Electrocyclic Ring-Opening of 1,2,4-Oxadiazole[4,5-a]piridinium Chloride: a New Route to 1,2,4-Oxadiazole Dienamino Compounds.

1,2,4-Oxadiazole[4,5-a]piridinium chloride adds nucleophiles to undergo electrocyclic ring opening affording 1,2,4-oxadiazole dienamino derivatives. These pyridinium salts represent a special class of Zincke salts that are prone to rearrange when treated with primary amines or in the presence of bicarbonate to give the pyridones. The pivotal tuning of the experimental conditions leads to a straightforward synthesis of valuable 1,2,4-oxadiazole dienamine derivatives. The mechanism is also discussed in the light of NMR experiments and theoretical calculations.

Ene Reaction of Nitrosocarbonyl Mesitylene with the Cinnamyl Alcohol: Metabolic Activity and Apoptosis of the Synthetized 6-Chloropurine N,O-Nucleoside Analogues.

Nitrosocarbonyl mesitylene intermediate undergoes an ene reaction with cinnamyl alcohol affording the corresponding 5-hydroxy-isoxazolidine in fair yields. The synthesized 5-acetoxy-isoxazolidine serves as synthon for the preparation of 6-chloropurine N,O-nucleoside analogues, according to the Vorbrüggen reaction. The compounds were evaluated for their metabolic and apoptotic activity, and their structure-activity relationship is discussed.

Ene Reactions of Nitrosocarbonyl Intermediates with Trisubstituted Cycloalkenes: "Cis Effect" and Steric and Conformational Factors Drive the Selectivity.

Nitrosocarbonyl intermediates, generated at room temperature by oxidation of nitrile oxides, undergo clean ene reactions with trisubstituted cycloalkenes. Nitrosocarbonyl benzene follows a Markovnikov orientation and abstracts preferentially the twix hydrogens over the lone ones. With the more sterically demanding nitrosocarbonyl mesitylene in the presence of 5- and 6-membered ring olefins, the Markovnikov directing effect is relieved, and twix and lone abstractions are observed. Endocyclic allylic hydrogens on the more congested side of the alkene are exclusively abstracted (the "cis effect") resembling the singlet oxygen behavior. The balance between steric and conformational factors, as well as the acylnitroso generation conditions, dictates the regioselectivity in some cases. Larger ring olefins undergo selective twix allylic hydrogen abstraction. The photochemical generation of nitrosocarbonyl is totally selective according to the Markovnikov orientation. The synthetic utility of the ene compounds is also accounted.

Cyclopenta[d]isoxazoline ß-Turn Mimics: Synthetic Approach, Turn Driving Force, Scope, and Limitations.

Model ß-turn inducers were prepared from constrained oxazanorbornene aminols. Taking advantage of the starting materials geometry, new diastereoisomeric compounds were synthesized, introducing different amino acidic residues. The products were spectroscopically characterized (VT and NMR titration). Temperature coefficients in dimethyl sulfoxide denote the existence of an intramolecular hydrogen bond. Chiroptical properties disclosed a ß-turn arrangement of the synthesized compounds. The fused isoxazoline ring constraints the cyclopentane moiety, stabilizing a boatlike conformation that ensures the turn efficiency but limiting the accessibility to hindered amino acids.

Generation and Trapping of Nitrosocarbonyl Intermediates.

The nitrosocarbonyls (R-CONO) are highly reactive species and remarkable intermediates toward different synthetic targets. This review will cover a research area whose impact in current organic synthesis is constantly increasing in the chemical community. This review represents the first and comprehensive picture on the generation and trapping of nitrosocarbonyls and is solidly built on more than 380 papers. Six different classes of key starting materials such as hydroxamic acids, N-hydroxy carbamates, N-hydroxyureas, nitrile oxides, and 1,2,4-oxadiazole-4-oxides were highlighted. The content of the review surveys all the methods to generate the nitrosocarbonyls through different approaches (oxidative, thermal, photochemical, catalytic, aerobic, and the less common ones) in the light of efficiency, yields, and mildness. The most successful trapping agents employed to catch these fleeting intermediates are reviewed, exploiting their superior dienophilic, enophilic, and electrophilic power. The work is completed by paragraphs dedicated to the detection of the intermediates, theoretical studies, and insights about the challenges and future directions for the field.

Design, Synthesis, and Conformational Analysis of Proposed ß-Turn Mimics from Isoxazoline-Cyclopentane Aminols.

Constrained aminols from oxazanorbornene derivatives have the geometrical features to be used as ß-turn inducers. Four different stereoisomers were prepared and spectroscopically characterized (MD calculations, NMR-titration and VT-NMR experiments). Temperature coefficients in DMSO are indicative for the existence of an intramolecular hydrogen bond. Chirooptical properties revealed a ß-turn arrangement of all the synthesized compounds, where, depending on the absolute configuration of the cyclopentane spacer, they can be labeled as left- or right-handed turns.

Three-dimensional heterocycles: new uracil-based structures obtained by nucleophilic substitution at the sp2 carbon of bromoisoxazoline.

The regioisomeric cycloadducts of bromonitrile oxide and N-benzoyl-2,3-oxaza-norborn-5-ene were easily prepared and elaborated into a novel class of uracil-based scaffolds. The key-synthetic step is the nucleophilic substitution at the sp2 carbon atom of the bromoisoxazoline three-dimensional heterocycles. The protocol to perform the nucleophilic substitution of uracil anions was optimized and adapted to the steric requirements of the substrates. A library of pyrimidine derivatives was prepared in very good yields and the products were fully characterized. They are proposed as nucleoside analogues and as synthons for ß-turn motifs within PNA structures.

#Nitrosocarbonyls 1: antiviral activity of N-(4-hydroxycyclohex-2-en-1-yl)quinoline-2-carboxamide against the influenza A virus H1N1.

Influenza virus flu A H1N1 still remains a target for its inhibition with small molecules. Fleeting nitrosocarbonyl intermediates are at work in a short-cut synthesis of carbocyclic nucleoside analogues. The strategy of the synthetic approaches is presented along with the in vitro antiviral tests. The nucleoside derivatives were tested for their inhibitory activity against a variety of viruses. Promising antiviral activities were found for specific compounds in the case of flu A H1N1.

Iminium ions as dienophiles in Aza-Diels-Alder reactions: a closer look.

This review highlights the state of the art of the use of iminium ions as dienophiles in Aza-Diels-Alder (ADA) cycloadditions. An historical survey spanning the very first discovery of the reaction to modern developments, mechanistic studies and synthetic applications of the iminium variant of the ADA (iADA) reaction are presented. The discussion is focused on the intermolecular and intramolecular versions of the iADA reactions that are conducted in aqueous solutions to generate, in situ, the reactive dienophile from an amine hydrochloride and either aliphatic or aromatic aldehydes in the presence of a variety of dienes. The retro-ADA reaction is also presented as an interesting method for the protection of amines. The use of Lewis acid catalysis in these reactions was thoroughly studied by the reactions of different amines and aldehydes conducted in the presence of lanthanide(III) complexes.

The chemoselective reduction of isoxazoline γ-lactams through iminium Aza-Diels-Alder reactions: a short-cut synthesis of aminols as valuable intermediates towards nucleoside derivatives.

Isoxazoline γ-lactams are prepared starting from the regioisomeric cycloadducts of benzonitrile oxide to the N-alkyl 2-azanorbornenes taking advantage of the efficient catalytic oxidation by RuO(4). The reduction of the amide groups is easily conducted in the presence of LiAlH(4) under mild conditions, which allowed for the chemoselective reduction of the amide moiety followed by ring opening to afford the desired conformationally locked isoxazoline-carbocyclic aminols, as valuable intermediates for nucleoside synthesis.