Cyclic Nitrones Research Articles

TMSOTf‐Mediated Aminocyclization/[1,3]‐Sulfonyl Migration of N‐Homopropargyl Hydroxylamines for the Stereoselective Synthesis of 3‐Sulfonyl Cyclic Nitrones

AbstractTMSOTf‐mediated 5‐endo‐dig aminocyclization followed by N‐ to C‐[1,3]‐sulfonyl migration on N‐homopropargyl hydroxylamines gave diastereoselective access to trisubstituted 3‐sulfonyl cyclic nitrone (3‐sulfonyl pyrroline N‐oxide) derivatives. The synthetic utility of the 3‐sulfonyl cyclic nitrone products was demonstrated through the diastereoselective synthesis of the sulfonyl‐substituted nonaromatic N‐heterocycles such as N‐hydroxypyrrolidine, pyrrolidine‐fused isoxazoline, and isoxazolidine derivatives.

Copper Powder‐Mediated Tandem Hydroamination Cyclization‐Hydrocyanation of Alkyne‐Tethered Ketoximes toward Cyano‐Featured Cyclic Nitrones

Copper Powder‐Mediated Tandem Hydroamination Cyclization‐Hydrocyanation of Alkyne‐Tethered Ketoximes toward Cyano‐Featured Cyclic Nitrones

Cyclic Nitronates via Sugar‐Derived Nitroalkenes in a Hetero‐Diels‐Alder/[3,3]‐Sigmatropic Rearrangement Pathway

AbstractDiels‐Alder between nitroalkenes derived from a sugar scaffold and cyclopentadiene were examined. Depending on chemical structure of nitroalkene and polarity of solvent used, the reaction proceeded via the formation of a nitronate intermediate. Cyclic nitronates highly functionalized were obtained as chemically stable and stereochemically pure compounds. [3,3] sigmatropic shift of these ones afforded the Diels Alder cycloadducts in quantitative yield. Mechanistic aspects of reaction between nitroalkenes and cyclopentadiene has been studied using DFT computational methods. Nitronate derivatives are attractive intermediates and open the way for the construction of valuable compounds with potential applications.

Accessing Polysubstituted NH Pyrroles from Nitroalkenes via [4+2]‐Cycloaddition/Reductive Ring Contraction Strategy

AbstractA novel two‐step access to polysubstituted pyrroles from nitroalkenes was developed. It involves [4+2]‐cycloaddition with enol ethers to give six‐membered cyclic nitronates followed by reductive ring contraction with Ra−Ni/AcOH or Ra−Ni/EtOH systems. The process is applicable to a variety of nitroalkenes and enol ethers bearing electron‐rich and electron‐poor substituents and functional groups. The anti‐inflammatory drug Bimetopyrol and its structural modifications were successfully synthesized by the strategy developed. The key side products were identified that provided an insight into the mechanism of the developed reductive ring contraction to pyrroles.

Design and synthesis of 6-C-alkyl-DMDP type nanomolar inhibitors of β-galactosidase and β-glucosidase based on broussonetine S and related derivatives

Broussonetine S (9), its C-1′ and C-10′ stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10′ epimer (10′-epi-9) were nanomolar inhibitors of bovine liver β-galactosidase and β-glucosidase; while their C-1′ stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1′ hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver β-glucosidase and β-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of β-glucosidase or β-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of β-glucosidase and β-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower β-glucosidase and β-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of β-galactosidase and β-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents.

A practical synthesis of nitrone-derived C5a-functionalized isofagomines as protein stabilizers to treat Gaucher disease.

Isofagomine (IFG) and its analogues possess promising glycosidase inhibitory activities. However, a flexible synthetic strategy toward both C5a-functionalized IFGs remains to be explored. Here we show a practical synthesis of C5a-S and R aminomethyl IFG-based derivatives via the diastereoselective addition of cyanide to cyclic nitrone 1. Nitrone 1 was conveniently prepared on a gram scale and in high yield from inexpensive (-)-diethyl D-tartrate via a straightforward method, with a stereoselective Michael addition of a nitroolefin and a Nef reaction as key steps. A 268-membered library (134 × 2) of the C5a-functionalized derivatives was submitted to enzyme- or cell-based bio-evaluations, which resulted in the identification of a promising β-glucocerebrosidase (GCase) stabilizer demonstrating a 2.7-fold enhancement at 25 nM in p.Asn370Ser GCase activity and a 13-fold increase at 1 μM in recombinant human GCase activity in Gaucher cell lines.

Theoretical analysis of mechanism and regio- and stereoselectivity of 1, 3-dipolar cycloaddition of cyclic nitrone and substituted alkenes by DFT method

Theoretical analysis of mechanism and regio- and stereoselectivity of 1, 3-dipolar cycloaddition of cyclic nitrone and substituted alkenes by DFT method

Crystallization-induced diastereomer transformation assists the diastereoselective synthesis of 4-nitroisoxazolidine scaffolds.

This communication describes a solution to the vexing problem of synthesis of 4-nitroisoxazolidine rings from cyclic nitrones and β-nitrostyrenes. The trans-endo adduct 2 is quantitatively synthesised from E-β-nitrostyrene under mild conditions avoiding purification, while the trans-exo adduct 4 is obtained at higher temperatures. Furthermore, a Crystallization-Induced Diastereomer Transformation (CIDT) process was used to epimerise the NO2 bond from 2 to the cis-exo adduct 3 with total conversion assisted by the para-halogen substitution of the aromatic ring without any additives. By combining these approaches, we can establish a simple synthetic methodology that allows the diastereoselective synthesis of three diastereoisomers, overcoming the previous problems described in the literature.

The Chemical Synthesis of the 1-C-Alkyl Substituted Pyrrolidine and Piperidine Iminosugar Natural Products and their Analogues

Abstract: A review of the chemical synthesis of the 1-C-alkyl substituted pyrrolidine and piperidine iminosugar natural products and their analogues (where the alkyl chain comprises two or more carbons) is provided. These syntheses can be grouped into nine different synthetic strategies that share a common approach toward installing the alkyl substituent. These include nucleophilic addition to aldimines; Grignard additions to glycosylamines, cyclic imides, and carbohydrates; Weinreb ketone synthesis; nucleophilic addition to cyclic nitrones; the Overmann rearrangement; the allylation of hemiaminals; and the Petasis borono-Mannich reaction. The broussonetine alkaloids have proven popular synthetic targets to develop new synthetic methods and verify these target molecules' structures and stereochemistry.

Construction of Cyclic Nitrones Enabled by Photodriven and Gold-Catalyzed 1,3-Azaprotio Transfer of Allenyloximes.

A protocol was developed to construct five- to seven-membered cyclic nitrones through the gold-catalyzed 1,3-azaprotio transfer of allenyloximes under photoirradiation. The photoisomerization of oximes was suggested to convert the inert stereoisomer to a reactive one. This photodriven and gold-catalyzed ring formation could be further extended to the thermodynamically stable aryl ketoximes with an E-configuration, which previously displayed chemical inertness in the absence of light irradiation.

Mechanistic Analysis of Bioorthogonal Double Strain-Promoted Alkyne-Nitrone Cycloadditions Involving Dibenzocyclooctadiyne.

The reactions of nitrones with cyclooctadiynes were studied to establish the relative rates of sequential reactions and to determine the limits and scope of this bioorthogonal chemistry. We have established the second-order rate constants for the consecutive additions of a variety of nitrones onto diyne and studied the structure-activity relationships via Hammett plots. Results show that the addition of the second nitrone to the monointermediate occurs significantly faster than the first, with both reactions being faster than analogous reactions with azides. Computational chemistry supports these observations. The rate of second addition increases with electron-deficient nitrones, as demonstrated by a large rho value of 2.08, suggesting that the reaction rate can be controlled by nitrone selectivity. To further investigate the kinetic parameters of the reaction, dinitrone monomers containing cyclic and diaryl-nitrones were designed for use in oligomerization applications. Oligomerization was used as a probe to test the limits of the reactivity and attempt to isolate monocycloaddition products. The oligomer formed from a cyclic nitrone reacts faster, and detailed MALDI mass spectrometry analysis shows that monoaddition products exist only transiently and are not isolatable. These studies inform on the scope and limits of this chemistry in a variety of applications. We successfully demonstrated bacterial cell wall labeling using heterogeneous dual cycloadditions involving nitrone and azide dipoles, where the nitrone was the faster reacting partner on the bacterial cell surface.

Revealing the influence of tether length on the intramolecular [3 + 2] cycloaddition reactions of nitrones from the molecular electron density theory perspective

AbstractThe influence of ethylene substitution and the tether length between the two reacting counterparts on the selectivity and reactivity of the intramolecular [3 + 2] cycloaddition (IM32CA) reactions of cyclic nitrones leading to tricyclic isoxazolidines have been studied within the Molecular Electron Density theory at the MPWB1K/6‐311G(d,p) computational level. These zw‐type IM32CA reactions follow one‐step mechanism, and the activation barrier decreases with the introduction of electron withdrawing (EW) substituent at the alkene moiety in both the intramolecular and intermolecular versions. The IM32CA reactions involving unsubstituted alkene have non‐polar character with minimal electron density flux classified as null electron density flux type, while that involving the EW nitro substituted ethylene is more facile with a strong electron density flux from the nitrone to the ethylene moiety, classified as forward electron density flux type. The increase in the polar character of the IM32CA reaction decreases the activation Gibbs free energies associated with these intramolecular processes, while the highly polar IM32CA reactions are disfavored with respect to the intermolecular ones. Interestingly, the preferred regioselectivity observed in low polar IM32CA reactions having three methylene units between the nitrone and ethylene frameworks is reversed to that in nitrones separated with four methylene units, in conformity with the experimental outcome. Finally, electron localization function and quantum theory of atoms‐in‐molecules studies reveal that, in general, these IM32CA reactions involve early transition state structures in which the formation of new C‐C and C‐O single bonds have not yet started.

Reductive Denitrogenation of Six‐membered Cyclic Nitronates to Densely Substituted Dihydrofurans with Raney® Nickel/AcOH System

AbstractA protocol for the synthesis of 2,3‐dihydrofurans by reductive denitrogenation/ring contraction of 6‐membered cyclic nitronates was developed. The process utilizes cheap Raney® nickel both as catalyst and stoichiometric agent without the need for high‐pressure equipment. The products are formed in high purity and column chromatography is often not required. Studies on the substrate scope, functional group tolerance, and mechanism were performed. The developed approach provides a straightforward two‐step access to densely substituted 2,3‐dihydrofurans from nitrostyrenes and alkenes.

Synthesis of Chiral α,α-Disubstituted Cyclic Nitrones from Secondary Lactams

Abstract Synthesis of chiral α,α-disubstituted cyclic nitrones from secondary lactams is reported. The method consists of two stages involving N-oxidation of the lactams and nucleophilic addition to the lactam carbonyls. The N-oxidation of secondary lactams with mCPBA via imidates provides cyclic nitrones with a chiral stereocenter adjacent to the nitrogen atom. A variety of α,α-disubstituted cyclic nitrones were quickly obtained simply by changing organolithium reagents in the nucleophilic addition to N-OSEM lactams.

Total Synthesis of Kopsone

A total synthesis of kopsone was achieved, featuring stereoselective preparation of an acyclic aldehyde having a protected hydroxylamine moiety via Ireland-Claisen rearrangement and intramolecular cycloaddition of an eight-membered cyclic nitrone to form the 2-azabicyclo[3.3.1]nonane skeleton.

3+3]-Annulation of Cyclic Nitronates with Vinyl Diazoacetates: Diastereoselective Synthesis of Partially Saturated [1,2]Oxazino[2,3-b][1,2]oxazines and Their Base-Promoted Ring Contraction to Pyrrolo[1,2-b][1,2]oxazine Derivatives

A rhodium(II)-catalyzed reaction of cyclic nitronates (5,6-dihydro-4H-1,2-oxazine N-oxides) with vinyl diazoacetates proceeds as a [3+3]-annulation producing bicyclic unsaturated nitroso acetals (4a,5,6,7-tetrahydro-2H-[1,2]oxazino[2,3-b][1,2]oxazines). Optimization of reaction conditions revealed the use of Rh(II) octanoate as the preferred catalyst in THF at room temperature, which allows the preparation of target products in good yields and excellent diastereoselectivity. Under basic conditions, namely, the combined action of DBU and alcohol, these nitroso acetals undergo ring contraction of an unsaturated oxazine ring into the corresponding pyrrole. Both transformations can be performed in a one-pot fashion, thus constituting a quick approach to oxazine-annulated pyrroles from available starting materials, such as nitroalkenes, olefins, and diazo compounds.

Nitronate-aryne cycloaddition as a concise route to stereochemically complex fused benzisoxazolines and amino alcohols.

The reaction of cyclic nitronates (isoxazoline N-oxides and 5,6-dihydro-4H-1,2-oxazine N-oxides) with Kobayashi's aryne precursors affords tricyclic benzene-fused nitroso acetals as a result of [3 + 2]-cycloaddition. The process is regio- and stereoselective in most cases and produces the target cycloadducts possessing up to four contiguous stereogenic centers. These nitroso acetals were shown to be convenient precursors of valuable polysubstituted aminodiols through catalytic hydrogenolysis of the N-O bonds. Also, the action of protic acids resulted in an unusual fragmentation of the cyclic nitroso acetal moiety through heterolytic N-O bond cleavage and Beckmann-type reaction. Using this acid-mediated reaction, the synthesis of a hitherto unknown hexahydrobenzo[4,5]isoxazolo[2,3-a]azepine scaffold was accomplished.

Interrupted Nef Reaction of Cyclic Nitronates: Diastereoselective Access to Densely Substituted α-Chloronitroso Compounds.

The reaction of cyclic nitronic esters (isoxazoline- and 5,6-dihydro-4H-1,2-oxazine-N-oxides) with hydrochloric acid affords geminal chloronitroso compounds bearing a distant hydroxyl group. The reaction is usually diastereoselective, and in some cases stereodivergent formation of isomers at different temperatures is observed. The discovered process represents the first example of an interrupted Nef reaction of nitronic esters. DFT calculations support the initial formation of N,N-bis(oxy)iminium cations (key intermediates in the Nef reaction), which are intercepted by the chloride anion followed by ring opening. The synthetic utility of the resulting functionalized chloronitroso compounds in the Diels-Alder reaction with cyclopentadiene was demonstrated.

Synthesis of Sterically Shielded Nitroxides Using the Reaction of Nitrones with Alkynylmagnesium Bromides.

Sterically shielded nitroxides, which demonstrate high resistance to bioreduction, are the spin labels of choice for structural studies inside living cells using pulsed EPR and functional MRI and EPRI in vivo. To prepare new sterically shielded nitroxides, a reaction of cyclic nitrones, including various 1-pyrroline-1-oxides, 2,5-dihydroimidazole-3-oxide and 4H-imidazole-3-oxide with alkynylmagnesium bromide wereused. The reaction gave corresponding nitroxides with an alkynyl group adjacent to the N-O moiety. The hydrogenation of resulting 2-ethynyl-substituted nitroxides with subsequent re-oxidation of the N-OH group produced the corresponding sterically shielded tetraalkylnitroxides of pyrrolidine, imidazolidine and 2,5-dihydroimidazole series. EPR studies revealed large additional couplings up to 4 G in the spectra of pyrrolidine and imidazolidine nitroxides with substituents in 3- and/or 4-positions of the ring.

Revealing the Unexplored Mechanism of Photochemical Oxaziridine Conversion Process of 2H‐imidazole 1‐oxides

The photochemistry of 2H-imidazole-1-oxides has been explored using the two well-known spin-trapping agents, TMIO and DMPIO as the representative systems of this cyclic nitrone category. Computational studies have revealed that the photo-excitation of these compounds involve a strongly allowed S0→S2 transition which is subsequently followed by S2/S1 and S0/S1 conical intersections to form the photo-product oxaziridine. The authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.