Cyclic Nitrones Research Articles

Synthesis of Cyclic Vicinal Trifluoromethylated Hydroxylamine and Nitrone Based on Perfluorodiacetyl

Perfluorodiacetyl (PFDA) demonstrates high‐synthetic potential in reaction with bifunctional nucleophilic reagents. Therefore, PFDA is a useful reagent in the synthesis of CF3‐substituted heterocycles. In this work, we explored the reaction of PFDA with a sterically hindered bis‐hydroxylamine, isolated the products and clarified their structures. It was found that the reaction initially gave the 5,5,6,6‐tetramethyl‐2,3‐bis(trifluoromethyl)pyperazine‐1,2,3,4‐tetraol heterocycle with a unique set of functional groups. This tetraol was shown to easily undergo dehydration with formation of the first cyclic α‐CF3‐substituted nitrone.

Synthesis and chemical transformations of six/six-membered bicyclic nitroso acetals

A synthesis of hitherto unknown bicyclic nitroso acetals possessing two annulated six-membered rings is accomplished. The synthesis comprises formal [3+3] cycloaddition of six-membered cyclic nitronates with donor-acceptor cyclopropanes. Some chemical transformations and conformational preferability of the obtained nitroso acetals are discussed.

Copper-Catalyzed Oxidative Oxyamination/Diamination of Internal Alkenes of Unsaturated Oximes with Simple Amines

A convenient and versatile oxidative intra/intermolecular oxyamination and diamination of unactivated alkenes has been developed through copper-catalyzed radical reactions of β,γ- and γ,δ-unsaturated ketoximes with electron-rich aryl and aliphatic amines. These reactions were carried out by employing di-tert-butyl peroxide (DTBP) or air as the terminal oxidant, and a series of useful nitrogen-containing 4,5-dihydroisoxazoles and cyclic nitrones were formed.

Stereoselective 1,3-dipolar cycloadditions of thioketones to carbohydrate-derived nitrones

A series of cycloaliphatic thioketones was reacted with selected enantiopure nitrones bearing carbohydrate-derived moieties leading to 1,4,2-oxathiazolidine derivatives in a highly stereoselective manner. Analysis of spectroscopic data supplemented by X-ray diffraction analysis of the major products confirmed the anti-configuration in the series derived from d-glyceraldehyde and l-erythrose-functionalized nitrones bearing a sugar moiety at the C atom. In the case of the model benzaldehyde-derived nitrone decorated at the N atom with carbohydrate auxiliary, and also for a l-erythrose-derived cyclic nitrone, in the reaction with sterically crowded 2,2,4,4-tetramethyl-3-thioxocyclobutanone the exclusive formation of single diastereoisomeric products was observed indicating an excellent steric match of the substrates. Dissociation constants of selected (3+2)-cycloadducts were determined by 1H NMR spectroscopy.

Synthesis of α‐Acyloxynitrones and Reactivity towards Samarium Diiodide

Upon treatment of fructose‐derived nitrone 1 with samarium diiodide, with the aim of inducing its umpolung and coupling with electrophiles, an unexpected β‐elimination of the benzyloxy group at C‐1 was observed, yielding nitrone 2. The mechanism and scope of this transformation were investigated, from nitrone 1 and from five other α‐alkoxy or α‐acyloxy nitrones. This paper describes the preparation of new nitrones 3 and 4 from d‐fructose; their synthesis demonstrates that acyl‐protected nitrones can be prepared efficiently by intramolecular N‐alkylation of sugar‐derived oximes, a strategy previously developed only for ether‐ or ketal‐protected cyclic nitrones. Nitrones 3 and 4 underwent fast β‐elimination upon treatment with SmI2. Contrastingly, no β‐elimination occurred with nitrones 5–7, suggesting a specific behavior of endocyclic keto nitrones.

1,3-Dipolar cycloaddition of a cyclic nitrone derived from 2-deoxy-D-ribose to α,β-unsaturated lactones: An entry to carbapenem antibiotics

1,3-Dipolar cycloadditions of 2-deoxy-D-ribose-derived L-threo five-membered cyclic nitrone to α,β-unsaturated γ- and δ-lactones were investigated. Cycloadducts obtained from δ-lactones, after NO bond cleavage, opening of the lactone ring, and protection of hydroxyl groups were subjected to β-lactam ring formation by using Mukaiyama's salt. Cycloadducts from γ-lactones subjected to the same reaction sequence undergo β-elimination of a water molecule to provide pyrrolidine-substituted unsaturated γ-lactones.

Stereoselective Ethynylation and Propargylation of Chiral Cyclic Nitrones: Application to the Synthesis of Glycomimetics

Ethynylation and propargylation of chiral nonracemic polyhydroxylated cyclic nitrones with Grignard reagents are efficient methods for preparing building blocks containing an alkyne moiety to be used in copper-catalyzed azide alkyne cycloaddition click chemistry. Whereas ethynylation takes place with excellent diastereoselectivity, propargylation afforded mixtures of diastereomers in some cases. The use of (trimethylsilyl)propargyl bromide as precursor of the Grignard reagent is necessary to avoid the formation of undesired allene derivatives. DFT calculations explain, within the experimental error, the observed behavior. Cycloaddition of the obtained pyrrolidinyl alkynes with sugar azides derived from β-(1,3)-glucans provides glycomimetics suitable to be used against fungal transglycosylases.

ChemInform Abstract: Fluorinated Radicamine A and B: Synthesis and Glycosidase Inhibition.

AbstractFluorinated derivatives of radicamine A (Ia‐d) and radicamine B (Ie,f) are synthesized from a D‐arabinose‐derived cyclic nitrone using established methods.

Phosphine-Catalyzed Intramolecular Cyclizations of α-Nitroethylallenoates Forming (Z)-Furanone Oximes.

A novel and efficient phosphine-catalyzed intramolecular cyclization of α-nitroethylallenic esters is reported. This process appears to be practical for the stereoselective syntheses of (Z)-furan-2(3H)-one oxime derivatives in excellent yields. Mechanistically, the reaction involves a phosphine-catalyzed Michael addition of an alkylideneazinate and rearrangement of the cyclic nitronate to the α-nitrosodihydrofuran.

Formal [3+2] Cycloaddition of Nitrosoallenes with Carbonyl and Nitrile Compounds to Form Functional Cyclic Nitrones.

The synthesis of functional cyclic nitrones via [3+2] cycloadditions of allenamide-derived nitrosoallenes with carbonyl/nitrile compounds, including ketones, esters, and nitriles, is presented herein. Rapid carbon-carbon, carbon-oxygen, and carbon-nitrogen bond formations were achieved with in situ prepared nitrosoallenes, and densely substituted oxacyclic and carbocyclic nitrones containing tetrasubstituted carbon centers were successfully synthesized. The spirocyclic nitrone products synthesized from cyclic dicarbonyl compounds underwent the unique skeletal rearrangements to cyclic α-ketonitrones.

An Iridium-Catalyzed Reductive Approach to Nitrones from N-Hydroxyamides.

An Ir-catalyzed reductive formation of functionalized nitrones from N-hydroxyamides was reported. The reaction took place through two types of iridium-catalyzed reactions including dehydrosilylation and hydrosilylation. The method showed high chemoselectivity in the presence of sensitive functional groups, such as methyl esters, and was successfully applied to the synthesis of cyclic and macrocyclic nitrones, which are known to be challenging compounds to access by conventional methods. (1)H NMR studies strongly supported generation of an N-siloxyamide and an N,O-acetal as the actual intermediates.

Studies on the Enantioselective Kinugasa Reaction: Efficient Synthesis of β‐Lactams Catalyzed by N‐PINAP/CuX Complexes

AbstractCatalytic enantioselective Kinugasa reactions between acyclic and, for the first time, cyclic nitrones and terminal alkynes are described herein. A catalytic amount of the readily available PINAP/CuX complexes, generated in situ, efficiently catalyzed the Kinugasa reactions, leading to a series of β‐lactams with good enantioselectivities and moderate diastereoselectivities and yields. A broad range of nitrones and terminal alkynes, including the seldom reported alkyl‐substituted alkynes, were tolerated under the reaction conditions. Further investigations proved that the PINAP/CuX catalytic system enabled the synthesis of monobactams on the gram scale (without loss of stereoselectivity and yield) and also both enantiomers by the appropriate choice of readily available atropisomeric N‐PINAP ligands.

Fluorinated Radicamine A and B: Synthesis and Glycosidase Inhibition

AbstractFluorinated derivatives of radicamine A and radicamine B have been synthesized from D‐arabinose‐derived cyclic nitrone. Structure–activity relationship studies showed that glycosidase inhibition of these fluorinated derivatives was significantly influenced by the position of the fluorine atom. C‐7 or C‐11 fluorination of the aromatic ring decreased α‐glucosidase inhibition of the derivatives, whereas C‐8 or C‐10 fluorination preserved glycosidase inhibitory activities.

A Stereoselective Synthesis of Lentiginosine.

A concise stereoselective synthesis of (-)-lentiginosine, an iminosugar endowed with an interesting proapoptotic activity, has been accomplished using an enantiopure pyrroline N-oxide building block derived from d-tartaric acid. Key steps are a totally diastereoselective nucleophilic addition to the cyclic nitrone followed by a combination of two simultaneous and two tandem reactions occurring under the same conditions in a single laboratory operation. Natural (+)-lentiginosine can be synthesized by the same method but starting from l-tartaric acid.

First total synthesis of (+)-broussonetine W: glycosidase inhibition of natural product & analogs.

The first total synthesis of (+)-broussonetine W (4), a naturally-occurring pyrrolidine iminosugar isolated from the traditional Chinese medical plant Broussonetia kazinoki SIEB (Moraceae), has been completed through a concise synthetic route starting from the readily available d-arabinose derived cyclic nitrone 10 in 11 steps and 31% overall yield, with regioselective installation of the α,β-unsaturated ketone functional group by the elimination of HBr from α-bromoketone as the key step. A number of analogs of (+)-broussonetine W (4) with variable side chain length, different polyhydroxylated pyrrolidine core configurations or saturated cyclohexanones have also been prepared to explore the glycosidase inhibition and the preliminary structure-activity relationship of this intriguing class of compounds. Glycosidase inhibition studies identified the natural product (+)-broussonetine W (4) as a selective and potent inhibitor of β-galactosidase (IC50 = 0.03 μM), while its enantiomer was a selective and potent inhibitor of α-glucosidase (IC50 = 0.047 μM). It was found that the configuration of the polyhydroxylated pyrrolidine ring played a key role on their glycosidase inhibitory activities. The length of side chain and α,β-unsaturated ketone functional group also exhibited some effect on their glycosidase inhibition.

Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars: synthesis and glycosidase inhibition.

Gem-difluoromethylated and trifluoromethylated derivatives of DMDP-related iminosugars have been synthesized from cyclic nitrones 12, 13, 18, ent-18 or 23 and nitrone-derived aldehydes 20 or ent-20. The fluorinated iminosugars were assayed against various glycosidases, and ent-8 showed moderate but selective α-l-rhamnosidase inhibition. Difluoro or trifluoro units influenced the inhibitory activities of iminosugars in a more complex manner than single fluoro substitution. This may be correlated with their highly hydrophobic character and strong electron-withdrawing effect.

Approach to Monobactams and Nocardicins via Diastereoselective Kinugasa Reaction.

A Kinugasa reaction between copper(I) acetylides and cyclic nitrones derived from chiral amino alcohols and glyoxylic acid is reported. The stereochemical preferences observed in this reaction are discussed. The alkyne molecule approaches the nitrone exclusively anti to the large substituent next to the nitrogen atom to provide the cis-substituted β-lactam ring preferentially. The six-membered oxazinone ring can be opened by reduction with lithium borohydride. Deprotection of the β-lactam nitrogen atom can be achieved by lithium in liquid ammonia reduction or by CAN oxidation, depending on the substituents attached to the four-membered azetidinone ring. The adducts obtained by the Kinugasa reaction provide an attractive entry to a variety of monocyclic β-lactam structures related to monobactams and nocardicins.

Insights into the diastereoselective control in the sulfa-Michael addition of thiols to nitroalkenes: stereoelectronic effect in the cyclic chelated transition state

The diastereoselective control in the sulfa-Michael addition of nitroalkenes and lithium thiolates followed by protonation was investigated. Lithium thiolates first added to nitroalkenes to afford cyclic lithium-chelated nitronates. The subsequent kinetic protonation of nitronates was proved to be the stereochemical determinant through the chelate-controlled six-membered half-chair transition state bearing two approximately 1,2-diaxial substituents due to stereoelectronic effect control. The stereoelectronic effect in the cyclic chelated transition state was probed and verified by tuning the steric bulkiness of the corresponding substituents. The reaction involving 1-nitrocyclohexene provided perfect support for the proposed diastereoselective control model. The current investigation provided not only comprehensive insights into the diastereoselective control in the sulfa-Michael addition of nitroalkenes and thiolates, but also an important role of the stereoelectronic effect in certain organic reactions involving cyclic chelate transition states.

ChemInform Abstract: Stereoselective Nucleophilic Addition of PhSCF2SiMe3 to Chiral Cyclic Nitrones: Asymmetric Synthesis of gem‐Difluoromethylenated Polyhydroxypyrrolizidines and ‐indolizidines.

AbstractThe title compounds are obtained by a general method involving the sequential stereoselective fluoride‐catalyzed nucleophilic addition of PhSCF2SiMe3 as gem‐difluoromethylene building block to easily available chiral nitrones followed by reductive cleavage of the hydroxy group, N‐alkylation of the obtained pyrrolidines, intramolecular radical cyclization, and hydrogenolysis of the protecting group.

Synthesis of Thienamycin methyl ester from 2-deoxy-D-ribose via Kinugasa reaction.

A novel synthesis of thienamycin is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from D-lactic acid and suitable, partially protected, five-membered cyclic nitrone obtained from 2-deoxy-D-ribose. The reaction was performed in the presence of tetramethylguanidine as a base to provide 5,6-trans substituted carbapenam as the main product. Thus obtained carbapenam 11 with (5R,6S) configuration at the azetidinone ring was subsequently subjected to oxidation/deprotection/oxidation reaction sequence to afford the β-keto ester 20, which was directly transformed into N,O-protected methyl ester of thienamycin.