Glycine Equivalents Research Articles

Ligand binding by the tandem glycine riboswitch depends on aptamer dimerization but not double ligand occupancy.

The glycine riboswitch predominantly exists as a tandem structure, with two adjacent, homologous ligand-binding domains (aptamers), followed by a single expression platform. The recent identification of a leader helix, the inclusion of which eliminates cooperativity between the aptamers, has reopened the debate over the purpose of the tandem structure of the glycine riboswitch. An equilibrium dialysis-based assay was combined with binding-site mutations to monitor glycine binding in each ligand-binding site independently to understand the role of each aptamer in glycine binding and riboswitch tertiary interactions. A series of mutations disrupting the dimer interface was used to probe how dimerization impacts ligand binding by the tandem glycine riboswitch. While the wild-type tandem riboswitch binds two glycine equivalents, one for each aptamer, both individual aptamers are capable of binding glycine when the other aptamer is unoccupied. Intriguingly, glycine binding by aptamer-1 is more sensitive to dimerization than glycine binding by aptamer-2 in the context of the tandem riboswitch. However, monomeric aptamer-2 shows dramatically weakened glycine-binding affinity. In addition, dimerization of the two aptamers in trans is dependent on glycine binding in at least one aptamer. We propose a revised model for tandem riboswitch function that is consistent with these results, wherein ligand binding in aptamer-1 is linked to aptamer dimerization and stabilizes the P1 stem of aptamer-2, which controls the expression platform.

Adding a functional handle to nature's building blocks: the asymmetric synthesis of β-hydroxy-α-amino acids.

β-Hydroxy-α-amino acids are not only used by synthetic chemists but are also found in natural products, many of which show anti-microbial or anti-cancer properties. Over the past 30 years, chemists have searched for many asymmetric routes to these useful building blocks. Initial attempts to synthesize these compounds utilized chiral auxiliaries and the reactions of glycine equivalents with aldehydes to form two stereocenters in one step. Other methods with the formation of specific intermediates or that were aimed at a specific amino acid have also been investigated. Asymmetric hydrogenation by dynamic kinetic resolution has emerged as a high-yielding method for the synthesis of an array of modified amino acids with good stereoselectivity. More recently, amino-acid functionalization and multicomponent reactions have increased the atom economy and simplified many long and difficult routes. In this Focus Review, many of the elegant syntheses of these compounds are explored. The applications of β-hydroxy-α-amino acids in natural-product synthesis are also mentioned.

ChemInform Abstract: Progress in the Glycine Equivalent Based α‐Amino Acids Synthesis

ChemInformVolume 44, Issue 47 Reviews ChemInform Abstract: Progress in the Glycine Equivalent Based α-Amino Acids Synthesis Anna Jakubowska, Anna Jakubowska Dep. Physicochem. Drug Anal., Jagiellonian Univ. Med. Coll., PL-30-688 Krakow, Pol.Search for more papers by this authorKatarzyna Kulig, Katarzyna Kulig Dep. Physicochem. Drug Anal., Jagiellonian Univ. Med. Coll., PL-30-688 Krakow, Pol.Search for more papers by this author Anna Jakubowska, Anna Jakubowska Dep. Physicochem. Drug Anal., Jagiellonian Univ. Med. Coll., PL-30-688 Krakow, Pol.Search for more papers by this authorKatarzyna Kulig, Katarzyna Kulig Dep. Physicochem. Drug Anal., Jagiellonian Univ. Med. Coll., PL-30-688 Krakow, Pol.Search for more papers by this author First published: 04 November 2013 https://doi.org/10.1002/chin.201347226AboutPDF 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 onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume44, Issue47November 19, 2013 RelatedInformation

ChemInform Abstract: Asymmetric Synthesis of α‐Amino Acids via Homologation of Ni(II) Complexes of Glycine Schiff Bases. Part 1. Alkyl Halide Alkylations

AbstractReview: 141 refs.

Asymmetric synthesis of α-amino acids via homologation of Ni(II) complexes of glycine Schiff bases; Part 1: alkyl halide alkylations

Alkylations of chiral or achiral Ni(II) complexes of glycine Schiff bases constitute a landmark in the development of practical methodology for asymmetric synthesis of α-amino acids. Straightforward, easy preparation as well as high reactivity of these Ni(II) complexes render them ready available and inexpensive glycine equivalents for preparing a wide variety of α-amino acids, in particular on a relatively large scale. In the case of Ni(II) complexes containing benzylproline moiety as a chiral auxiliary, their alkylation proceeds with high thermodynamically controlled diastereoselectivity. Similar type of Ni(II) complexes derived from alanine can also be used for alkylation providing convenient access to quaternary, α,α-disubstituted α-amino acids. Achiral type of Ni(II) complexes can be prepared from picolinic acid or via recently developed modular approach using simple secondary or primary amines. These Ni(II) complexes can be easily mono/bis-alkylated under homogeneous or phase-transfer catalysis conditions. Origin of diastereo-/enantioselectivity in the alkylations reactions, aspects of practicality, generality and limitations of this methodology is critically discussed.

Progress in the Glycine Equivalent Based α-Amino Acids Synthesis

α-Amino acids play vital roles in protein and synthetic chemistries. Access to those molecules has been an intensive focus of research in recent years, and new methods are continuously being explored. The present review gives an overview of syntheses of α- amino acids based on glycine equivalents. Keywords: Glycine equivalent, α-amino acids.

The Synthesis of Enantiomers of 6-tert-Butyl-6-methylmorpholine-2,5- dione Using Wang Resin Supported Mukaiyama Reagent

The synthesis of enantiomers of 6-tert-butyl-6-methylmorpholine-2,5-dione (3) using Wang resin supported 2- chloro- or 2-bromo- pyridinium triflate is described. The applied methodology could be considered as an interesting alternative to “classical” one and enables the synthesis of 6-tert-butyl-6-methylmorpholine-2,5-dione with higher yields and the isolation of product (3) is significantly easier. Keywords: Wang resin supported Mukaiyama reagent, enantiomers of 6-tert-butyl-6-methylmorpholine-2, 5-dione, glycine equivalent.

ChemInform Abstract: Asymmetric Synthesis of Sterically and Electronically Demanding Linear ω‐Trifluoromethyl Containing Amino Acids via Alkylation of Chiral Equivalents of Nucleophilic Glycine and Alanine.

AbstractA simple, efficient, and highly enantioselective method to prepare biologically important title amino acids like (III) and (V) is reported.

Asymmetric Synthesis of Sterically and Electronically Demanding Linear ω-Trifluoromethyl Containing Amino Acids via Alkylation of Chiral Equivalents of Nucleophilic Glycine and Alanine

An operationally convenient, scalable asymmetric synthesis of linear, ω-trifluoromethyl-containing amino acids, which were not previously produced in their enantiomerically pure form, has been developed via alkylation of chiral equivalents of nucleophilic glycine and alanine. The simplicity of the experimental procedures and high stereochemical outcome (yields up to 90% and diastereoselectivity up to 99%) of the presented method render these fluorinated amino acids readily available for systematic medicinal chemistry studies and de novo peptide design.

A new approach to 3-substituted tetrahydro-β-carboline derivative via diethyl acetamidomalonate

Strategically a new approach for the synthesis tetrahydro-β-carboline unit with the aid of diethyl acetamidomalonate as a glycine equivalent has been described.

Synthesis of α-Amino Acids Based on Chiral Tricycloiminolactone Derived from Natural (+)-Camphor

Amino acids are one of the most important classes of the building blocks of life: they are the structural subunits of proteins, peptides, and many secondary metabolites. In addition to the 20 α-amino acids that constitute the backbone of proteins, hundreds of other natural α-amino acids have been discovered either in free form or as components in natural products. The difference between these molecules is the substituents at the chiral carbon situated between the amino and carboxyl moieties; this carbon (and any atom along a chain attached to it) is thus an important synthetic target. Because tailor-made α-amino acids are increasingly popular in biochemistry and organic synthesis, further refinement in synthetic methods to generate both natural (L-configuration) and unnatural (D-configuration) amino acids is a very active area of current research. In this Account, we examine the tricycloiminolactones, which are versatile glycine equivalents derived from natural camphor. We have developed the tricycloiminolactones in our laboratory and used them in the synthesis of several kinds of enantiopure α-amino acids. As nucleophiles, enolated tricycloiminolactones were shown to successfully participate in alkylations, Aldol reactions, Michael additions, and Mannich reactions. These reactions all gave excellent stereoselectivities and high yields. Simple conversion of the products offered α-alkyl-α-amino acids, α,α-dialkyl-α-amino acids, β-hydroxy-α-amino acids, α,γ-diamino acids, and α,β-diamino acids. One particular advantage is that the same electrophile can react with two chiral templates in the same way, thus affording access to both enantiomeric amino acids. In other words, some natural (L-configuration) α-amino acids and their unnatural (D-configuration) counterparts can be prepared very conveniently. The relation between substrate structures and product stereoconformations derived from our investigations serves as a convenient guide in the synthesis of useful chiral amino acids. In addition, highly stereoselective 1,3-diploar cycloadditions between alkenes and chiral nitrones derived from tricycloiminolactones provide a potential method for the synthesis of γ-hydroxy-α-amino acids. We also discuss applications of our methods in the synthesis of complex natural products, including conagenin, polyoxamic acid, lactacystin, and sphingofungin F. The preparation of some clinically important drug molecules, such as thiaphenicol, florfenicol, and chloramphenicol, was greatly simplified with our methods. The tricycloiminolactones offer a number of advantages in the synthesis of both natural and unnatural α-amino acids and provide many useful building blocks in the synthetic pursuit of complex molecules.

ChemInform Abstract: Diversity‐Oriented Approach to 1,2,3,4‐Tetrahydroisoquinoline‐3‐carboxylic Acid (TIC) Derivatives Using Diethyl Acetaminomalonate as a Glycine Equivalent: Further Expansion by Suzuki—Miyaura Cross‐Coupling Reaction.

AbstractVarious 1,2,3,4‐tetrahydroisoquinoline‐3‐carboxylic acid (Tic) derivatives of type (III), (V), (VII), and (IX) are prepared from dibromo(chloro) derivatives and diethyl acetaminomalonate (II).

ChemInform Abstract: Asymmetric Syntheses of Unnatural Amino Acids and Hydroxyethylene Peptide Isosteres

Unnatural and naturally occurring nonproteinogenic α-amino acids have become important building blocks for the synthesis of biologically active peptides and peptidomimetic drug molecules. The asymmetric synthesis of α-amino acids has therefore become quite important as an indispensable research tool in academic, government, and industrial laboratories, and methodologies have been reviewed extensively. The established methods for the asymmetric synthesis of amino acids can be divided into roughly six categories (1). (1) The highly stereoselective hydrogenation of chiral, nonracemic dehydro amino acid derivatives or the asymmetric hydrogenation of prochiral dehydro amino acid derivatives. Chiral glycine equivalents serve as useful α-amino acid templates undergoing homologation via carbon-carbon bond formation at the α-position through nucleophilic carbanion alkylation (2) or electrophilic carbocation substitution (3). In addition both nucleophilic amination (4) and electrophilic amination (5) of optically active carbonyl derivatives has very recently been developed. (6) Enzymatic and whole-cell-based syntheses have recently become more attractive in terms of substrate versatility, cost, and scale. All of these methods have their relative strengths and weaknesses; the optimum method for each individual application must still be considered on a case-by-case basis with respect to functionality, quantity desired, cost, and time. The focus of this chapter will illustrate the utility of chiral, nonracemic glycinates which are commercially available and can be manipulated in a variety of ways to access structurally diverse classes of α-amino acids.

ChemInform Abstract: Chiral (Z)-α,β-Didehydroamino Acid Derivatives from a New Chiral Glycine Equivalent with a 1,2,3,6-Tetrahydropyrazin-2-one Structure: Applications to the Synthesis of 1-Aminocyclopropanecarboxylic Acids and Bicyclic α-Amino Acids.

ChemInform 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: Ethyl Isocyanoacetate as a Useful Glycine Equivalent

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: 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.

Ethyl Isocyanoacetate as a Useful Glycine Equivalent

In this account, we describe a useful synthetic approach to construct diverse constrained α,α-dialkylated amino acid derivatives using ethyl isocyanoacetate as a glycine equivalent. Various unusual amino acid derivatives, such as cyclophane-, benzocyclo­butene-, and diene-containing systems, are reported here.

Diversity-Oriented Approach to 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Tic) Derivatives Using Diethyl Acetamidomalonate as a Glycine Equivalent: Further Expansion by Suzuki–Miyaura Cross-Coupling Reaction

Synthesis of diverse 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives and its higher analogues are reported using diethyl acetamidomalonate as a glycine equivalent. In addition, various substituted Tic derivatives are assembled by application of Suzuki―Miyaura cross-coupling reaction as a key step.

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.