Synthesis of Isoxazolines from Nitroalkanes via a [4+1]‐Annulation Strategy

Luo J., Chen R., Fan X., Gong J., Han J., He Z.

A highly enantioselective catalytic asymmetric (4 + 1) annulation reaction of nitroalkenes and ammonium ylides is reported for the first time.

Li Q., Wu X., Yang Y., Zhang Y., He F., Xu X., Zhang Z., Tao L., Luo C.

Substance P (SP) is believed to play a role in traumatic brain injury (TBI), and the inhibition of binding of SP to the tachykinin neurokinin-1 receptor (NK1R) using NK1R antagonists had made favorable effects on TBI. Our current study addresses the functional roles and underlying mechanisms of SP and NK1R antagonist L-733,060 following TBI. Adult male wild type C57BL/6 J and SP knock out (SPKO) mice received a controlled cortical impact and outcome parameters were assessed. The results showed that TBI-induced motor and spatial memory deficits, lesion volume, brain water content and blood-brain barrier disruption were alleviated both in L-733,060-treated C57BL/6 J mice and vehicle-treated SPKO mice. L-733,060 treatment and SP deletion inhibited TBI-induced the release of cytochrome c from mitochondria to cytoplasm, activation of caspase-3, oxidative stress and neuroinflammation. Higher SP levels in serum and cortex were observed in wild type mice undergoing TBI relative to wild type sham group, but very little expression of cortical SP was detected in the SP-/- mice either TBI or not. Upregulation of NK1R expression after TBI was observed, and there was no significant difference between wild type and SPKO groups. in vitro, L-733,060 and SP deletion inhibited scratch injury-induced cell death, loss of mitochondrial membrane potential and reactive oxygen species (ROS) production following TBI. Together, the results of this study implicate a functional role for NK1-R antagonist L-733,060 and deletion of SP in TBI-induced neurological outcome, oxidative damage, neuroinflammation and cell death. Upregulation of NK1R maybe a consequence of TBI, independent of the levels of substance P. This study raises the possibility that targeting SP through its receptor NK1R or genetic deletion may have therapeutic efficacy in TBI.

Zhao S., Wang H., Sun S., Guo H., Chen Z., Wang J., Wang L., Liang S., Wang G.

2-Isoxazolines were synthesized efficiently from a formal [4+1] cycloaddition of nitrosoalkenes and sulfur ylides, which were generated in situ from α-haloketone oximes and dimethyl sulfonium salts. This approach provides a new method to synthesize a range of 2-isoxazolines in high yields and high regioselectivity.

Kalaria P.N., Karad S.C., Raval D.K.

The upward extend of malaria collectively with the emergence of resistance against predictable drugs has put enormous pressure on public health systems to introduce new malaria treatments. Heterocycles play an important role in the design and discovery of new malaria active compounds. Heterocyclic compounds have attracted significant attention for malaria treatment because of simplicity of parallelization and the examining power with regard to chemical space. Introduction of a variety of heterocyclic compounds have enabled to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species. In this review, we present an overview of recent literature to provide imminent into the applications of different heterocyclic scaffolds in fighting against malaria.

Naumovich Y.A., Golovanov I.S., Sukhorukov A.Y., Ioffe S.L.

The regioselectivity of the addition of HO-acids to the activated π bond in N,N-bis(oxy)enamines has been found to be dramatically dependent upon the solvent. Mechanistic investigations and quantum-chemical calculations revealed that solvent affects the reaction pathway. In basic solvents (DMF, NMP, DMSO), N,N-bis(oxy)enamines were converted into nitrosoalkenes by a Lewis base promoted process followed by oxy-Michael addition of the HO-acid. In non-polar solvents (toluene, CH2Cl2), the reaction occurs by an acid-promoted SN′ substitution of the N-oxy-group via a highly reactive N-vinyl-N-alkoxynitrenium species. Based on these studies, general and efficient protocols for the oximinoalkylation of various HO-acids (carboxylic acids, phenols, hydroxamic, phosphoric and sulfonic acids) employing readily available N,N-bis(oxy)enamines were developed. These methods proved to be applicable to the post-modification of natural molecules bearing acidic OH groups (such as steroidal hormones, bile acids, protected amino acids and peptides) and ligands (BINOL). The resulting α-oxyoximes were demonstrated to be useful precursors of valuable 1,2-amino alcohol or 1,2-hydroxylamino alcohol derivatives, including the antiarrhythmic drug Mexiletine and a potent matrix metalloproteinase inhibitor.

Huang H., Li F., Xu Z., Cai J., Ji X., Deng G.

AbstractA base‐promoted [3+2]‐annulation of ketoxime esters and aldehydes is disclosed for the facile and rapid synthesis of 3,5‐disubstituted and 3,4,5‐trisubstituted isoxazolines. The key to our success is the pivalate leaving group of the oxime substrates, combined with cesium carbonate as promoter. This chemistry allows the assembly of a vast array of isoxazoline derivatives under simple base conditions in a method complementary to the classic isoxazoline formation via [3+2]‐dipolar cycloaddition of nitrile oxides and olefins. It also represents a new reaction pattern involving electrophilic amination/N–O bond substitution.magnified image

Tabolin A., Sukhorukov A., Ioffe S., Dilman A.

Due to their availability and versatile reactivity, nitronates have become important building blocks in the stereoselective synthesis of bioactive molecules. This short review provides a summary of recent developments on the synthesis, chemistry and applications of O-alkyl and O-silyl nitronates.1 Introduction2 Approaches to the Synthesis of Nitronates2.1 Synthesis of Six-Membered Cyclic Nitronates2.1.1 Formal [4+2] Approaches2.1.2 Formal [3+3] Approaches2.1.3 Other Approaches2.2 Synthesis of Five-Membered Cyclic Nitronates2.2.1 Formal [3+2] Approaches2.2.2 Formal [4+1] Approaches2.2.3 Oxidation Approaches3 Chemistry of Nitronates3.1 Nitronates as α-C-Nucleophiles3.2 Nitronates as α-C-Electrophiles3.3 Nitronates in [3+n]-Annulation Reactions3.4 Reactions Involving the β-Carbon Atom of Nitronates3.5 Miscellaneous Transformations4 Conclusion

Jiang M., Feng L., Feng J., Jiao P.

1,3-Dipolar cycloadditions of 2-alkylacroleins or atropaldehyde with triisopropylsilyl nitronates bearing an α-aryl group produced 3-aryl-2-isoxazolines having a chiral quaternary center in up to 94% ee and up to 88% yield with the aid of Corey's oxazaborolidine catalyst. Specifically, the TIPS nitronate with an α-(p-methoxyphenyl) group gave mainly the 2-isoxazolines having an all-carbon quaternary center.

Pairas G.N., Perperopoulou F., Tsoungas P.G., Varvounis G.

AbstractMental disorders are neuropsychiatric conditions that are marked by unusual or irregular thinking, feelings, or behavior, and lead to distress and/or impaired functions. Major psychiatric conditions are depression, anxiety, and psychoses of various types. Their etiopathogeneses, of a primary or secondary origin, are associated with genetic and environmental factors. They are commonly treated with psychoactive drugs (also known as psychotropics), which target serotonin, dopamine, norepinephrine, glutamate, and nuclear receptors (NRs), including retinoic acid receptor‐related orphan receptors (RORs) and other receptors in the central nervous system (CNS). Herein we present a diverse array of isoxazole derivatives, among which are some prominent marketed drugs. Some of the derivatives and forms, including N‐oxides, are under either (pre)clinical evaluation or patent protection as new generation of psychotropics, and a few have effective blood–brain barrier (BBB) permeability. Various drug‐like isoxazol(in)es and their structural features and efficiency, modified through scaffold hopping, are described and discussed in the context of treating neuropsychiatric conditions.

Maestri G., Cañeque T., Della Ca’ N., Derat E., Catellani M., Chiusoli G.P., Malacria M.

A method to obtain aryl nitriles from the corresponding halides by Pd catalysis, in the absence of any cyanide source, is reported. The reaction of an aryl halide, ethyl nitroacetate, and an olefin readily delivers an aromatic nitrile. A variety of aryl iodides/bromides have been converted into the corresponding cyanoarenes in fair to excellent yields. The reaction likely involves the following steps: (a) Pd-catalyzed α-arylation of ethyl nitroacetate; (b) nitrile oxide formation;

Sukhorukov A.Y., Sukhanova A.A., Zlotin S.G.

Naumovich Y.A., Buckland V.E., Sen'ko D.A., Nelyubina Y.V., Khoroshutina Y.A., Sukhorukov A.Y., Ioffe S.L.

α-Nitroxy oxime derivatives have been synthesized by a metal-assisted addition of nitrate anion to bis(oxy)enamines.

Choe H., Pham T.T., Lee J.Y., Latif M., Park H., Kang Y.K., Lee J.

The first total synthesis and structure revision of (-)-11β-hydroxycurvularin (1b), a macrolide possessing a β-hydroxyketone moiety, were accomplished. The β-hydroxyketone moiety in this natural product was introduced by cleavage of the N-O bond in an isoxazoline ring that was formed diastereoselectively in a 1,5-remote stereocontrolled fashion by employing intramolecular nitrile oxide cycloaddition.

Kesornpun C., Aree T., Mahidol C., Ruchirawat S., Kittakoop P.

Kesornpun C., Aree T., Mahidol C., Ruchirawat S., Kittakoop P.

Conventional methods generate nitrile oxides from oxime halides in organic solvents under basic conditions. However, the present work revealed that water-assisted generation of nitrile oxides proceeds under mild acidic conditions (pH 4-5). Cycloadditions of nitrile oxides with alkynes and alkenes easily occurred in water without using catalysts, thus yielding isoxazoles and isoxazolines, respectively, with excellent stereoselectivity toward five- and six-membered cyclic alkenes. A double stereoselective cycloaddition of two units of a nitrile oxide with cyclohexene was also achieved, thus yielding 1,2,4-oxadiazole derivatives having a unique hybrid isoxazoline-oxadiazole skeleton. Enantiomerically pure isoxazolines were prepared from monoterpenes with a ring strain. In one case, the isoxazoline with a butterfly-like structure was simply prepared, and it might be used as a ligand in asymmetric catalysis.

Ushakov P.Y., Sukhorukov A.Y.

Over the past 25 years, the isoxazoline route to aldols has proven to be a powerful synthetic tool. This review discusses more than 50 syntheses of natural products, including macrolides, alkaloids, terpenoids, pseudosugars, and sulfolipids.

Okladnikov I.V., Aksenova S.A., Ioffe S.L., Sukhorukov A.Y.

Lin C., Wang M., Wei P., Xing Q., Liu C.

AbstractHerein a concise and efficient method for the synthesis of aziridines has been developed. The reaction proceeds through a formal intermolecular [2+1] cycloaddition reaction of saccharin‐derived cyclic ketimines with sulfur ylides. This methodology features high atom‐economy, broad substrate scope and an operationally simple procedure, affording the aziridines with excellent yields and diastereoselectivity (>20 : 1 dr). In the presence of base, the aziridine products could be readily converted to benzothiazines by an unusual rearrangement reaction.

Krompiec S., Lodowski P., Kurpanik-Wójcik A., Gołek B., Mieszczanin A., Fijołek A., Matussek M., Kaszuba K.

The involvement of 1,3-dipolar cycloaddition (1,3-DP), double bond migration, metathesis, and nitrile oxide (including in situ-generated nitrile oxide) as dipoles, together with the C=C bond containing dipolarophiles, in the syntheses of 2-isoxazolines is presented. Methods for synthesizing isoxazolines (other than 1,3-DP cycloaddition) were also presented briefly. Various methods of nitrile oxide preparation, especially in situ-generated procedures, are presented. Special attention was paid to the application of various combinations of 1,3-DP cycloaddition with double bond migration (DBM) and with alkene metathesis (AM) in the syntheses of trisubstituted isoxazolines. Allyl compounds of the type QCH2CH=CH2 (Q = ArO, ArS, Ar, and others) play the role of dipolarophile precursors in the combinations of DPC mentioned, DBM and AM. Mechanistic aspects of cycloadditions, i.e., concerted or stepwise reaction mechanism and their regio- and stereoselectivity are also discussed from experimental and theoretical points of view. Side reactions accompanying cycloaddition, especially nitrile oxide dimerization, are considered. 2-Isoxazoline applications in organic synthesis and their biological activity, broad utility in medicine, agriculture, and other fields were also raised. Some remaining challenges in the field of 1,3-DP cycloaddition in the syntheses of isoxazolines are finally discussed.

Liu L., Dai M., Song L., Chen H., Bian M., Gao Y., Liu Z.

Ushakov P.Y., Ioffe S.L., Sukhorukov A.Y.

In this review, the advances made over the last 6 years in [4 + 1]-annulation reactions involving sulfonium, sulfoxonium and ammonium ylides, as well as diazo compounds and carbenes are summarized.

Ushakov P.Y., Ioffe S.L., Sukhorukov A.Y.

A “renewed isoxazoline route” toward densely functionalized ketones avoiding the use of unstable and hazardous nitrile oxide intermediates has been developed.

Hua T., Ma Y., He X., Wang L., Yan J., Yang Q.

A formal [4 + 1] cycloaddition reaction of Baylis–Hillman adducts with sulfur ylides has been developed for the first time.

Cordero F.M., Giomi D., Machetti F.

Isoxazoles, isoxazolines and isoxazolidines are a class of heterocyclic compounds having a remarkable number of applications and are very versatile building blocks in organic synthesis. The developments concerning the synthesis of the above monocyclic systems reported in the literature from 2007 to 2019 are reviewed. Some data related to theoretical methods, experimental structural methods, and thermodynamic aspects for this class of heterocycles are also reported.

Chalyk B.A., Khutorianskyi A.V., Vashchenko B.V., Danyleiko K., Grynyova A., Osipova A.O., Kozytskiy A., Syniuchenko D., Tsymbaliuk A., Gavrilenko K.S., Biitseva A.V., Volochnyuk D.M., Komarov I.V., Grygorenko O.O.

An efficient synthesis (up to a 200 g scale) of 3-hydroxypyrrolidin-2-ones bearing alkyl substituents or functional groups at the C-5 position is described. The reaction sequence started from 1,3-dipolar cycloaddition of in situ generated nitrile oxides with (meth-)acrylates into 3-substituted isoxazoline-5-carboxylates. The catalytic hydrogenolysis of the isoxazoline N-O bond was optimal upon using H2 (1 atm) at rt, with the following order of the catalyst activity: Pd-C > Pd(OH)2-C > Pt-C. The reactions with Pt-C were more selective for the synthesis of pyrrolidones, while Pd-C provided the fastest conversion rates. The stirring efficiency had a positive impact on conversion rather than elevated temperatures (up to 40 °C) or pressure (up to 50 atm). The diastereoselectivity was governed mainly by steric factors, with a dr of 1:1 to 3:1 (cis- and trans-isomers could be separated). Higher homologues (isoxazolinylacetates and -propanoates) were suitable for the synthesis of 6- or 7-substituted 4-hydroxypiperidones and 5-hydroxyazepanones, respectively. The proposed methods are tolerant to functional groups, including CF3 (but not CHF2 or CH2Cl), ester, and most N-Boc-protected amines. The utility of hydroxyl groups in lactams was shown by functional group transformations. Hydrogenolysis of C(5)-functionalized isoxazolines, bearing trimethylsilyl, phosphonate, or sulfone groups, was also studied to demonstrate limitations.

Kang X., Liang X., Zeng Q.

A new class of Corey-Chaykovsky reagent type five-membered heterocycles with an oxosulfonium ylide moiety has been synthesized by the water-mediated intramolecular cyclization/oxidation of α-carbonyl sulfur ylides generated in situ from sulfonium salts under mild conditions.

Akhmirov R.T., Ioffe S.L., Yu. Sukhorukov A.

A novel approach to conjugated enone oximes from aliphatic nitro compounds deals with double silylation of N,N -bis(silyloxy) enamines followed by a stereoselective reaction with an ester-stabilized sulfur ylide. The proposed mechanism involves the generation of labile nitrosoalkenes as intermediates, which react with the sulfur ylide to give target enone oximes.

Liu L., Ma C., He Q., Huang Y., Duan W.

Two novel tyrosine-modified pillar[5]arenes have been synthesized and applied as chiral NMR solvating agents to establish an efficient 1H NMR method for enantioselective recognition and configuration assignment towards α-aromatic ethylamines.

Ushakov P.Y., Sukhorukov A.Y., Ioffe S.L., Tabolin A.A.

AbstractSuzuki–Miyaura cross‐coupling reaction of 3‐bromomethyl isoxazolines with arylboronic acids was suggested as final C−C bond forming step in convenient diastereoselective route to trisubstituted isoxazolines. The required bromides were readily available from nitroalkenes and sulfonium ylides through an efficient sequence of formal [4+1]‐cycloaddition and C−H functionalization of intermediate isoxazoline N‐oxides. The synthetic utility of the obtained isoxazolines was demonstrated by their conversion into valuable products such as hydroxy ketone, pyrrolidinone, etc.

Hua T., Liu C., Hu W., Wang L., Yang Q.

An efficient [4 + 1] annulation between α-bromooximes and sulfur ylides via in situ generation of nitrosoalkenes under mild basic reaction conditions has been developed, providing an expeditious and scalable approach to synthesize biologically interesting isoxazoline derivatives with good to excellent yields.