. Given the structural instability of unsubstituted rac -(5-phenylfuran-2-yl)-β-alanine ethyl ester, we used the stable hydrochloride salt of this rac -heteroaryl-3-aminopropanoic acid ethyl ester as potential substrate to increase the scope of the reaction. Optimization experiments revealed an efficient procedure for both analytical- and preparative-scale ( S )-selective hydrolysis of several racemic β-amino ester hydrochlorides in NH 4 OAc buffer (20 m m , pH 5.8) at 30 °C. Enzymatic resolutions were performed with covalently bound lipase AK from Pseudomonas fluorescens and lipase PS from Burkholderia cepacia on Immobead T2-150 as catalyst. Seven out of eight new resolution products were successfully isolated and appropriately characterized.