Stable 2-Azaallyl Salts as a Bridge between 2H-Azirines and Densely Functionalized 2H-Pyrroles.

An efficient protocol for the synthesis of stable 2-azaallyl anion salts by the reaction of alkyl 2-bromo-2H-azirine-2-carboxylates with trimethylsilyl cyanide/Bu4NF has been developed. The domino reaction proceeds in four steps via the cleavage of the azirine C-C bond to provide the tetrabutylammonium salts of stereochemically pure 2-azaallyl anions having U-configuration relative to the cyano groups. The anions with an ortho-substituted aryl group or styryl group exist as a mixture of two geometrical isomers across the N2-C3 bond. 2-Azaallyl anion salts have been shown to be convenient substrates for the one-pot synthesis of densely functionalized 2H-pyrroles by the alkylation-cyclization sequence.

Triethylamine-Promoted Oxidative Cyclodimerization of 2H-Azirine-2-carboxylates to Pyrimidine-4,6-dicarboxylates: Experimental and DFT Study.

An unprecedented oxidative cyclodimerization reaction of 2H-azirine-2-carboxylates to pyrimidine-4,6-dicarboxylates under heating with triethylamine in air is described. In this reaction, one azirine molecule undergoes formal cleavage across the C-C bond and another across the C=N bond. According to the experimental study and DFT calculations, the key steps of the reaction mechanism include nucleophilic addition of N,N-diethylhydroxylamine to an azirine to form an (aminooxy)aziridine, generation of an azomethine ylide, and its 1,3-dipolar cycloaddition to the second azirine molecule. The crucial condition for the synthesis of pyrimidines is generation of N,N-diethylhydroxylamine in the reaction mixture in a very low concentration, which is ensured by the slow oxidation of triethylamine with air oxygen. Addition of a radical initiator accelerated the reaction and resulted in higher yields of the pyrimidines. Under these conditions, the scope of the pyrimidine formation was elucidated, and a series of pyrimidines was synthesized.

Copper(II)-Catalyzed (3+2) Cycloaddition of 2H-Azirines to Six-Membered Cyclic Enols as a Route to Pyrrolo[3,2-c]quinolone, Chromeno[3,4-b]pyrrole, and Naphtho[1,8-ef]indole Scaffolds.

A method for the [2+3] pyrroline annulation to the six-membered non-aromatic enols using 3-aryl-2H-azirines as annulation agents is developed in the current study. The reaction proceeds as a formal (3+2) cycloaddition via the N1-C2 azirine bond cleavage and is catalyzed by both Cu(II) and Cu(I) compounds. The new annulation method can be applied to prepare pyrrolo[3,2-c]quinoline, chromeno[3,4-b]pyrrole, and naphtho[1,8-ef]indole derivatives in good to excellent yields from enols of the quinolin-2-one, 2H-chromen-2-one, and 1H-phenalen-1-one series.

Blue Light-Promoted Cross-Coupling of α-Diazo Esters with Isocyanides: Synthesis of Ester-Functionalized Ketenimines.

A metal-free scalable synthesis of functionalized ketenimines from alkyl α-(aryl/heteroaryl)-α-diazoacetates and alkyl isocyanides induced by blue light irradiation has been developed. The reaction proceeds at room temperature without any photocatalyst and provides ketenimines in moderate to good yields. Density functional theory (DFT) calculations and the experimental study showed that aryl(alkoxycarbonyl)carbenes in both singlet and triplet states can react with isocyanides but only the reaction of the former leads to the smooth formation of ketenimines. The obtained ketenimines were used for the synthesis of functionalized amidines under mild metal-free conditions.

ATP-Independent Initiation during Cap-Independent Translation of m6A-Modified mRNA.

The methylation of adenosine in the N6 position (m6A) is a widely used modification of eukaryotic mRNAs. Its importance for the regulation of mRNA translation was put forward recently, essentially due to the ability of methylated mRNA to be translated in conditions of inhibited cap-dependent translation initiation, e.g., under stress. However, the peculiarities of translation initiation on m6A-modified mRNAs are not fully known. In this study, we used toeprinting and translation in a cell-free system to confirm that m6A-modified mRNAs can be translated in conditions of suppressed cap-dependent translation. We show for the first time that m6A-modified mRNAs display not only decreased elongation, but also a lower efficiency of translation initiation. Additionally, we report relative resistance of m6A-mRNA translation initiation in the absence of ATP and inhibited eIF4A activity. Our novel findings indicate that the scanning of m6A-modified leader sequences is performed by a noncanonical mechanism.

Azirine-containing dipeptides and depsipeptides: synthesis, transformations and antibacterial activity.

Azirine-containing dipeptides and depsipeptides with a wide range of substituents have been synthesized in high yields via the Passerini and Ugi multicomponent reactions (MCRs) using 2H-azirine-2-carboxylic acids as the acid component. The obtained MCR adducts have been transformed to lactam-fused aziridines, as well as pyrrole, imidazole, aziridine, and other derivatives, containing the dipeptide or depsipeptide moiety. The azirine-containing depsipeptides exhibit antibacterial activity against the ESKAPE pathogens, especially Gram-positive bacterial strains (E. faecium - MIC 16 µg mL-1, S. aureus - MIC 9 µg mL-1).

Regiodivergent Synthesis of Butenolide-Based α- and ß-Amino Acid Derivatives via Base-Controlled Azirine Ring Expansion.

A method for the preparation of 5-aminobutenolides from 2-bromo-2H-azirine-2-carboxylic esters/amides with arylacetic acids has been developed. The reaction regioselectivity can be switched by a change of the basic catalyst, making it possible to prepare both butenolide-based α- and ß-amino acid derivatives. The change in the regioselectivity is interpreted in terms of the stability and reactivity of the enolates formed during the SN2' substitution of the bromine in the azirine by the carboxylate ion.

Selective Cu-Catalyzed Intramolecular Annulation of 3-Aryl/Heteryl-2-(diazoacetyl)-1H-pyrroles: Synthesis of Benzo/Furo/Thieno[e]-Fused 1H-Indol-7-oles and Their Transformations.

The Co(III)-catalyzed reaction of 1,3-dicarbonyl compounds with 2-(diazoacetyl)-2H-azirines, prepared by a simplified procedure from 2H-azirin-2-carbonyl chlorides, led in high yields to the formation of 2-(diazoacetyl)pyrroles, while leaving the diazoacetyl function intact. The intramolecular aromatic substitution reaction of 2-(diazoacetyl)pyrroles, catalyzed by Cu(OTf)2, provided selectively previously unknown benzo[e]- and hetero[e]-fused indol-7-oles in good yields. Formylation of benzo[e]indol-4-ol led selectively to the 5-formyl derivative, which is a good precursor for an unusual salen ligand and its Ni-complex. Triflates prepared from benzo[e]indol-4-oles gave various 4-substituted benzo[e]indoles carrying aryl, 2-thienyl, 2-pyridyl, and alkynyl groups, in excellent yields using cross-coupling reactions. 4-(2-Pyridyl)benzo[e]indoles, upon treatment with BF3·Et2O/Et3N, afforded a new type of fluorescent boron complexes with large Stokes shifts.

2 H-Azirines as C-C Annulation Reagents in Cu-Catalyzed Synthesis of Furo[3,2- c]quinolone Derivatives.

A method of furo-annulation of 4-hydroxy-2-oxoquinoline-3-carboxylates with 3-arylazirines under Cu(II) catalysis was developed to synthesize a variety of 2,3-dihydrofuro[3,2- c]quinolones bearing a carbamate group at the C2 position. The reaction involves an azirine ring opening across the N-C2 bond and formation of a dihydrofuran ring with the inclusion of two azirine carbon atoms, accompanied by a shift of the ester group to the nitrogen. The discovered reaction is the first example of the use of 2 H-azirines for furo-annulation.

Non-natural 2H-azirine-2-carboxylic acids: an expedient synthesis and antimicrobial activity.

Non-natural 2H-azirine-2-carboxylic acids were obtained in high yields by FeCl2-catalyzed isomerization of 5-chloroisoxazoles to azirine-2-carbonyl chlorides followed by their hydrolysis. The 3-aryl- and 3-heteroaryl-substituted acids are stable during prolonged storage, exhibit antibacterial activity against ESKAPE pathogens and show a low level of cytotoxicity.

2-Diazoacetyl-2 H-azirines: Source of a Variety of 2 H-Azirine Building Blocks with Orthogonal and Domino Reactivity.

A synthesis of 2-diazoacetyl-2 H-azirines was developed starting from 2 H-azirine-2-carbonyl chlorides, generated by Fe(II)-catalyzed isomerization of 5-chloroisoxazoles. 2-Diazoacetyl-2 H-azirines easily undergo reactions characteristic of α-diazo ketones with preservation of the azirine ring. Reactions with hydrohalogenic, carboxylic, and p-toluenesulfonic acids provide novel 1-(3-aryl-2 H-azirin-2-yl)-2-halo- and 2-(R-oxy)ethan-1-ones in good yields. The synthesized 2 H-azirines can offer many possibilities for chemical manipulation in heterocyclic synthesis, due to the presence of highly reactive azirine and the exocyclic C(O)-CHN2 or C(O)-CH2X functionalities, which can show orthogonal or domino reactivity. The synthetic usefulness of the developed building blocks was demonstrated by the preparation of new types of heterocyclic dyads (azirine-oxazole, azirine-pyrazoline, azirine-thiazole, azirine-oxirane, pyrrole-oxazole) as well as an azirine chalcone analogue, 2-azidoacetyl-2 H-azirine, and 2-diazoacetylaziridine derivatives.

Facile access to 2-acyloxy-, aryloxy- and alkenyloxy-2H-azirines via an SN2'-SN2' cascade in 2-halo-2H-azirines.

Various 2-oxygen-substituted 2H-azirine-2-carboxylic acid derivatives were synthesized in high yields under mild conditions from readily available precursors, 2-halo-2H-azirines and OH-reagents having pKa values in the range of 3-10. This reaction is the first example of substitution at the azirine carbon atom for which an unusual SN2'-SN2' cascade mechanism was revealed.

Cu(I)-NHC-Catalyzed (2 + 3)-Annulation of Tetramic Acids with 2H-Azirines: Stereoselective Synthesis of Functionalized Hexahydropyrrolo[3,4-b]pyrroles.

A stereoselective and high-yield synthesis of hexahydropyrrolo[3,4-b]pyrroles from tetramic acids and 2H-azirines under Cu(I)-NHC catalysis is developed. An unusual N-C2 azirine bond cleavage, initiated by a copper enolate, was rationalized in terms of a free radical reaction mechanism.

Internal translation initiation and eIF4F/ATP-independent scanning of mRNA by eukaryotic ribosomal particles.

The recombinant mRNAs with 5'-untranslated region, called omega leader, of tobacco mosaic virus RNA are known to be well translated in eukaryotic cell-free systems, even if deprived of cap structure. Using the method of primer extension inhibition (toe-printing), the ribosomal particles were shown to initiate translation at uncapped omega leader when its 5'-end was blocked by a stable RNA-DNA double helix, thus providing evidence for internal initiation. The scanning of the leader sequence and the formation of ribosomal 48S initiation complexes at the initiation AUG codon occurred in the absence of ATP-dependent initiation factor eIF4F, as well as without ATP. The latter results implied the ability of ribosomal initiation complexes for ATP-independent, diffusional wandering (also called bi-directional movement) along the leader sequence during scanning.