α,α-Dialkylglycines obtained by solid phase Ugi reaction performed over isocyanide functionalized resins

The multicomponent Ugi reaction is a straightforward method that can be used for the synthesis of highly hindered C-tetrasubstituted amino acids by reacting an amine, a ketone or aldehyde, a carboxylic acid and an isocyanide. In the present work, the synthesis of several α,α-dialkylglycines (α,α-diethylglycine, Deg; α,α-dipropylglycine, Dpg; 1-amino-1-cyclohexanecarboxylic acid, Ac₆c) was achieved by solid phase Ugi reaction using resins functionalized with the isocyanide group. Since no resins with these features were available commercially, the functionalization of an aminomethylated resin started by the use of glycine (Gly), β-alanine (β-Ala) and γ-aminobutyric acid (GABA) as spacers. After spacer N-formylation, followed by dehydration, isocyanide functionalised resins were obtained. The resins were then used in solid phase Ugi reaction, using phenylacetic acid as the acid component, 4-methoxybenzylamine as the amine component and different ketones, to afford the desired N-acylated α,α-dialkylglycines in good overall yields (60–80%), after acidolytic cleavage from the resin, thus proving the feasibility of this approach.     

Study on the propylphosphonic anhydride (T3P®) mediated Ugi-type three-component reaction. Efficient synthesis of an α-amino amide library

In the present work, a mild and simple synthesis of α-amino amides has been developed via the one-pot three-component ABC type Ugi reaction of a wide variety of aromatic aldehydes and primary aromatic amines, and two different aliphatic isocyanides. The reactions took place rapidly at room temperature in the presence of 1-propanephosphonic acid cyclic anhydride (T3P^®), rendering possible the highly efficient preparation of an α-amino amide library in medium to excellent yields. This study represents the first case in which T3P^® has been used in the Ugi reaction.     

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.     

Facile,efficient and diastereoselective synthesis of α-hydrazine tetrazoles through a novel one-pot four-component reaction

A novel and efficient method for the diastereoselective synthesis of α-hydrazine tetrazoles via an isocyanide-based multicomponent reaction is reported in good yields. The α-hydrazine tetrazoles were obtained by a facile azide Ugi four-component reaction (U-4CR) using cyclic ketones, trimethylsilyl azide, hydrazides, and corresponding isocyanide without any catalyst and with high bond forming efficiency at room temperature.     

Propylphosphonic anhydride (T3P®) mediated synthesis of 3-oxoisoindoline-1-carboxamides from 2-formylbenzoic acid,amines, and isocyanides. Preparation of isoindolinone alkaloids

Propylphosphonic anhydride (T3P®) was successfully applied to the synthesis of an isoindolinone library by the utilization of an Ugi four-center, three-component reaction (Ugi-4C-3CR). The use of T3P® significantly shortened the required reaction time and the corresponding products were obtained in good to high yields. Moreover, a side-reaction was observed when phenylethylamine derivatives and tryptamine were used as the amine component. The latter reaction was applied to the microwave-assisted, one-pot synthesis of the isoquinoline alkaloid (±)-nuevamine. Surprisingly, the traditional Ugi four-component reaction (Ugi-4CR) was unsuccessful in the presence of T3P®. In this case an α-amino amide was produced excluding the carboxylic acid from the multicomponent reaction.     

An expedient synthesis of α,α-difluoro-β-hydroxy ketones via decarboxylative aldol reaction of α,α-difluoro-β-keto acids with aldehydes

A novel decarboxylative aldol reaction of α,α-difluoro-β-keto acids with aldehydes in the absence of any base and metal catalysts has been developed. This reaction provides a highly convenient and efficient method for the synthesis of structurally diverse α,α-difluoro-β-hydroxy ketones in good to excellent yields.     

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.     

Synthesis of tripeptides containing a very crowded α,α-disubstituted glycine with pyridine rings by solid-phase Ugi reaction

Tripeptides containing a novel α,α-disubstituted glycine with two pyridine rings, α,α-di(2-pyridyl)glycine (2Dpy), were synthesized by the solid-phase Ugi reaction using di(2-pyridyl)methanimine attached directly to a Rink amide resin. Thereby, yields of the tripeptides, Z-AA₁-2Dpy-AA₃-OMe (AA₁ and AA₃ = Gly or Aib), were markedly improved, compared with yields by the solution method.     

The Ugi reaction with CF3-carbonyl compounds: effective synthesis of α-trifluoromethyl amino acid derivatives

The Ugi reaction with CF₃-carbonyl compounds is described in detail. The method is efficient for the multicomponent preparation of α-trifluoromethyl (Tfm) amino acids, α-Tfm containing dipeptides, and iminodicarboxylic acids. In addition, the first protected CF₃-opine derivative was prepared. The scope, limitations, and stereochemistry of the approach are discussed.     

A versatile synthesis of fused triazolo derivatives by sequential Ugi/alkyne-azide cycloaddition reactions

We report a facile synthesis of fused dihydrotriazolo[1,5-a]pyrazinones and triazolobenzodiazepines by an Ugi/alkyne-azide cycloaddition synthetic sequence. The coupling of the Ugi multi-component reaction with the intramolecular alkyne-azide cycloaddition provides access to highly functionalized heterocyclic ring systems in two steps from easily available starting materials in excellent overall yields.     

Novel succinct routes to quinoxalines and 2-benzimidazolylquinoxalines via the Ugi reaction

This Letter reveals a unique, user-friendly, concise two-step, one-pot protocol for the synthesis of highly substituted quinoxalines. Conducting the Ugi reaction with appropriately functionalized classical Ugi reagents with subsequent acid treatment of the Ugi adduct affords collections of diversified quinoxalines in good to excellent yields. The methodology exploits what may be viewed as a ‘convertible carboxylic acid’, which in addition may be captured in an intramolecular sense to generate structurally complex 2-benzimidazolylquinoxalines in a mere two steps.     

A novel highly selective chiral auxiliary for the asymmetric synthesis of L- and D-alpha-amino acid derivatives via a multicomponent Ugi reaction

This paper describes the synthesis of a bicyclic beta-amino acid scaffold in both pure enantiomeric forms and its application as chiral auxiliary in an intramolecular version of the Ugi multicomponent reaction (U-5C-4CR) to prepare alpha-amino acid derivatives of both D- and L-series in a straightforward and very stereoselective manner. The mild conditions required for the Ugi condensation and for the removal of the chiral auxiliary make this method very attractive to prepare a wide range of differently structured N-alkylated and unalkylated amino acid derivatives.     

Four-Component Ugi Reaction for Optical Chirality Sensing and Surface Nanoengineering of Chiral Self-Assemblies

Using green chemistry to control chirality at hierarchical levels as well as chiroptical activities endows with new opportunities to the development of multiple functions. Here, the four-component Ugi reaction is introduced for the general and precise optical chirality sensing of amines as well as the surface nanoengineering of chiral soft self-assemblies. To overcome the relatively weak Cotton effects, direct synthesis of a folded peptide structure on a rotatable ferrocene core with axial chirality was accomplished from chiral amine, 1,1’-ferrocenyl dicarboxylic acid, formaldehyde and isocyanide. Enhanced Cotton effects benefiting from the folded structure allow for the precise and quantitative sensing of natural and synthetic chiral amines covering alkyl, aromatic amines and amino acid derivatives. In addition, aqueous reaction enables the modification of amine-bearing dye to microfibers self-assembled from π-conjugated amino acids. Surface dye-modification via Ugi reaction barely changes the pristine morphology, showing non-invasive properties in contrast to dye staining, which is applicable in soft nano/microarchitectures from self-assembly. This work which combines the four-component Ugi reaction to enable precise ee% detection and surface nanoengineering of soft chiral assemblies sheds light on the advanced application of green chemistry to chirality science.     

A dual-catalysis approach to the asymmetric Steglich rearrangement and catalytic enantioselective addition of O-acylated azlactones to isoquinolines

A dual-catalysis approach, namely the combination of an achiral nucleophilic catalyst and a chiral anion-binding catalyst, was applied to the Steglich rearrangement to provide α,α-disubstituted amino acid derivatives in a highly enantioselective fashion. Replacement of the nucleophilic co-catalyst for isoquinoline resulted in a divergent reaction pathway and an unprecedented transformation of O-acylated azlactones. This strategy provided highly substituted α,β-diamino acid derivatives with excellent levels of stereocontrol.     

Application of the Cleavable Isocyanide in Efficient Approach to Pyroglutamic Acid Analogues with Potential Biological Activity

Two efficient procedures have been developed for the synthesis of pyroglutamic acid analogues 28, 29, and 34. According to the first method the Ugi (4C3C) reaction is followed by a post-transformation reaction, and the second method involves the Michael addition reaction. The present methodologies demonstrate the applicability of 1-(2,2-dimethoxyethyl)-2-isocyanobenzene (15) as a cleavable isocyanide in the Ugi/ post-transformation reaction and a strong nucleophile in the Michael addition reaction. The framework of pyroglutamic acid analogues has been constructed by the selective cleavage of the C-terminal amide bond and nucleophilic addition to the activated α,β-unsaturated carbonyl group.

     

Synthesis of β-lactam peptidomimetics through Ugi MCR: first application of chiral N-Fmoc amino alkyl isonitriles in MCRs

Chiral N^β-Fmoc amino alkyl isonitriles were employed in Ugi multi component reactions (Ugi 4C-3CR) to obtain functionalized β-lactam peptidomimetics with l-aspartic acid α-methyl ester/peptide ester and organic aldehydes. The reactions were carried out in MeOH. Thirteen Ugi products have been prepared in good to moderate yields with good diastereoselectivities.     

Enzymatic Ugi Reaction with Amines and Cyclic Imines

The application of the Ugi reaction to the construction of new peptide scaffolds is an important goal of organic chemistry. To date, there are no examples of the Ugi reaction being performed with a cyclic imine and amine simultaneously. The application of 2‐substituted cyclic imines in an enzymatic three‐component Ugi‐type reaction provides an elegant and attractive synthesis of substituted pyrrolidine and piperidine derivatives in up to 60 % yield. Results on studies of the selection of an enzyme, amount of water, and solvent used in a novel three‐component Ugi reaction and the limitations thereof are reported herein. The presented methodology exploiting enzyme promiscuity in the multicomponent reaction fulfills the requirements associated with green chemistry. Several methods, such as isotope labeling and enzyme inhibition, were used to probe the possible mechanism of this complex synthesis. This research is the first example of an enzyme‐catalyzed Ugi‐type reaction with an imine, amine, and isocyanide.     

Diversity oriented and chemoenzymatic synthesis of densely functionalized pyrrolidines through a highly diastereoselective Ugi multicomponent reaction

A highly diastereoselective Ugi reaction involving a chiral cyclic imine, two enantiomerically pure isocyanides and various carboxylic acids was employed for the synthesis of polyfunctionalized pyrrolidines. Both chiral substrates have been efficiently prepared by chemoenzymatic methodologies from readily available achiral substrates. This highly convergent approach can find an application in the fragment-based drug discovery process.     

Sulfanyl-methylene-5(4H)-oxazolones and β-sulfanyl-α-nitroacrylates as appealing dienophiles for the synthesis of conformationally constrained cysteine analogues

A new class of masked constrained cysteine derivatives containing the norbornen/ane scaffold were prepared by the way of Diels–Alder cycloaddition reaction by exploitation of two different dienophiles, sulfanyl-methylene-5(4H)-oxazolones and β-sulfanyl-α-nitroacrylates. The new norbornen/ane amino acid derivatives can be considered versatile building blocks due to the presence of the α,α-disubstituted amino acid function, suitable for peptide synthesis, but also by the carbon–carbon norbornene double bond, which could be variously functionalized.     

Asymmetric Michael addition of malonic diesters to acrylates by phase-transfer catalysis toward the construction of quaternary stereogenic α-carbons

A highly enantioselective construction of an all-carbon quaternary stereogenic center at the α-position of malonic diesters has been achieved by Michael addition using phase-transfer catalysis. The reaction of α-monosubstituted malonates with acrylates in the presence of N-(9-anthracenylmethyl)quininium chloride as a phase-transfer catalyst afforded the corresponding α,α-disubstituted malonic diesters in high chemical yields (up to >95% yield) with high enantioselectivities (up to 95% ee). Furthermore, the product was amenable to chemoselective transformation and could be successfully converted to the corresponding α,α-disubstituted amino acid derivatives through Curtius rearrangement.