Cyclic Β-amino Acids Research Articles

A preorganized β-amino acid bearing a guanidinium side chain and its use in cell-penetrating peptides.

A cyclic β-amino acid (APC(Gu)) bearing a side-chain guanidinium group has been developed. The APC(Gu) residue was incorporated into an α/β-peptide based on the Tat(47-57) fragment, leading to an oligomer with substantial helicity in methanol that enters HeLa cells much more readily than does the corresponding Tat α-peptide.

Unusual temperature-induced retention behavior of constrained β-amino acid enantiomers on the zwitterionic chiral stationary phases ZWIX(+) and ZWIX(-).

The effects of temperature on the chiral recognition of cyclic β-amino acid enantiomers on zwitterionic [Chiralpak ZWIX(+) and ZWIX(-)] chiral stationary phases were investigated. Experiments were performed at different mobile phase compositions and under 10°C column temperature increments in the temperature range 10-50°C. Apparent thermodynamic parameters and T(iso) values were calculated from plots of ln k and ln α versus 1/T, respectively. Unusual temperature behavior was observed, especially on the ZWIX(-) column, where the application of MeOH/MeCN (50/50 v/v) containing 25 mM triethylamine and 50 mM formic acid as mobile phase led to nonlinear van't Hoff plots and increasing retention time with increasing temperature. On both columns, both enthalpically and entropically driven separations were observed.

Helical folding of α/β-peptides containing β-amino acids with an eight-membered ring constraint

αβα-Tripeptide that contains a cyclic β-amino acid with an eight-membered ring, a cis-2-aminocyclooct-5-enecarboxylic acid (cis-ACOE) or a cis-2-aminocyclooctanecarboxylic acid (cis-ACOC) displayed an 11/9-helical turn in the crystal state. The related α/β-peptide oligomers were shown to adopt 11/9-helical conformations in solution.

Preparation of Cyclic β-Amino Acid Derivatives with Quaternary Carbon Center via a Radical Addition-Cyclization Sequence

Preparation of Cyclic β-Amino Acid Derivatives with Quaternary Carbon Center via a Radical Addition-Cyclization Sequence

Synthesis of furan derivatives of cyclic β-amino acid cispentacin via intramolecular nitrile oxide cycloaddition

Two furan derivatives of cispentacin have been synthesized starting from a d-mannitol derived conjugated nitroolefin through intramolecular nitrile oxide cycloaddition (INOC) as a key step.

Syntheses of Isoxazoline-Based Amino Acids by Cycloaddition of Nitrile Oxides and Their Conversion into Highly Functionalized Bioactive Amino Acid Derivatives

The present account illustrates the syntheses of isoxazoline-based amino acids by the cycloaddition of 1,3-dipolar nitrile oxides to the C–C double bond of unsaturated amino acid derivatives, with focus on the regio- and stereoselectivities of the transformations. Emphasis is also placed on the syntheses of highly functionalized amino acids by means of isoxazoline ring opening. The syntheses of various pharmacologically active compounds and their analogues via the above strategies are described. 1 Introduction 2 1,3-Dipolar Cycloadditions of Nitrile Oxides 3 Syntheses of Isoxazoline-Based Amino Acids 3.1 Syntheses of Isoxazoline α-Amino Acids 3.2 Syntheses of Isoxazoline γ-Amino Acids and Their Transformation into Bioactive Derivatives 3.3 Syntheses of Isoxazoline β-Amino Acids 3.3.1 Syntheses of Highly Functionalized Cyclic β-Amino Acids by 1,3-Dipolar Cycloaddition of Nitrile Oxides 4 Cycloaddition of Nitrile Oxides to Amino Acid Precursors 5 Summary and Outlook

Pyrrolidinyl Peptide Nucleic Acid Homologues: Effect of Ring Size on Hybridization Properties

The effect of ring size of four- to six-membered cyclic β-amino acid on the hybridization properties of pyrrolidinyl peptide nucleic acid with an alternating α/β peptide backbone is reported. The cyclobutane derivatives (acbcPNA) show the highest T(m) and excellent specificity with cDNA and RNA.

Evaluation of an aza-Michael approach for the synthesis of 3,3-dimethyl-2-aminocyclobutane-1-carboxylic acid

The aza-Michael addition reaction of a dibenzylic amide anion with t-butyl 3,3-dimethylcyclobutene-1-carboxylate was investigated as a route to the title compound, a cyclic β-amino acid. In analogy with the known 5- and 6-membered ring homologues, the addition reaction proceeds smoothly, but with moderate diastereomeric and enantiomeric selectivities. The trans isomer of the title β-amino acid was obtained, for the first time, with a modest enantiomeric excess

Intramolecular Ester Enolate–Imine Cyclization Reactions for the Asymmetric Synthesis of Polycyclic β-Lactams and Cyclic β-Amino Acid Derivatives

Enolates of chiral N-(α-methyl-p-methoxybenzyl)-ω-imino-esters undergo intramolecular cyclization reactions to afford (syn)-aza-anions of β-amino esters in high dr that cyclize to afford N-(α-methyl-p-methoxybenzyl)-β-lactams that can be readily deprotected to afford their corresponding cyclic NH-β-lactams, β-amino esters, or β-amino acids.

Design and synthesis of trans-3-aminopyran-2-carboxylic acid (APyC) and α/β-peptides with 9/11-helix

A new β-amino acid, trans-3-aminopyran-2-carboxylic acid (APyC), was designed and synthesized from (R)-glyceraldehyde derivative and used in the synthesis of α/β-peptides in a 1 : 1 alternating pattern with d-Ala. The presence of oxygen atom at the Cβ(2)-position in APyC was envisaged to provide opportunity for additional interaction. These hybrid peptides have shown the presence of 9/11-helix through extensive NMR and MD studies. The amide protons of d-Ala, in addition to participating in 9-mr H-bonding with CO of succeeding β-residue, were also involved in additional electrostatic interaction with pyran ring oxygen of preceding β-residue, which facilitated further stabilization to the 9/11-mixed helix. The study thus results in a new 'motif' for a 9/11-helix, and the first example from a cyclic β-amino acid.

Enantiomeric discrimination of cyclic β-amino acids using (18-crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids with cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, bicyclo[2.2.1]heptane, and bicyclo[2.2.1]heptene rings. The crown ether was added to the neutral β-amino acids in methanol- d 4. A neutralization reaction between the crown ether and β-amino acid forms the ammonium ion needed for favorable association. Enantiomeric discrimination of the two hydrogen atoms α to the amine and carboxylic acid moieties of the β-amino acid was observed with every substrate studied. Trends in the order of the enantiomeric discrimination of certain hydrogen atoms for substrates of similar structures correlate with the absolute configuration.

ChemInform Abstract: The Synthesis of Novel Cyclic β-Amino Acids as Intermediates for the Preparation of Bicyclic β-Lactams.

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Selective Syntheses of Functionalized Cyclic β-Amino Acids via Transformation of the Ring C-C Double Bonds

This report provides an overview of the most important aspects of the syntheses of functionalized cyclic β-amino acids in recent years. The presentation focuses in particular on strategies involving the selective functionalization of unsaturated alicyclic β-amino acids. The limitations and shortcomings of the synthetic methods are emphasized, and the possible new challenges and developments in this field in the near future are outlined.

(18-Crown-6)-2,3,11,12-tetracarboxylic acid as a chiral NMR solvating agent for determining the enantiomeric purity and absolute configuration of β-amino acids

(18-Crown-6)-2,3,11,12-tetracarboxylic acid is an excellent chiral NMR solvating agent for cyclic β-amino acids and acyclic derivatives with aliphatic, aromatic, and heterocyclic aromatic moieties. The β-amino acids are mixed with the crown ether in methanol- d 4 in either their neutral or protonated form. Substantial enantiomeric discrimination typically occurs for the resonances of the α-methylene and β-methine hydrogen atoms. Resonances of the substituent group of the β-amino acid often exhibit enantiomeric discrimination. The enantiomeric discrimination of the α-methylene and β-methine resonances of specific groups of compounds shows consistent patterns that correlate with the absolute configuration.

Synthesis of α-Cyclopropyl-β-homoprolines

1-(2-Pyrrolidinyl)cyclopropanecarboxylic acids (alpha-cyclopropyl-beta-homoprolines) were prepared by 1,3-dipolar cycloadditions of cyclic nitrones onto bicyclopropylidene followed by trifluoroacetic acid induced thermal fragmentative rearrangement. With the use of enantiopure pyrroline N-oxides derived from easily available chiral pool molecules, beta-homoprolines were formed with high stereocontrol. The incorporation of one of these new cyclic beta-amino acids into a simple tripeptide was also evaluated. In particular, the sterically hindered nitrogen atom of the highly substituted pyrrolidine 30 was smoothly acylated through the intermediate formation of a mixed anhydride.

Cross-Metathesis Reactions as an Efficient Tool in the Synthesis of Fluorinated Cyclic β-Amino Acids

The synthesis of enantiomerically pure, cyclic, gamma,gamma-difluorinated beta-amino acids with various ring sizes has been carried out with a cross-metathesis (CM) reaction being one of the key steps, followed by a Dieckmann-type condensation to bring about the cyclization. Subsequent catalytic hydrogenation under microwave irradiation with (-)-8-phenylmenthol as a chiral auxiliary led to the successful chemo- and diastereoselective chemical reduction of the resulting cyclic beta-enamino esters. The efficiency and scope of the CM reaction with different types of fluorinated imidoyl chlorides and unsaturated esters has also been studied in order to determine the optimal reaction conditions with regard to selectivity and reactivity.

From nature, through chemical synthesis, toward use in agriculture: Oryzoxymycin case study

Abstract The Diels-Alder adducts of ethyl (E)-3-nitroacrylate and furan provided a common and versatile template for the stereocontrolled synthesis of an isomer of the natural product oryzoxymycin and polyhydroxylated cyclohexyl β-amino acid derivatives. The strategy for the synthesis of the polyhydroxylated cyclic β-amino acid derivatives involved base-induced fragmentation of the oxanorbornene skeleton and face selective oxidation reactions. A Pd-catalyzed transfer hydrogenation reaction in the presence of organic acids is also described. This reaction is amenable to being enantioselective through use of optical pure chiral organic acids.

The iodolactone approach to enantiopure oxiranes of constrained chiral cyclic β-amino acids

A simple and efficient method has been developed for the synthesis of enantiopure epoxide derivatives of some constrained chiral cyclic β-amino acids via iodolactonization and alkaline de-iodation. Lower stereoselectivities were observed when the classical method using mCPBA was used when a bicyclic β-amino acid was involved leading to a quasi-inseparable mixture of two epoxides.

Establishing Effective Simulation Protocols for β- and α/β-Peptides. II. Molecular Mechanical (MM) Model for a Cyclic β-Residue

All-atom molecular mechanical (MM) force field parameters are developed for a cyclic beta-amino acid, amino-cyclo-pentane-carboxylic acid (ACPC), using a multi-objective evolutionary algorithm. The MM model is benchmarked using several short, ACPC-containing alpha/beta-peptides in water and methanol with SCC-DFTB (self consistent charge-density functional tight binding)/MM simulations as the reference. Satisfactory agreements are found between the MM and SCC-DFTB/MM results regarding the distribution of key dihedral angles for the tetra-alpha/beta-peptide in water. For the octa-alpha/beta-peptide in methanol, the MM and SCC-DFTB/MM simulations predict the 11- and 14/15-helical form as the more stable conformation, respectively; however, the two helical forms are very close in energy (2-4 kcal/mol) at both theoretical levels, which is also the conclusion from recent NMR experiments. As the first application, the MM model is applied to an alpha/beta-pentadeca-peptide in water with both explicit and implicit solvent models. The stability of the peptide is sensitive to the starting configuration in the explicit solvent simulations due to their limited length ( approximately 10-40 ns). Multiple ( approximately 20 x 20 ns) implicit solvent simulations consistently show that the 14/15-helix is the predominant conformation of this peptide, although substantially different conformations are also accessible. The calculated nuclear Overhauser effect (NOE) values averaged over different trajectories are consistent with experimental data, which emphasizes the importance of considering conformational heterogeneity in such comparisons for highly dynamical peptides.

Benzofuran-Derived Cyclic β-Amino Acid Scaffold for Building a Diverse Set of Flavonoid-Like Probes and the Discovery of a Cell Motility Inhibitor

We report here a practical, enantioselective synthesis of benzofuran-derived, cyclic trans-beta-amino acid scaffold. In two cases, tricyclic derivatives having six- and eight-membered unsaturated lactams were obtained from this versatile scaffold. To explore the biological applications, these compounds were subjected to cell-based assays, using NIH3T3 mouse cells to examine their potency as cell motility inhibitors and identified 18 as a potent cell motility inhibitor (IC50 approximately 40 microM in chamber cell migration assay).