Nucleophilic Glycine Equivalents Research Articles

Synthesis of trifluoromethyl substituted nucleophilic glycine equivalents and the investigation of their potential for the preparation of α-amino acids

Abstract The synthetic preparation of several Ni(II) complexed Schiff Bases of glycine will be introduced, as well as investigations into their reactivity and utility. Key to these investigations is the incorporation of electron-withdrawing trifluoromethyl groups within the framework of the conjugated system that stabilizes the enolate derived from the glycine component. Reactivity was evaluated for each of the complexes under phase transfer catalyzed alkylations with hydroxide bases, as well as the DBU catalyzed Michael Additions of optically active 3′-substituted-2-oxazoladinone amides of unsaturated carboxylic acids. It was found that the trifluoromethyl containing nucleophilic glycine equivalents were more reactive than their non-trifluoromethyl analogues in both reaction types. Therefore, the application of these modified Ni(II) complexes of glycine Schiff Bases are useful for the preparation of α-amino acids through phase transfer catalyzed alkylation as well as the preparation of optically pure β-substituted pyroglutamic acid precursors.

Development of Hamari Ligands for Practical Asymmetric Synthesis of Tailor-Made Amino Acids.

Enantiomerically pure tailor-made amino acids are in extremely high demand in nearly every sector of the health-related industries. In particular, the rapidly growing number of amino-acid-based pharmaceuticals calls for the development of advanced synthetic approaches featuring practicality and commercial viability. Here we provide a brief summary of the development of axially chiral tridentate Hamari ligands and their application for general asymmetric synthesis of various structural types of amino acids. The methodological diversity includes: dynamic kinetic resolution and (S)-/(R)-interconversion of unprotected amino acids and homologation of nucleophilic glycine equivalents via alkyl halide alkylation reactions as well as multiple-step transformations allowing preparation of polyfunctional and cyclic derivatives. The practicality of these methods is critically discussed.

ChemInform Abstract: Practical Synthesis of Fluorine-Containing α- and β-Amino Acids: Recipes from Kiev, Ukraine

Naturally occurring compounds containing a C-F bond are extremely rare; only a handful of fluorine-containing carboxylic acids have been described so far. By contrast, man-made fluorine-containing derivatives of all major classes of biologically important compounds are extremely promising medicinal targets used in the elucidation of biochemical, metabolic transformations and the development of new pharmaceuticals. Among the fluorine-containing derivatives of natural products, fluorinated analogs of amino acids are of particular interest and medicinal potential. This article presents a concise review of various synthetic methods, developed by the Kiev's school of bioorganic chemistry, for the preparation of fluorine-containing analogs of α- and β-amino acids, α-hydroxy acids, amines, as well as their phosphorus and sulfur-derived compounds, in enantiomerically pure form. One of the major methodological goals of the study was practicality, which is understood by us as stereochemical generality, operational convenience and synthetic affordance for each reaction step and isolation of the target products. The synthetic methods developed by our group can be roughly divided in two general categories: fluorine-adaptation of known synthetic approaches and discovery of new reactions. The former approach is most prominently represented by asymmetric homologation of nucleophilic glycine equivalents using fluorinated substrates via alkyl halide alkylations, aldol and Michael addition reactions. A plethora of discovered unexpected reaction outcomes, in particular stereochemical, are emphasized in this review and the particular role of fluorine, in altering the 'normal' reaction result, is explained. The latter direction is notably represented by the novel 1,3-proton shift reaction, a biomimetic reductive amination of fluorinated carbonyl compounds to the corresponding amines and amino acids, as well as the development of α-fluoroalkyl epoxides as true fluorinated synthons for generalized asymmetric synthesis of various biologically relevant compounds. Despite the highly anticipated potential of fluorine-containing amino compounds, their medicinal chemistry still remains underexplored. The major obstacle, in our opinion, is that these selectively fluorinated compounds are generally unavailable to the medicinal chemists for comprehensive, systematic study. We hope this review of synthetic methods will highlight and bring attention to particular types of fluorinated amino acids and related compounds readily available on a laboratory scale using methods developed by our group.

ChemInform Abstract: Michael Addition Reactions Between Nucleophilic Glycine Equivalents and Acrylic Acid Derivatives as a Practical and Generalized Approach to the Asymmetric Synthesis of β‐Substituted α‐Amino Acids

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Modular Approach to the Design of Nucleophilic Glycine Equivalents with Tailorable Physicochemical Properties

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Michael addition reactions between various nucleophilic glycine equivalents and ( S, E)-1-enoyl-5-oxo- N-phenylpyrrolidine-2-carboxamide, an optimal type of chiral Michael acceptor in the asymmetric synthesis of β-phenyl pyroglutamic acid and related compounds

( S)-5-Oxo- N-phenyl-1-[( E)-3-phenylacryloyl]pyrrolidine-2-carboxamide, easily prepared from inexpensive and readily available, in both enantiomeric forms, glutamic/pyroglutamic acid was designed as an optimal type of chiral Michael acceptor for reactions with a series of nucleophilic glycine equivalents. A study of the corresponding Michael addition reactions revealed that the new generation of modular glycine derivatives, as a counterpart to the Michael acceptor, provides for operationally convenient preparation of β-phenyl pyroglutamic acids and related compounds with virtually complete chemical and stereochemical outcomes.

Practical Synthesis of Fluorine-Containing α- and β-Amino Acids: Recipes from Kiev, Ukraine

Naturally occurring compounds containing a C-F bond are extremely rare; only a handful of fluorine-containing carboxylic acids have been described so far. By contrast, man-made fluorine-containing derivatives of all major classes of biologically important compounds are extremely promising medicinal targets used in the elucidation of biochemical, metabolic transformations and the development of new pharmaceuticals. Among the fluorine-containing derivatives of natural products, fluorinated analogs of amino acids are of particular interest and medicinal potential. This article presents a concise review of various synthetic methods, developed by the Kiev's school of bioorganic chemistry, for the preparation of fluorine-containing analogs of α- and β-amino acids, α-hydroxy acids, amines, as well as their phosphorus and sulfur-derived compounds, in enantiomerically pure form. One of the major methodological goals of the study was practicality, which is understood by us as stereochemical generality, operational convenience and synthetic affordance for each reaction step and isolation of the target products. The synthetic methods developed by our group can be roughly divided in two general categories: fluorine-adaptation of known synthetic approaches and discovery of new reactions. The former approach is most prominently represented by asymmetric homologation of nucleophilic glycine equivalents using fluorinated substrates via alkyl halide alkylations, aldol and Michael addition reactions. A plethora of discovered unexpected reaction outcomes, in particular stereochemical, are emphasized in this review and the particular role of fluorine, in altering the 'normal' reaction result, is explained. The latter direction is notably represented by the novel 1,3-proton shift reaction, a biomimetic reductive amination of fluorinated carbonyl compounds to the corresponding amines and amino acids, as well as the development of α-fluoroalkyl epoxides as true fluorinated synthons for generalized asymmetric synthesis of various biologically relevant compounds. Despite the highly anticipated potential of fluorine-containing amino compounds, their medicinal chemistry still remains underexplored. The major obstacle, in our opinion, is that these selectively fluorinated compounds are generally unavailable to the medicinal chemists for comprehensive, systematic study. We hope this review of synthetic methods will highlight and bring attention to particular types of fluorinated amino acids and related compounds readily available on a laboratory scale using methods developed by our group.

ChemInform Abstract: New Generation of Modular Nucleophilic Glycine Equivalents for the General Synthesis of α‐Amino Acids

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

New Generation of Modular Nucleophilic Glycine Equivalents for the General Synthesis of α-Amino Acids

A review of the advances in the synthesis of sterically constrained α-amino acids, specifically the preparation of optically active β-substituted pyroglutamic acids via the homologation of a new generation of modular nickel(II)-complexed glycine equivalents, is herein presented. Following a brief overview of the general methods for the preparation of α-amino acids, paying close attention to the homologation of achiral glycine equivalents, the majority of this review is dedicated to the accomplishments of a new generation of modularly designed nucleophilic glycine equivalents. As one will see from this review, the key advantage of this new series of glycine equivalents is that the physical and chemical properties of these compounds can be altered to fit the requirements of the homologation technique desired. This modular approach has already been exploited to fine-tune the nickel(II)-complexed glycine equivalent for the asymmetric synthesis of a variety of β-substituted pyroglutamic acids via its Michael addition reaction with various (S)-3-(E)-enoyl-4-phenyloxazolidin-2-ones.

Design, Synthesis, and Evaluation of a New Generation of Modular Nucleophilic Glycine Equivalents for the Efficient Synthesis of Sterically Constrained α-Amino Acids

A new generation of modular achiral glycine equivalents have been evaluated with respect to their synthetic utility for the production of tailor-made, sterically constrained alpha-amino acids, which proved to be the most efficient approach developed to date for the synthesis of symmetrical alpha,alpha-disubstituted-alpha-amino acids. Among the new series of achiral glycine equivalents, one was found to be a superior glycine derivative for the Michael additions with various (R)- or (S)-N-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones representing a general and practical synthesis of sterically constrained beta-substituted pyroglutamic acids. In particular, the application of these complexes allowed for the preparation of several beta-substituted pyroglutamic acids which include electron-releasing and sterically demanding substituents in the structure thus increasing the synthetic efficiency and expanding the generality of these Michael addition reactions.

Operationally convenient, efficient asymmetric synthesis of enantiomerically pure 4-aminoglutamic acids via methylene dimerization of chiral glycine equivalents with dichloromethane

This paper presents a practical and efficient asymmetric synthesis of enantiomerically pure 4-aminoglutamic acids using a quite unusual methylene dimerization of chiral nucleophilic glycine equivalents with dichloromethane under phase-transfer catalysis (PTC) conditions. From a synthetic standpoint, the reported procedure is highly operationally convenient and scalable as it does not require any chromatographic purification of the intermediate products.

Design and Synthesis of a New Generation of ‘NH’-Ni(II) Complexes of Glycine Schiff Bases and their Unprecedented C-H vs. N-H Chemoselectivity in Alkyl Halide Alkylations and Michael Addition Reactions

Within this manuscript the synthesis of a new generation of Ni(II) complexes that contain a secondary rather than a tertiary amino group, as well as the unusual chemoselectivity, was demonstrated in alkyl halide alkylations and Michael addition reactions. The complete C-H chemoselectivity observed in these reactions suggests that coordination of nitrogen to a metal has a significant synthetic potential as protecting a group without the need of introducing a transient N-C substituent. These new complexes have also proven highly synthetically useful nucleophilic glycine equivalents for the simple and highly diastereoselective synthesis of β-sub­stituted pyroglutamic acids via their reactions with chiral Michael acceptors.

Application of Modular Nucleophilic Glycine Equivalents for Truly Practical Asymmetric Synthesis of β‐Substituted Pyroglutamic Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

New generation of nucleophilic glycine equivalents

A new generation of nucleophilic glycine equivalents, designed to contain a functional framework, that allows control over the physical properties as well as the reactivity, is described. The reactivity of these nucleophilic glycine equivalents have been compared to previously described examples with the application of various transformations such as alkyl halide alkylations, Michael additions, and aldol condensations.

Application of modular nucleophilic glycine equivalents for truly practical asymmetric synthesis of β-substituted pyroglutamic acids

A new series of achiral glycine equivalents have been evaluated with respect to their synthetic utility for the production of β-substituted pyroglutamic acid derivatives. Among them, the piperidine-derived complex was found to be a superior glycine derivative for the Michael additions with various ( R)- N-( E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones representing a general and practical synthesis of sterically constrained β-substituted pyroglutamic acids. In particular, application of complex allowed for the first time preparation of the corresponding isopropyl derivatives thus increasing the synthetic efficiency and expanding generality these Michael addition reactions.

Virtually complete control of simple and face diastereoselectivity in the Michael addition 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 beta-substituted pyroglutamic acids and prolines.

This study demonstrates a new strategy for controlling the stereochemical outcome of the Michael addition reactions between nucleophilic glycine equivalents and alpha,beta-unsaturated carboxylic acid derivatives: The addition reactions between achiral Ni(II)-complex of the Schiff base of glycine with o-[N-alpha-pycolylamino]acetophenone and (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones were shown to occur at room temperature in the presence of nonchelating organic bases and, most notably, with very high stereoselectivity at both newly formed stereogenic centers. Thus, the chiral 4-phenyl-1,3-oxazolidin-2-one moiety was found to control efficiently both face diastereoselectivities of the glycine derived enolate and the C,C double bond of the Michael acceptor. The new strategy developed in this work is methodologically superior to previous methods, most notably in terms of generality and synthetic efficiency. Excellent chemical yields and diastereoselectivities, combined with the simplicity of the experimental procedures, render the present method of immediate use for preparing various 3-substituted pyroglutamic acids and related amino acids (glutamic acids, glutamines, prolines, etc.) available via conventional transformations of the former.

Highly Diastereoselective Michael Addition Reactions Between Nucleophilic Glycine Equivalents and β‐Substituted α,β‐Unsaturated Carboxylic Acid Derivatives: A General Approach to the Stereochemically Defined and Sterically χ‐Constrained α‐amino Acids

AbstractFor Abstract see ChemInform Abstract in Full Text.

Highly Diastereoselective Michael Addition Reactions between Nucleophilic Glycine Equivalents and β-substituted-α,β-Unsaturated Carboxylic acid Derivatives a General Approach to the Stereochemically Defined and Sterically χ-Constrained α-Amino Acids

Highly Diastereoselective Michael Addition Reactions between Nucleophilic Glycine Equivalents and β-substituted-α,β-Unsaturated Carboxylic acid Derivatives a General Approach to the Stereochemically Defined and Sterically χ-Constrained α-Amino Acids

ChemInform Abstract: N,O Highly Regio‐ and Stereoselective Alkylation of Nucleophilic Glycine Equivalents with Carbonates of Allylic α‐ Hydroxyphosphonates: A Convenient Route to Racemic 2‐Amino‐5‐phosphono‐ 4‐pentenoic Acids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Highly regio‐ and stereoselective alkylation of nucleophilic glycine equivalents with carbonates of allylic α‐hydroxyphosphonates: A convenient route to racemic 2‐amino‐5‐phosphono‐4‐pentenoic acids

Liebigs AnnalenVolume 1997, Issue 9 p. 2003-2003 CorrectionFree Access Highly regio- and stereoselective alkylation of nucleophilic glycine equivalents with carbonates of allylic α-hydroxyphosphonates: A convenient route to racemic 2-amino-5-phosphono-4-pentenoic acids Elisabeth Öhler, Elisabeth ÖhlerSearch for more papers by this authorSilvia Kanzler, Silvia KanzlerSearch for more papers by this author Elisabeth Öhler, Elisabeth ÖhlerSearch for more papers by this authorSilvia Kanzler, Silvia KanzlerSearch for more papers by this author First published: August 22, 1997 https://doi.org/10.1002/jlac.199719970929AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume1997, Issue9August 22, 1997Pages 2003-2003 RelatedInformation