Cyclic Nitrones Research Articles

Asymmetric Synthesis of a Pyrrolizidinone‐Based hNK1 Antagonist through Reductive Ring Contraction of a Six‐Membered Cyclic Nitronate

AbstractA concise seven‐step asymmetric synthesis of MSD's potent hNK1 antagonist containing a pyrrolizidinone core bearing two fluorine‐substituted aryl groups was developed. The pyrrolizidinone unit was constructed by reductive recyclization of a properly functionalized cyclic nitronate, which was assembled by stereoselective [4+2]‐cycloaddition of a nitroalkene with a vinyl ether bearing a Whitesell's chiral auxiliary group. The configuration of the hNK1 antagonist, which was previously suggested based on bioactivity data, was confirmed by X‐ray analysis. The crystal structure features multiple weak interactions involving fluorine atoms that are also found in a complex with the hNK1 receptor simulated by molecular docking.

Iron‐Catalyzed Oxidative Hydroxyamination of Alkenes of Unsaturated Keto Oximes with TBHP as the Hydroxy Source

AbstractA new iron‐catalyzed hydroxyamination of alkenyl ketoximes using TBHP as the hydroxy source to selectively assemble cyclic nitrones is described. Using inexpensive FeCl3 as the catalyst and TBHP as both the oxidant and hydroxy source, this reaction enables the formation of two new bonds, one C−N bond and one C−O bond, in a single reaction initiating from the oxime side through the nitrogen‐center radical geneation, radical addition across the C=C bond and radical hydroxylation cascades. This reaction has advantages of exquisite selectvity and excellent functional group tolerance, thus providing an economical and efficient strategy for the construction of complex heterocyclic compounds.

Titania-mediated photoinduced fluorination of nitrone spin traps in acetonitrile (an EPR study)

Cyclic nitrone spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and its derivatives were applied in an EPR study of paramagnetic intermediates generated by in situ photoexcitation of TiO2 nanoparticles dispersed in acetonitrile with fluorinated ions. The UVA irradiation of deoxygenated acetonitrile titania suspensions containing the spin traps in the presence of fluoride or tetrafluoroborate, and Ag(I) or Cu(II) as photoelectron acceptors, resulted in the generation of the corresponding fluorine spin-adducts with well-resolved EPR signals. The EPR spectra of β-fluorine spin-adducts of the DMPO analogs, featuring ethoxycarbonyl (EMPO), diethoxyphosphoryl (DEPMPO), or diisopropoxyphosphoryl (DIPPMPO) groups at position 5 of the pyrroline ring, are reported for the first time. The reaction mechanisms leading to the β-fluorine spin-adduct formation in the given photocatalytic system are discussed.

Catalyst-free [3 + 2] cycloaddition reaction of oxa-, aza-, and thio-bicyclic alkenes with cyclic and acyclic nitrones: A mechanistic study

The azole heterocyclic compounds and their derivatives have achieved much significance in medicinal chemistry. We present results on the mechanism of [3 + 2] cycloaddition (32CA) reactions of bicyclic alkenes with cyclic and acyclic nitrones to furnish isoxazolines at the M06-2X/6–311++G(d,p) level of theory. A key finding of this study is the preferred formation of the exo cycloadducts over the endo cycloadducts in the reaction of both cyclic and acyclic nitrones to bicyclic alkenes which is in good agreement with the experimental work of Yao et. al. (Org. Chem. Front., 2019, 6, 3360–3364). A one-step asynchronous mechanism of cycloaddition is observed in the titled reaction. Global reactivity parameters describe the significant influence of the electronic nature of the substituent on the flux of electron density between the reagents. Substituents affect the magnitude of the activation barriers but do not change the selectivity of the reactions.

Trans, trans-2-C-Aryl-3,4-dihydroxypyrrolidines as potent and selective β-glucosidase inhibitors: Pharmacological chaperones for Gaucher disease

Enantiomeric series of C-4 hydroxymethyl depleted DAB and LAB derivatives (trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines), designed as β-glucosidase inhibitors by molecular docking calculations, have been synthesized in 2 steps from l- and d-tartaric acid derived enantiomeric cyclic nitrones 29L and 29D, respectively. Both series of C-4 hydroxymethyl depleted DAB and LAB derivatives 28Da-e and 28La-e, which are structurally trans, trans-2-C-aryl-3,4-dihydroxypyrrolidines, were potent and selective human lysosome acid β-glucosidase (GCase) inhibitors, of which 28Dd and 28Ld with C-4 biphenyls showed the highest potency relative to other compounds of the same series. The work provided a series of pyrrolidine-type potent and selective GCase inhibitors with minimal hydroxyl substitutions and synthetic procedures. Structure-activity relationship study revealed not only the rationality of hydrophobic and aromatic properties of the binding sites in GCase, but also the great potential of pyrrolidine family in development of new GCase inhibitors with minimized undesirable side effects. The results indicate a strategy for the development of drugs for the treatment of related diseases targeting acid β-glucosidase, such as Gaucher disease and Parkinson's disease.

Synthesis of Nitrone-derived Pyrrolidine Scaffolds and Their Combinatorial Libraries to Develop Selective α-l-Rhamnosidase Inhibitors.

A general and flexible approach toward the development of α-l-rhamnosidase (α-l-Rha-ase) inhibitors is described. Five enantiopure poly-substituted pyrrolidine-based scaffolds bearing the C1-aminomethyl moiety were designed and synthesized from five-membered cyclic nitrones. Each structurally diversified amide library of these scaffolds was rapidly generated via combinatorial parallel synthesis and applied for in-situ inhibition study against α-l-Rha-ase, allowing us to efficiently identify new inhibition hits. Surprisingly, all promising inhibitors are derived from the same scaffold 3. Among them, the most potent and selective inhibitor is pyrrolidine 19 with Ki =0.24 μM, approximately 24-fold more potent than the reference compound DAA (Ki =5.7 μM). It is the first study to comprehensively prepare pyrrolidine-based scaffolds and libraries for inhibition study against α-l-Rha-ase.

Deoxygenative Arylation of 5,6-Dihydro-4H-1,2-oxazine-N-oxides with Arynes.

Six-membered cyclic nitronates (5,6-dihydro-4H-1,2-oxazine-N-oxides) react with Kobayashi's aryne precursors producing 3-(2-hydroxyaryl)-substituted 1,2-oxazines via deoxygenative C-H arylation. The process involves a hitherto unknown 1,3-dipolar cycloaddition of nitronate to the aryne to give an unusual tricyclic nitroso acetal, in which the N-O bond of the isoxazoline ring is selectively cleaved upon the action of a base (CsF) or an acid (TFA). The transient cycloadducts were isolated and characterized in some cases. The synthetic potential of the obtained 3-(2-hydroxyaryl)-substituted 1,2-oxazines was demonstrated by their stereoselective reduction to 1,4-amino alcohols and reductive 1,2-oxazine ring contraction to tetrahydrofuran derivatives.

A Molecular Design of Cyclic Nitronate Dye Based on the Halochromism of Fluoran Leuco Dyes as a New Latent Fingerprint Development Agent and Quantitative Structure-Property Relationships

새로운 잠재지문 현출제로서 fluoran leuco dye의 할로변색 반응에 근거하여 Me too approach 방법에 따라 cyclic nitronate (A 및 C) 분자를 설계하였다. 그리고 염료 분자들의 경계분자궤도(FMO) 에너지(ev.)를 밀도범함수론(DFT)으로 계산하고 2차원적인 정량적 구조와 성질과의 관계(2D-QSPRs)를 검토하였다. 그 결과로부터, 형광 양자수율(Φ)은 주로 전자끌게(Σσ>0; ρ > δ) 그리고 소수성(logP>0)은 입체적으로 큰 치환기(R1-R3) 효과(ΣEs<0; δ > ρ)에 의하여 증가하였다. 또한, 분자간 FMO 에너지 차이(ΔE) 의 비교로부터, C 분자에 대한 반응성은 친수성 아미노산(P)이 소수성 지방산(F)보다 큰 경향(P>F)이었다. 그러므로 C 분자는 잠재지문 현출반응의 조건에 따라 양자성 용매(logP<0)에서는 아미노산, 그리고 비양자성(logP>0) 또는 분말 조건(감열지)에서는 지방산을 대상으로 하는 두 가지 잠재지문 현출용도로 적합할 것이라 예상되었다

Design, synthesis and glycosidase inhibition of C-4 branched LAB and DAB derivatives

Two series of C-4 alkylated and arylated LAB (1,4-dideoxy-1,4-imino-l-arabinitol) and DAB (1,4-dideoxy-1,4-imino-d-arabinitol) derivatives, synthesized in 6 steps from enantiomeric cyclic nitrones derived from l- and d-tartaric acid, were designed and assayed against various glycosidases. C-4 Branched LAB alkyl and phenyl derivatives 5La-d showed potent α-glucosidase inhibition, particularly against human lysosomal acid α-glucosidase; C-4 DAB derivatives 5Da-d, with small alkyl groups, showed enhanced inhibition of rat intestinal maltase and sucrase. Both enantiomeric C-4 arylated derivatives 5Lf-l and 5Df-l exhibited potent and selective α-glucosidase inhibition; and compound 5Li with a para-electron donating group (EDG) on its C-4 aryl group, showed the most potent rat intestinal sucrase inhibition. Docking studies showed similar hydrogen bonding modes for the iminosugar skeletons of DAB (1) and LAB (2) with ntMGAM,. While C-4 alkylated LAB derivatives showed high similarity in their binding modes with the active site of ntMGAM, binding modes of the DAB derivatives relied on the size of C-4 alkyl groups with methyl and butyl showed the optimum interactions. Furthermore, C-4 arylation improved the interactions of LAB derivatives with enzymes by T-shaped π-π stack with residue Trp-406; for C-4 arylated DAB derivatives, the π-π stack interactions were found with distinct planar distortions caused by EDGs or EWGs on the C-4 aryls. The results reported herein provided insights for the design and development of DAB and LAB related α-glucosidase inhibitors, and may also contribute to the future development of anti-viral, anti-diabetic and anti-Pompe disease drugs.

Metal‐free Kinugasa reaction catalyzed by external electric field

AbstractOriented external electric field (OEEF) is in recent interest for its ability to promote reactivity and selectivity in chemical transformations. This article reports facile metal‐free [3 + 2] cycloaddition for the Kinugasa reaction in the presence of OEEF. The free energy of activation is reduced by 4.9 kcal/mol due to a parallel electric field in the orthogonal direction to the reaction axis, Fy = 5.0 V Å−1. As a proof‐of‐principle of this model, a multidrug‐resistant (MDR) antibiotic, carbapenem could be envisioned from the [3 + 2] cycloaddition of a cyclic nitrone and an acetonide substituted acetylene. This reaction shows an interesting ambiaxial electric field‐induced catalysis with a reduced reaction barrier for anti‐parallel fields, −Fx (reaction axis) and −Fz and parallel field along +Fy. This is due to the out‐of‐plane bending of the acetonide unit containing two highly electronegative oxygen atoms. As a result, off‐axial tensorial responses to the electric‐fields on the barriers are observed. Such ambiaxial OEEF driven catalysis is interesting because it expands the utility of electric fields for large enzymes. Disorder and dynamical effects of side chains are envisioned to cause non‐null responses to applied field for parallel or anti‐parallel directions along axes.

Copper-catalyzed aerobic hydroxyamination of alkenes of unsaturated keto oximes in EtOH toward cyclic nitrones

Copper-catalyzed aerobic hydroxyamination of unsaturated keto oximes with O2 in EtOH for accessing cyclic nitrones is disclosed.

Efficient Synthesis of Isoquinoline Derivatives through Sequential Cyclization–Deoxygenation Reaction of 2-Alkynylbenzaldoximes

AbstractWe describe a novel, simple, robust, and efficient cyclization/deoxygenation approach for the synthesis of functionalized isoquinoline derivatives. Over the course of continued studies on o-alkynylbenzaldoxime cyclization reactions, the formation of cyclic nitrones through 6-endo-dig cyclization was achieved using silver triflate or bromine as an electrophile, and subsequently, the deoxygenation process was carried out in the presence of CS2 in good to high yields.

Unveiling the non-polar [3+2] cycloaddition reactions of cyclic nitrones with strained alkylidene cyclopropanes within a molecular electron density theory study.

The role of cyclopropane substitution on the ethylene in zw-type [3+2] cycloaddition (32CA) reactions of cyclic nitrones has been studied within Molecular Electron Density Theory (MEDT) at the ωB97X-D/6-311G(d,p) computational level. Electron Localization Function (ELF) analysis of the ethylenes shows that the presence the cyclopropane only slightly increases the electron density in the C–C bonding region. Analysis of the Conceptual DFT reactivity indices indicates that the presence of the cyclopropane does not produce any remarkable change in the reactivity of these strained ethylenes. The marginal electrophilic character of ethylene makes the zw-type 32CA reactions of non-polar character. The presence of the cyclopropane in the ethylene decreases the activation enthalpy of the 32CA reactions by only 1.7 and 2.6 kcal mol−1, and also decreases the ortho regioselectivity. The loss of the strain present in the cyclopropane is responsible for the reduction of the activation enthalpy and the increase of the reaction enthalpy in these non-polar 32CA reactions. The presence of the cyclopropane does not cause any change, neither in the transition state structure (TS) geometries nor in their electronic structure. The very low global electron density transfer (GEDT) computed at the TSs confirms the non-polar character of these 32CA reactions. The ortho regioselectivity experimentally observed in these non-polar 32CA reactions is determined by the most favorable two-center interaction between the less electronegative C1 carbon of nitrone and the non-substituted methylene C5 carbon of the ethylenes.

Construction of Saturated Oxazolo[3,2-b][1,2]oxazines via Tandem [3+2]-Cycloaddition/[1,3]-Rearrangement of Cyclic Nitronates and Ketenes.

Reaction of six-membered cyclic nitronates with disubstituted ketenes affords hitherto unknown saturated oxazolo[3,2-b][1,2]oxazines possessing up to four contiguous stereogenic centers. The process involves a tandem of [3+2]-cycloaddition across the C═O bond of ketene, followed by a spontaneous [1,3]-rearrangement of transient vinylidene-substituted bicyclic nitrosoacetals. DFT calculations of the mechanism suggest that the [1,3]-O,C-shift proceeds through a recyclization of a biradical intermediate formed by an unusually mild homolytic cleavage of the N-O bond. The resulting products can be utilized as precursors of other fused 1,2-oxazines derivatives, in particular 1,2-oxazino-1,2,4-triazin-3-ones.

Synthesis and glycosidase inhibition of 5-C-alkyl-DNJ and 5-C-alkyl-l-ido-DNJ derivatives.

5-C-Alkyl-DNJ and 5-C-alkyl-l-ido-DNJ derivatives have been designed and synthesized efficiently from an l-sorbose-derived cyclic nitrone. The DNJ and l-ido-DNJ derivatives with C-5 alkyl chains ranging from methyl to dodecyl were assayed against various glycosidases to study the effect of chain length on enzyme inhibition. Glycosidase inhibition study of DNJ derivatives showed potent and selective inhibitions of α-glucosidase; DNJ derivatives with methyl, pentyl to octyl, undecyl and dodecyl as C-5 branched chains showed significantly improved rat intestinal maltase inhibition. In contrast, most 5-C-alkyl-l-ido-DNJ derivatives were weak or moderate inhibitors of the enzymes tested, with only three compounds found to be potent α-glucosidase inhibitors. Docking studies showed different interaction modes of 5-C-ethyl-DNJ and 5-C-octyl-DNJ with ntMGAM and also different binding modes of 5-C-alkyl-DNJ and 5-C-alkyl-l-ido-DNJ derivatives; the importance of the degree of accommodation of the C-5 substituent in the hydrophobic groove and pocket may account for the variation of glycosidase inhibition in the two series of derivatives. The results reported herein are helpful in the design and development of α-glucosidase inhibitors; this may lead to novel agents for the treatment of viral infection and type II diabetes.

Cyclisations and Strategies for Stereoselective Synthesis of Piperidine Iminosugars.

This personal account focuses on synthesis of polyhydroxylated piperidines, a subset of compounds within the iminosugar family. Cyclisations to form the piperidine ring include reductive amination, substitution via amines, iminium ions and cyclic nitrones, transamidification (N-acyl transfer), addition to alkenes, ring contraction and expansion, photoinduced electron transfer, multicomponent Ugi reaction and ring closing metathesis. Enantiomerically pure piperidines are obtained from chiral pool precursors (e. g. sugars, amino acids, Garner's aldehyde) or asymmetric reactions (e. g. epoxidation, dihydroxylation, aminohydroxylation, aldol, biotransformation). Our laboratory have contributed cascades based on reductive amination from glycosyl azide precursors as well as Huisgen azide-alkene cycloaddition. The latter's combination with allylic azide rearrangement has given substituted piperidines, including those with quaternary centres adjacent to nitrogen.

The Molecular Mechanism of the Formation of Four-Membered Cyclic Nitronates and Their Retro (3 + 2) Cycloaddition: A DFT Mechanistic Study.

In the present work, the formation of the four-membered cyclic nitronates and the retro (3 + 2) cycloaddition (retro-32CA) reaction of the 4H-[1,2]oxazete 2-oxide were studied using the density functional theory method at the MPWB1K/6-311G(d,p) theoretical level. The electronic structure of 3-tert-butyl-4,4-dimethyl-1,2-dinitro-pent-2-ene was known through electron localization function analysis, natural population analysis, and molecular electrostatic potential analysis. The formation of 4,4-di-tert-butyl-3-nitromethyl-4H-[1,2]oxazete 2-oxide proceeds through a one-step mechanism. The mechanism of the retro-32CA leading to di-tert-butyl ketone and nitrile oxide derivative should be described as an asynchronous two-stage one-step process. The bonding evolution theory study was carried out to clarify the mechanisms of the formation of 4H-[1,2]oxazete 2-oxide and their retro-32CA.

Contrasting Diastereoselectivity between Cyclic Nitrones and Azomethine Ylides. Stereocontrolled Pathways to cis-anti-anti-cis-Oxazatetraquinanes from a Bicyclic Nitrone.

A study of [3 + 2] cycloaddition reactions of a bicyclic nitrone with various cyclopentenes has clarified the diastereomeric preferences as a function of the olefinic structure. It has also identified an important stereochemical difference between nitrones and the analogous azomethine ylides in [3 + 2] cycloaddition reactions.

Spectroscopic Character of New Designed Cyclic Nitronate Dye Molecules, and Approach for the Detectability of Latent Fingerprints

Spectroscopic Character of New Designed Cyclic Nitronate Dye Molecules, and Approach for the Detectability of Latent Fingerprints

Synthesis and evaluation of cyclic nitrone derivatives as potential anti-cancer agents

Nitrones have been found to exhibit attractive biological values as immuno spin trapping agents. However, successful clinical cases of nitrone therapeutics are still lacking. Herein we report the synthesis and antiproliferative activity of a series of structurally diverse nitrone derivatives against a panel of 5 cancer cell lines, based on which indole- and pyrrole-fused were further evaluated by analogue preparation and in-vitro screening. Analogues with moderate to good potency were identified. This study shows the promise for further pursuit of nitrone-type small molecules in chemotherapy.