ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS(Review)

Michael addition reactions involving nucleophilic glycine equivalents and α,β-unsaturated carboxylic acid derivatives offer a concise and generalized methodological approach to synthesizing a family of χ-constrained five-carbon-atom amino acids. These amino acids play a crucial role in de novo pepti...

Повний опис

Збережено в:

Бібліографічні деталі
Дата:	2024
Автори:	Wzorek, Alicja, Sorochinsky, Alexander, Klika, Karel, Ono, Taizo, Han, Jianlin, Soloshonok, Vadim
Формат:	Стаття
Мова:	Англійська
Опубліковано:	V.I.Vernadsky Institute of General and Inorganic Chemistry 2024
Онлайн доступ:	https://ucj.org.ua/index.php/journal/article/view/685
Теги:	Додати тег Немає тегів, Будьте першим, хто поставить тег для цього запису!
Назва журналу:	Ukrainian Chemistry Journal
Завантажити файл:

Репозитарії

Ukrainian Chemistry Journal

_version_	1871466071638147072
author	Wzorek, Alicja Sorochinsky, Alexander Klika, Karel Ono, Taizo Han, Jianlin Soloshonok, Vadim
author_facet	Wzorek, Alicja Sorochinsky, Alexander Klika, Karel Ono, Taizo Han, Jianlin Soloshonok, Vadim
author_institution_txt_mv	[ { "author": "Alicja Wzorek", "institution": "Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25-406 Kielce, Poland" }, { "author": "Alexander Sorochinsky", "institution": "Department of Fine Organic Synthesis, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry, The National Academy of Sciences of Ukraine, 1 Murmanska str., Kyiv 02094, Ukraine" }, { "author": "Karel Klika", "institution": "Molecular Structure Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120 Heidelberg, Germany" }, { "author": "Taizo Ono", "institution": "National Institute of Advanced Industrial Science and Technology, 463-8560, Nagoya, Japan" }, { "author": "Jianlin Han", "institution": "Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China" }, { "author": "Vadim Soloshonok", "institution": "University of Basque Country" } ]
author_sort	Wzorek, Alicja
baseUrl_str	https://ucj.org.ua/index.php/journal/oai
collection	OJS
datestamp_date	2026-07-22T08:23:54Z
description	Michael addition reactions involving nucleophilic glycine equivalents and α,β-unsaturated carboxylic acid derivatives offer a concise and generalized methodological approach to synthesizing a family of χ-constrained five-carbon-atom amino acids. These amino acids play a crucial role in de novo peptide design and the elucidation of peptide/protein three-dimensional structures and their biological functions/activities. This review encapsulates the significant synthetic and methodological advancements in the field to date. Each method discussed includes an evaluation of synthetic opportunities and limitations, practicality and efficiency of the procedures, and mechanistic rationale behind the observed stereochemical preferences.
doi_str_mv	10.33609/2708-129X.90.8.2024.83-108
first_indexed	2025-09-24T17:43:58Z
format	Article
fulltext	83 UDC 546.26-162: 541.13:549.21 doi: 10.33609/2708-129X.90.8.2024.83-108 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS Alicja Wzorek1, Alexander E. Sorochinsky2, Karel D. Klika3, Taizo Ono4, Jianlin Han5, Vadim A. Soloshonok6,7 1 Institute of Chemistry, Jan Kochanowski University in Kielce, Uniwersytecka 7, 25–406 Kielce, Poland; 2 Department of Fine Organic Synthesis, V.P. Kukhar Institute of Bioorganic Chemistry and Petro- chemistry, The National Academy of Sciences of Ukraine, 1 Murmanska str., Kyiv 02094, Ukraine; 3 Molecular Structure Analysis, German Cancer Research Center (DKFZ), ImNeuenheimer Feld 280, 69120 Heidelberg, Germany; 4 National Institute of Advanced Industrial Science and Technology, 463–8560, Nagoya, Japan; 5 Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China; 6 Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/ EHU, Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain; 7 IKERBASQUE, Basque Foundation for Science, María Díaz de Haro 3, Plaza Bizkaia, 48013 Bilbao, Spain. e-mail: vadimsoloshonok@gmail.com Michael addition reactions involving nucleophilic glycine equivalents and α,β-unsaturated carboxylic acid derivatives offer a concise and generalized methodological approach to syn- thesizing a family of χ-constrained five-carbon-atom amino acids. These amino acids play a crucial role in de novo peptide design and the elucidation of peptide/protein three-dimen- sional structures and their biological functions/activities. This review encapsulates the signi ficant synthetic and methodological advancements in the field to date. Each method discussed includes an evaluation of synthetic opportunities and limitations, practicality and efficiency of the procedures, and mechanistic rationale behind the observed stereochemical preferences. Keywords: Asymmetric synthesis, Michael additions, glycine equivalents, metal comp lexes, Schiff bases, conformations, steric constrain. Glutamic acid, pyroglutamic acid, proline. 84 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY INTRODUCTION. Amino acids (AAs) are fundamental to the fabric of life, acting as the building blocks of proteins that drive countless biological processes [1]. In general sciences, their study has provided crucial insights into the mechanisms of life, from understanding metabolic pathways to uncovering the gene tic code. Researchers delve into amino acid sequences to elucidate protein structure and function, enabling advances in fields like bio chemistry, molecular biology, and genetics. The versatility and functionality of AAs make them indispensable for exploring the intrica- cies of cellular functions and organismal deve lopment [2–6]. In the pharmaceutical industry, amino acids hold a pivotal role in the development of drugs and therapeutic agents [7–10]. Many medica- tions are designed to mimic or modulate the activity of naturally occurring AAs and their derivatives, targeting specific pathways to treat a variety of diseases. For instance, amino acid derivatives are used in the synthesis of antivi- ral drugs, antibiotics, and treatments for me tabolic disorders[11–13]. Additionally, the role of AAs in protein synthesis is harnessed to de- velop biologics, such as monoclonal antibodies and vaccines, which are essential for modern medicine. The continuous exploration of AAs and their properties drives innovation, leading to more effective and targeted therapies that improve human health and well-being[14–20]. Glutamic acid and its cyclic derivative, py- roglutamic acid, play pivotal roles in peptides and drug design [21]. Glutamic acid, an essen- tial amino acid, contributes to protein structure and function through its side chain, which can participate in ionic interactions and hydrogen bonding. This property is critical in stabilizing protein structures and facilitating enzyme ca- talysis [22]. Pyroglutamic acid, formed by the cyclization of glutamic acid, introduces rigidity into peptide chains, thereby reducing confor- mational flexibility. This structural constraint is advantageous in drug design, as it enhances binding specificity and stability, improving the efficacy of peptide-based therapeutics [23]. Both glutamic and pyroglutamic acids are in- tegral in designing peptides with optimized pharmacological properties, making them invaluable in the development of novel drugs and therapeutic agents [24]. In this review article, we will discuss the synthesis of a specialized class of glutamic acid and related compounds: stereochemically con- strained glutamic/pyroglutamic acids formed via the Michael addition reaction of nucleo philic glycine equivalents. These amino acids (AAs) adopt a relatively limited number of conformations and play a crucial role in the de novo design of peptides with predetermined 3D structures and enhanced peptide-receptor interactions. Role of χ(chi)-constrained amino acids in the de novo design of peptides and peptidomimetics. Reducing the number of amino acid (AA) conformations is crucial for optimizing pep- tide-receptor interactions, which play a vital role in various biological processes and the rapeutic applications [25]. By limiting the con- formational flexibility of peptides, researchers can design more specific and stable interac- tions between peptides and their target recep- tors. This precision enhances binding affinity and selectivity, leading to improved efficacy and reduced off-target effects in drug deve lopment. Tailoring peptide structures to adopt fewer conformations not only streamlines the identification of potent therapeutic candi- 85https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 dates but also contributes to the stability and bioavailability of the peptides in physiological environments. Ultimately, this approach holds promise for developing highly effective and targeted treatments for a wide range of disea ses [26]. The 3D structure of peptides is determined by three key components: peptide sequence (primary structure), conformation (secondary structure), and the topographical positioning of side-chain functional groups. While the importance of peptide sequence and confor- mation in biological activity has been widely acknowledged, the third factor – the spatial arrangement of side chains on the peptide backbone (referred to as χ-space) – has only recently gained attention [26].The importance of the torsional angles φ (phi), ψ (psi), and ω (omega) (Figure 1. A) in determining the 3D structure of the peptide backbone [27–30], as well as the χ (chi) torsional angles (Figure 1, B) in defining the position of side-chain function- al groups, for elucidating peptide biological ac- tivity, has been demonstrated [31–37]. While φ, ψ, and ω angles are generally influenced by the nature of amino acid residues and the peptide’s secondary structure (e.g., cyclization or global constraints), controlling χ angles is much more challenging. Fig. 1. Dihedral angles φ (phi), ψ (psi), ω (omega) (A), and χ (chi) (B), leading to numerous conformations of amino acid residues in peptides. It was demonstrated that, in contrast to α-substitution in amino acids, which has little effect on the χ angles, the introduction of a methyl group in the β-position substantially enhances the population of one out of three [gauche-(+), trans, and gauche-(-)] χ1-rota mers. For instance, as illustrated for methyl phenylalanines 1 (Figure 2), unfavorable steric interactions between the vicinal sub- stituents (β-methyl and amino/carboxylic groups) resulted in a strong preference for the corresponding trans rotamer over the two gauche conformations [38, 39]. Considering β-substituted prolines 2, as proline-phenyla- lanine chimeras, one could expect that rota- tional freedom in these derivatives might be much more limited for χ1, compared to that of β-methyl substituted phenylalanine1 [40– 42]. Indeed, it was shown that in both cis and trans diastereomers of 2, the corresponding (-)-gauche conformers are physically inac- cessible. Moreover, molecular calculations of proline-tyrosine chimeras of type2 revealed that the trans rotamer is preferred by up to 2 kcal/mol over the corresponding (-)-gauche conformer [43–64]. Fig. 2. β-Substitution and proline chimera with limited rotational freedom around the χ1 (chi) tor- sional angle. The challenge associated with the asym- metric synthesis of χ-constrained amino acids stems from their sterically congested nature, the presence of at least two stereogenic centers, and the necessity of preparing all (in most ca ses four) stereoisomers for SAR studies. The 3     C O N H R H O N H C C O N H H O N H C R  A B Fig. 1. Dihedral angles φ (phi), ψ (psi), ω (omega) (A), and χ (chi) (B), leading to numerous conformations of amino acid residues in peptides. It was demonstrated that, in contrast to α-substitution in amino acids, which has little effect on the χ angles, the introduction of a methyl group in the β-position substantially enhances the population of one out of three [gauche-(+), trans, and gauche- (-)] χ1-rotamers. For instance, as illustrated for methylphenylalanines 1 (Figure 2), unfavorable steric interactions between the vicinal substituents (β-methyl and amino/carboxylic groups) resulted in a strong preference for the corresponding trans rotamer over the two gauche conformations [38, 39]. Considering β-substituted prolines 2, as proline-phenylalanine chimeras, one could expect that rotational freedom in these derivatives might be much more limited for χ1, compared to that of β-methyl substituted phenylalanine1 [40–42]. Indeed, it was shown that in both cis and trans diastereomers of 2, the corresponding (-)-gauche conformers are physically inaccessible. Moreover, molecular calculations of proline-tyrosine chimeras of type2 revealed that the trans rotamer is preferred by up to 2 kcal/mol over the corresponding (-)-gauche conformer [43–64]. CO2H NH2 1 N CO2H H 2 Fig. 2. -Substitution and proline chimera with limited rotational freedom around the χ1 (chi) torsional angle. The challenge associated with the asymmetric synthesis of χ-constrained amino acids stems from their sterically congested nature, the presence of at least two stereogenic centers, and the necessity of preparing all (in most cases four) stereoisomers for SAR studies. The unique potential of χ-constrained amino acids in the rational design of peptides and peptide mimetics has generated significant research efforts aimed at developing various synthetic methods to prepare these amino acids in stereochemically defined forms. Asymmetric Michael addition reactions of glycine equivalents. The ever-growing demand for proteinogenic and tailor-made amino acids has spurred extensive research in the field of asymmetric synthesis of amino acids [55–64]. Chiral glycine equivalents have garnered significant attention, as nucleophilic or electrophilic homologation of glycine offers a generalized approach to synthesizing various α-amino acids. The primary challenge in designing chiral nucleophilic glycine equivalents lies in controlling enolate face selectivity, i.e., the configuration of the α- stereogenic center in the resulting amino acids. Conversely, the Michael addition reactions of glycine equivalents with β-substituted acrylic acid derivatives present an 3     C O N H R H O N H C C O N H H O N H C R  A B Fig. 1. Dihedral angles φ (phi), ψ (psi), ω (omega) (A), and χ (chi) (B), leading to numerous conformations of amino acid residues in peptides. It was demonstrated that, in contrast to α-substitution in amino acids, which has little effect on the χ angles, the introduction of a methyl group in the β-position substantially enhances the population of one out of three [gauche-(+), trans, and gauche- (-)] χ1-rotamers. For instance, as illustrated for methylphenylalanines 1 (Figure 2), unfavorable steric interactions between the vicinal substituents (β-methyl and amino/carboxylic groups) resulted in a strong preference for the corresponding trans rotamer over the two gauche conformations [38, 39]. Considering β-substituted prolines 2, as proline-phenylalanine chimeras, one could expect that rotational freedom in these derivatives might be much more limited for χ1, compared to that of β-methyl substituted phenylalanine1 [40–42]. Indeed, it was shown that in both cis and trans diastereomers of 2, the corresponding (-)-gauche conformers are physically inaccessible. Moreover, molecular calculations of proline-tyrosine chimeras of type2 revealed that the trans rotamer is preferred by up to 2 kcal/mol over the corresponding (-)-gauche conformer [43–64]. CO2H NH2 1 N CO2H H 2 Fig. 2. -Substitution and proline chimera with limited rotational freedom around the χ1 (chi) torsional angle. The challenge associated with the asymmetric synthesis of χ-constrained amino acids stems from their sterically congested nature, the presence of at least two stereogenic centers, and the necessity of preparing all (in most cases four) stereoisomers for SAR studies. The unique potential of χ-constrained amino acids in the rational design of peptides and peptide mimetics has generated significant research efforts aimed at developing various synthetic methods to prepare these amino acids in stereochemically defined forms. Asymmetric Michael addition reactions of glycine equivalents. The ever-growing demand for proteinogenic and tailor-made amino acids has spurred extensive research in the field of asymmetric synthesis of amino acids [55–64]. Chiral glycine equivalents have garnered significant attention, as nucleophilic or electrophilic homologation of glycine offers a generalized approach to synthesizing various α-amino acids. The primary challenge in designing chiral nucleophilic glycine equivalents lies in controlling enolate face selectivity, i.e., the configuration of the α- stereogenic center in the resulting amino acids. Conversely, the Michael addition reactions of glycine equivalents with β-substituted acrylic acid derivatives present an 86 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY unique potential of χ-constrained amino acids in the rational design of peptides and peptide mimetics has generated significant research efforts aimed at developing various synthe tic methods to prepare these amino acids in stereochemically defined forms. Asymmetric Michael addition reactions of glycine equivalents. The ever-growing demand for proteinogen- ic and tailor-made amino acids has spurred ex- tensive research in the field of asymmetric syn- thesis of amino acids [55–64]. Chiral glycine equivalents have garnered significant attention, as nucleophilic or electrophilic homologation of glycine offers a generalized approach to syn- thesizing various α-amino acids. The primary challenge in designing chiral nucleophilic gly- cine equivalents lies in controlling enolate face selectivity, i.e., the configuration of the α-ste- reogenic center in the resulting amino acids. Conversely, the Michael addition reactions of glycine equivalents with β-substituted acrylic acid derivatives present an issue with Michael acceptor face selectivity, crucial for determin- ing the configuration of the β-carbon stereo- genic center. Most well-designed chiral glycine equiva lents achieve high levels of stereocontrol at the α-stereogenic carbon when reacting with β-substituted acrylic acid derivatives, but they are less effective in controlling the absolute configuration at the β-position. However, in certain cases, the stereochemical requirements of both the chiral glycine derivative and the Michael acceptor can align, resulting in a syn- thetically valuable stereochemical outcome. Bis-lactim ether methodology (Scheme 1) [65] has been widely used for preparing var- ious α-amino acids. The corresponding anion is typically generated by treating the bis-lac- tim ether of cyclo-(R)-Val-Gly 3 with BuLi at –78 °C. Electrophilic attack on the in situ generated anion by alkyl halides, carbonyl compounds, or acrylic acid derivatives occurs almost exclusively from the least hindered face, away from the bulky iso-Pr group, giving rise to the corresponding derivatives of α-amino acids with an α-(S) absolute configuration and very high enantiomeric excess (ee) [65]. In the original protocol [66], the Michael addition of alkyl crotonates4 to (R)-3 produced a mixture of two diastereomeric products, (2S, 3R) and (2S, 3S) 5, in a ratio of 3 to 1. However, another report on the same reaction claimed much higher stereoselectivity, with no other di- astereomers identified among the by-products [67]. The reactions of 3 with alkyl trans-cin- namates led to the formation of the corre- sponding derivatives of (2S, 3R)-3-phenylglu- tamic acid [68] in synthetically useful chemical yields (>75%) and with high diastereoselecti vity (>90% de). In this case, there is no discre pancy between the original report [66] and the followingreports reproducing these additions on a relatively large scale (>25 g) [69]. The bis-lactim ether method also provides access to cis-diastereomers of glutamic/pyro- glutamic acids 10 as illustrated in Scheme 1, through additions of 3 with cis-configured Mi- chael acceptors. Thus, the reactions of 3 with alkyl cis-crotonates and -cinnamates gave rise to the corresponding addition products 7 as the major product, along with three other dia stereomeric products [65–67, 69]. The stereo- chemical outcome in this case is slightly lower compared to the additions with trans-confi gured Michael acceptors. 87https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 Scheme 1. bis-Lactim ether methodology for Machiel addition reactions. 4 issue with Michael acceptor face selectivity, crucial for determining the configuration of the β-carbon stereogenic center. Most well-designed chiral glycine equivalents achieve high levels of stereocontrol at the α-stereogenic carbon when reacting with β-substituted acrylic acid derivatives, but they are less effective in controlling the absolute configuration at the β-position. However, in certain cases, the stereochemical requirements of both the chiral glycine derivative and the Michael acceptor can align, resulting in a synthetically valuable stereochemical outcome. Bis-lactim ether methodology (Scheme 1) [65] has been widely used for preparing various α-amino acids. The corresponding anion is typically generated by treating the bis- lactim ether of cyclo-(R)-Val-Gly 3 with BuLi at –78 °C. Electrophilic attack on the in situ generated anion by alkyl halides, carbonyl compounds, or acrylic acid derivatives occurs almost exclusively from the least hindered face, away from the bulky iso-Pr group, giving rise to the corresponding derivatives of α-amino acids with an α-(S) absolute configuration and very high enantiomeric excess (ee) [65]. In the original protocol [66], the Michael addition of alkyl crotonates4 to (R)-3 produced a mixture of two diastereomeric products, (2S, 3R) and (2S, 3S) 5, in a ratio of 3 to 1. However, another report on the same reaction claimed much higher stereoselectivity, with no other diastereomers identified among the by-products [67]. The reactions of 3 with alkyl trans-cinnamates led to the formation of the corresponding derivatives of (2S, 3R)-3-phenylglutamic acid [68] in synthetically useful chemical yields (>75%) and with high diastereoselectivity (>90% de). In this case, there is no discrepancy between the original report [66] and the followingreports reproducing these additions on a relatively large scale (>25 g) [69]. N N MeO OMe R CO2R1 BuLi THF, -78 oC 3 N N MeO OMe 5 R CO2R1 R = Me, Ph; R1 = Me, Et 4 N R CO2H H O 11 HCl HO2C NH2 CO2H R 13 R = Me (2S,3S) R = Ph (2S,3R) CO2R1 BuLi THF, -78 oC 6 N N MeO OMe 7 R CO2R1 R N R CO2H H O 10 R2 CO2R R2 = Me, Ph, 4-Py 8 BuLi THF, -78 oC N N MeO OMe 9 R CO2R1 HCl HO2C NH2 CO2H R 12 R = Me (2S,3R) R = Ph (2S,3S) Scheme 1. bis-Lactim ether methodology for Machiel addition reactions. The additions between (S)-3 and methyl 2,4-pentadienoates 8 (Scheme 1) were repor ted to proceed with virtually complete diaste reoselectivity [70]. The reaction conducted under standard conditions for this method resulted in only one detectable diastereomer by NMR, with spectral characteristics consis tent with the corresponding 1,6-addition pro duct 9. Unfortunately, the stereochemistry of the β-stereogenic center of the newly formed amino acid residue was not determined, while the configuration of the α-carbon atom was found to be (R) [70]. In principle, the bis-lactim ether method al- lows for generalized access to various β-alkyl and β-aryl substituted glutamic/pyroglutamic acids, including both cis and trans-diaste reomeric forms. However, this method has several inherent drawbacks that make it less attractive from a synthetic standpoint. Be- sides usually moderate chemical yields and, in most cases, incomplete stereoselectivity at the β-stereogenic carbon of the target glutamic/ pyroglutamic acids, hydrolysis of the addition products 7, 5, 9 to the target amino acids in- volves painstaking separations, usually by dis- tillation, of the resultant amino acid esters from methyl valinatecoming from the starting chiral auxiliary. Since this type of separation depends on the physical properties of the compounds, it necessitates the development of a work-up procedure for each particular case. Another highly diastereoselective approach to β-substituted glutamic/pyroglutamic acids is based on Michael addition reactions of the enolate of (S)-imidazolidinone 14 (Scheme 2). These reactions were studied using conventio nal alkyl esters (Me, Et) of β-substituted acry lic acids 15 as well as specially designed «ste rically protected but electronically effective» 88 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY 2,6-di-t-butyl-4-methoxyphenyl esters 16 [71, 72]. The stereochemical outcome of the addi- tions between anion (S)-14 and alkyl esters 15 was rather disappointing. The addition pro ducts 17 were isolated in moderate chemical yields [68% (Me), 78% (Et)] and with low dias- tereoselectivity (20–40% de). In contrast, the reactions of (S)-14 with 2,6-di-t-butyl-4-methoxyphenyl esters 16 oc- curred at higher reaction rates, resulting in sole diastereomeric products 17 with good chemi- cal yields (78–96%) and complete (>99% de) diastereoselectivity. The stereochemical out- come in these addition reactions is assumed to be kinetically controlled. It is important to emphasize that this approach offers cis-pyro- glutamic acids, which are hardly attainable by the bis-lactim ether method. Scheme 2. Imidazolidinonederived chiral glycine equivalent in Michael addition reactions. 5 The bis-lactim ether method also provides access to cis-diastereomers of glutamic/pyroglutamic acids 10 as illustrated in Scheme 1, through additions of 3 with cis-configured Michael acceptors. Thus, the reactions of 3 with alkyl cis-crotonates and - cinnamates gave rise to the corresponding addition products 7 as the major product, along with three other diastereomeric products [65–67, 69]. The stereochemical outcome in this case is slightly lower compared to the additions with trans-configured Michael acceptors. The additions between (S)-3 and methyl 2,4-pentadienoates 8 (Scheme 1) were reported to proceed with virtually complete diastereoselectivity [70]. The reaction conducted under standard conditions for this method resulted in only one detectable diastereomer by NMR, with spectral characteristics consistent with the corresponding 1,6-addition product 9. Unfortunately, the stereochemistry of the β-stereogenic center of the newly formed amino acid residue was not determined, while the configuration of the α-carbon atom was found to be (R) [70]. In principle, the bis-lactim ether method allows for generalized access to various β-alkyl and β-aryl substituted glutamic/pyroglutamic acids, including both cis and trans- diastereomeric forms. However, this method has several inherent drawbacks that make it less attractive from a synthetic standpoint. Besides usually moderate chemical yields and, in most cases, incomplete stereoselectivity at the β-stereogenic carbon of the target glutamic/pyroglutamic acids, hydrolysis of the addition products 7, 5, 9 to the target amino acids involves painstaking separations, usually by distillation, of the resultant amino acid esters from methyl valinatecoming from the starting chiral auxiliary. Since this type of separation depends on the physical properties of the compounds, it necessitates the development of a work-up procedure for each particular case. Another highly diastereoselective approach to β-substituted glutamic/pyroglutamic acids is based on Michael addition reactions of the enolate of (S)- imidazolidinone 14 (Scheme 2).These reactions were studied using conventional alkyl esters (Me, Et) of β-substituted acrylic acids 15 as well as specially designed "sterically protected but electronically effective" 2,6-di-t-butyl-4-methoxyphenyl esters 16 [71,72]. The stereochemical outcome of the additions between anion (S)-14 and alkyl esters 15 was rather disappointing. The addition products 17 were isolated in moderate chemical yields [68% (Me), 78% (Et)] and with low diastereoselectivity (20–40% de). In contrast, the reactions of (S)-14 with 2,6-di-t-butyl-4-methoxyphenyl esters 16 occurred at higher reaction rates, resulting in sole diastereomeric products 17 with good chemical yields (78–96%) and complete (>99% de) diastereoselectivity. The stereochemical outcome in these addition reactions is assumed to be kinetically controlled. It is important to emphasize that this approach offers cis-pyroglutamic acids, which are hardly attainable by the bis-lactim ether method. N N O Boc t-Bu BuLi THF, -78 oC 14(S) CO2Alk O O t-Bu t-Bu O N N O Boc t-Bu CO2R N CO2H O H 15 16 17 10 20-40% de > 99% de Scheme 2. Imidazolidinonederived chiral glycine equivalent in Michael addition reactions. The mechanistic rationale for the very high stereoselectivity at the α-stereogenic center of the newly formed amino acids is rather straight- forward, as the Michael acceptor attacks the corresponding anion generated from 14 almost exclusively from the side opposite the bulky t-buty l group. On the other hand, explaining the virtually complete face- and diastereoselec- tivity observed in the additions of (S)-14 with bulky aryl esters 16 was not straightforward. Molecular mechanics calculations revealed that the energy difference between two conformers, s-cis 18 and s-trans 19 (Fig. 3), of the Michael acceptor is minimal. However, the calculations suggested that the s-cis 18 conformer should be substantially more reactive than the s-trans 19 because the reactive β-carbon atom in the for- mer is shielded by bulky t-butyl groups. This ra- tionale seems reasonable and, most important- ly, emphasizes for the first time the relevance of s-cis and s-trans conformers of the Michael acceptor to the stereochemical outcome in these addition reactions. Fig. 3. s-cis and s-trans Conformers of 2,6-di-t- butyl-4-methoxyphenyl esters 16. Considering the substrate generality (alkyl, i-Pr, Bn, aryl groups), high chemical yields, and virtually complete diastereoselectivity, the imidazolidinonemethod could be regarded as nearly perfect for preparing cis-configured py- roglutamic/glutamic acids and their derivatives. However, from the standpoint of synthetic effi- ciency and practicality, this method is hardly at- 6 The mechanistic rationale for the very high stereoselectivity at the α-stereogenic center of the newly formed amino acids is rather straightforward, as the Michael acceptor attacks the corresponding anion generated from 14 almost exclusively from the side opposite the bulky t-buty l group. On the other hand, explaining the virtually complete face- and diastereoselectivity observed in the additions of (S)-14 with bulky aryl esters 16 was not straightforward. Molecular mechanics calculations revealed that the energy difference between two conformers, s-cis 18 and s-trans 19 (Fig. 3), of the Michael acceptor is minimal. However, the calculations suggested that the s-cis 18 conformer should be substantially more reactive than the s-trans 19 because the reactive β-carbon atom in the former is shielded by bulky t-butyl groups. This rationale seems reasonable and, most importantly, emphasizes for the first time the relevance of s-cis and s-trans conformers of the Michael acceptor to the stereochemical outcome in these addition reactions. O O O O s-cis-18 s-trans-19 O O Fig. 3. s-cis and s-trans Conformers of 2,6-di-t-butyl-4-methoxyphenyl esters 16. Considering the substrate generality (alkyl, i-Pr, Bn, aryl groups), high chemical yields, and virtually complete diastereoselectivity, the imidazolidinonemethod could be regarded as nearly perfect for preparing cis-configured pyroglutamic/glutamic acids and their derivatives. However, from the standpoint of synthetic efficiency and practicality, this method is hardly attractive for multigram preparation of the target compounds. Besides the general disadvantages of the Seebach method, such as the generation of the enolate of 14 at –78 °C with BuLi and the relatively drastic reaction conditions required to remove the chiral auxiliary (0.75 N HCl for 16 h at 105 °C), the multistage (3–4 stages) preparation of the aryl esters 16, as well as the oxidative deprotection of the ester moiety with Ce(IV) [73–77], render the whole procedure problematic for large-scale preparations. The application of chiral equivalents of nucleophilic glycine, characterized by the high CH acidity of the glycine methylene group, offers a significant synthetic advantage. In this approach, the corresponding enolate can be generated under mild reaction conditions, which are much easier to control and more practical than using highly reactive and hygroscopic BuLi at –78 °C. It was demonstrated that the generation of the corresponding enolate from Schiff base 20 (Scheme 3) could be easily achieved by treating 20, derived from t-butyl glycinate and natural (1R, 4R)-camphor, with a mixture of LiBr and triethylamine in THF [78]. The enolate thus generated readily reacted at room temperature with methyl acrylate21, furnishing a mixture of two b-(R)- and b-(S)- diastereomers in a ratio of up to 84/16, respectively, indicating relatively poor face- diastereoselectivity in the addition. The Michael addition of 20 with methyl crotonate 22 completely failed, presumably due to the greater steric bulkiness and lower electrophilicity of the latter. 89https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 tractive for multigram preparation of the target compounds. Besides the general disadvantages of the Seebach method, such as the generation of the enolate of 14 at –78 °C with BuLi and the relatively drastic reaction conditions required to remove the chiral auxiliary (0.75 N HCl for 16 h at 105 °C), the multistage (3–4 stages) prepara- tion of the aryl esters 16, as well as the oxidative deprotection of the ester moiety with Ce(IV) [73–77], render the whole procedure proble matic for large-scale preparations. The application of chiral equivalents of nu- cleophilic glycine, characterized by the high CH acidity of the glycine methylene group, offers a significant synthetic advantage. In this approach, the corresponding enolate can be generated under mild reaction conditions, which are much easier to control and more practical than using highly reactive and hygro- scopic BuLi at –78 °C. It was demonstrated that the generation of the corresponding enolate from Schiff base 20 (Scheme 3) could be easily achieved by treating 20, derived from t-butyl glycinate and natural (1R, 4R)-camphor, with a mixture of LiBr and triethylamine in THF [78]. The enolate thus generated readily reacted at room temperature with methyl acrylate21, fur- nishing a mixture of two b-(R)- and b-(S)-dia stereomers in a ratio of up to 84/16, respectively, indicating relatively poor face-diastereoselec- tivity in the addition. The Michael addition of 20 with methyl crotonate 22 completely failed, presumably due to the greater steric bulkiness and lower electrophilicity of the latter. Scheme 3. Michael addition reactions of Schiff base 20 derived fromt-butyl glycinate and (1R, 4R)-camphor. 7 N O t-Bu-O (1R,4R)-20 LiBr/NEt3 or LiBr/DBU CO2Me CO2Me 21 22 N R CO2H H O 11 20-40 %de Scheme 3. Michael addition reactions of Schiff base 20 derived fromt-butyl glycinate and (1R, 4R)-camphor. It was found that the application of α-methoxycarbonyl-substituted derivatives 23 (Scheme 4) led to a significant increase in the diastereoselectivity of the additions. Except for the reaction of 20 with dimethyl ethylidenemalonate 23 (R = Me), which furnished a mixture of two diastereomeric products (ratio 86/15), all other studied additions yielded only a single diastereomer in the reaction mixture. The remarkable difference in the stereochemical outcomes between the reactions of ethylidenemalonate 23 (R = Me) (72% de) and propylidenemalonate 23 (R = Et) (over 99% de) with enolate of 20 was attributed by the authors to the simple difference in steric bulk between the Me and Et groups. To the best of our knowledge, this is a rare example of such dramatic stereochemical consequences resulting from the difference in steric bulk between methyl and ethyl groups [79]. The transformation of the addition products 24 to the final amino acids 26 involves simple hydrolytic removal of the chiral auxiliary and decarboxylation of the intermediate 25. N O t-Bu-O (1R,4R)-20 LiBr/DBU 23 N R CO2H H O (2R,3S)-26 R CO2Me CO2Me N O t-Bu-O R CO2Me MeO2C R = Me, Et, t-Bu, Ph, (E)-MeCH=CH (E)-PhCH=CH (E)-MeOCH=CH 24 N R CO2Me H O (2R,3S)-25 MeO2C Scheme 4. Michael addition reactions of Schiff base 20 with a-methoxycarbonyl-substituted acrylic acids 23. This method appears to be quite general for preparing various β-substituted pyroglutamic/glutamic acid derivatives. Of particular importance is the successful reaction of 2,2-dimethylpropylidenemalonate 23 (R = t-Bu) with 20, which ultimately leads to sterically constrained β-t-butyl derivatives of the target amino acids 26. Notably, in contrast to the bis-lactim ether methodology(Scheme 1), the reactions between 20 and derivatives 23 containing conjugated C,C double bonds featured only 1,4-addition. This It was found that the application of α-meth- oxycarbonyl-substituted derivatives 23 (Sche me 4) led to a significant increase in the dia stereoselectivity of the additions. Except for the reaction of 20 with dimethyl ethylidene malonate 23 (R = Me), which furnished a mixture of two diastereomeric products (ra- tio 86/15), all other studied additions yielded only a single diastereomer in the reaction mix- ture. The remarkable difference in the stereo- chemical outcomes between the reactions of ethylidenemalonate 23 (R = Me) (72% de) and propylidenemalonate 23 (R = Et) (over 99% de) with enolate of 20 was attributed by the authors to the simple difference in steric bulk between the Me and Et groups. To the best of our knowledge, this is a rare example of such dramatic stereochemical consequences result- ing from the difference in steric bulk between methyl and ethyl groups [79]. The transforma- tion of the addition products 24 to the final amino acids 26 involves simple hydrolytic re- moval of the chiral auxiliary and decarboxyla- tion of the intermediate 25. 90 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY Scheme 4. Michael addition reactions of Schiff base 20 with a-methoxycarbonyl-substituted acrylic acids 23. 7 N O t-Bu-O (1R,4R)-20 LiBr/NEt3 or LiBr/DBU CO2Me CO2Me 21 22 N R CO2H H O 11 20-40 %de Scheme 3. Michael addition reactions of Schiff base 20 derived fromt-butyl glycinate and (1R, 4R)-camphor. It was found that the application of α-methoxycarbonyl-substituted derivatives 23 (Scheme 4) led to a significant increase in the diastereoselectivity of the additions. Except for the reaction of 20 with dimethyl ethylidenemalonate 23 (R = Me), which furnished a mixture of two diastereomeric products (ratio 86/15), all other studied additions yielded only a single diastereomer in the reaction mixture. The remarkable difference in the stereochemical outcomes between the reactions of ethylidenemalonate 23 (R = Me) (72% de) and propylidenemalonate 23 (R = Et) (over 99% de) with enolate of 20 was attributed by the authors to the simple difference in steric bulk between the Me and Et groups. To the best of our knowledge, this is a rare example of such dramatic stereochemical consequences resulting from the difference in steric bulk between methyl and ethyl groups [79]. The transformation of the addition products 24 to the final amino acids 26 involves simple hydrolytic removal of the chiral auxiliary and decarboxylation of the intermediate 25. N O t-Bu-O (1R,4R)-20 LiBr/DBU 23 N R CO2H H O (2R,3S)-26 R CO2Me CO2Me N O t-Bu-O R CO2Me MeO2C R = Me, Et, t-Bu, Ph, (E)-MeCH=CH (E)-PhCH=CH (E)-MeOCH=CH 24 N R CO2Me H O (2R,3S)-25 MeO2C Scheme 4. Michael addition reactions of Schiff base 20 with a-methoxycarbonyl-substituted acrylic acids 23. This method appears to be quite general for preparing various β-substituted pyroglutamic/glutamic acid derivatives. Of particular importance is the successful reaction of 2,2-dimethylpropylidenemalonate 23 (R = t-Bu) with 20, which ultimately leads to sterically constrained β-t-butyl derivatives of the target amino acids 26. Notably, in contrast to the bis-lactim ether methodology(Scheme 1), the reactions between 20 and derivatives 23 containing conjugated C,C double bonds featured only 1,4-addition. This This method appears to be quite general for preparing various β-substituted pyroglutamic/ glutamic acid derivatives. Of particular impor- tance is the successful reaction of 2,2-dimethyl propylidenemalonate 23 (R = t-Bu) with 20, which ultimately leads to sterically constrained β-t-butyl derivatives of the target amino acids 26. Notably, in contrast to the bis-lactim ether methodology(Scheme 1), the reactions be- tween 20 and derivatives 23 containing conju- gated C,C double bonds featured only 1,4-ad- dition. This allowed for the preparation of the corresponding pyroglutamic/glutamic acids bearing potentially useful unsaturated func- tionality. However, the general applicability of this method is greatly limited by the use of na turally occurring camphor as a chiral auxilia- ry, as its (1S, 4S) enantiomeric form is scarcely available. Another example of Michael addition re- actions between chiral Schiff bases of glycine and α, β-unsaturated carboxylic acid deriva- tives was developed based on Ni(II) complex 27shown in Scheme 5 [80–83]. The Ni(II) com- plex 27 was found to react easily in MeOH and in the presence of NaOMe as a base, with me- thyl cinnamate and methacrylate, giving rise to the corresponding diastereomeric products 28 and 29. In both cases, the enolate face-dia stereoselectivity was very high as α-(R)-confi gured products were not detected in noticeable amounts. However, diastereoselectivity at C-3 and C-4 positions was disappointingly low, furnishing the products in approximately a 2/1 and 1/1 ratio respectively. It is interesting to note that in this case the stereochemical out- come is kinetically controlled, these reactions are highly reversible and thus the ratios of dia stereomeric products are thermodynamically controlled. Taking advantage of high C-H acidity of the glycine methylene group in 27, it was found that the corresponding Michael addition reac- tions with ethyl crotonate, 4,4,4-trifluorocro- tonate andcinnamate [84,85]can be conducted in DMF in the presence of DBU as a base. The stereochemical outcome of the reactions was found to be kinetically controlled. The diaste- reoselectivity in the additions of (S)-27 with ethyl crotonate and cinnamate was found to be noticeably better compared to the outcomes observed under the thermodynamically con- 91https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 trolled conditions (Scheme 5).The major pro ducts 30(R = Me, Ph) were obtained in a ratio of 4/1, respectively. The stereochemical out- come of the reaction between (S)-27 and ethyl 4,4,4-trifluorocrotonate was slightly higher, with a diastereomeric ratio of up to 5.6/1. This can be attributed to the more sterically de- manding nature of the trifluoromethyl group [86–88]. The major diastereomers 30 were pu- rified by crystallization of the reaction mixture and disassembled to afford the target pyroglu- tamic acids 31, along with the recovery of the chiral ligand (S)-32. The ability to recycle the chiral ligand (S)-32, which can be reused for preparation of new batches of Ni(II) complex 27 is a significant advantage of this method. 8 allowed for the preparation of the corresponding pyroglutamic/glutamic acids bearing potentially useful unsaturated functionality. However, the general applicability of this method is greatly limited by the use of naturally occurring camphor as a chiral auxiliary, as its (1S, 4S) enantiomeric form is scarcely available. Another example of Michael addition reactions between chiral Schiff bases of glycine and α, β-unsaturated carboxylic acid derivatives was developed based on Ni(II) complex 27shown in Scheme 5 [80–83]. The Ni(II) complex 27 was found to react easily in MeOH and in the presence of NaOMe as a base, with methyl cinnamate and methacrylate, giving rise to the corresponding diastereomeric products 28 and 29. In both cases, the enolate face-diastereoselectivity was very high as α-(R)-configured products were not detected in noticeable amounts. However, diastereoselectivity at C-3 and C-4 positions was disappointingly low, furnishing the products in approximately a 2/1 and 1/1 ratio respectively. It is interesting to note that in this case the stereochemical outcome is kinetically controlled, these reactions are highly reversible and thus the ratios of diastereomeric products are thermodynamically controlled. NNO N OO Ni Ph Ph (S)-27 Ph O OMe NaOMe MeOH NNO N OO Ni Ph Ph O OMe Ph (S)(2S3R)-28 + (S)(2S3S) O OMe NNO N OO Ni Ph Ph O OMe Me (S)(2S4S)-29 + (S)(2S4R) Scheme 5. Michael addition reactions of chiral Ni(II) complex 27. Taking advantage of high C-H acidity of the glycine methylene group in 27, it was found that the corresponding Michael addition reactions with ethyl crotonate, 4,4,4- trifluorocrotonate andcinnamate [84,85]can be conducted in DMF in the presence of DBU as a base. The stereochemical outcome of the reactions was found to be kinetically controlled. The diastereoselectivity in the additions of (S)-27 with ethyl crotonate and cinnamate was found to be noticeably better compared to the outcomes observed under the thermodynamically controlled conditions (Scheme 5).The major products 30(R = Me, Ph) were obtained in a ratio of 4/1, respectively. The stereochemical outcome of the reaction between (S)-27 and ethyl 4,4,4-trifluorocrotonate was slightly higher, with a diastereomeric ratio of up to 5.6/1. This can be attributed to the more sterically demanding nature of the trifluoromethyl group [86–88]. The major diastereomers 30 were purified by crystallization of the reaction mixture and disassembled to afford the target pyroglutamic acids 31, along with the recovery of the chiral ligand (S)-32. The ability to recycle the chiral ligand (S)-32, which can be reused for preparation of new batches of Ni(II) complex 27 is a significant advantage of this method. Scheme 5. Michael addition reactions of chiral Ni(II) complex 27. Scheme 6. DBU-catalysed Michael addition reactions of chiral Ni(II) complex 27. 9 NNO N OO Ni Ph Ph (S)-27 DBU DMF NNO N OO Ni Ph Ph O OMe R 30 6M HCl THF, rt O OMeR R = Ph, CH3, CF3 R = Ph (S)(2S3R) R = CH3, CF3 (S)(2S3S) N R CO2H H O 31 ONHO N Ph Ph + Ni(II) Gly 32 Scheme 6. DBU-catalysed Michael addition reactions of chiral Ni(II) complex 27. Of particular interest are the reactions between the Ni complex (S)-27 and bis-substituted Michael acceptors 33 and 34 (Scheme 7) [89]. For instance, the simultaneous formation of α-, β-, and γ-stereogenic centers (eight theoretically possible stereoisomers) in the reaction of complex (S)-27 with ester 33 represents a challenging stereochemical problem. The Michael addition between (S)-27 and 33, conducted in DMF in the presence of DBU, resulted in only two diastereomers (major 35), in a synthetically useful ratio of 17/1, respectively. The reaction of complex (S)-27 with ester 36, conducted under the same reaction conditions, proceeded with virtually complete diastereoselectivity, furnishing a sole reaction product 36. Diastereomerically pure products 35 and 36 were disassembled to release interesting bis-substituted pyroglutamic acids 37 and 38. The high diastereoselectivity in these reactions, particularly the complete stereochemical discrimination between the methyl and trifluoromethyl groups in the addition of (S)-27, can be attributed to the steric and electronic effects of the trifluoromethyl group [90, 91]. NNO N OO Ni Ph Ph (S)-27 DBU DMF NNO N OO Ni Ph Ph O OMe CF3 35 6M HCl THF, rt O OEtF3C (S)(2S3S,4R) N CF3 CO2H H O 37 + 32 CH333 NNO N OO Ni Ph Ph O OMe 36(S)(2S,3S) O OEtF3C 34 CH3 N CF3 CO2H H O (2S3S,4R) 38(2S3S)CH3 CF3 CH3 Me Me Scheme 7. Michael addition reactions of complex 27 with fluorinated derivatives 33 and 34. 92 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY Of particular interest are the reactions be- tween the Ni complex (S)-27 and bis-substi- tuted Michael acceptors 33 and 34 (Scheme 7) [89]. For instance, the simultaneous forma- tion of α-, β-, and γ-stereogenic centers (eight theoretically possible stereoisomers) in the reaction of complex (S)-27 with ester 33 rep- resents a challenging stereochemical problem. The Michael addition between (S)-27 and 33, conducted in DMF in the presence of DBU, resulted in only two diastereomers (major 35), in a synthetically useful ratio of 17/1, respec- tively. The reaction of complex (S)-27 with ester 36, conducted under the same reaction conditions, proceeded with virtually complete diastereoselectivity, furnishing a sole reaction product 36. Diastereomerically pure products 35 and 36 were disassembled to release inte resting bis-substituted pyroglutamic acids 37 and 38. The high diastereoselectivity in these reactions, particularly the complete stereo- chemical discrimination between the methyl and trifluoromethyl groups in the addition of (S)-27, can be attributed to the steric and elect ronic effects of the trifluoromethyl group [90, 91]. 9 NNO N OO Ni Ph Ph (S)-27 DBU DMF NNO N OO Ni Ph Ph O OMe R 30 6M HCl THF, rt O OMeR R = Ph, CH3, CF3 R = Ph (S)(2S3R) R = CH3, CF3 (S)(2S3S) N R CO2H H O 31 ONHO N Ph Ph + Ni(II) Gly 32 Scheme 6. DBU-catalysed Michael addition reactions of chiral Ni(II) complex 27. Of particular interest are the reactions between the Ni complex (S)-27 and bis-substituted Michael acceptors 33 and 34 (Scheme 7) [89]. For instance, the simultaneous formation of α-, β-, and γ-stereogenic centers (eight theoretically possible stereoisomers) in the reaction of complex (S)-27 with ester 33 represents a challenging stereochemical problem. The Michael addition between (S)-27 and 33, conducted in DMF in the presence of DBU, resulted in only two diastereomers (major 35), in a synthetically useful ratio of 17/1, respectively. The reaction of complex (S)-27 with ester 36, conducted under the same reaction conditions, proceeded with virtually complete diastereoselectivity, furnishing a sole reaction product 36. Diastereomerically pure products 35 and 36 were disassembled to release interesting bis-substituted pyroglutamic acids 37 and 38. The high diastereoselectivity in these reactions, particularly the complete stereochemical discrimination between the methyl and trifluoromethyl groups in the addition of (S)-27, can be attributed to the steric and electronic effects of the trifluoromethyl group [90, 91]. NNO N OO Ni Ph Ph (S)-27 DBU DMF NNO N OO Ni Ph Ph O OMe CF3 35 6M HCl THF, rt O OEtF3C (S)(2S3S,4R) N CF3 CO2H H O 37 + 32 CH333 NNO N OO Ni Ph Ph O OMe 36(S)(2S,3S) O OEtF3C 34 CH3 N CF3 CO2H H O (2S3S,4R) 38(2S3S)CH3 CF3 CH3 Me Me Scheme 7. Michael addition reactions of complex 27 with fluorinated derivatives 33 and 34. Scheme 7. Michael addition reactions of complex 27 with fluorinated derivatives 33 and 34. Interesting results were obtained in the reac- tions of chiral Ni-complex (S)-27 [92–94] with oxazolinin-2-one derived Michael acceptors 39 (Scheme 8). These additions were studied us- ing DMF as a solvent and DBU as a base. The reactions were found tooccur at high reaction rates with perfect simple diastereoselectivity. On the other hand, the glycinecomplex enolate re/siface-selectivity was rather poorresulting generally in mixtures of two diastereomeric products 40. The highest diastereoselectivity, 5.2/1ratio of (S)(2S3S) and (S)(2R3R) diaste reomers 40, in the aliphatic series was obtained in thereaction of (S)-27 with i-Pr-containing 39. Rather interesting and unexpected results were observedin the reactions of (S)-27 with Michael acceptors bearing aromatic substi tuents. Thus, the addition between (S)-27 and 93https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 phenyl-containing 39 furnished a mixture of diastereomers 40 in a ratio of 4/1, respectively. In sharp contrast,the reaction between (S)-27 and pentafluorophenyl-containing 39 occurred almost instantly (<2 min) giving rise to product 40 with excellent diastereoselectivity (ratio > 26/1). Further detailed study of the electronic and steric effects ofthe substituents on stereo- chemical outcome in these reactions revealed a general trend that presence of the electron with drawing substituents on starting 39 led to higher reaction rates and diastereoselectivity, while the presence ofthe electron-releasing substituents resulted in low rates and moderate selectivity. To account for these electronic effects drama tically influencing the stereochemical outcome, one can consider electron donor-acceptor at- tractive interactions between electrondeficient aromatic rings, such as pentafluorophenyl [95–97] in particular, and the ketimine phenyl of the starting Ni-complex 27. The target pyro- glutamic acids 38 were obtained after standard disassembly procedure along with the recovery of chiral auxiliary (S)-32. Scheme 8. Michael addition reactions ofchiral N(II) complex 27 with oxazolinin-2-one derived Michael acceptors 39. 10 Interesting results were obtained in the reactions of chiral Ni-complex (S)-27 [92–94] with oxazolinin-2-one derived Michael acceptors 39 (Scheme 8). These additions were studied using DMF as a solvent and DBU as a base. The reactions were found tooccur at high reaction rates with perfectsimple diastereoselectivity. On the other hand, the glycinecomplex enolate re/siface-selectivity was rather poorresulting generally in mixtures of two diastereomericproducts 40. The highest diastereoselectivity, 5.2/1ratio of (S)(2S3S) and (S)(2R3R) diastereomers 40, in the aliphatic series was obtained in thereaction of (S)-27 with i-Pr-containing 39. Rather interesting and unexpected results were observedin the reactions of (S)-27 with Michael acceptors bearingaromatic substituents. Thus, the addition between (S)-27andphenyl-containing 39 furnished a mixture of diastereomers40in a ratio of 4/1, respectively. In sharp contrast,the reaction between (S)-27 and pentafluorophenyl-containing 39 occurred almost instantly (<2 min) giving rise to product 40 with excellent diastereoselectivity (ratio > 26/1).Further detailed study of the electronic and steric effects ofthe substituents on stereochemical outcome in these reactionsrevealed a general trend that presence of the electronwithdrawingsubstituents on starting 39 led to higherreaction rates and diastereoselectivity, while the presence ofthe electron-releasing substituents resulted in low rates andmoderate selectivity. To account for these electronic effectsdramatically influencing the stereochemical outcome, one can consider electron donor-acceptor attractive interactions betweenelectrondeficient aromatic rings, such as pentafluorophenyl [95–97] inparticular, and the ketimine phenyl of the starting Ni- complex 27. The target pyroglutamic acids 38 were obtained after standard disassembly procedure along with the recovery of chiral auxiliary (S)-32. NNO N OO Ni Ph Ph (S)-27 DBU DMF NNO N OO Ni Ph Ph O N R 40 6M HCl THF, rt (S)(2S3S) + (S)-32 O NR 39 N R CO2H H O 38(2S3S) O O O O (S)(2R3R)+ R = Me, Et, n-Pr, i-Pr, t-Bu, Ph, a-naphthyl, b-naphthyl, 2-MeO-C6H4, 3-MeO-C6H4, 4-MeO-C6H4, 2-CF3-C6H4, 3-CF3-C6H4, 4-CF3-C6H4, N-Mts-b-indolyl, C6F5, 2,6-F2-C6H3, 2-F-C6H4, 3,4-F2-C6H3, 4-MeO-C6F4, 3,4-Cl2-C6H3, 4-NO2 -C6H4 Scheme 8. Michael addition reactions ofchiral N(II) complex 27 with oxazolinin-2-one derived Michael acceptors 39. Considering the strong stereocontrolling effect of oxazolinin-2-one chiral auxiliaries [98– 100], it was interesting to investigate the corresponding Michael addition reactions using chiral Michael acceptors 41 and 42 (Scheme 9) with the chiral Ni(II) complex 27 [101– 103]. The addition reaction between (S)-27 and crotonyl-derived (S)-41, conducted in DMF/DBU at ambient temperature, proceeded to completion at a high rate, furnishing a sole reaction product 43 with the (2S, 3S) configuration of the glutamic acid residue in quantitative chemical yield. This outcome was considered a match case, as both chiral auxiliaries showed a preference for the α-(S) configuration of the addition product. The reaction of (S)-27 with crotonyl-derived (R)-42 was expected to be a mismatch case. The addition was conducted under the same conditions and occurred at a slightly slower rate, giving rise to a sole diastereomerically pure product 44. The absolute configuration of the glutamic residue in 44 was found to be (2R, 3R). This result was quite unexpected, Considering the strong stereocontrolling ef- fect of oxazolinin-2-one chiral auxiliaries [98– 100], it was interesting to investigate the corre- sponding Michael addition reactions using chi- ral Michael acceptors 41 and 42 (Scheme 9) with the chiral Ni(II) complex 27 [101–103]. The ad- dition reaction between (S)-27 and crotonyl-de- rived (S)-41, conducted in DMF/DBU at ambi- ent temperature, proceeded to completion at a high rate, furnishing a sole reaction product 43 with the (2S, 3S) configuration of the glutamic acid residue in quantitative chemical yield. This outcome was considered a match case, as both chiral auxiliaries showed a preference for the α-(S) configuration of the addition product. The reaction of (S)-27 with crotonyl-derived (R)-42 was expected to be a mismatch case. The addi- tion was conducted under the same conditions and occurred at a slightly slower rate, giving rise to a sole diastereomerically pure product 44. The absolute configuration of the glutamic re sidue in 44 was found to be (2R, 3R). This result was quite unexpected, suggesting that the ste reochemical preferences of the chiral Michael acceptor 42 completely overwhelmed those of the chiral Ni-complex (S)-27. 94 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY Scheme 9. Michael addition reactions between chiral Ni(II) complex 27 and Michael acceptors 41 and 42. 11 suggesting that the stereochemical preferences of the chiral Michael acceptor 42 completely overwhelmed those of the chiral Ni-complex (S)-27. NNO N OO Ni Ph Ph (S)-27 DBU DMF N (Z) NO N OO Ni Ph Ph O N R 43 6M HCl THF, rt (S)(2S3S) N R CO2H H O 45 + 32 NNO N OO Ni Ph Ph O N 44(S)(2R,3R) N R CO2H H O (2S3S,4R) 46 O NR 41 O O O NR 42 O O Ph (S) (R) Ph (2R3R) O O O O Ph Ph R = Me; Et; n-Pr; i-Pr; Bn; Ph; b-naphthyl; 4-MeO-C6H4; 3-MeO-C6H4; N-Mts-b-indolyl; 4-CF3-C6H4 Scheme 9. Michael addition reactions between chiral Ni(II) complex 27 and Michael acceptors 41 and 42. The same pattern of reactivity and stereochemical preferences was observed in the reactions of (S)-27 with various Michael acceptors 41 and 42, bearing, in principle, any alkyl or aromatic substituents (Scheme 9). Of particular interest was the addition between (S)-27 and the bulky i-Pr-containing 41/42. When (S)-41 (R = i-Pr) was used, the reaction proceeded to completion in 30 minutes, affording the product (2S, 3R)-43 in quantitative chemical yield. In the mismatch case, the addition between (S)-27 and (R)-42 (R = i-Pr) was considerably slower and accompanied by the formation of some by-products. Nevertheless, within 4 hours the reaction was completed, and the target product (2R, 3S)- 44 was isolated in 67% yield [101–103]. The results obtained clearly indicated that the steric and electronic nature of the substituents on the starting Michael acceptors 41/42 do not influence the stereochemical outcome of reactions with (S)-27, suggesting that the substituents on the C,C double bond of 41/42 are not involved in the stereocontrolling step of the additions. This observation highlighted the generality of the method and underscored the intriguing stereocontrolling power of the chiral oxazolidine-2-one- derived Michael acceptors 41/42 [101–103].The final amino acids 45 and 46 were prepared by acidic disassembly of the addition products, along with the recovery and reuse of the chiral ligand 32. To take advantage of this discovery, the reactions of achiral Ni(II) complex 47 (Scheme 10) with chiral Michael acceptors 41/42 were investigated [104–106]. Picolinic acid- derived achiral complex 47 [107] was reacted with Michael acceptor 42 in DMF at room temperature in the presence of 15 mole % DBU. The addition occurred at a high rate, affording a sole reaction product 48 in quantitative chemical yield. Application of (S)- configured 41 mirrored the result obtained for (R)-42, affording individual product 48 containing the (2S, 3S)-enantiomer of β-methyl glutamic acid. The same excellent stereochemical outcome was observed in the reaction of all alkyl-containing 41/42 (R = Et, n-Pr, Bn), except for the addition between complex 47 and bulky i-Pr-containing 41/42. In this case, the reaction proceeded very slowly, allowing for about 30% conversion of the starting compounds in 4 hours. Though the corresponding products 48 The same pattern of reactivity and stereo chemical preferences was observed in the reactions of (S)-27 with various Michael ac- ceptors 41 and 42, bearing, in principle, any alkyl or aromatic substituents (Scheme 9). Of particular interest was the addition between (S)-27 and the bulky i-Pr-containing 41/42. When (S)-41 (R = i-Pr) was used, the reac- tion proceeded to completion in 30 minutes, affording the product (2S, 3R)-43 in quanti- tative chemical yield. In the mismatch case, the addition between (S)-27 and (R)-42 (R = i-Pr) was considerably slower and accompa- nied by the formation of some by-products. Nevertheless, within 4 hours the reaction was completed, and the target product (2R, 3S)-44 was isolated in 67% yield [101–103]. The re- sults obtained clearly indicated that the steric and electronic nature of the substituents on the starting Michael acceptors 41/42 do not influ- ence the stereochemical outcome of reactions with (S)-27, suggesting that the substituents on the C,C double bond of 41/42 are not involved in the stereocontrolling step of the additions. This observation highlighted the generality of the method and underscored the intriguing stereocontrolling power of the chiral oxazoli- dine-2-one-derived Michael acceptors 41/42 [101–103].The final amino acids 45 and 46 were prepared by acidic disassembly of the ad- dition products, along with the recovery and reuse of the chiral ligand 32. To take advantage of this discovery, the reac- tions of achiral Ni(II) complex 47 (Scheme 10) with chiral Michael acceptors 41/42 were in- vestigated [104–106]. Picolinic acid-derived achiral complex 47 [107] was reacted with Mi- chael acceptor 42 in DMF at room temperature in the presence of 15 mole % DBU. The addition occurred at a high rate, affording a sole reac- tion product 48 in quantitative chemical yield. Application of (S)-configured 41 mirrored the result obtained for (R)-42, affording individual product 48 containing the (2S, 3S)-enantiomer of β-methyl glutamic acid. The same excellent stereochemical outcome was observed in the reaction of all alkyl-containing 41/42 (R = Et, n-Pr, Bn), except for the addition between 95https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 complex 47 and bulky i-Pr-containing 41/42. In this case, the reaction proceeded very slow- ly, allowing for about 30% conversion of the starting compounds in 4 hours. Though the corresponding products 48 and 49 were iso- lated in 15% yield, these results suggested that the present method could not be extended to substrates containing tertiary alkyl groups. To examine the applicability of the method to an aromatic series, which would lead to the synthesis of the corresponding 3-aryl substi- tuted amino acids, the reactions of complex 47 with (S)- and (R)-configured Michael ac- ceptors 41/42 containing classical phenyl and naphthyl groups, as well as derivatives bearing a phenyl ring with electron-withdrawing and electron-donating substituents, were studied. In all cases, regardless of the steric or electronic nature of the substituent on the starting 41/42, major products 48 or 49 were obtained with at least 95% de and excellent chemical yields. In both aliphatic and aromatic series, the stereo- chemical outcome was shown to be kinetical- ly controlled, affording products with relative topicity like. Scheme 10. Michael additions between achiral Ni(II) complex 47 and chiral acceptors 41 and 42. 12 and 49 were isolated in 15% yield, these results suggested that the present method could not be extended to substrates containing tertiary alkyl groups. To examine the applicability of the method to an aromatic series, which would lead to the synthesis of the corresponding 3-aryl substituted amino acids, the reactions of complex 47 with (S)- and (R)-configured Michael acceptors 41/42 containing classical phenyl and naphthyl groups, as well as derivatives bearing a phenyl ring with electron-withdrawing and electron-donating substituents, were studied. In all cases, regardless of the steric or electronic nature of the substituent on the starting 41/42, major products 48 or 49 were obtained with at least 95% de and excellent chemical yields. In both aliphatic and aromatic series, the stereochemical outcome was shown to be kinetically controlled, affording products with relative topicity like. NNO N OO Ni Ph 47 DBU DMF NNO N OO Ni Ph O N R 48 6M HCl THF, rt (S)(2S3S) N R CO2H H O 45 NNO N OO Ni Ph O N 49(S)(2R,3R) N R CO2H H O (2S3S,4R) 46 O NR 41 O O O NR 42 O O Ph (S) (R) Ph (2R3R) O O O O Ph Ph R = Me; Et; n-Pr; i-Pr; Bn; Ph; b-naphthyl; 4-MeO-C6H4; 3-MeO-C6H4; N-Mts-b-indolyl; 4-CF3-C6H4 Scheme 10. Michael additions between achiral Ni(II) complex 47 and chiral acceptors 41 and 42. To demonstrate the synthetic efficiency of this method, >25 g of enantiomerically pure β-phenyl pyroglutamic acid (2S, 3R)-45 was prepared in >85% total yield in less than 14 hours. In this case, the crystalline product 49 of the addition between 47 and (R)-42 was isolated simply by filtration after pouring the reaction mixture into water. Without additional purification, product 49 was disassembled to afford the target amino acid 46. The relatively broad substrate generality, excellent chemical yields and diastereoselectivity, combined with the simplicity of the experimental procedures, render the present method synthetically superior to the literature method for preparing various 3-substituted pyroglutamic acids and related amino acids. Apparent success of these Ni(II) complexes in the asymmetric Michael addition reactions stimulatedinterest in the developing of new types of chiral as well as achiral Ni(II) complexes [108–111]. Figure 4 presents just a few most prospective types. To demonstrate the synthetic efficiency of this method, >25 g of enantiomerically pure β-phenyl pyroglutamic acid (2S, 3R)-45 was prepared in >85% total yield in less than 14 hours. In this case, the crystalline product 49 of the addition between 47 and (R)-42 was iso- lated simply by filtration after pouring the re- action mixture into water. Without additional purification, product 49 was disassembled to afford the target amino acid 46. The relatively broad substrate generality, ex- cellent chemical yields and diastereoselectivity, combined with the simplicity of the experi- mental procedures, render the present method synthetically superior to the literature method for preparing various 3-substituted pyroglu- tamic acids and related amino acids. Apparent success of these Ni(II) complexes in the asymmetric Michael addition reactions stimulatedinterest in the developing of new types of chiral as well as achiral Ni(II) com- plexes [108–111]. Figure 4 presents just a few most prospective types. 96 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY Fig. 4. New generation of chiral and achiral Ni(II) complexes. 13 NNO N OO Ni Cl Cl Cl (S)-50 NNO N OO Ni Cl (S)(S)-51 Cl NNO N OO Ni Cl (SC)(SN)-52 CH3 H NNO N OO Ni Cl (S)-53 NNO N OO Ni Cl 54 Me Me NNO N OO Ni Cl 55 Fig. 4. New generation of chiral and achiral Ni(II) complexes. For example, chlorinated Ni(II) complex 50, available in both enantiomeric forms [112] possesses exceptional stereocontrolling properties [113,114] due to electrostatic interactions between electron-rich benzophenone phenyl and electron-deficientchlorine- containing rings [115].Thus, complex (S)-50 was successfully used in Michael addition for the synthesis of (2S, 3S)‑3‑methylglutamine, the key compound used in the total synthesis of cytotoxic marine peptides callipeltin O and Q [116]. As presented in Scheme 11, glycine Ni(II) complex 50 was reacted with Michael acceptor 51 under specially designed conditions to keep intact the allyl ester moiety [117]. NNO N OO Ni Ph Cl Cl Cl (S)-50 O OAllyl 56 K2CO3, iPrOH NNO N OO Ni Ph Cl Cl Cl O OAllyl Me (S)(2S,3S)-57 6M HCl, THF, rt AllylO O Me NH3Cl CO2H XanHN O Me NHFmoc CO2H (2S,3S)-58 (2S,3S)-59 5 steps Scheme 11. Synthesis of properly protected (2S,3S)‑3‑methylglutamine59 using rationally designed chlorinated Ni(II)-complex (S)-50. For example, chlorinated Ni(II) complex 50, available in both enantiomeric forms [112] possesses exceptional stereocontrolling pro perties [113,114] due to electrostatic interac- tions between electron-rich benzophenone phenyl and electron-deficientchlorine-con- taining rings [115].Thus, complex (S)-50 was successfully used in Michael addition for the synthesis of (2S, 3S)‑3‑methylglutamine, the key compound used in the total synthesis of cytotoxic marine peptides callipeltin O and Q [116]. As presented in Scheme 11, glycine Ni(II) complex 50 was reacted with Michael acceptor 51 under specially designed condi- tions to keep intact the allyl ester moiety [117]. The acidic disassembly of the major dia stereomeric product (S)(2S3S)-57 was also performed under strictly controlled condi- tions using THF as a solvent. Allyl ester hy- drochloride 58 was subsequently transformed into the target properly protected for peptide synthesis glutamine derivative 59 in five steps. It was demonstrated that the substitution of phenylalanine in endogenous peptides with a bulkier and more lipophilic β-phenylphenyl alanine (diphenylalanine, DPA) usually leads to improved binding to the apolar site of the targeted receptors. In particular, DPA-modi- fied peptides were found to possess enhanced biological profiles in the series of thrombin inhibitors [118], angiotensin-converting en- zyme (ACE) inhibitors [119], HIV protease inhibitors [120], pain-related norepineph- rine transporter inhibitors [121], μ and δ opioid receptors [122]. In this regard, 2-ami- no-4,4-bis-(phenylsulfonyl)butanoic acid 60 (Scheme 12) is one of the promising structures featuring enhanced steric bulk and lipophili city. Chiral Schiff base complex 50 was selected for preparation of this amino acids via Michael addition using specially designed vinyl–disul- fonyl Michael acceptor 61 [123, 124]. 97https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 13 NNO N OO Ni Cl Cl Cl (S)-50 NNO N OO Ni Cl (S)(S)-51 Cl NNO N OO Ni Cl (SC)(SN)-52 CH3 H NNO N OO Ni Cl (S)-53 NNO N OO Ni Cl 54 Me Me NNO N OO Ni Cl 55 Fig. 4. New generation of chiral and achiral Ni(II) complexes. For example, chlorinated Ni(II) complex 50, available in both enantiomeric forms [112] possesses exceptional stereocontrolling properties [113,114] due to electrostatic interactions between electron-rich benzophenone phenyl and electron-deficientchlorine- containing rings [115].Thus, complex (S)-50 was successfully used in Michael addition for the synthesis of (2S, 3S)‑3‑methylglutamine, the key compound used in the total synthesis of cytotoxic marine peptides callipeltin O and Q [116]. As presented in Scheme 11, glycine Ni(II) complex 50 was reacted with Michael acceptor 51 under specially designed conditions to keep intact the allyl ester moiety [117]. NNO N OO Ni Ph Cl Cl Cl (S)-50 O OAllyl 56 K2CO3, iPrOH NNO N OO Ni Ph Cl Cl Cl O OAllyl Me (S)(2S,3S)-57 6M HCl, THF, rt AllylO O Me NH3Cl CO2H XanHN O Me NHFmoc CO2H (2S,3S)-58 (2S,3S)-59 5 steps Scheme 11. Synthesis of properly protected (2S,3S)‑3‑methylglutamine59 using rationally designed chlorinated Ni(II)-complex (S)-50. Scheme 11. Synthesis of properly protected (2S,3S)‑3‑methylglutamine59 using rationally designed chlorinated Ni(II)-complex (S)-50. 14 The acidic disassembly of the major diastereomeric product (S)(2S3S)-57 was also performed under strictly controlled conditions using THF as a solvent. Allyl ester hydrochloride 58 was subsequently transformed into the target properly protected for peptide synthesis glutamine derivative 59 in five steps. It was demonstrated that the substitution of phenylalanine in endogenous peptides with a bulkier and more lipophilic β-phenylphenylalanine (diphenylalanine, DPA) usually leads to improved binding to the apolar site of the targeted receptors. In particular, DPA- modified peptides were found to possess enhanced biological profiles in the series of thrombin inhibitors [118], angiotensin-converting enzyme (ACE) inhibitors [119], HIV protease inhibitors [120], pain-related norepinephrine transporter inhibitors [121], μ and δ opioid receptors [122]. In this regard, 2-amino-4,4-bis-(phenylsulfonyl)butanoic acid 60 (Scheme 12) is one of the promising structures featuring enhanced steric bulk and lipophilicity. Chiral Schiff base complex 50 was selected for preparation of this amino acids via Michael addition using specially designed vinyl–disulfonyl Michael acceptor 61 [123, 124]. 60 NNO N OO Ni Ph Cl Cl Cl (S)-50 NNO N OO Ni Ph Cl Cl Cl (S)(2S)-62 HN CO2H S SMeCN, TEA, 50 °C, 13 h yield 99% dr 93:7 1) 6N HCl, MeOH, 50 °C, 2 h 2) EDTA-2Na, Na2CO3, Fmoc-OSu, H2O/MeCN Fmoc S S O O Ph O O Ph S S O O O O Ph Ph 61 O S O O Scheme 12. Asymmetric synthesis of sterically bulky and lipophilic 2-amino-4,4-bis- (phenylsulfonyl)butanoic acid (S)-60. It was found that due to the high electrophilicity of reagent61, the corresponding Michael addition with chiral glycine complex 50 can be efficiently conducted using triethylamine as base. Optimization of the reaction conditions allowed for preparation of the diastereomeric products with an excellent yield (99%) and excellent diastereoselectivity (93/7). The major product 62 was transformed into the corresponding Fmoc derivative of 2-amino-4,4-bis-(phenylsulfonyl)butanoic acid 60 under standard conditions. Rather unexpected resultswere reported for the Michael addition between chiral glycine Ni(II) complex 50 and Michael acceptor 63 bearing a tosylate leaving group (Scheme 13) [125]. The original goal of this research was preparation of addition product 64 containing the corresponding β-methyl-unsaturated amino acid moiety. However, quite surprisingly, compound 65 was isolated as the major reaction product. (S)-3- Methyleneglutamic acid 66 was previously unknown in enantiomerically pure form. One can assume that the target addition product 64 underwent base-catalyzed isomerization to 65. Major product (S)(S)-65 was isolated in diastereomerically pure form and disassembled to release the unsaturated amino acid (S)-66 along with the chiral ligand (S)-67, which was recycled and reused for preparation of new portions of starting chiral glycine Schiff base Ni(II) complex (S)-50. It was found that due to the high electro- philicity of reagent61, the corresponding Mi- chael addition with chiral glycine complex 50 can be efficiently conducted using triethyl- amine as base. Optimization of the reaction conditions allowed for preparation of the dia stereomeric products with an excellent yield (99%) and excellent diastereoselectivity (93/7). The major product 62 was transformed into the corresponding Fmoc derivative of 2-ami- no-4,4-bis-(phenylsulfonyl)butanoic acid 60 under standard conditions. Rather unexpected resultswere reported for the Michael addition between chiral glycine Ni(II) complex 50 and Michael acceptor 63 bearing a tosylate leaving group (Scheme 13) [125]. The original goal of this research was preparation of addition product 64 containing the corresponding β-methyl-unsaturated ami- no acid moiety. However, quite surprisingly, compound 65 was isolated as the major reac- tion product. (S)-3-Methyleneglutamic acid 66 was previously unknown in enantiomeri- cally pure form. One can assume that the tar- get addition product 64 underwent base-cata- lyzed isomerization to 65. Major product (S) (S)-65 was isolated in diastereomerically pure form and disassembled to release the unsatu- rated amino acid (S)-66 along with the chiral ligand (S)-67, which was recycled and reused for preparation of new portions of starting chi- ral glycine Schiff base Ni(II) complex (S)-50. Scheme 12. Asymmetric synthesis of sterically bulky and lipophilic 2-amino-4,4-bis-(phenylsulfonyl)butanoic acid (S)-60. 98 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY Scheme 13. Asymmetric synthesis of (S)-3-methyleneglutamic acid 66 via Michael addition reaction. 15 (S)-50 NNO N OO Ni Ph Cl Cl Cl (S)-66 63 TsO Me CO2Et NNO N OO Ni Ph Cl Cl Cl (S)(S)-64 Me CO2Et NNO N OO Ni Ph Cl Cl Cl CO2Et (S)(S)-65 K2CO3, MeOH K2CO3, MeOH HCl NH2 CO2H O HO + (S)-67 ONHO N Ph Cl Cl Cl Gly Ni(II) Scheme 13. Asymmetric synthesis of (S)-3-methyleneglutamic acid 66 via Michael addition reaction. Achiral complex 55 was selected for preparation of 4-substituted configurationally stable thalidomide derivatives 68 (Scheme 14) [126,127]. As illustrated in Scheme 14, key step in the multistep synthesis of the thalidomide derivatives is Michael addition reaction of achiral glycineSchiff base derivatives 55 with chiral (R)- or (S)-N- (E-enoyl)-4-phenyl-1,3-oxazolidine-2-one 69 were conducted in DMF using DBU as a base.The resultant addition products 70 were isolated as individual diastereoisomers in quantitative chemical yields.Products 70 can be easily hydrolyzed under mild conditionsand, upon a workup procedure, transformed to the pyroglutamicacids 71 along with recovery of ligand 72 which can be used for preparation of the starting complex 55. Hydrolysis of pyroglutamic acids 71 with 3N HCl at reflux afforded 3-substituted glutamicacids 73 in high chemical yield. Achiral complex 55 was selected for prepa- ration of 4-substituted configurationally sta- ble thalidomide derivatives 68 (Scheme 14) [126,127]. As illustrated in Scheme 14, key step in the multistep synthesis of the thalidomide derivatives is Michael addition reaction of achiral glycine Schiff base derivatives 55 with chiral (R)- or (S)-N-(E-enoyl)-4-phenyl-1,3- oxazolidine-2-one 69 were conducted in DMF using DBU as a base.The resultant addition products 70 were isolated as individual dia stereoisomers in quantitative chemical yields. Products 70 can be easily hydrolyzed under mild conditions and, upon a workup proce- dure, transformed to the pyroglutamic acids 71 along with recovery of ligand 72 which can be used for preparation of the starting complex 55. Hydrolysis of pyroglutamic acids 71 with 3N HCl at reflux afforded 3-substituted glu- tamic acids 73 in high chemical yield. The next step, transformation of acid 73 to N-phthaloyl anhydrides 74, was an important step as it was expected that during this process the corresponding alpha-stereogenic carbon would undergo epimerization setting up the trans-configuration in the final products 74 [128]. Indeed the transformation of acids 73 to N-phthaloyl anhydrides 74, occurred as ex- pected furnishing a single diastereomers 74 in up to 70% (two steps)yield. The final transfor- mation of enantio- and diastereomerically pure 74 to the target 4-substituted thalidomides 68, was conducted in two major steps under the standard conditions [129]. After hydrolysis of anhydrate 74 with water in acetone, the corre- sponding intermediates were smooth lytrans formed to 68 using trifluoroacetamide as a source of nitrogen. The target products 68 were isolated in good yields (~70% for two steps) as single diastereomers. 99https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 Scheme 14. Asymmetric synthesis of 4-substituted thalidomide derivatives via Michael addition reactions. 16 68 NNO N OO Ni Ph Cl (R)-69 R 55 N O O Ph O DBU/DMF NNO N OO Ni Ph Cl 70 R O N O O Ph HCl H2O ONHO N Ph Cl 72 N H R CO2H O + R = Me, CF3, Ph 1) HCl 2) O R CO2HHO2C NH2 1) Phthalic anhydride, PyH 2) Ac2O N O R O OO O 1) H2O/Me2CO 2) CF3CONH2 HOBt, EDCl 3) Net3N NH R O OO O 71 73 74 Scheme 14. Asymmetric synthesis of 4-substituted thalidomide derivatives via Michael addition reactions. The next step,transformation of acid 73 to N-phthaloyl anhydrides 74, was an important step as it was expected that during this process the corresponding alpha-stereogenic carbon would undergo epimerization setting up the trans-configuration in the final products 74 [128]. Indeed the transformation of acids 73 to N-phthaloyl anhydrides 74, occurred as expected furnishing a single diastereomers 74 in up to 70% (two steps)yield. The final transformation of enantio- and diastereomericallypure 74 to the target 4- substituted thalidomides 68, was conducted in two major steps under the standard conditions [129]. After hydrolysis of anhydrate 74 with water in acetone, the corresponding intermediateswere smoothlytrans formed to 68 using trifluoroacetamide as a source of nitrogen. The target products 68 were isolated in good yields (~70% for two steps) as single diastereomers. With the goal of developing a new approach for preparing analogs of oxazolomycin family products 78 (Scheme 15), the reaction of achiral Ni(II) complex 55 with disubstituted chiral Michael acceptor 75 was considered a key step, allowing the formation of the structural frame as well as the three required stereogenic centers.Interestingly, the reaction of 55 with 75 conducted in DMF/DBU did not proceed at all, resulting in complete recovery of the starting material. Eventually, after numerous attempts to find the right conditions, 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD), slightly more basic than DBU, was found to catalyze the reaction, affording a mixture of the Michael addition products. It was determined that the reaction mixture consisted of six diastereomers obtained in a ratio of 68:8:7:7:7:3. The major product was separated by silica gel column chromatography to give 76 in 62% isolated yield [130]. Scheme 15. Asymmetric synthesis of 3,4-disubstituted pyroglutamic acid 77 via Michael addition reaction of achiral N(II) complex 55. 17 NNO N OO Ni Ph Cl (S)-75 55 N O O Ph O TBD/DMF NNO N OO Ni Ph Cl 76 O N O O Ph HCl H2O ONHO N Ph Cl 72 N H OBn CO2H O + BnO OBn NO O O CO2Me 77 78 Scheme 15. Asymmetric synthesis of 3,4-disubstituted pyroglutamic acid 77 via Michael addition reaction of achiral N(II) complex 55. Under standard acidic conditions, the major diastereomer 76 was disassembled to release the target pyroglutamic acid 77 along with the reusable tridentate ligand 72. Key amino acid 77 was then transformed into oxazolomycin analog 78 using literature procedures. Application of this Ni(II) complex methodology is not limited to glutamic acids and can be extended to preparing various other derivatives using, to mention just a few, alkyl halide alkylations [131–133], aldol [134–136], Mannich [113,137] addition reactionsand DKR [138,139]. CONCLUSIONS. This review has sought to emphasize the key synthetic and methodological concepts developed to control both simple and facial stereoselectivity in Michael addition reactions involving nucleophilic glycine equivalents and α, β- unsaturated carboxylic acid derivatives. While some methods discussed hold historical significance, others present practical, generalized, and synthetically efficient solutions. However, various synthetic and stereochemical challenges remain, particularly in reactions involving α-, α, β-bis-, and β, β-bis-substituted α,β-unsaturated carboxylic acid derivatives. As the importance of sterically constrained glutamic/pyroglutamic acids and related amino acids continues to grow, Michael addition reactions–offering the most straightforward and generalized approach to this family of amino acids—will remain a fascinating and challenging area in the field of asymmetric synthesis. ACKNOWLEDGMENTS. We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21761132021) and the Qing-Lan Project of Jiangsu Province (for Han) and IKERBASQUE, Basque Foundation for Science (for Soloshonok). АСИМЕТРИЧНИЙ СИНТЕЗ ГЛУТАМІНОВИХ КИСЛОТ З ОБМЕЖЕННЯМ ПОХІТАПОВ'ЯЗАНИХ СПОЛУК ШЛЯХОМ РЕАКЦІЙ МІХАЕЛЯ Аліція Взорек, Олександр Е. Сорочинський, Карел Д. Кліка, Таїзо Оно, Цзяньлінь Хань, Вадим А. Солошонок With the goal of developing a new approach for preparing analogs of oxazolomycin fami ly products 78 (Scheme 15), the reaction of achiral Ni(II) complex 55 with disubstituted chiral Michael acceptor 75 was considered a key step, allowing the formation of the struc- tural frame as well as the three required ste- reogenic centers.Interestingly, the reaction of 55 with 75 conducted in DMF/DBU did not proceed at all, resulting in complete recovery of the starting material. Eventually, after nu- merous attempts to find the right conditions, 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD), slightly more basic than DBU, was found to catalyze the reaction, affording a mixture of the Michael addition products. It was determined 100 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY that the reaction mixture consisted of six dia stereomers obtained in a ratio of 68:8:7:7:7:3. The major product was separated by silica gel column chromatography to give 76 in 62% iso- lated yield [130]. Under standard acidic conditions, the major diastereomer 76 was disassembled to release the target pyroglutamic acid 77 along with the reusable tridentate ligand 72. Key amino acid 77 was then transformed into oxazolomycin analog 78 using literature procedures. Application of this Ni(II) complex metho dology is not limited to glutamic acids and can be extended to preparing various other deriva tives using, to mention just a few, alkyl halide alkylations [131–133], aldol [134–136], Man- nich [113, 137] addition reactionsand DKR [138, 139]. CONCLUSIONS. This review has sought to emphasize the key synthetic and methodolo gical concepts developed to control both sim- ple and facial stereoselectivity in Michael ad- dition reactions involving nucleophilic glycine equivalents and α, β-unsaturated carboxylic acid derivatives. While some methods dis- cussed hold historical significance, others present practical, generalized, and syntheti- cally efficient solutions. However, various syn- thetic and stereochemical challenges remain, particularly in reactions involving α-, α, β-bis-, and β, β-bis-substituted α,β-unsaturated car- boxylic acid derivatives. As the importance of sterically constrained glutamic/pyroglutam- ic acids and related amino acids continues to grow, Michael addition reactions–offering the most straightforward and generalized ap- proach to this family of amino acids – will re- main a fascinating and challenging area in the field of asymmetric synthesis. We gratefully acknowledge the finan- cial support from the National Natu- ral Science Foundation of China (No. 21761132021) and the Qing-Lan Pro- ject of Jiangsu Province (for Han) and IKERBASQUE, Basque Foundation for Science (for Soloshonok). АСИМЕТРИЧНИЙ СИНТЕЗ ХІРО-ОБМЕЖЕНИХ ГЛУТАМІНОВИХ КИСЛОТ І СПОРІДНЕНИХ СПОЛУК ЗА ДОПОМОГОЮ РЕАКЦІЙ МІХАЕЛЯ Аліція Взорек, Олександр Е. Сорочинський, Карел Д. Кліка, Таїзо Оно, Цзяньлінь Хань, Вадим А. Солошонок 1Інститут хімії, Університет імені Яна Кохановського в Кельце, вул. Університецька 7, 25–406 Кельце, Польща; 2Відділ тонкого органічного синтезу, Інс титут біоорганічної хімії та нафтохімії ім. В. П. Кухаря, Національна академія наук України, вул. Мурманська 1, Київ 02094, Україна; 3Аналіз молекулярних структур, Німець- кий центр дослідження раку (DKFZ), Ім-Нойенгеймер-Фельд 280, 69120 Гайдель- берг, Німеччина; 4Національний інститут передових про- мислових наук і технологій, 463–8560, Нагоя, Японія; 5Цзянсуський центр спільних інновацій з ефективного оброблення та використання лісових ресурсів, Коледж хімічної інженерії, Нанкінський лісотехнічний університет, Нанкін 210037, Китай; 6Кафедра органічної хімії I, Хімічний фа- культет, Університет Країни Басків UPV/ EHU, проспект Мануеля Лардисабаля 3, 20018 Сан-Себастьян, Іспанія; 7IKERBASQUE, Баскський фонд науки, вул. Марії Діасде Харо 3, площа Бізкайя, 48013 Більбао, Іспанія. email: vadimsoloshonok@gmail.com 101https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 Реакції Міхаеля, що включають нуклео- фільні еквіваленти гліцинута α, β-ненасиче- ні похідні карбонових кислот, пропонують короткий та узагальнений методологічний підхід до синтезу сімейства амінокислот з xi-обмеженням, що містять п’ять атомів вуглецю. Ціамінокислоти відіграють вирі- шальну роль у дизайні нових пептидів та в з’ясуванні тривимірної структури пепти- дів/білків та їхніх біологічних функцій/ак- тивності. У цьому огляді узагальнено знач- ні синтетичні та методологічні досягнення у зазначеній галузі на сьогодні. Кожен роз- глянутий метод включає оцінку синтетич- них можливостей і обмежень, практичнос- ті та ефективності процедур і механістичне обґрунтування спостережуваних стереохі- мічних переваг. Ключові слова: асиметричний синтез, реакції Міхаеля, еквіваленти гліцину, мета- локомплекси, шіфові основи, конформації, стеричне обмеження, глутамінова кислота, піроглутамінова кислота, пролін. REFERENCES 1. Vickery H. B., Schmidt C. L. A. The history of the discovery of the amino acids. Chem. Rev. 1931. 9: 169–318. 2. Fieulaine S., Boularot A., Artaud I., et al. Trapping Conformational States Along Li- gand-Binding Dynamics of Peptide Deformy lase: The Impact of Induced Fit on Enzyme Ca- talysis. PLOS Biology. 2011. 9: e1001066. 3. Kaiser A., Coin I. Capturing Peptide–GPCR Interactions and Their Dynamics. Molecules. 2020. 25: 4724. 4. Rosenblum D., Joshi N., Tao W. et al. Progress and challenges towards targeted delivery of cancer therapeutics. Nature Communications. 2018. 9: 1410. 5. Mitchell M. J., Billingsley M. M., Haley R. M. et al. Engineering precision nanoparticles for drug delivery. Nature Reviews Drug Discovery. 2021. 20: 101–124. 6. Muttenthaler M., King G. F., Adams D. J., Ale- wood, P. F. Trends in peptide drug discovery. Nature Reviews Drug Discovery. 2021. 20: 309– 325. 7. Han J., Konno H., Sato T. et al. Tailor-made amino acids in the design of small-molecule blockbuster drugs. Eur. J. Med. Chem. 2021. 220: 113448. doi.org/10.1016/j.ejmech.2021.113448. 8. Liu J., Han J., Izawa K. et al. Cyclic tailor-made amino acids in the design of modern pharma- ceuticals. Eur. J. Med. Chem. 2020. 208: 112736. Doi:10.1016/j.ejmech.2020.112736. 9. Mei H., Han J., White S. et al. Tailor-made ami- no acids and fluorinated motifs as prominent traits in modern pharmaceuticals. Chem.–Eur. J. 2020. 26: 11349–11390. https://doi.org/10.1002/chem.202000617. 10. Ma J.S. Unnatural amino acids in drug disco very. Chim Oggi-Chem Today. 2003 21: 65–68. 11. Fosgerau K., Hoffmann T. Peptide therapeu- tics: Current status and future directions. Drug Discov Today. 2015. 20: 122–128. 12. Asymmetric Synthesis and Application of α-Amino Acids. ACS Symposium Series #1009, Soloshonok V.A., Izawa K. Eds. Oxford Univer- sity Press. 2009. 13. Hodgson D.R.W., Sanderson J.M. The synthesis of peptides and proteins containing non-natural amino acids. Chem. Soc. Rev. 2004. 33: 422–430. 14. Henninot A., Collins J. C., Nuss J. M. The cur- rent state of peptide drug discovery: Back to the future? J. Med. Chem. 2018. 61: 1382–1414. 15. Mei H., Han J., Klika K. D. et al. Applications of fluorine containing amino acids for drug de- sign. Eur. J. Med. Chem. 2020. 186: 111826. https://doi.org/10.1016/j.ejmech.2019.111826. 16. Craik D. J., Fairlie D. P., Liras S., Price D. The future of peptide based drugs. Chem. Biol. Drug. Des. 2013. 81: 136–147. 17. Han J., Sorochinsky A. E., Ono T. et al. Biomi- metic Transamination – a Metal-Free Alterna- tive to the Reductive Amination. Application 102 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY for Generalized Preparation of Fluorine-Con- taining Amines and Amino Acids. Cur. Org. Synthesis 2011. 8: 281–294. 18. Stevenazzi A., Marchini M., Sandrone G. at al. Amino acidic scaffolds bearing unnatural side chains: An old idea generates new and versatile tools for the life sciences. Bioorg. Med. Chem. Lett. 2014. 24: 5349–5356. 19. Han J., Konno H., Sato T. et al. Peptidomi- metics and Peptide-Based Blockbuster Drugs. Curr. Org. Chem. 2021. 25: 1627–1658. DOI: 10.2174/1385272825666210610155047 20. Han J., Wzorek A., Dhawan G. et al. New drugs appearing on the market in 2023: molecules containing fluorine and fragments of tai- lor-made amino acids. Ukr. Bioorg. Acta 2024. 19 (1): 3–20. https://doi.org/10.15407/bioorganica2024.01. 003 21. Pagire S. H., Lee E., Pagire H. S. et al. Design, synthesis and biological evaluation of glutam- ic acid derivatives as anti-oxidant and anti-in- flammatory agents. Bioorg. Med. Chem. Lett. 2017. 28: 5290–5321. 22. Panday S. K. Pyroglutamic Acid and its Deriv- atives: The Privileged Precursors for the Asym- metric Synthesis of Bioactive Natural Products. Bentham Science. 2020. 17(6): 626–6462. 23. Sun M., Han L., Li A. et al. Design, synthesis, and evaluation of novel L-pyroglutamic acid derivatives as potent antifungal agents. Chemis- try of Natural Compounds. 2021. 57(6): 10814. 24. Meldrum B. S. Glutamate as a neurotrans- mitter in the brain: Review of physiology and pathology. Journal of Nutrition. 2000. 130: 1007S–1015S. 25. Luo W., Fang X., Wang C. et al. Terminus-im- mobilization effect on peptide conformations and peptide–peptide interactions. Nano Re- search. 2023. 16: 13498–13508. 26. Hruby V. J. Conformational restrictions of bi- ologically active peptides via amino acid side chain groups Life Sci. 1982. 31: 189–199. 27. Balaram P., Ramaseshan S., Eds. Molecular Conformation and Biological Interactions. In- dian Academy of Science, Bangalore. 1991. 28. Ramachandran G.N, Sasisekharan V. Confor- mation of polypeptides and proteins. Adv Pro- tein Chem. 1968. 23: 283–438. doi: 10.1016/s0065-3233(08)60402-7. 29. Scheraga H.A. Theoretical and experimen- tal studies of conformations of polypeptides. Chem. Rev. 1971.71: 195–217. doi: 10.1021/cr60270a003. 30. Bloom S. M., Fasman G. D.,deLoze C., Blout E. R.The Effect of Amino Acid Composition on the Conformations of Synthetic Polypep- tides, Polymers and Copolymers of L-Methio- nine S-Methyl-L-cysteine and L-Valine. J. Am. Chem. Soc. 1962. 84: 458–463. DOI: 10.1021/ja00862a027. 31. Gibson S. E., Guillo N., Tozer M. J. Towards Control of χ‐Space: Conformationally Con- strained Analogues of Phe, Tyr, Trp, and His. Tetrahedron. 1999. 55: 585–601. DOI:10.1002/CHIN.199923302 32. Ellis T. K., Martin C. H., Tsai G. M.et al. Effi- cient Synthesis of Sterically Constrained Sym- metrically α,α-Disubstituted α-Amino Acids under Operationally Convenient Conditions. J. Org. Chem. 2003. 68: 6208–6214. 33. Soloshonok V. A., Sorochinsky A. E. Practical Methods for the Synthesis of Symmetrically α,α-Disubstituted-α-Amino Acids, Synthesis 2010. 14: 2319–2344. 34. Ellis T. K., Martin C. H., Ueki H., Soloshonok V. A. Efficient, Practical Synthesis of Symmet- rically α,α-Disubstituted α-Amino Acids. Tet- rahedron Lett. 2003. 44: 1063–1066. 35. Sato T., Izawa K., Aceña J. L. et al. Tailor-Made α-Amino Acids in Pharmaceutical Indus- try: Synthetic Approaches to (1R,2S)-1-Ami- no-2-vinylcyclopropane-1-carboxylic Acid (Vi nyl-ACCA). Eur. J. Org. Chem. 2016. 2757–2774. DOI: 10.1002/ejoc.201600112. 36. Taylor S. M., Yamada T., Ueki H., Soloshonok V. A. Asymmetric Synthesis of Enantiomeri- cally Pure 4-Aminoglutamic Acids via Methy lenedimerization of Chiral Glycine Equivalents with Dichloromethane under Operational- ly Convenient Conditions. Tetrahedron Lett. 2004. 45: 9159–9162. 103https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 37. Ellis T. K., Hochla V. M., Soloshonok V. A. Effi- cient Synthesis of 2-Aminoindane-2-Carboxylic Acid via Dialkylation of Nucleophilic Glycine Equivalent. J. Org. Chem. 2003. 68: 4973–4976. 38. Hruby V. J., Li G., Haskell-Luevano C., Shen- derovich M. D. Design of peptides, proteins, and peptidomimetics in chi space. Biopolymers. 1997. 43: 219–266. doi: 10.1002/bip.10970282. 39. Qiu W., Gu X., Soloshonok V. A. et al. Stere- oselective synthesis of conformationally con- strained reverse turn dipeptide mimetics. Tet- rahedron Lett. 2001. 42: 145–148. 40. Hruby V.J. Conformational and topographical considerations in the design of biologically active peptides. Biopolymers. 1993. 33: 1073– 1082. doi: 10.1002/bip.360330709. 41. Cai M., Cai C., Mayorov A. V. et al. Biologi- cal and conformational study of β-substituted prolines in MT-II template: steric effects lead- ing to human MC5 receptor selectivity. J. Pept. Res.2004. 63: 116–131. 42. Hruby V. J., Al-Obeidi F., Kazmierski W. M. Emerging approaches in the molecular design of receptor-selective peptide ligands: confor- mational, topographical and dynamic consi derations. Biochemical J. 1990. 268: 249–262. doi: 10.1042/bj2680249. 43. O’Donnell M. J., Bennett W. D. Wu S. The ste- reoselective synthesis of α-amino acids using phase-transfer catalysis. Tetrahedron. 2013. 69(2): 123–130. 44. Kim Y., Park J., Kim M.J. Dynamic kinetic res- olution of amines and amino acids by enzyme- metal cocatalysis. Chem. Cat. Chem. 2011. 3: 271–277. 45. Takeda R., Kawamura A., Kawashima A. et al. Chemical Dynamic Kinetic Resolution and (S)/ (R)-Interconversion of Unprotected a-Amino Acids. Angew. Chem., Int. Ed. 2014. DOI: 10.1002/anie.201407944. 46. So S.M., Kim H., Mui L., Chin J. Mimicking na- ture to make unnatural amino acids and chiral diamines. Eur. J. Org. Chem. 2012. 229–241. 47. D’Arrigo P., Servi S. at al. Synergy between ca talysts: enzymes and bases. Catal. Sci. Technol. 2012. 2: 1606–1616. 48. Bera K., Namboothiri I. Asymmetric synthesis of quaternary α-amino acids and their phos- phonate analogues. Asian J. Organ. Chem. 2014. 3: 1234–1260. 49. He G., Wang B., Nack W.A., Chen, G. Syntheses and tansformations of α-amino acids via palladi- um-catalyzed auxiliary-directed sp3 C-H func- tionalization. Acc. Chem.Res. 2016. 49: 635–645. 50. Wang Y., Song X., Wang J. et al. Recent ap- proaches for asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes. Amino Acids. 2017. 49: 1487–1520. DOI: 10.1007/s00726-017-2458-6. 51. Sorochinsky A. E., Aceña J. L., Moriwaki H. et al. Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases; Part 1: Alkyl halide alkylations. Amino Acids. 2013. 45: 691–718. DOI: 10.1007/s00726-013-1539-4. 52. Sorochinsky A. E., Aceña J. L., Moriwaki H. et al. Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases. Part 2: Aldol, Mannich addition reactions, deracemization and (S) to (R) in- terconversion of α-amino acids. Amino Acids. 2013. 45: 1017–1033. DOI 10.1007/s00726-013-1580-3. 53. O’Donnell M. J., Boniece J. M. Enantioselective synthesis of α-amino acids via phase-transfer catalysis. Tetrahedron. 2015. 71(4): 456–462. 54. Nian Y., Wang J., Zhou S. et al. Recyclable Li gands for the Non-Enzymatic Dynamic Kinetic Resolution of Challenging α-Amino Acids. An- gew. Chem., Int. Ed. 2015. 54: 12918–12922. DOI: 10.1002/anie.201507273. 55. O’Donnell M. J., Earp S. E. Advances in the asymmetric synthesis of α-amino acids. Tetra- hedron2017. 73(5): 567–575. 56. Soloshonok V. A., Kirilenko A. G., Fokina N. A. et al. Chemo-Enzymatic Approach to the Synthesis of Each of the Four Isomers of α-Alkyl-β-Fluoroalkyl-Substituted β-Amino Acids. Tetrahedron: Asymmetry. 1994. 5: 1225– 1228. 104 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY 57. O’Donnell M. J., Wu S. Phase-transfer catalysis in the synthesis of α-amino acids: Recent deve lopments. Tetrahedron. 2019. 75(3): 432–440. 58. O’Donnell M. J., Bennett W. D. Stereocontrolled synthesis of α-amino acids using phase-transfer catalysis. Tetrahedron. 2021. 77(2): 289–297. 59. Soloshonok V. A., Ono T., Soloshonok I. V. Enantioselective Biomimetic Transamination of β-Keto Carboxylic Acid Derivatives. An Efficient Asymmetric Synthesis of β-Fluoro- alkyl-β-Amino Acids. J. Org. Chem.1997. 62: 7538–7539. 60. Shioiri T., Hamada, U. Efficient Syntheses of Biologically Active Peptides of Aquatic Origin Involving Unusual Amino Acids, Synlett. 2001. 184–201. DOI: 10.1055/s-2001-10758. 61. Han J., Sorochinsky A. E., Ono T. et al. Biomi- metic Transamination – a Metal-Free Alterna- tive to the Reductive Amination. Application for Generalized Preparation of Fluorine-Con- taining Amines and Amino Acids. Cur. Org. Synthesis. 2011. 8: 281–294. 62. Cativiela C., Diaz-de-Villegas M. D. Stereose- lective Synthesis of Quaternary Alpha-Amino Acids. Part 2: Cyclic Compounds. Tetrahedron: Asymmetry. 2000. 11: 645–698. DOI 10.1016/j.tetasy.2000.11.001. 63. Abellan T., Chinchilla R., Galindo N.et al. New Oxazinone and Pyrazinone Derivatives as Chi- ral Reagents for the Asymmetric Synthesis of α‐Amino Acids. Eur. J. Org. Chem. 2000. 2689– 2698. DOI:10.1002/CHIN.200039248. 64. Shibata N., Nishimine T., Shibata N., et al. Or- ganic base-catalyzed stereodivergent synthesis of (R)- and (S)-3-amino-4,4,4-trifluorobutanoic acids. Chem. Commun. 2012. 48: 4124–4126. DOI: 10.1039/C2CC30627A. 65. Schöllkopf U.,Grioth U., Deng C.Enantioselec- tive Synthesis of (R)-α-Vinylamino Acids. An- gew. Chem. Int.Ed. Engl. 1981. 20: 798–803. https://doi.org/10.1002/anie.198109771. 66. Schöllkopf U.,Pettig D., Busse U. Asymmet- ric Synthesis via Heterocyclic Intermediates; XXXI: Asymmetric Synthesis of Glutamic Acids and Derivatives thereof by the Bislac- tim-Ether Method. Synthesis 1986. 737–740. DOI 10.1055/s-1986-31760. 67. Hartzoulakis B., Gani D. J. Syntheses of (2S,3R)- and (2S,3S)-3-methylglutamic Acid. Chem. Soc. Perkin Trans. 1994. 2525–2529. DOI 10.1039/CT994122525. 68. Cahn R. S., Ingold C. K., Prelog V. Specification of Molecular Chirality. Angew. Chem., Int. Ed. 1966. 5: 385–415. 69. Hartwig W., Born L. Diastereoselective and enantioselective total synthesis of the hepato- protective agent clausenamide. J. Org. Chem. 1987. 52: 4352–4358. 70. Pettig D., Schöllkopf U. Asymmetric Synthe- sis via Heterocyclic Intermediates; XXXVII1 Asymmetric Synthesis of Dimethyl (R)-2- Amino-(E)-hept-4-enedioates by the Bislactim Ether Method. Synthesis. 1988. 173–175. 71. Suzuki K., Seebach D. threo‐3‐Alkyl‐and‐Aryl- glutamic Acid Derivatives by Michael Addi- tions of Boc‐BMI Li‐Enolates to 2, 6‐Di‐t‐bu- tyl‐4‐methoxyphenyl Alkenoates on the Di- astereoselectivity of the Coupling of Trigonal Centers Involving Heterocyclic Li‐Enolates. Liebigs Annalen der Chemie. 1992. 13(1): 51– 61. 72. Schlecker R., Seebach D., Lubosch W. CH-aci dity in the α-position to the N-atom in N,N-di- alkylamides with a sterically protected car- bonyl group for nucleophilic aminoalkylation. Helv. Chim. Acta. 1978. 61(1): 512–526. 73. Seebach D., Locher R. α, β‐Unsaturated Car- bonyl Compounds with Sterically Protected Carbonyl Groups–Enforced a3 versus a1 Re- activity. Angew. Chem. In. Ed. 1979. 18(12): 957–958. 74. Seebach D., Häner R., Vettiger T. Nucleophilic ring opening of α-nitrocyclopropanecarboxylic acid-arylesterns with sterically protected but electronically active carbonyl and nitro groups. A new principle of α-amino acid synthesis (2-aminobutanoic acid a4-synthon). Helv. Chim. Acta. 1987. 70(6): 1507–1515. 75. Seebach D., Vettiger T., Müller H.M. et al. Ste- reoselective hydroxyalkylations of (S)‐2‐azeti- 105https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 dinecarboxylic acid. Liebigs Annalen der Che- mie. 1990. 7: 687–95. 76. Seebach D., Ertas ̨ M., Locher R., Bernd Schwei zer W. Trityl ketone and trityl enone. Contri- butions to sterically enforced Michael addition and diastereoselective aldol addition. Helv. Chim. Acta. 1985. 68 (1): 264–82. 77. Cooke Jr MP. Sterically directed conjugate ad- dition reactions of unsaturated esters. J. Org. Chem. 1986. 51(9): 1637–1638. 78. Kanemasa S., Tatsukawa A., Wada E. Highly diastereoselective Michael addition of lithiat- ed camphor imines of glycine esters to. Alpha-, beta-unsaturated esters. Synthesis of optically pure 5-oxo-2, 4-pyrrolidinedicarboxylates of unnatural stereochemistry. J. Org. Chem. 1991. 56(8): 2875–83. 79. Soloshonok V. A., Kacharov A. D., Avilov D. V., et al. Transition Metal/Base-Catalyzed Aldol Reactions of Methyl α-Isocyanoacetate with Prochiral Ketones, a Straightforward Approach to Stereochemically Defined β, β-Disubsti- tuted-β-Hydroxy-α-Amino Acids. Scope and Limitations. J. Org. Chem. 1997. 62: 3470–3479. 80. Belokon Y. N.,Bulychev A. G., Ryzhov M. G. et al. General method of diastereo- and enanti- oselective synthesis of β-hydroxy-α-amino ac- ids by condensation of aldehydes and ketones with glycine. J. Chem. Soc. Perkin Trans. I. 1986. 1865–1877. DOI:10.1021/ja00300a030. 81. Belokon Y. (s)-2-[N-(N’-Benzylprolyl) Amino] Benzophenone (BPB)-A Reagent for the Syn- thesis of Optically Pure -Amino Acids. Janssen Chim. Acta. 1992. 10: 4–15. 82. Belokon YN. Chiral complexes of Ni (II) Cu (II), and Cu (I) as reagents, catalysts and recep- tors for asymmetric synthesis and chiral recog- nition of amino acids. Pure and applied chemis- try. 1992. 64(12): 1917–24. 83. Ueki H., Ellis T. K., Martin C. H. et al. Improved Synthesis of Proline Derived Ni(II)-Complexes of Glycine, a Versatile Chiral Equivalents of Nucleophilic Glycine for General Asymmet- ric Synthesis of α-Amino Acids. J. Org. Chem. 2003. 68: 7104–7107. DOI: 10.1021/jo0301494. 84. Soloshonok V. A., Avilov D. V., Kukhar V. P., et al. An Efficient Asymmetric Synthesis of (2S, 3S)-3-Trifluoromethylpyroglutamic Acid. Tet- rahedron Lett. 1997. 38: 4903–4904. 85. Soloshonok V. A., Cai C., Hruby V. J. et al. Ste- reochemically Defined C-Substituted Gluta mic Acids and their Derivatives. 1. An Efficient Asymmetric Synthesis of (2S, 3S)-3-Methyl- and -3-Trifluoromethylpyroglutamic Acids. Tetrahedron1999. 55: 12031–12044. 86. Soloshonok V. A., Kirilenko A. G., Kukhar V. P., Resnati G. Transamination of Fluorinated β-Keto Carboxylic Esters. A Biomimetic Ap- proach to β-Polyfluoroalkyl-β-Amino Acids, Tetrahedron Lett. 1993. 34: 3621–3624. 87. Soloshonok V. A., Kirilenko A. G., Galushko S. V., Kukhar V. P. Catalytic Asymmetric Syn- thesis of β-Fluoroalkyl-β-Amino Acids via Biomimetic [1,3]-Proton Shift Reaction. Tetra- hedron Lett.1994. 35: 5063–5064. 88. Bravo P., Capelli S., Meille S. V. et al. Synthesis of Optically Pure (R)- and (S)-a-Trifluorome- thyl-Alanine. Tetrahedron: Asymmetry1994. 5: 2009–2018. 89. Soloshonok V. A., Cai C., Hruby V. J., Meervelt L. V. Asymmetric Synthesis of Novel Highly Sterically Constrained (2S, 3S)-3-Methyl-3- Trifluoromethyl- and (2S, 3S, 4R)-3-Trifluo- romethyl-4-Methylpyroglutamic Acids, Tetra- hedron. 1999. 55: 12045–12058. 90. Soloshonok V. A., Kukhar V. P., Galushko S. V., et al. General method for the synthesis of enan- tiomerically pure β-hydroxy-α-amino acids, containing fluorine atoms in the side chains. Case of stereochemical distinction between methyl and trifluoromethyl groups. X-ray crystal and molecular structure of the Nick- el(II) complex of (2S,3S)-2-(trifluoromethyl) threonine. J. Chem. Soc., Perkin Trans. 1. 1993. 3143–3155. 91. Soloshonok V. A., Avilov D. V., Kukhar V. P. Highly Diastereoselective Asymmetric Aldol Reactions of Chiral Ni(II)-Complex of Glycine with Trifluoromethyl Ketones. Tetrahedron: Asymmetry. 1996. 7: 1547–1550. 106 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY 92. Cai C., Soloshonok V. A., Hruby V. J. Michael Addition Reactions Between Chiral Ni(II) Complex of Glycine and 3-(trans-enoyl)oxa zolidin-2-ones. A Case of Electron Donor-Ac- ceptor Attractive Interactions-Controlled Face Diastereoselectivity. J. Org. Chem. 2001. 66: 1339–1350. 93. Soloshonok V. A., Cai C., Hruby V. J. Asym- metric Michael Addition Reactions of Chiral Ni(II) Complex of Glycine with N-(Enoyl)oxa zolidinones: Improved Reactivity and Stereo- chemical Outcome. Tetrahedron: Asymmetry. 1999. 10: 4265–4269. 94. Soloshonok V. A., Cai C., Hruby V. J. Toward Design of a Practical Methodology for Stereo- controlled Synthesis of χ-Constrained Pyroglu- tamic Acids and Related Compounds. Virtually Complete Control of Simple Diastereoselecti vity in the Michael Addition Reactions of Gly- cine Ni(II) Complexes with N-(Enoyl)oxazo- lidinones. Tetrahedron Lett. 2000. 41: 135–139. 95. Soloshonok V. A., Hayashi T., Ishikawa K., Na- gashima N. Highly Diastereoselective Aldol Reaction of Fluoroalkyl Aryl Ketones with Me- thyl Isocyanoacetate Catalyzed by Silver(I)/Tri- ethylamine. Tetrahedron Lett. 1994. 35: 1055– 1058. 96. Soloshonok V. A., Hayashi T. Gold(I)-Catalyz- ed Asymmetric Aldol Reaction of Fluorinated Benzaldehydes with α-Isocyanoacetamide. Tet- rahedron: Asymmetry 1994. 5: 1091–1094. 97. Soloshonok V. A., Kacharov A. D., Hayashi T. Gold(I)-Catalyzed Asymmetric Aldol Reac- tions of Isocyanoacetic Acid Derivatives with Fluoroaryl Aldehydes. Tetrahedron. 1996. 52: 245–254. 98. Evans D.A., Chapman K.T., Bisaha J. Asym- metric Diels-Alder cycloaddition reactions with chiral. alpha., beta-unsaturated N-acy- loxazolidinones. J. Am. Chem. Soc. 1988. 110(4):1238–56. 99. Bordwell F.G. Equilibrium acidities in dime- thyl sulfoxide solution. Acc. Chem. Res. 1988. 21(12): 456–63. 100. Evans D.A., Anderson J.C., Taylor M.K. Stu dies directed toward the design of chiral acy lating agents. The utility of chiral N-benzoy limides in enantioselective alcohol acylation. Tetrahedron letters. 1993. 34: 5563–6. 101. Soloshonok V. A., Cai C., Hruby V. J. A Practi- cal Asymmetric Synthesis of Enantiomerically Pure 3-Substituted Pyroglutamic Acids and Related Compounds. Angew. Chem., Int. Ed. 2000. 39: 2172–2175. 102. Soloshonok V. A., Cai C., Yamada T., et al. Michael Addition Reactions Between Chiral Equivalents of a Nucleophilic Glycine and (S)- or (R)-3-(E-Enoyl)-4-phenyl-1,3-oxazoli- din-2-ones as a General Method for Efficient Preparation of β-Substituted Pyroglutamic Acids. Case of Topographically Controlled Stereoselectivity. J. Am. Chem. Soc. 2005. 127: 15296–15303. 103. Soloshonok V. A., Cai C., Hruby V. J. et al. Rational Design of Highly Diastereoselective, Organic Base-Catalyzed, Room Temperature Michael Addition Reactions, J. Org. Chem. 2000. 65: 6688–6696. 104. Soloshonok V. A., Ueki H., Tiwari R., et al. Virtually Complete Control of Simple and Face Diastereoselectivity in the Michael Ad- dition Reactions between Achiral Equivalents of a Nucleophilic Glycine and (S)- or (R)-3- (E-Enoyl)-4-phenyl-1,3-oxazolidin-2-ones: Practical Method for Preparation of β-Substi- tuted Pyroglutamic Acids and Prolines. J. Org. Chem. 2004. 69: 4984–4990. 105. Soloshonok V. A., Cai C., Hruby V. J. A Unique Case of Face Diastereoselectivity in the Michael Addition Reactions Between Ni(II)-Complex- es of Glycine and Chiral 3-(E-enoyl)-1,3-oxa zolidin-2-ones. TetrahedronLett. 2000. 41: 9645–9649. 106. Soloshonok V. A., Cai C., Hruby V. J. (S)- or (R)-N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2- ones: Ideal Michael Acceptors to Afford a Vir- tually Complete Control of Simple and Face Diastereoselectivity in Addition Reactions with Glycine Derivatives. Org. Lett. 2000. 2: 747–750. 107. Ueki H., Ellis T. K., Martin C. H., Soloshonok V. A. Efficient Large-Scale Synthesis of Pico 107https://ucj.org.ua Alicja Wzorek, Alexander E. Sorochinsky, Karel D. Klika, Taizo Ono, Jianlin Han, Vadim A. Soloshonok UCJ № 8 / Vol. 90 linic Acid Derived Ni(II)-Complexes of Gly- cine. Eur. J. Org. Chem. 2003. 1954–1957. DOI: 10.1002/ejoc.200200688 108. Soloshonok V. A., Ueki H., Ellis T. K. et al. Application of Modular Nucleophilic Glycine Equivalents for Truly Practical Asymmet- ric Synthesis of β-Substituted Pyroglutamic Acids. Tetrahedron Lett. 2005. 46: 1107–1110. 109. Ellis T. K., Ueki H., Yamada T. et al. The Design, Synthesis and Evaluation of a New Generation of Modular Nucleophilic Glycine Equivalents for the Efficient Synthesis of Sterically Con- strained a-Amino Acids. J. Org. Chem. 2006. 71: 8572–8578. 110. Zou Y., Han J., Saghyan A. S. et al.Asymmetric Synthesis of Tailor-Made Amino Acids Using Chiral Ni(II)-Complexes of Schiff Bases; An Update of the Recent Literature. Molecules. 2020. 25: 2739. doi:10.3390/molecules25122739. 111. Soloshonok V. A., Ueki H., Ellis T. K. New Generation of Nucleophilic Glycine Equiva- lents, Tetrahedron Lett. 2005. 46: 941–944. 112. Romoff T. T., Palmer A. B., Mansour N. et al. Scale-up Synthesis of (R)- and (S)-N-(2-Ben- zoyl-4-chlorophenyl)-1-(3,4-dichlorobenzyl) pyrrolidine-2-carboxamide Hydrochloride, a Versatile Reagent for Preparation of Tai- lor-made α- and β-AminoAcids in Enantio- merically Pure Form. Org. Process Res. Dev. 2017. 21:732–739. DOI: 10.1021/acs.oprd.7b00055. 113. Kawamura A., Moriwaki H., Röschenthaler G.-V., et al. Synthesis of (2S,3S)-β-(trifluo- romethyl)-α,β-diamino acid by Mannich ad- dition of glycine Schiff base Ni(II) complexes to N-tert-butylsulfinyl-3,3,3-trifluoroacetaldi mine. J. Fluor. Chem. 2015. 171: 67–72. DOI: 10.1016/j.jfluchem.2014.09.013. 114. Li T., Zhou S., Wang J., et al. Asymmetric synthesis of a-(1-oxoisoindolin-3-yl)glycine: synthetic and mechanistic challenges. Chem. Commun. 2015. 51: 1624–1626. DOI: 10.1039/C4CC05659K. 115. Nian Y., Wang J., Moriwaki H. et al. Analysis of crystallographic structures of Ni(II) complex- es of α-amino acid Schiff bases; Elucidation of the substituents effect on stereochemical pref- erences. Dalton Trans. 2017. 46: 4191–4198. DOI: 10.1039/C7DT00014F. 116. Stierhof M., Hansen K. Ø.,Sharma M. et al. New cytotoxic callipeltins from the Solomon Island marine sponge Asteropussp. Tetrahe- dron. 2016. 72: 6929–6934. 117. Tokairin Y., Soloshonok V. A., Moriwaki H., Konno H. Asymmetric synthesis of (2S,3S)-3- Me-glutamine and (R)-allo-threonine deriva- tives proper for solid phase peptide coupling. Amino Acids. 2019. 51: 419–432. https://doi. org/10.1007/s00726-018-2677-5. 118. Cheng L., Goodwin C. A., Schully M. F. et al. Synthesis and biological activity of ketome thylene pseudopeptide analogs as thrombin inhibitors. J. Med. Chem. 1992. 35: 3364– 3369. 119. Pavar M. C., Hanif K., Azam A. et al. Struc- ture–activity relationship study between or- nithyl-proline and lysyl-proline based tripep- tidomimics as angiotensinconverting enzyme inhibitors. Bioorg. Med. Chem. Lett. 2006. 16: 2117–2121. 120. Stranix B. R., Lavallée J.-F., Sévigny G., et al. Lysine sulfonamides as novel HIV-protease inhibitors: Nε-acyl aromatic a-amino acids. Bioorg. Med. Chem. Lett. 2006. 16: 3459–3462. 121. Brust A., Palant E., Croker D. E., et al. x-Cono- peptide pharmacophore development: toward a novel class of norepinephrine transporter inhibitor (Xen2174) for pain. J. Med. Chem. 2009. 52: 6991–7002. 122. Lee Y. S., Nyberg J., Moye S., et al. Understand- ing the structural requirements of 4-anilidop- iperidine analogues for biological activities at m and s opioid receptors. Bioorg. Med. Chem. Lett. 2007. 17: 2161–2165. 123. Zhu Y., Zhang W., Mei H., et al. Catalytic enan- tioselective Michael addition reactions of ter- tiary enolates generated by detrifluoroacety lation. Chem.–Eur. J. 2017. 23: 11221–11225. DOI: 10.1002/chem.201702091. 124. Nagaoka K., Mei H., Guo Y., et al. Michael ad- dition reactions of chiral glycine Schiff base Ni 108 ISSN 2708-129X. Укр. хім. журн., 2024 ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONSORGANIC CHEMISTRY (II)‐complex with 1‐(1‐phenylsulfonyl)ben- zene. Chirality 2020. 32: 885–893. https://doi.org/10.1002/chir.23203. 125. Shigeno Y., Han J., Soloshonok V. A., et al. Asymmetric synthesis of (S)-3-methylene- glutamic acid and its N-Fmoc derivative via Michael addition of chiral glycine Schiff base Ni(II) complex with enol tosylates. Chirality 2021. 33: 115–123. 126. Yamada T., Okada T., Sakaguchi K., et al. Effi- cient Asymmetric Synthesis of Novel 4-Substi- tuted and Configurationally Stable Analogs of Thalidomide. Org. Lett. 2006. 8: 5625–5628. 127. Soloshonok V. A., Yamada T., Sakaguchi K., Ohfune Y. Concise Asymmetric Synthesis of Configurationally Stable 4-trifluoromethyl Thalidomide. Future Med. Chem. 2009. 1: 897– 908. doi.org/10.4155/fmc.09.63. 128. King F. E., Kidd D. A. Novel Method for the Synthesis of γ-L-Glutamyl Dipeptides Based on a Complexing Co-protection Strategy. J. Org. Chem. 1949. 14: 3315–3321. 129. Flaih N., Pham-Huy C., Galons H. An expe- ditious synthesis of cyclic imides. Tetrahedron Lett. 1999. 40: 3697–8369. 130. Yamada T., Sakaguchi K., Shinada T., et al. Efficient asymmetric synthesis of the func- tionalized pyroglutamate core unit common to oxazolomycin and neooxazolomycin using Michael reaction of nucleophilic glycine Schiff base with α,β-disubstituted acrylate. Tetrahe- dron: Asymmetry. 2008. 19: 2789–2795. doi.org/10.1016/S0040-4020(98)00779-0. 131. Jörres M., Aceña J. L., Soloshonok V. A., Bolm C. Asymmetric Carbon-Carbon Bond Forma- tions under Solvent-Less Conditions in Ball Mills, Chem. Cat. Chem. 2015. 7: 1265–1269; DOI: 10.1002/cctc.201500102. 132. Bergagnini M., Fukushi K., Han J. et al. NH- type of chiral Ni(II) complexes of glycine Schiff base: design, structural evaluation, reac- tivity and synthetic applications. Org. Biomol. Chem. 2014. 12: 1278–1291. DOI: 10.1039/C3OB41959B. 133. Wang J., Lin D., Zhou S. et al. Asymmetric Synthesis of Sterically Constrained Linear Trifluoromethyl Containing Amino Acids via Alkylation of Chiral Equivalents of Nucleop- hilic Glycine and Alanine. J. Org. Chem. 2011. 76: 684–687. 134. Soloshonok V. A., Avilov D. V., Kukhar V. P. Asymmetric Aldol Reactions of Trifluorome- thyl Ketones with a Chiral Ni(II) Complex of Glycine: Stereocontrolling Effect of the Tri- fluoromethyl Group. Tetrahedron. 1996. 52: 12433–12442. 135. Soloshonok V. A., Avilov D. V., Kukhar V. P. Asymmetric Aldol Reactions of Chiral Ni(II)-Complex of Glycine with Aldehydes. Stereodivergent Synthesis of syn-(2S)- and syn-(2R)-β-Alkylserines, Tetrahedron: Asym- metry 1995.6: 1741–1756. 136. JörresM., Chen X., AceñaJ. L. et al. Asymmet- ric Synthesis of α-Amino Acids under Oper- ationally Convenient Conditions, Adv. Synth. Catal. 2014. 356: 2203–2208. DOI: 10.1002/adsc.201400405. 137. Soloshonok V. A., Avilov D. V., Kukhar V. P., et al. Highly Diastereoselective aza-Aldol Re- actions of a Chiral Ni(II) Complex of Glycine with Imines. An Efficient Asymmetric Ap- proach to 3-Perfluoroalkyl-2,3-Diamino Acids. Tetrahedron Lett. 1997. 38: 4671–4674. 138. Sorochinsky A. E., Ueki H., Aceña J. L. et al. Chemical approach for interconversion of (S)- and (R)-α-amino acids. Org. Biomol. Chem. 2013. 11: 4503–4507. DOI:10.1039/C3OB40541A. 139. Zhou S., Wang J., Chen X. et al. Chemical Kinetic Resolution of Unprotected β-Substi- tuted-β-Amino Acids Using Recyclable Chi- ral Ligands. Angew. Chem. Int. Ed. 2014. 53: 7883–7886. DOI: 10.1002/anie.201403556. Cтаття надійшла 25.05.2024.
id	oai:ojs2.1444248.nisspano.web.hosting-test.net:article-685
institution	Ukrainian Chemistry Journal
keywords_txt_mv	keywords
language	English
last_indexed	2026-07-23T01:12:06Z
publishDate	2024
publisher	V.I.Vernadsky Institute of General and Inorganic Chemistry
record_format	ojs
resource_txt_mv	ucjorgua/27/5accabb595d363d1b7edbfc0dc711527.pdf
spelling	oai:ojs2.1444248.nisspano.web.hosting-test.net:article-6852026-07-22T08:23:54Z ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS(Review) Wzorek, Alicja Sorochinsky, Alexander Klika, Karel Ono, Taizo Han, Jianlin Soloshonok, Vadim Asymmetric synthesis, Michael additions, glycine equivalents, metal complexes, Schiff bases, conformations, steric constrain. Glutamic acid, pyroglutamic acid, proline. Michael addition reactions involving nucleophilic glycine equivalents and α,β-unsaturated carboxylic acid derivatives offer a concise and generalized methodological approach to synthesizing a family of χ-constrained five-carbon-atom amino acids. These amino acids play a crucial role in de novo peptide design and the elucidation of peptide/protein three-dimensional structures and their biological functions/activities. This review encapsulates the significant synthetic and methodological advancements in the field to date. Each method discussed includes an evaluation of synthetic opportunities and limitations, practicality and efficiency of the procedures, and mechanistic rationale behind the observed stereochemical preferences. V.I.Vernadsky Institute of General and Inorganic Chemistry 2024-09-27 Article Article Organic chemistry Органическая xимия Органічна xімія application/pdf https://ucj.org.ua/index.php/journal/article/view/685 10.33609/2708-129X.90.8.2024.83-108 Ukrainian Chemistry Journal; Vol. 90 No. 8 (2024): Ukrainian Chemistry Journal; 83-108 Украинский химический журнал; ##issue.vol## 90 ##issue.no## 8 (2024): Ukrainian Chemistry Journal; 83-108 Український хімічний журнал; Том 90 № 8 (2024): Ukrainian Chemistry Journal; 83-108 2708-129X 2708-1281 en https://ucj.org.ua/index.php/journal/article/view/685/340 Copyright (c) 2024 Alicja Wzorek, Alexander Sorochinsky, Karel Klika, Taizo Ono, Jianlin Han, Vadim Soloshonok https://creativecommons.org/licenses/by-nc/4.0
spellingShingle	Wzorek, Alicja Sorochinsky, Alexander Klika, Karel Ono, Taizo Han, Jianlin Soloshonok, Vadim ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS(Review)
title	ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS(Review)
title_full	ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS(Review)
title_fullStr	ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS(Review)
title_full_unstemmed	ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS(Review)
title_short	ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS(Review)
title_sort	asymmetric synthesis of chi-constrained glutamic acids and related compounds via michael addition reactions(review)
topic_facet	Asymmetric synthesis Michael additions glycine equivalents metal complexes Schiff bases conformations steric constrain. Glutamic acid pyroglutamic acid proline.
url	https://ucj.org.ua/index.php/journal/article/view/685
work_keys_str_mv	AT wzorekalicja asymmetricsynthesisofchiconstrainedglutamicacidsandrelatedcompoundsviamichaeladditionreactionsreview AT sorochinskyalexander asymmetricsynthesisofchiconstrainedglutamicacidsandrelatedcompoundsviamichaeladditionreactionsreview AT klikakarel asymmetricsynthesisofchiconstrainedglutamicacidsandrelatedcompoundsviamichaeladditionreactionsreview AT onotaizo asymmetricsynthesisofchiconstrainedglutamicacidsandrelatedcompoundsviamichaeladditionreactionsreview AT hanjianlin asymmetricsynthesisofchiconstrainedglutamicacidsandrelatedcompoundsviamichaeladditionreactionsreview AT soloshonokvadim asymmetricsynthesisofchiconstrainedglutamicacidsandrelatedcompoundsviamichaeladditionreactionsreview

ASYMMETRIC SYNTHESIS OF CHI-CONSTRAINED GLUTAMIC ACIDS AND RELATED COMPOUNDS VIA MICHAEL ADDITION REACTIONS(Review)

Репозитарії

Схожі ресурси