Solid-supported synthesis of a peptide beta-turn mimetic

[structure: see text]The solid-supported synthesis of a bicyclic diketopiperazine, a potential peptide beta-turn mimetic, is described. The Ugi reaction between the resin ester of alpha-N-Boc-diaminopropionic acid (an amine input), alpha-bromo acid, aldehyde, and isocyanide is the key step in the proposed protocol.     

Stereoselective synthesis of novel dipeptide beta-turn mimetics targeting melanocortin peptide receptors

[reaction: see text] The novel dipeptide beta-turn mimetic, 4,8-disubstituted azabicyclo[4.3.0]nonane amino acid ester (15), has been synthesized to serve as a peptide mimetic of the dipeptide Phe-Arg, which contains two important pharmacophore elements in melanotropin peptides. Introduction of side-chain functionality at C-8 was achieved by using beta-functionalized pyroglutamate (8) as a synthetic precursor. The side chain at C-4 was introduced by bromination of dehydroamino acid intermediate (10) followed by Suzuki cross-coupling.     

Rapid synthesis of diketopiperazine macroarrays via Ugi four-component reactions on planar solid supports

Libraries of diketopiperazines have been generated in high purity using the small molecule macroarray synthesis platform.     

Chirospecific synthesis of spirocyclic beta-lactams and their characterization as potent type II beta-turn inducing peptide mimetics

[reaction: see text] Starting from natural proline, a practical chirospecific synthesis of spirocyclic beta-lactams of type 2 is described when a methylene moiety showing minimal steric demand is employed as a constraint element for adjusting the dihedral angle psi(i + 1). Employing the concept of self-reproduction of chirality, C-formylation of the oxazolidinone 5 afforded the key intermediate 7 taking advantage of an intermediate protection of the bridging element as a vinyl moiety. NMR- and IR-based conformational studies clearly indicated that spiro-beta-lactams of type 2 can serve as efficient beta-turn nucleators.     

Liquid-phase combinatorial synthesis of alicyclic beta-lactams via Ugi four-component reaction

[reaction: see text] Alicyclic beta-lactams were successfully synthesized via a parallel liquid-phase Ugi four-center three-component reaction (U-4C-3CR), starting from alicyclic beta-amino acids such as cis-2-aminocyclohexanecarboxylic acid, cis-2-aminocyclopentanecarboxylic acid, 2,3-diexo-3-aminobicyclo[2.2.1]heptane-2-carboxylic acid and some of their partially unsaturated analogues. A six-membered mixture-based combinatorial library of beta-lactams was also generated.     

改进的Ugi法应用于胺烷基二茂铁衍生物的合成

选择不同的按或酰胺组分, 利用改进的Ugi法合成了一系歹含有烷胺烷基、芳胺烷基或酰胺烷基的二茂铁衍生物, 研究了反应的投料比, 反应底物, 反应温域等因素对反应的影响, 并对反应机理进行了探讨。     

Diastereoselective synthesis of multisubstituted isoindolines via Sequential Ugi and aza-Michael addition reaction

A new efficient and diastereoselective synthesis of multisubstituted isoindolines with two stereogenic centers via sequential Ugi/aza-Michael addition reaction was developed. Ugi-3CR of aldehydes 1, amines 2 and isocyanates 3 in the presence of catalytic amount of H₃PO₄ produced intermediates 4, which were then transformed to isoindolines 5 with good 1,3-trans diastereoselectivity in the presence of K₂CO₃ by intramolecular aza-Michael addition. Sequential Ugi-azide and aza-Michael addition reaction of aldehydes 1, amines 2 and trimethylsilyl azide 6 also produced 4-tetrazolyl substituted isoindolines 8 with good 1,3-trans diastereoselectivity in the presence of potassium carbonate.     

Direct synthesis of the arylboronic acid analogues of phenylglycine via microwave-assisted four-component Ugi reaction

A four-component Ugi reaction (Ugi-4CR) utilizing formylphenyl boronic acids under mild condition was developed for the synthesis of arylboronic acid analogs. The reactions were performed in methanol and accelerated by microwave irradiation, which makes this strategy suitable for constructing boronic-containing chemical libraries. Two of the synthesized analogs were found to have cytotoxic activity against HepG2, MDA-MB231, and A549 cancer cell lines, demonstrating the potential application of this approach in developing novel boron-containing pharmaceuticals.     

Oxazolopiperidin-2-ones as type II' beta-turn mimetics: synthesis and conformational analysis

We describe a straightforward synthesis of 9-substituted 3-aminooxazolidinopiperidin-2-ones 4. Some derivatives were prepared for use in peptide synthesis as rigidified surrogates of the Ala-Pro dipeptide. Analysis of the amide derivatives 14 by NMR experiments and molecular mechanics/dynamics calculations shows that the major isomer 14a has a stronger propensity than the minor isomer 14b to adopt beta-turn conformations, and the calculations indicate that in water 14a adopts a stable betaII' turn conformation.     

Amperometric enzyme biosensor for hydrogen peroxide via Ugi multicomponent reaction

A novel strategy based on the Ugi multicomponent reaction was employed for immobilizing horseradish peroxidase on sodium alginate-coated gold electrode. The electrode was employed for constructing an amperometric biosensor device using 1 mM hydroquinone as electrochemical mediator. The electrode showed linear response (poised at −300 mV vs Ag/AgCl) toward H₂O₂ concentration between 70 μM and 8.8 mM at pH 7.0. The biosensor reached 95% of steady-state current in about 12 s and its sensitivity was 33.8 mA/M cm². The electrode retained full initial activity after 30 days of storage at 4 °C in 50 mM sodium phosphate buffer, pH 7.0.     

Stereoselective synthesis of individual isomers of Leu-enkephalin analogues containing substituted beta-turn bicyclic dipeptide mimetics

Novel constrained beta-turn dipeptide mimetics, 8-phenyl thiaindolizidinone amino acids 3, have been synthesized stereoselectively and incorporated into Leu-enkephalin peptides as a replacement of dipeptide Gly3-Phe4 to afford four individual isomers of Leu-enkephalin analogues 6.     

Synthesis of peptidomimetic-spirostane hybrids via Ugi reaction: a versatile approach for the formation of peptide-steroid conjugates

A general approach towards the preparation of peptide-steroid conjugates has been addressed. Utilizing the Ugi reaction, five peptidomimetic-steroid hybrids were achieved in good to excellent yields from carboxy- and amino-spirostanes and mono-protected α-amino acids. Diverse synthetic routes, specially focused on the formation of secosteroids, were implemented to introduce Ugi-type functionalities at different positions of the steroidal nucleus. This versatile approach is suitable for the formation of stable conjugates of steroids with other biologically relevant molecules.     

Aldehyde components for use in four-component condensation (“4CC”) Ugi reaction peptide synthesis

The use of 9-formylfluorene as the aldehyde component in four-component condensation (4CC) fragment strategy peptide synthesis has been investigated in the synthesis of model dipeptides.     

Diversity-oriented pyrazol-3-one synthesis based on hydrazinodipeptide-like units prepared via the Ugi reaction

N-Cyanoacetyl-N′-trifluoroacetyl-N′-alkylhydrazines, prepared via hydrazino-Ugi reaction, provided different pyrazol-3-ones when exposed to mildly acidic and mildly basic conditions at 60 °C. These approaches offer a facile access to two different pyrazol-3-one-containing chemotypes in a diversity-oriented fashion, in only two chemical operations from simple precursors.     

Chemoenzymatic synthesis and application of a new,easily chiral auxiliary for the synthesis of peptidomimetics via an Ugi reaction

A new chiral auxiliary derived from α-phenylethylamine, α-(2,4-dimethoxyphenyl)ethylamine is presented. It significantly expands upon the application of α-phenylethylamine derivatives used as chiral auxiliaries. A straightforward, chemoenzymatic synthesis of non-racemic α-(2,4-dimethoxyphenyl)ethylamine is described and the new chiral auxiliary applied to an asymmetric Ugi reaction. The mild conditions used for the cleavage of the auxiliary allowed to obtain chiral, non-racemic peptidomimetics possessing reactive α,β-unsaturated double bonds.     

Spiro beta-lactams as beta-turn mimetics. Design, synthesis, and NMR conformational analysis

Molecular modeling calculations using high-level ab initio methods (MP2/6-31+G) of a new type of spiro beta-lactams predict that these systems could adopt a beta-turn secondary structure in solution. Strong intramolecular hydrogen bonds stabilize the beta-turn conformation with a geometry that is very close to the ideal type II beta-turns. The synthesis of the spiro beta-lactams is achieved by Staudinger reaction of a cyclic ketene derived from N-bencyloxycarbonyl-L-proline acid chloride with an imine. This reaction allows the formation of the spiranic backbone in a single-step with high diastereoselectivity and good yields. The new spiro beta-lactams obtained are the core for the preparation of different types of peptidomimetics using well-established peptide chemistry. The NMR conformational analysis shows that these compounds adopt beta-turn conformation as predicted by the theoretical studies.     

General inverse solid-phase synthesis method for C-terminally modified peptide mimetics

Peptide mimetics are of considerable interest as bioactive agents and drugs. C-terminally modified peptide mimetics are of particular interest given the synthetic versatility of the carboxyl group and its derivatives. A general approach to C-terminally modified peptide mimetics, based on a urethane attachment strategy and amino acid t-butyl ester-based N-to-C peptide synthesis, is described. This approach is compatible with the reaction conditions generally employed for solution-phase peptide mimetic synthesis. To develop and demonstrate this approach, it was employed for the solid-phase synthesis of peptide trifluoromethyl ketones, peptide boronic acids, and peptide hydroxamic acids. The development of a versatile general approach to C-terminally modified peptides using readily available starting materials provides a basis for the combinatorial and parallel solid-phase synthesis of these peptide mimetic classes for bioactive agent screening and also provides a basis for the further development of solid-phase C-terminal functional group elaboration strategies.     

Asymmetric synthesis of highly substituted azapolycyclic compounds via 2-alkenyl sulfoximines: potential scaffolds for peptide mimetics

The application of metalated, enantiomerically pure acyclic and cyclic 2-alkenyl sulfoximines for the synthesis of highly substituted aza(poly)cyclic ring systems is described. The method relies on a one-pot combination of a reagent-controlled allyl transfer reaction to alpha- or beta-amino aldehydes, followed by a Michael-type cyclization of the intermediate vinyl sulfoximines generated in the first step. The sulfur-free target compounds are preferentially obtained by samarium iodide treatment of the sulfonimidoyl substituted heterocycles. In addition to this methodological work, initial results on the biological activity of selected examples are reported. Furthermore, a concept for the transformation of peptidic lead structures into non-peptide mimetics is described, and the relevance of the new approach to highly substituted azaheterocycles in this context is discussed.     

Application of Ugi three component reaction for the synthesis of quinapril hydrochloride

Abstract

A novel, efficient and concise synthesis of chirally pure quinapril hydrochloride is described. The key step is the formation of α-amino amide backbone in one step using Ugi three component reaction. This method allows short access to α-amino amide chain which is a part of many drugs used for treatment of high blood pressure. A large molecular library can be synthesized by changing the components in Ugi reaction.