Asymmetric Ugi Research Articles

Enantioselective Ugi and Ugi-azide reactions catalyzed by anionic stereogenic-at-cobalt(III) complexes

Ugi reactions and related variations are proven to be atom and step-economic strategies for construction of highly valuable peptide-like skeletons and nitrogenous heterocycles. The development of structurally diverse range of novel catalytic systems and the discovery of new approaches to accommodate a broader scope of terminating reagents for asymmetric Ugi four-component reaction is still in high demand. Here, we report a strategy that enables enantioselective Ugi four-component and Ugi-azide reactions employing anionic stereogenic-at-cobalt(III) complexes as catalysts. The key nitrilium intermediates, generated through the nucleophilic addition of isocyanides to the chiral ion-pair which consists of stereogenic-at-cobalt(III) complexes counteranion and a protonated iminium, are trapped by either carboxylic acids or in situ-generated hydrazoic acid, delivering α-acylamino amides and α-aminotetrazoles in good to excellent enantioselectivities (up to 99:1 e.r.).

New Developments in Chiral Phosphoric Acid Catalysis for Amine Synthesis

Abstract:Asymmetric catalysis with chiral phosphoric acids (CPAs) has impacted a wide range of organic reactions, including those that generate chiral amines of interest in medicinal and natural products chemistry. Phosphodiester derivatives (RO)2PO2H offer linkages to various chiral alcohols and diols, permitting the CPA to transmit stereochemical information to reactants via ion-pairing and/or H-bonding interactions of the P=O and O–H bonds. This minireview presents selected recent developments in CPA-catalyzed asymmetric synthesis of amines, emphasizing innovations from the literature of 2017–2021, with a few earlier examples to provide additional context. The coverage includes additions to imines, asymmetric protonation, induction of axial asymmetry, asymmetric Ugi and Passerini multicomponent coupling reactions, hydroaminations, and Minisci-type additions to heteroaromatic systems.

ChemInform Abstract: Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct.

AbstractReaction of isonitriles with 3‐(arylamino)isobenzofuran‐1(3H)‐ones in the presence of a catalytic amount of an octahydro (R)‐binol‐derived chiral phosphoric acid affords 3‐oxo‐2‐arylisoindoline‐1‐carboxamides in high yields with good to high enantioselectivities.

Asymmetric Ugi Reaction Catalyzed by a Chiral Phosphoric Acid

Asymmetric Ugi Reaction Catalyzed by a Chiral Phosphoric Acid

Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct

AbstractReaction of isonitriles with 3‐(arylamino)isobenzofuran‐1(3H)‐ones in the presence of a catalytic amount of an octahydro (R)‐binol‐derived chiral phosphoric acid afforded 3‐oxo‐2‐arylisoindoline‐1‐carboxamides in high yields with good to high enantioselectivities. An enantioselective Ugi four‐center three‐component reaction of 2‐formylbenzoic acids, anilines, and isonitriles was subsequently developed for the synthesis of the same heterocycle. Mechanistic studies indicate that the enantioselectivity results from the dynamic kinetic resolution of the primary Ugi adduct, rather than from the C−C bond‐forming process. The resulting heterocycle products are of significant medicinal importance.

Chiral Phosphoric Acid Catalyzed Asymmetric Ugi Reaction by Dynamic Kinetic Resolution of the Primary Multicomponent Adduct.

Reaction of isonitriles with 3-(arylamino)isobenzofuran-1(3H)-ones in the presence of a catalytic amount of an octahydro (R)-binol-derived chiral phosphoric acid afforded 3-oxo-2-arylisoindoline-1-carboxamides in high yields with good to high enantioselectivities. An enantioselective Ugi four-center three-component reaction of 2-formylbenzoic acids, anilines, and isonitriles was subsequently developed for the synthesis of the same heterocycle. Mechanistic studies indicate that the enantioselectivity results from the dynamic kinetic resolution of the primary Ugi adduct, rather than from the C-C bond-forming process. The resulting heterocycle products are of significant medicinal importance.

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives.

An efficient Ugi three-component reaction of a preformed chiral ketimine derived from isatin with various isonitrile and acid components has been developed. The reactions proceeded smoothly and in a stereocontrolled manner with regard to the new center of the Ugi products due to the stereoinduction of the amine chiral residue. A wide variety of novel chiral 3,3-disubstituted 3-aminooxindoles were obtained, a selection of which were subjected to post-Ugi transformations, paving the way to application as peptidomimetics.

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.

An Approach to the Synthesis of Enantiopure Tetrahydroisoquinoline via a Key Asymmetric Ugi Reaction

An approach to the synthesis of the multisubstituted ­tetrahydroisoquinoline featuring an asymmetric Ugi reaction of α-amino acid, aromatic aldehyde and an isocyanide has been developed. The promising utility of the strategy is demonstrated by a ­synthesis of an enantiopure functionalized 1,3- trans -tetrahydroisoquinolin-4-ol from natural l -valine. The configuration of the two stereocenters at C-1 and C-4, generated in the Ugi reaction and Pomeranz–Fritsch-type cyclization separately, was controlled very well and determined by NMR studies.

ChemInform Abstract: An Asymmetric Ugi Three‐Component Reaction Induced by Chiral Cyclic Imines: Synthesis of Morpholine— or Piperazine—Ketocarboxamide Derivatives.

AbstractTreatment of chiral cyclic imines like (I) and (VII) with acids and isocyanides allows an efficient and stereoselective access to novel morpholines.

An Asymmetric Ugi Three-Component Reaction Induced by Chiral Cyclic Imines: Synthesis of Morpholin– or Piperazine–Keto-carboxamide Derivatives

A series of chiral 5,6-dihydro-1,4-oxazin-2-one substrates, as preformed cyclic aldimines and ketoimines, were employed to develop a new asymmetric Ugi three-component reaction for the first time. The Ugi reaction of the imines, isocyanides, and carboxylic acids opens an efficient access to novel morpholin-2-one-3-carboxamide compounds. The chiral imines showed promising stereoinduction for the new chiral center of the Ugi products, and predominant trans-isomers were obtained in the most cases. Addition of some Lewis acids or proton acids could improve the diastereoselectivity further but usually led to a drop in total yield. The Ugi-3CR could be extended to the stereoselective synthesis of ketopiperazine-2-carboxamide derivatives.

Diastereoselective Ugi Reaction Without Chiral Amines: The Synthesis of Chiral Pyrroloketopiperazines

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, please click on HTML or PDF.

Diastereoselective Ugi reaction without chiral amines: the synthesis of chiral pyrroloketopiperazines

The three-component Ugi reaction with chiral 2-(2-formyl-1 H-pyrrol-1-yl)acetic acids prepared from natural l-aminoacids was investigated. The reaction opens a new route to chiral substituted pyrroloketopiperazines. One of the first examples of an asymmetric Ugi reaction without chiral amines is described. The reaction proceeds with moderate diastereoselectivity to give the target compounds in good yields. The scope and limitation of the approach are discussed.

Enhanced Diastereoselectivity in the Asymmetric Ugi Reaction Using a New “Convertible” Isonitrile.

Enhanced Diastereoselectivity in the Asymmetric Ugi Reaction Using a New “Convertible” Isonitrile.

ChemInform Abstract: Enhanced Diastereoselectivity in the Asymmetric Ugi Reaction Using a New “Convertible” Isonitrile.

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.

Enhanced Diastereoselectivity in the Asymmetric Ugi Reaction Using a New “Convertible” Isonitrile

Enhanced Diastereoselectivity in the Asymmetric Ugi Reaction Using a New “Convertible” Isonitrile