New Advances in the Synthetic Application of Enantiomeric 1-Phenylethylamine (α-PEA): Privileged Chiral Inducer and Auxiliary.

New developments in the synthesis, resolution, and synthetic applications of chiral 1-phenylethylamine (α-PEA) reported in the last decade have been reviewed. In particular, improvements in the synthesis of α-PEA and its derivatives and chiral resolution, as well as their applications in the resolution of other compounds, were discussed. α-PEA was used as a chiral auxiliary in the diastereoselective synthesis of medicinal substances and natural products. Chiral ligands with α-PEA moieties were applied in asymmetric reactions, and effective modular chiral organocatalysts were constructed with α-PEA fragments and used in important synthetic reactions.

1. Introduction

Chirn class="Chemical">aln> inducers and auxiliaries frequently play a key role in the practical synthesis of enantio-pure products, often drugs or agrochemicals. Introduced by A. W. Ingersoll in 1937 [1], nowadays chiral 1-phenylethylamine (α-PEA) belongs to the ancillary compounds most often used for the synthesis of enantiomeric products. This cheap primary amine, available in both enantiomeric forms, offers a structural motif frequently applied in the synthesis of chiral building blocks, useful in divergent asymmetric synthesis. Due to successful applications in various chiral recognition processes, α-PEA can be considered a privileged chiral inducer and auxiliary. Its essential synthetic applications have been included in several volumes of the encyclopedic Fieser and Fieser’s series on reagents for organic synthesis [2]. The topic was specifically reviewed by E. Juaristi in 1989 [3], 1999 [4], and 2010 [5], and briefly in 2012 by C. Kouklovsky and T. J. Wenzel [6]. However, the last decade has witnessed many interesting advancements, and over eighty new original papers have supplemented the previous works.

2. Improvements in the Synthesis of α-PEA and Its Derivatives

The most straightforward synthetic procedure for the preparation of α<span class="Chemical">-phenylethylaminen> uses the reductive amination of <span class="Chemical">acetophenones, and many variants of this reaction have been developed (Scheme 1) [1,2].

Scheme 1

General synthetic scheme for the preparation of chiral α-phenylethylamines.

An interesting improvement to the electrochemicn class="Chemical">aln> synthesis of α-PEA is cathode activation by introducing EDTA and pyrophosphato zinc complexes into the catholyte during the reduction of acetophenone oxime [7].

Recently, a new enantioselective chemo-enzymatic method for the transformation of <span class="Chemical">styrenen> to <span class="Chemical">(R)-α-PEA has been developed. It is based on the one-pot <span class="Chemical">Pd/Cu-catalyzed Wacker oxidation of styrene to acetophenone combined with its reductive amination. Ammonia was applied as a nitrogen source, while d-glucose with glucose dehydrogenase (GDH) was used as a reductant. The catalysts were separated through membrane filtration, giving almost quantitative styrene conversion and 99% enantiomeric excess of the amine. The entire process ultimately represents the asymmetric hydroamination of styrene with ammonia (Scheme 2) [8].

Scheme 2

General scheme of the asymmetric hydroamination of styrene through a combination of Wacker oxidation and amine dehydrogenase (AmDH)-catalyzed reductive amination.

3. Chiral Resolution of α-PEA and Its Derivatives

Essentin class="Chemical">aln>ly, both enantiomers of α-PEA are easily attained by an effective resolution of the racemate as diastereomeric salts with chiral acids, e.g., tartaric acid, O-functionalized natural lactic acid, and others. Further, some direct stereoselective syntheses have been reported. Despite many earlier successful resolutions, interesting observations concerning the enantioseparation of rac-α-PEA through diastereomeric salt precipitation were noted by the Hirose group [9]. They demonstrated that the selectivity of the diastereomeric salt formation between rac-α-PEA and N-(p-toluenesulfonyl)-(S)-phenylalanine dramatically changed from (S,S) to (R,S) with the use of solvent compounds with a six-membered ring structure, namely tetrahydropyran (THP) or cyclohexene as compared to 2-propanol. The X-ray analysis confirmed that THP was included in the (R,S) salt and stabilized it without any hydrogen bonds [9].

A simple batch procedure was developed for the solvent-free kinetic resolution of racemic primary <span class="Chemical">aminesn> by their acylation with equimolar amounts of <span class="Chemical">isopropyl methoxyacetate. The process was cat<span class="Chemical">alyzed by Candida Antarctica lipase B (Novozym 435 and sol-gel CALB). R-α-PEA was resolved giving (S)-α-PEA and (R)-α-PEA-amide with good yields and ee ≥ 95%. The other nine structurally different amines were resolved by this procedure with high yield and enantioselectivity [10].

Recently, for the synthesis of ring-substituted, optic<span class="Chemical">aln>ly active isomers of <span class="Chemical">1-phenylethylamines, the chemo-enzymatic method has <span class="Chemical">also been developed [11]. The method is particularly attractive because of the commercial availability of the immobilized enzymes. Thus, for (S)-1-(4-chlorophenyl)ethylamine, a key intermediate for the synthesis of the corresponding acetamide (a herbicide), the resolution catalyzed by the immobilized lipase (Novozym 435) was chosen (Scheme 3) [11].

Scheme 3

The Novozym 435-catalyzed resolution of (R,S)-1-(4-chlorophenyl)ethylamine to synthesize enantiomeric triazolopyrimidine herbicide.

Other separation procedures for α-PEA derivatives have been developed using enzymatic or chemicn class="Chemical">aln> combined with enzymatic methods. Thus, primary benzyl amines effectively underwent a selective dynamic kinetic resolution (DRK) using palladium nanoparticles as a racemization catalyst, and lipase-catalyzed acylation with methoxyacetate ester (Scheme 4) [12].

Scheme 4

Selective dynamic kinetic resolution (DRK) of primary benzyl amines with palladium nanoparticles as the racemization (dehydrogenation–hydrogenation) catalyst and lipase as the methoxyacetylation catalysts.

Furthermore, new synthetic techniques were applied in the deracemization. The continuous flow kinetic resolution of racemic α-PEA with C<span class="Chemical">ALn>B immobilized on <span class="Chemical">acrylic resin (Novozyme 435) using <span class="Chemical">ethyl acetate as the acylating reagent with a short residence time (40 min) gave high enantiomeric excesses. The non-acylated product was racemized (catalyzed dehydrogenation–hydrogenation) and again used for the lipase-catalyzed acylation. The process is suitable for automatization and can be scaled up for industrial purposes (Scheme 5) [13].

Scheme 5

Kinetic resolution of rac-α-phenylethylamine under continuous flow conditions.

For the kinetic resolution of racemic <span class="Chemical">aminesn>, another new operation<span class="Chemical">al synthetic technique, namely high-speed ball milling (HSBM), was used by Juaristi and coworkers [14]. The catalyzed by CALB reaction afforded acylated products with high conversion and often excellent enantiopurity (ee > 99%). A short reaction time was required (typically 90 min), either with 1,4-dioxane as an additive present in a minute amount or using only the acylating agent. Several acylating agents and additives were tested in the procedure, and the best outcomes resulted in isopropyl acetate as an acylating agent (Scheme 6) [14].

Scheme 6

Mechanoenzymatic resolution of rac-α-PEA using isopropyl acetate.

Further, Cn class="Chemical">ALn>B-catalyzed acylation and catalyzed by ruthenium complex racemization (dehydrogenation–hydrogenation) was applied in the dynamic kinetic resolution (DKR) of rac-α-PEA (Scheme 7). Here, as before (Scheme 4 and Scheme 5), the Ru catalyst causes dehydrogenation–hydrogenation, thus racemizing the slowly acylated enantiomer and dynamically supplying the quickly reacting one. The reaction conditions were optimized, and alkyl methoxyacetates as acyl donors at low catalyst loadings were more effective (higher ees) than isopropyl acetate [15].

Scheme 7

Kinetic resolution of rac-α-PEA.

The Poppe group carried out further optimization of the resolution of racemic primary n class="Chemical">aminesn> under batch and continuous-flow conditions [16]. Particularly, they tested yield and enantiomeric excess of the N-acylation products obtained in the reactions catalyzed by immobilized lipase B (CALB-CV-T2-150) with isopropyl esters of several 2-alkoxyacetic acids. For rac-α-PEA and three other primary amines, the best results were attained using isopropyl 2-propoxyacetate. Under the optimized continuous-flow conditions, the amines underwent kinetic resolutions with high conversions and nearly quantitative enantiomeric excesses. Moreover, for five additional amines (substituted derivatives of α-PEA), 2-propoxyacetate was the preferred acylating agent, leading to the corresponding (R)-propoxyacetamides with very high ee (Scheme 8) [16].

Scheme 8

Kinetic resolution of α-PEA using isopropyl 2-propoxyacetate as an acylating agent.

In conclusion, the recently reported enzymatic methods for the kinetic resolution of racemic α-PEA reve<span class="Chemical">aln>ed <span class="Chemical">2-alkoxyacetate esters as particularly useful acylating re<span class="Chemical">agents. The lipase-catalyzed N-acylation gave the corresponding products with high conversion and excellent enantiopurity (ee > 99%).

4. Application of Enantiomeric α-PEA in Chiral Resolution

Since both antipodes of α-PEA are so easily available and inexpensive, these compounds were often used to resolve various racemic derivatives. In particular, enantioresolution by cryst<n class="Chemical">span class="Chemical">allization of <spn>an class="Chemical">diastereomeric salt with enantiomeric α-PEA still enjoys much interest. This operationally simple and high-yielding methodology has been exploited and optimized for the preparation of numerous optically active acids.

Easy crystn class="Chemical">aln>lization of the less soluble diastereomeric salt formed between (R)-N-benzyl-α-PEA and racemic 2-chloromandelic acid was used for its resolution. The structure of the grown crystals was examined in detail by X-ray analyses. Preferential host-guest interactions, stabilizing the salt of lower solubility, were interpreted by a “lock-and-key” packing and CH/π interactions within the hydrophobic moieties. The authors recommended improving the amine chiral discrimination properties by introducing a larger aromatic system to the resolving agent [17].

Racemic n class="Chemical">2-methoxy-2-(1-naphthyl)propionic acidn> (MNPA) underwent efficient enantio-resolution with (R)-α-PEA, giving enantiopure (R)-MNPA. Thus, the precipitated crystalline salt of (R)-α-PEA and (R)-enriched-MNPA was separated, and then the acid was liberated (41%, 95% ee). This scalemic product was dissolved in aqueous ethanol and treated again with (R)-α-PEA to give the corresponding salt. This salt, after acidification, afforded 29% of (R)-MNPA (>99% ee). A mother liquor from the first crystallization was evaporated, and (S)-MNPA (95% ee) was finally isolated by a sequential crystallization. The X-ray analysis uncovered four independent hydrogen bonds and one CH/π interaction stabilizing the first precipitated diastereomeric salt (Scheme 9) [18].

Scheme 9

Experimental procedure for the separation of enantiomers of MNPA.

Furthermore, racemic n class="Chemical">5-oxo-1-phenylpyrazolidine-3-carboxylic acidn> was resolved into enantiomers. The racemate was treated with a half equivalent of (R)-α-PEA, giving mostly (R,R)-salt precipitated from the solution. The remaining part, enriched in the (S)-acid, was worked up with (S)-α-PEA, as shown in Scheme 10 [19].

Scheme 10

(R)- and (S)-α-PEA resolution of 5-oxo-1-phenylpyrazolidine-3-carboxylic acid.

Investigation of the resolution of racemic α-hydroxy-(o-chlorophenyl)methyl]<span class="Chemical">phosphinic acidn> with <span class="Chemical">(R)-α-PEA via <span class="Chemical">diastereomeric salt formation revealed that the (R,R)-salt precipitation from 2-propanol was an efficient resolving method for obtaining a single enantiomer of phosphinic acid. Resolving rac-phosphinic acid with (S)-α-PEA in EtOH by the same procedure gave access to (S)-acid in 32% yield (Scheme 11) [20].

Scheme 11

(R)- and (S)-α-PEA resolution of rac-α-hydroxy-(o-chlorophenyl)methyl]phosphinic acid.

The optic<span class="Chemical">aln> resolution of <span class="Chemical">rac-trans-2,2-dichloro-3-methylcyclopropanecarboxylic acid was reported by Kov<span class="Chemical">alenko and Kulinkovich [21]. Thus, the racemic acid in acetone treated with (R)-α-PEA precipitated the diastereomericaly enriched (1S,3R)-(R)-salt, which after two recrystallizations from 90% aqueous acetone and subsequent treatment with dilute sulfuric acid gave the levorotary enantiomer (1S,3R)-acid in 23% yield. The remaining mother liquor and (S)-α-PEA gave the respective salt, that after acidification gave (1R,3S)-acid in 29% yield (Scheme 12) [21].

Scheme 12

Optical resolution of rac-trans-2,2-dichloro-3-methylcyclopropanecarboxylic acid.

Similarly, enantiomers of <span class="Chemical">trans-norborn-5-ene-2,3-dicarboxylic acid mono-methyl estern> were separated by cryst<span class="Chemical">allization of the respective <span class="Chemical">salts with (R)- and (S)-α-PEA (Scheme 13) [22]. Both simple procedures produced interesting chiral building blocks for further synthesis.

Scheme 13

Separation of enantiomers of trans-norborn-5-ene-2,3-dicarboxylic acid mono-methyl ester into enantiomers.

Volochnyuk and coworkers reported a multigram synthesis of D3-symmetric <span class="Chemical">tris-homon class="Chemical">cubane-4-carboxylic acid. Its optic<spn>an class="Chemical">al resolution was achieved through the recrystallization of salt with (R)-α-PEA. The absolute configuration (R) of pure (+)-enantiomeric form was assigned by X-ray crystal structure analysis (Scheme 14) [23].

Scheme 14

Optical resolution of D3-symmetric tris-homocubane-4-carboxylic acid.

In 2019, Zhao and coworkers published the synthesis of natur<span class="Chemical">aln> <span class="Chemical">Iotrochamide B, earlier isolated from the marine sponge <span class="Chemical">Iotrochota sp. A key intermediate in the synthesis was (S)-6-bromo-tryptophan obtained from the corresponding racemic N-acetyltryptophan by its resolution with (S)-α-PEA (Scheme 15) [24].

Scheme 15

Optical resolution of rac-6-bromo-N-acetyltryptophan, intermediate in the synthesis of Iotrochamide B.

An interesting resolution of α-amino acids has been developed using re<span class="Chemical">agentsn> derived from α-PEA. Thus, the group of Soloshonok reported that chir<span class="Chemical">ally modified <span class="Chemical">ketone reacts with racemic α-amino acids (rac-α-AAs) in nearly quantitative yield, giving two major and two minor diastereomeric nickel complexes. Thus, the complexes (RC,RN,RC)-A (major) along with (RC,SN,RC, minor) coming from (R) α-amino acids, and (RC,SN,SC)-B (major) along with (RC,RN,SC, minor) derived from α-amino acids of (S) configuration were formed in nearly equal amounts and excellent yield. The major complexes A and B were easily separated and gave the corresponding pure enantiomers of the amino acids. The resolving agent’s recovery and recycling make the complete separation process very attractive (Scheme 16) [25].

Scheme 16

Reactions of the ligand derived from (R)-α-PEA with racemic α-amino acids.

The same group designed and synthesized a similar ligand to convert natur<span class="Chemical">aln> <span class="Chemical">(S)-α-amino acids into the unnatur<span class="Chemical">al (R)-enantiomers. They prepared (S)-α-PEA-derived benzophenone forming the respective Schiff bases with various (S)-α-amino acids. After Ni(II) complexation, epimerization at the amino acid stereogenic center occurred. The formation of the new diastereomeric complex took place in a thermodynamically controlled manner. Later, the pure diastereomeric complex was hydrolyzed, and the chiral benzophenone and resulting (R)-amino acid were isolated by cation exchange chromatography (Scheme 17) [26].

Scheme 17

Conversion of (S)-amino acids to (R)-amino acids.

An interesting option for the resolution of a racemic mixture of host molecules is the formation of the ren class="Chemical">spective inclusion complexes with an enantiomeric guest, here α-PEA. This idea was applied by the group of Kaku and Tsunoda to carry out the optic<span class="Chemical">al resolution of <span class="Chemical">rac-tetrahydroxytetraphenylene (THTP) to afford (S,S)-THTP in good yield and high ee (Scheme 18). They also obtained (R,R)-THTP using (R)-α-PEA. The thermal analyses (TGA and DSC) suggested that the S,S-S complex was a less stable clathrate than the S,S-R complex [27].

Scheme 18

Enantiomeric enrichment of (S,S)-(−)-THTP using (S)- α-PEA.

When n class="Chemical">diastereomericn> α-phenylethylammonium salts do not differ enough, the simple resolution of racemic acid is impossible. In that case, the corresponding diastereomeric amides can be successfully used. This strategy has been applied for the highly effective resolution of racemic 1,4-benzodioxane-2-carboxylic acid by precipitation of the less soluble amide diastereomer of unlike configuration (>98% de) (Scheme 19) [28].

Scheme 19

Resolution of racemic 1,4-benzodioxane-2-carboxylic acid via diastereomeric phenylethylamides.

The determination of the enantiomeric purity of various chirn class="Chemical">aln> compounds can be achieved by applying chiral derivatizing agents (CDAs). The Bull group developed α-PEA-containing chiral boronic acid as a CDA to determine the enantiomeric purity of vic-diols [29]. Recently, de Ferra and coworkers [30] described a similar procedure for the determination of enantiomeric excess of α-glycerophosphocholine with a CDA prepared according to Anslyn’s procedure (Scheme 20) [31].

Scheme 20

Synthesis and analytical application as a chiral derivatizing agent (CDA) of α-PEA-containing chiral boronic acid.

Highly demanded chirn class="Chemical">aln> fluoro-compounds find application as chiral solvating agents (CSAs) in 1H and 19F NMR. Cavalluzzi and collaborators obtained (−)-(R)-2-(pentafluorophenoxy)-2-(phenyl-d5)acetic acid (Scheme 21a) of (98% ee) by resolution of a racemate with (−)-(R)-α-PEA. The obtained chiral CSA was successfully used for the direct 1H NMR determination of enantiomeric excess of chiral quinoline-containing antimalarial drugs, namely mefloquine, chloroquine, and hydroxychloroquine [32].

Scheme 21

Resolution of fluoro-derivatized mandelic acid as a chiral solvating agent (CSA): (a) the resolution of (rac)-2-(pentafluorophenoxy)-2-(phenyl-d5)acetic acid, (b) the resolution of (rac)-α-(nonafluoro-tert-butoxy)carboxylic acid.

Similarly, Béni’s group resolved α-(nonafluoro-tert-butoxy)n class="Chemical">carboxylicn> acid using enantiomeric (S)-α-PEA (Scheme 21b) [33]. The enantioenriched fluoro-derivatized CSA gave 19F NMR chemical shift differences (Δδ) 0.006–0.028 ppm in CDCl3 and 0.010 and 0.014 ppm in apolar C6D6 with biologically active amines [33].

A different synthetic approach was used for the resolution of racemic <span class="Chemical">salicylaldehydesn> containing an isobornyl substituent. The <span class="Chemical">aldehydes were converted with <span class="Chemical">(R)-α-PEA into the corresponding Schiff bases, and the diastereomeric imines were separated by fractional crystallization from pentane. Diastereomers were hydrolyzed, giving enantioenriched aldehydes along with the recovered chiral auxiliary (Scheme 22) [34].

Scheme 22

Resolution of racemic salicylaldehydes containing an isobornyl substituent.

Vorontsova and coworkers elaborated a procedure for the synthesis of ligands based on n class="Chemical">4-acyl-13-bromo-5-hydroxy[2.2]paracyclophanen>. The enantiomers of planar chiral ketones were reacted with (S)-α-PEA in the catalytic presence of Et2SnCl2, giving nearly quantitative amounts of an equimolar mixture of two diastereomeric Schiff bases. Their separation and hydrolysis furnished an enantiomer (for the acetyl-derivative) (Rp) ( + 363.3, toluene) in 79% yield and (Sp), ( 361.5, toluene), with 67% yield (Scheme 23) [35].

Scheme 23

Resolution of 4-acyl-13-bromo-5-hydroxy[2.2]paracyclophane into enantiomers.

5. Enantiomeric Enrichment of α-PEA and Its Derivatives—Self-Disproportionation of Enantiomers (SDE)

When parti<span class="Chemical">aln>ly non-racemic samples are crystallized or undergo chromatography, often enantiomeric molecules act vs. the aggregate of both enantiomers (racemate) as diastereomers. In effect, under totally achiral external conditions, the scalemic samples are additionally enantioenriched. This process is known as the self-disproportionation of enantiomers (SDE) [36]. The SDE effect has also been observed for the amides of α-PEA. Thus, the medium-pressure liquid chromatography of non-racemic acetamide derivatives showed clear splitting into two separate fractions, both corresponding to the acetamide. For the material of the less polar fraction, significant enantiomeric enrichment was observed. Simultaneously, the more polar fraction material had the ee value considerably reduced [37,38,39]. The SDE effects were also described in achiral column chromatography of a series of N-fluoroacetylated α-PEA-amides [40]. The SDE consequences, potential problems, and prospective applications have recently been reviewed and discussed [41].

6. α-PEA as a Chiral Auxiliary in Diastereoselective Synthesis

6.1. Synthesis of Compounds with Biological Activity

The synthesis of compounds with the prospective biologic<n class="Chemical">span class="Chemical">al activity in the pure enantiomeric form is of particular interest in medicin<spn>an class="Chemical">al chemistry. Quite often, only one specific stereoisomer is responsible for the therapeutic effect, whereas the other can cause harmful side effects. In this context, a wide variety of compounds have been synthesized using α-PEA as a chiral auxiliary or a building block.

In line with this genern class="Chemical">aln> goal, an economically viable strategy for the synthesis of (+)-Rivastigmine and (+)-calcimimetic NPS R-568 has been devised by Rao and collaborators (Scheme 24) [42]. The method was based on the reductive amination of 3′-hydroxyacetophenone with (S)-α-PEA or (R)-α-PEA in the presence of titanium(IV)isopropoxide and NaBH4. The α-PEA moieties were cleaved in regioselective hydrogenation of the bis amines to yield the required chiral amines with excellent enantioselectivity.

Scheme 24

Syntheses of Rivastigmine and NPS R-568.

Nair and coworkers explored the <n class="Chemical">span class="Chemical">acetate <spn>an class="Chemical">aldol reaction designed for the stereoselective synthesis of (S) and (R)-Fluoxetine [43]. This compound in racemic form is a potent, selective serotonin reuptake inhibitor, whereas the separated enantiomeric forms have different therapeutic effects. The synthesis started from the acetate aldol reaction of N-acetyl-(S)-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one. The product was converted into (S)-3-hydroxy-N-methyl-3-phenyl propanamide. After reduction and aromatic substitution on 4-fluorobenzotrifluoride, (S)-fluoxetine was obtained in enantiopure form and excellent yield. (R)-Fluoxetine was obtained in a similar procedure (Scheme 25). With (R) or (S)-α-PEA moiety, the aldol reaction gave a high yield and anti-aldol selectivity. Interestingly, the configuration of α-PEA did not influence the product’s stereochemistry as both enantiomers of this group afforded similar yields and the same selectivity. Moreover, the placement of benzylamine or tert-butylamine moieties instead of α-PEA resulted in yield and selectivity deterioration. The authors ascribed the influence of α-PEA to the stereoelectronic effects, enhancing the enolate reactivity [43].

Scheme 25

Stereoselective synthesis of (S)-Fluoxetine.

The totn class="Chemical">aln> synthesis of trans-quinolizidine derivatives, namely (+)-myrtine and cis-2,4,6-trisubstituted piperidone alkaloid (+)-241D, was described by Hurvois and coworkers [44]. The first step was performed according to the procedure reported earlier by Pawłowska and Czarnocki [45] (see below), and here α-PEA allowed an efficient 1–3 stereoinduction. Then, the key intermediate was transformed by different steps, giving (+)-myrtine and alkaloid(+)-241D with a total yield of 68 and 38%, respectively (Scheme 26).

Scheme 26

General scheme for the synthesis of (+)-myrtine and (+) alkaloid 241D.

The Czarnocki group developed the synthesis of <span class="Chemical">(+)-lortalaminen>, starting with <span class="Chemical">(S)-α-PEA as a chir<span class="Chemical">al auxiliary [45]. The method was based on the preparation of N-[(S)-α-phenylethyl]-4-piperidone (Scheme 27), a procedure advanced earlier by Kuehne et al. [46]. The corresponding nucleophilic substitution (ammonium salt + amine) results in a ring opening–ring closure sequence, leading to the key chiral intermediate.

Scheme 27

(S)-α-PEA as a chiral auxiliary in the synthesis of (+)-lortalamine.

α-PEA is n class="Chemical">aln>so used as an important chiral auxiliary in the synthesis of (R)-ramatroban [47]. This sulfonamide was developed to treat allergic rhinitis and asthma and could have a therapeutic effect on coronary artery diseases. The amination was performed using ω-transaminases (ω-TA). Correspondingly, the most important synthetic step is the ω-TA-catalyzed transformation of the ketone to enantiopure (R)-2,3,4,9-tetrahydro-1H-carbazol-3-amine. In this reaction, (R)-α-PEA was used as an amine donor. In that case, only the desired product was obtained, whereas with 2-propylamine, various unwanted side products were formed (Scheme 28).

Scheme 28

Synthesis of the enantiopure (R)-2,3,4,9-tetrahydro-1H-carbazol-3-amine, a key intermediate for the preparation of (R)-ramatroban.

A practicn class="Chemical">aln> asymmetric synthesis of Sitagliptin, an approved drug for treating type 2 diabetes mellitus, was elaborated by the Kozlowski and Bandichhor groups [48]. The adopted approach used α-PEA as a chiral auxiliary, allowing for stereoinduction in the reductive amination (Scheme 29). This strategy offers a very simple diastereoselective and efficient procedure.

Scheme 29

Synthetic route to Sitagliptin.

In 2017, Brenna described the procedure for the synthesis of both enantiomers of 1-(m-hydroxyphenyl)ethyl<span class="Chemical">aminen>, an important intermediate for the preparation of v<span class="Chemical">aluable active pharmaceuticals [49]. The procedure was based on using (R)- or (S)-α-PEA-imines as chiral building blocks. The trichlorosilane reduction of the imines followed by selective hydrogenolysis under batch as well as flow conditions gave the desired product with almost complete stereochemical induction and high yields (Scheme 30). This product is a key intermediate in the synthesis of compounds with pharmaceutical properties. The same group also reported applying a similar method for the preparation of the intermediate for the other biologically important compounds, such as Rasagiline and Tamsulosin [50]. In that case, the cyclopentadienone-based iron complexes were used to catalyze the diastereoselective hydrogenation of enantiopure α-PEA-imines successfully.

Scheme 30

Reductive amination in the synthesis of a key intermediate for the synthesis of compounds with biological activity.

Natur<n class="Chemical">span class="Chemical">al <spn>an class="Chemical">pyrrolizidine alkaloids consist of two fused five-membered rings with a nitrogen atom at the bridgehead (Scheme 31). Many of them have interesting biological activities. Davies and coworkers have developed an effective method for the synthesis of a collection of pyrrolizidine alkaloids, starting with the preparation of (−)-(1R,7aS)-absouline [51]. The method is based on the diastereoselective conjugate addition of lithium (S)-N-benzyl-N-(α-methylbenzyl)amide to an enantiopure α,β-unsaturated ester derived from L-proline (Scheme 31). Later, the same strategy was applied for the synthesis of (−)-isoretronecanol and (−)-trachelantamidine [52] (Scheme 31). Following the elaborated synthetic methodology, this research group obtained the next compounds of this class [53,54] (Scheme 30).

Scheme 31

The Davis’ syntheses of substituted pyrrolizidine derivatives.

6.2. Synthesis of Imides

Genern class="Chemical">aln>ly, the most often used chiral auxiliaries rely on their cyclic structure (e.g., Evans’ oxazolidinones, Oppolzer’s sultams, or SAMP/RAMP compounds) that limit the presence of different conformers that could diminish the selectivity. For example, see Scheme 25, [43]. However, acyclic chiral auxiliaries are also of interest. Their flexibility may allow for the reactions to be hampered by the stiffness of the established cyclic auxiliaries.

Hernández-Rodríguez, looking for a new acyclic auxiliary, described interesting diastereoselectivity in the α-<span class="Chemical">aln>kylation of chir<span class="Chemical">al <span class="Chemical">propionimide [55]. The reaction of (S)-α-PEA as with propionyl anhydride and then benzoyl chloride gave a chiral auxiliary. The obtained compound was used in the alkylation of the prochiral fragment to form, diastereoselectively, the respective chiral imide (Scheme 32). The selectivity was due to the chelate structure with the carbonyl of the auxiliary and the allylic 1,3-strain of the amide that froze the conformation between the stereocenter of the auxiliary and the nitrogen.

Scheme 32

Synthesis of acyclic chiral auxiliary and its use in the alkylation reaction.

6.3. α-PEA and Its Derivatives in the Diastereoselective Cyclization Reaction

Synthesis of chirn class="Chemical">aln> heterocyclic compounds via cyclization constitutes an important part of organic chemistry. Stereoselective cyclizations are often key reactions in the synthesis of natural products. α-PEA and its derivatives have recently been used as chiral auxiliaries in the corresponding diastereoselective reactions. These processes were applied to obtain piperidin-2-ones, lactams, imidazole, and indole derivatives, the compounds expected to exhibit biological activities. Thus, in 2014, Terán and coworkers described an effective procedure for the synthesis of cyclic α-amino acids, specifically 4-substituted piperidine-2-carboxylic acid and its derivatives with pharmacological activity [56]. The procedure was based on ring-closing metathesis (RCM) to build the α,β-unsaturated piperidin-2-ones derived from (S)-α-PEA (Scheme 33).

Scheme 33

Synthesis of α,β-unsaturated piperidin-2-ones.

Another strategy for the synthesis of cyclic compounds is using the Pomeranz–Fritsch–Bobbitt and the Petasis reactions. The Rozwadowska group used this method for the preparation of (+)-6,7-dimethoxy1,2,3,4-tetrahydroiso<span class="Chemical">quinolinen>-1-<span class="Chemical">carboxylic acid (90% ee) [57]. In the first step, <span class="Chemical">dimethoxyacetaldehyde reacted with chiral amines such as (S)-α-PEA, followed by a NaBH4 reduction at reflux to give the appropriate acetate in 90% yield. Then, these compounds were transformed into the appropriate acid (Scheme 34) [57].

Scheme 34

Synthesis of (+)-6,7-dimethoxy1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid.

Other important compounds synthesized by cyclization are chir<span class="Chemical">aln> <span class="Chemical">tetrahydro-3-benzazepines. These derivatives interact with σ1 receptors, which play a key role in controlling the activity of various ion-channels and neurotransmitter systems. Therefore, the synthesized compounds are prospective psychoactive drugs. In their synthesis, the important first step required enantiomeric<span class="Chemical">ally pure (R)-α-PEA as a chiral auxiliary for the formation of diastereomeric lactams in 80:20 dr (Scheme 35) [58].

Scheme 35

Synthesis of chiral benzoazepines which can interact with σ1 receptors.

n class="Chemical">3-Substituted-3-hydroxy-2-oxindolesn> are key intermediates for the synthesis of furoindolines and pyrroloindole-based natural products [59]. Their synthesis was based on the application of an α-PEA-containing chiral auxiliary. The acetate aldol reaction, which was developed earlier by the same group [43], when run with N-substituted isatin, afforded the corresponding adducts with high yields and diastereoselectivity (Scheme 36) [59].

Scheme 36

Syn-selective acetate aldol reaction of chiral imidazolidin-2-one.

Recently, chirn class="Chemical">aln> 1,3-oxazolidin-2-ones have been devised as an efficient chiral auxiliary to synthesize carboxylic compounds [60]. Consequently, (R)- or (S)-α-PEA fragment was used for the diastereoselective induction in the 4-oxazolin-2-one scaffold at the C-4 and C-5 stereocenters (Scheme 37).

Scheme 37

Thermal and microwave (MW)-promoted synthesis of oxazolin-2-ones.

6.4. Asymmetric Aminocarbonylation of Iodoalkenes

The n class="Chemical">palladiumn>-catalyzed aminocarbonylation of alkenyl iodides enjoys interest as an important method for the introduction of new carbonyl functionality in organic compounds. Kollár’s group described the stereochemistry of products obtained in the asymmetric aminocarbonylation of iodoalkenes [61]. They presented the reaction of chiral iodoalkenes with α-PEA in the presence of Pd catalyst. All possible epimers were synthesized and fully characterized. However, very low (mostly negligible) diastereoselectivities were observed (Scheme 38).

Scheme 38

Aminocarbonylation of 2-iodobornene with α-PEA.

6.5. Multicomponent Amino Alkylations

Multicomponent amino n class="Chemical">aln>kylations are preferentially used to build two new bonds in one step. Primary amines reacting with carbonyl derivatives (aldehydes or ketones) form reactive Schiff bases, to which, in turn, various nucleophiles can be added.

The Kabachik–Fields condensation of <span class="Chemical">aldiminesn> is one of the most commonly used reactions to prepare α-aminophosphonate derivatives. Recently, a solvent-free method for the synthesis of optically active α-aminophosphonates has been described [62]. The authors used microwave (MW)-assisted Kabachnik–Fields condensations of (S)-α-PEA (A), <span class="Chemical">paraformaldehyde (B), and various R2P(O)H (C) reagents. Depending upon the A/B/C molar ratio (1:1:1 or 1:2:2) of substrates, either (S)-diphenyl-α-phenylethylaminomethylphosphine oxide or (S)-bis(diphenylphosphinoylmethyl)- α-phenylethylamine was obtained as a product (Scheme 39). The products were isolated in 97% and 92% yields, respectively. After deoxygenation with phenylsilane, the optically active bis-phosphine was converted to chiral platinum(II) complexes, including an unusual tetradentate structure [62].

Scheme 39

Synthesis of mono- and bis-phosphine oxides and phosphine with chiral α-PEA moiety.

Since the preparation of single stereoisomers of aminon class="Chemical">aln>kylation products is of considerable synthetic importance, there is still much interest in new gentle and direct approaches, including applying the Mannich reaction and Betti synthesis. Palmieri described a short synthesis of benzo[f]chromen-3-amine derivatives using a three-component aromatic Betti-type reaction [63]. The enantiomerically pure products were obtained from β-naphthol, chiral α-PEA, and α,β-unsaturated aldehydes (Scheme 40) [63].

Scheme 40

Three-component aromatic Betti-type reaction.

Another three-component Mannich-type synthesis was developed for the simple preparation of enantiomeric<span class="Chemical">aln>ly pure <span class="Chemical">3-indolylglycines (Scheme 41). Despite the medium diastereoselectivity of the Mannich reaction (80/20 dr), the pure diastereomer was easily separated, and the selective <span class="Chemical">N-debenzylation was performed with triethylammonium formate catalyzed by Pd/C, resulting in the enantiomerically pure (S)-indolylglycine [64].

Scheme 41

Three-component Mannich-type reaction gave the (R,S)-diastereomer, transformed by selective N-debenzylation to enantiopure (S)-indolylglycine.

6.6. Novel Derivatives of α-PEA. Synthesis of Enantiomeric Guanidines and Guanidinium Salts

n class="Chemical">Guanidinesn> and guanidinium salts are often used in organic synthesis (strong bases, catalysts, or ionic liquids) and also constitute a part of natural compounds (L-arginine, polycyclic marine alkaloids). Jäger and coworkers described the new efficient synthesis of chiral guanidines and guanidinium salts based on optically active α-PEA (Scheme 42) [65]. Unfortunately, the attempted catalytic use of the obtained guanidine and guanidinium iodide in asymmetric transformations (Morita–Baylis–Hillman, Michael, and epoxidation reactions) did not result in a noteworthy stereoinduction [65].

Scheme 42

Synthesis of chiral (S,S,S)-tris-(1-phenylethyl)guanidine and guanidinium salts from (S)-α-PEA.

6.7. Novel Derivatives of α-PEA. Synthesis of Enantiomeric Derivative of Imidazole N-Oxides

Chirn class="Chemical">aln> amines, including α-PEA, are often used as a starting material for the synthesis of novel, optically active heterocyclic systems. The products are designed as the prospective chiral ligands. For this purpose, an efficient method for preparing enantiomeric imidazole N-oxides was developed by Mlostoń and coworkers [66]. Chiral acetylacetate amide was prepared by the reaction of acetylketene with (S)-α-PEA. Subsequent nitrosation of β-oxoamide led to the intermediate being transformed into enantiomerically pure 3-oxidoimidazole-4-carboxamides with good yield (Scheme 43).

Scheme 43

Synthesis of imidazole N-oxides.

6.8. α-PEA in the Strecker Reaction

An interesting study on the stereochemistry of the synthesis of new <span class="Chemical">2-amino-2-C-D-glycosyl-acetonitrilesn> was carried out using the Strecker reaction. The products are important building blocks for synthetic <span class="Chemical">carbohydrate chemistry. Various <span class="Chemical">C-glycosyl aldehydes were reacted with (R)- or (S)-α-PEA to afford the respective Schiff bases. The thiourea-catalyzed reaction with a cyanide donor occurred at re-face in both cases, and the nucleophilic addition of HCN gave predominantly R-configured C-glycosyl aminoacetonitriles. Higher diastereoselection was observed for (S)-α-PEA-imine than for the (R)-α-PEA analog. The origin of this difference remains obscure (Scheme 44) [67].

Scheme 44

Preparation of d-galactal-linked α-aminonitriles via preformed galactal imines.

6.9. Synthesis of Chiral Amino Alcohols and Diamines from α-PEA

Enantiomericn class="Chemical">aln>ly pure β-amino alcohols and diamines are important chiral building blocks and catalysts in asymmetric reactions. Recently, the synthesis of chiral 2-pyridinyl- and 6-(2,2′-bipyridinyl)-β-amino alcohols was reported [68]. The products were formed by ring opening of the corresponding 2-oxiranyl-compounds with chiral α-PEA and in the catalytic presence of scandium(III) trifluoromethanesulfonate (Scheme 45). The enantiomerically pure pyridine-β-amino alcohols were tested as chiral ligands in the zinc-catalyzed asymmetric aldol reaction with up to 55% ee outcome [68]. These compounds were further transformed into the respective diamines in a sequence of reactions involving the ring opening of the intermediate aziridines with HN3. Moreover, the enantiomerically pure β-amino alcohols were transformed into cyclic sulfamidates, and these compounds were reacted with sodium azide. After the Staudinger reduction, a series of diastereomeric vic-diamines with different stereo- and regiochemistry was obtained (Scheme 45) [69].

Scheme 45

Synthesis of chiral β-amino alcohols and diamines.

6.10. Removal of α-PEA Used as Chiral Auxiliary

Simple acidic extraction (aqueous 2M <span class="Chemical">HCln> or 10% <span class="Chemical">H2SO4) allowed for recovery of chiral α-PEA after its use in optical resolution via diastereomeric salt formation, cf. Scheme 9. However, when α-PEA was employed as a chiral auxiliary, its liberation usually required splitting the corresponding chemical bonds. If an imide connection (a Schiff base) was applied, then again aqueous HCl was mostly enough for the α-PEA recovery. In some cases, the hydrolysis must be facilitated by the addition of NaHSO3 and thus the formed bisulfite allows for the removal of the carbonyl partner from the equilibrium, cf. Scheme 23. The cleavage of α-PEA-amides was usually carried out by hydrolysis in 6N HCl at 90 °C, cf. Scheme 29. For the splitting of the whole α-(methyl)benzyl moiety, catalyzed direct hydrogenolysis (Pd/C, H2, e.g., see, Scheme 30) or hydrogen-transfer debenzylation (see, Scheme 41) was used.

7. Synthesis and Application of Chiral Ligands with α-PEA Fragments in Asymmetric Reactions

7.1. Enantioselective Arylation of N-Heteroaryl Aldimines and Hydrogenation Catalyzed by Ligands with PEA Fragments

An efficient stereoselective synthesis of chirn class="Chemical">aln> secondary amines attracts much interest because of the products’ potential pharmaceutical use. Recently, Zhou and coworkers described copper-catalyzed enantioselective arylation [70]. The catalytic reaction of N-azaaryl aldimines with arylboroxines was carried out in the presence of the prepared chiral phosphorus ligands with chiral α-PEA fragments. The best catalytic effects (up to 95% yield and 90% ee) were observed for the modular ligands with α-PEA moieties (Scheme 46).

Scheme 46

Screening chiral phosphoramidites for the arylation reaction.

Other groups have synthesized a library of modular ligands with chirn class="Chemical">aln> α-PEA and phosphine-phosphoramidite fragments [71]. For the ligand synthesis, see below Scheme 50. The described dia- and enantioselective Ir-catalyzed hydrogenation of 3-alkyl-2-arylquinolines gave the product with a high yield and up to 94% ee (Scheme 47).

Scheme 47

Unsymmetrical hybrid chiral phosphine–phosphoramidite ligands for asymmetric catalytic hydrogenation.

7.2. Catalyzed Enantioselective Addition of Organo-Zinc to Aldehydes

The asymmetric addition of n class="Chemical">organo-zincn> compounds to ketones or aldehydes leads to important chiral building blocks. Particularly, the catalytic transfer of the phenyl entity to aromatic aldehydes has attracted attention. For this purpose, new chiral tertiary aminonaphthol ligands were obtained in the reaction of 2-naphthol, (S)-α-PEA, and substituted benzaldehydes [72]. The ligands were screened in the Zn(II)-catalyzed asymmetric phenyl transfer from phenylboronic acid to the carbonyl of p-chlorobenzaldehyde. The reaction was run in toluene, in the presence of poly(ethylene glycol) dimethyl ether (DiMPG, 10 mol%). The arylation product was formed with high yield and enantioselectivity (up to 91%, 94% ee) (Scheme 48).

Scheme 48

The asymmetric phenyl transfer reaction using various chiral aminonaphthol ligands.

A series of chirn class="Chemical">aln> 1,3-aminonaphthols was synthesized using a Betti-type reaction between mono- or dihydroxy naphthalenes, aldehydes, and (S)-α-PEA [73]. Thus, the obtained modular ligands were applied in the enantioselective addition of Et2Zn and alkynyl-Zn to ferrocencarbaldehyde (Scheme 49). All the ligands with (S)-α-PEA fragments gave the R isomer of the product with good yield and enantioselectivity [73].

Scheme 49

Addition of diethylzinc and alkynyl-Zn-reagents to aldehydes.

Asami and coworkers synthesized a library of thirteen n class="Chemical">1,4-amino alcoholsn>, which were checked in the enantioselective addition of diethylzinc to benzaldehydes [74]. In all cases, 1-phenyl-1-propanol (S configuration) was obtained in high yield and enantioselectivity, regardless of the configuration at the second center of the ligand (Scheme 50).

Scheme 50

Enantioselective addition of diethylzinc to benzaldehyde.

7.3. Asymmetric Hydrogenation Reactions

Similar n class="Chemical">1,4-amino alcoholn> ligands derived from (S)-α-PEA were prepared by a one-pot ortho-lithiation followed by a reaction with the carbonyls. Xiang-Ping Hu and coworkers used chiral amino alcohols as effective catalysts in the Ru-catalyzed asymmetric transfer hydrogenation of aromatic alkyl ketones [75]. The authors concluded that the amino alcohols’ structure influenced the conversion and enantioselectivity, and the less sterically demanding ligand gave higher enantioselectivity (Scheme 51).

Scheme 51

Ru-catalyzed asymmetric transfer hydrogenation of acetophenone.

Catn class="Chemical">aln>ytic hydrogenation is one of the most powerful and practical ways to access chiral compounds. Bidentate phosphorus ligands were used as efficient catalysts in this type of reaction. The Xiao-Mao Zhou group transformed enantiomeric α-PEA to prepare a series of chiral phosphine-aminophosphine ligands (Scheme 52) [76]. They used these ligands in the Rh-catalyzed asymmetric hydrogenation of olefins. Many different ligands were tested, and various functionalized olefins were transformed into the products with almost complete conversion and high enantioselectivity (Scheme 52).

Scheme 52

Rh-catalyzed asymmetric hydrogenation of olefins.

The same group reported another class of n class="Chemical">phosphinen>-phosphoramide chiral ligands with a 3,3′-substituted chiral binaphthyl fragment. These compounds were successfully tested in the catalytic reaction of asymmetric hydrogenation. Thus, ethyl (Z)-β-phenyl-β-(acetylamino)acrylate in methanol was reacted with gaseous hydrogen in the catalytic presence of Rh complexed with the new ligands. (S)-β-phenyl-β-(acetylamino)propanoate was obtained with excellent substrate conversion and enantioselectivity (Scheme 53) [77].

Scheme 53

Chiral P,N-donating ligands tested in Rh-catalyzed asymmetric hydrogenation.

7.4. Deprotonations of Bicyclic Amino Ketones

Asymmetric deprotonation combined with the n class="Chemical">aldoln> reaction allows for the enantioselective formation of a new C-C bond. Nodzewska and coworkers described a simple procedure for the synthesis of N-benzhydryl-derivatives of α-PEA via direct N-alkylation [78]. The lithium amides of this chiral secondary amine were used in the asymmetric deprotonation of tropinone analogs, followed by the aldol reaction with aldehydes giving products in high diastereomeric purities and enantiomeric excesses of 77 to 96% (Scheme 54) [78].

Scheme 54

Deprotonations and aldol reactions of bicyclic amino ketones.

7.5. Polymerization of Rac-Lactide

Chirn class="Chemical">aln> ligands with α-PEA fragments have been synthesized and used to synthesize four novel chiral zinc and aluminum complexes. Their structures were confirmed by X-ray diffraction analyses. All complexes were active catalysts for the stereoselective polymerization of rac-lactide to isotactic polylactide, and the product was obtained in up to 97% yield (Scheme 55) [79].

Scheme 55

Synthesis of polylactide catalyzed by Zn and Al complexes.

8. α-PEA and Its Derivatives in Organocatalysis

8.1. Direct Use of α-PEA as an Organocatalyst

In some cases, smn class="Chemical">aln>l chiral molecules, as enantiomeric α-PEA itself, exhibited interesting catalytic properties. In the last decade, three organocatalytic reactions of this type have been reported. Specifically, the intramolecular tandem Michael–Henry reaction [80], α-fluorination of ketones [81], and Wittig rearrangement of ketones [82] were effectively carried out with α-PEA as an organocatalyst.

The first organocatn class="Chemical">aln>yzed reaction was the enantioselective formal [3  +  2] cyclization between 2,3-butanedione and conjugated nitroolefins in the presence of α-PEA (20 mol%). The reaction led to good yield and substantial diastereoselectivity of enantiomerically enriched 2-hydroxy-3-nitrocyclopentanones (Scheme 56) [80].

Scheme 56

Reactions between 2,3-butanedione and conjugated nitroolefins catalyzed by α-PEA.

The second example refers to the enantioselective synthesis of both enantiomers of <span class="Chemical">cis-1-Boc-3-fluoropiperidin-4-oln> by fluorination catalyzed through chir<span class="Chemical">al primary amines. The reaction catalyzed by commercially available amines, including α-PEA, resulted in similar enantioselectivity levels as attained with epi-9-aminoquinine. The piperidinols readily crystallized to the enantiopure material (Scheme 57). The products are important building blocks for the synthesis of pharmacologically active compounds [81].

Scheme 57

The enantioselective α-fluorination of 4-piperidones.

The third case involves the organocat<span class="Chemical">aln>ytic effect of α-PEA in sigmatropic [2,3]-Wittig rearrangement of <span class="Chemical">allyloxyketones described in 2019 by the Šebesta group. Cat<span class="Chemical">alytic studies were carried out on many substrates, and numerous products were obtained in good yields and high enantiomeric excesses (Scheme 58) [82].

Scheme 58

The products of the Wittig rearrangement catalyzed by α-PEA.

8.2. Enantioselective Aldol Addition

The products of direct asymmetric n class="Chemical">aldoln> reactions are molecular fragments of important molecules, often required by the pharmaceutical industry. This application creates persisting interest in the development of appropriate organocatalysts, thus avoiding metal catalysts, which are difficult to remove.

Thus, Yadav and Singh described the synthesis of <span class="Chemical">trans-4-hydroxy-(S)-prolinamiden> with α-PEA fragments [83]. These <span class="Chemical">organocatalysts were used with good results in the model <span class="Chemical">aldol reaction between cyclohexanone and p-nirobenzaldehyde. The corresponding product was formed with almost complete conversion and high enantioselectivity up to 97% ee for the anti diastereoisomer (Scheme 59).

Scheme 59

Asymmetric direct aldol reaction catalyzed by 4-hydroxy-(S)-prolinamide.

The next class of compounds devised as catn class="Chemical">aln>ysts for the aldol reaction was chiral tetraoxacalix[2]arene[2]triazines. These organocatalysts based on chiral α-PEA were tested in the asymmetric aldol reaction of ketones with various aldehydes [84]. The adducts were obtained in 71–92% yields with good to excellent enantioselectivities (78–99%) (Scheme 60).

Scheme 60

Tetraoxacalix[2]arene[2]triazine-based organocatalysts for enantioselective aldol reactions.

8.3. Enantioselective Micheal Addition

An interesting example of the enantioselective Michael reaction was recently described for chir<span class="Chemical">aln> α-PEA-containing <span class="Chemical">organocatalysts. The work published concerned the cat<span class="Chemical">alytic performance of chiral bifunctional thioureas N-substituted with methyl or trifluoromethyl groups in the Baylis–Hillman and Michael reactions [85]. In the presence of organocatalysts containing α-PEA fragments, the addition of isobutyraldehyde to N-phenylmaleimide gave the respective product with high yield and ee (Scheme 61). Noticeably, the observed asymmetric induction was governed by the configuration of the 1,2-diaminocyclohexane part.

Scheme 61

Catalytic evaluation in the Michael addition of isobutyraldehyde to N-phenylmaleimide with α-PEA-containing organocatalysts.

9. Summary and Outlook

Despite the commerci<n class="Chemical">span class="Chemical">al availability of enantiomeric α-PEA, new advancements in its preparation and resolution were recorded. The <spn>an class="Gene">lipase-catalyzed dynamic kinetic resolution was efficient with α-alkoxyacetic acid esters, and new synthetic techniques were used for these processes. Further, the effective resolution of other acidic compounds was carried out with enantiomeric α-PEA. For the amides of α-PEA, a self-disproportionation of enantiomers was documented. The use of α-PEA as a chiral auxiliary was mostly directed to the synthesis of medicinal substances and natural products, including 5-, 6-, and 7-membered chiral nitrogen heterocycles. It is noteworthy that even if the observed reaction diastereoselectivity was poor or medium, the α-PEA stereodifferentiating properties allowed simple separation of diastereomers by crystallization or chromatography. Particularly promising were numerous catalytic applications of modular chiral ligands and organocatalysts with α-PEA moieties.

Thus, the last decade witnessed successful syntheses using α-PEA-based chir<span class="Chemical">aln> auxiliaries and encouraging outcomes of cat<span class="Chemical">alytic experiments. These recently achieved results stimulate further research, and rapid development in this field is anticipated.