Experimental and theoretical studies on Mannich-type reactions of chiral non-racemic N-(benzyloxyethyl) nitrones

The nucleophilic addition of both silyl ketene acetals and lithium enolates derived from methyl acetate to chiral non-racemic N-(benzyloxyethyl)nitrones has been studied both experimentally and theoretically. Aromatic nitrones showed lower reactivity that aliphatic nitrones and the addition of the silyl ketene acetal led to lower selectivities than the addition of the corresponding lithium enolate. Whereas low selectivity was obtained for the addition of the silyl ketene acetal, only one diastereomer could be detected in all cases for the addition of lithium enolate to aliphatic nitrones. The synthetic utility of the two chiral auxiliaries employed lies in the preparation of enantiomeric compounds. DFT theoretical calculations confirmed the stepwise mechanism for the addition of silyl ketene acetals to nitrones and are in good agreement with the observed experimental results.     

High stereocontrol in the allylation of chiral non-racemic α-alkoxy and α-amino nitrones

The stereocontrolled addition of allylic metals to chiral non-racemic nitrones promoted by the addition of Lewis acids is described. Whereas for α-alkoxy nitrones the stereocontrol depends on the Lewis acid used as an activator, for α-amino nitrones the diastereofacial course of the reaction depends on the protection of the α-amino group. The successful implementation of the methodology is represented by the enantiodivergent synthesis of d- and l-allylglycine.     

Theoretical study of the spin trapping of hydroxyl radical by cyclic nitrones: a density functional theory approach

The hydroxyl radical (*OH) is an important mediator of biological oxidative stress, and this has stimulated interest in its detection. 5,5-Dimethyl-1-pyrroline N-oxide (DMPO) and its alkoxycarbonyl and alkoxyphosphoryl analogues have been employed as spin traps for electron paramagnetic resonance (EPR) spectroscopic radical detection. Energies of optimized geometries of nitrones and their corresponding *OH adducts were calculated using density functional theory (DFT) at the B3LYP/6-31+G//B3LYP/6-31G level. Calculations predict that the trans adduct formation is favored in alkoxycarbonyl nitrones, while cis adducts with intramolecular H-bonding is favored for alkoxyphosphoryl nitrones. Addition of *OH to a phosphoryl-substituted nitrone is more exoergic than the carbonylated nitrones. Charge and spin densities on the nitrone spin traps were correlated with their rates of addition with *OH, and results show that the charge density on the nitronyl C, the site of *OH addition, is more positive in phosphorylated nitrones compared to DMPO and the alkoxycarbonyl nitrones. The dihedral angle between the beta-H and nitroxyl O bonds is smaller in phosphorylated nitrones, and that aspect appears to account for the longer half-lives of the spin adducts compared to those in DMPO and alkoxycarbonyl nitrones. Structures of nitrones with trifluoromethyl-, trifluoromethylcarbonyl-, methylsulfonyl-, trifluoromethylsulfonyl-, amido-, spiropentyl-, and spiroester substituents were optimized and their energies compared. Amido and spiroester nitrones were predicted to be the most suitable nitrones for spin trapping of *OH due to the similarity of their thermodynamic and electronic properties to those of alkoxyphosphoryl nitrones. Moreover, dimethoxyphosphoryl substitution at C-5 was found to be the most efficient substitution site for spin trapping of *OH, and their spin adducts are predicted to be the most stable of all of the isomeric forms.     

A general synthesis of N-vinyl nitrones

A general synthesis of a new type of heterodiene, the N-vinyl nitrone, is described. The synthetic sequence begins with the conjugate addition of benzeneselenol to nitroalkenes (in turn derived from Henry reaction of an aldehyde and a nitroalkane) to provide 2-selenenylnitroalkenes. These selenonitroalkanes are reduced to the corresponding hydroxylamines which are combined with aldehydes to form nitrones. The phenylselenenyl-containing nitrones are then oxidized to selenoxides which undergo syn-selenoxide elimination to provide N-vinyl nitrones. Three X-ray crystal structures of substituted N-vinyl nitrones were obtained. In addition, the first [4+2] cycloaddition of an N-vinyl nitrone is reported.     

A General Method for the Vinylation of Nitrones. Synthesis of Allyl Hydroxylamines and Allyl Amines

An examination of the vinylation of several nitrones is presented. Whereas a complete diastereofacial discrimination was observed upon the addition of vinyl organometallic reagents to α-alkoxy nitrones, the same reaction with α-amino nitrones gave syn adducts in all cases, with the only exception of a L-serine-derived α-amino monoprotected nitrone. The obtained allyl hydroxylamines were easily transformed into synthetically valuable allyl amines.     

Rate constants of hydroperoxyl radical addition to cyclic nitrones: a DFT study

Nitrones are potential synthetic antioxidants against the reduction of radical-mediated oxidative damage in cells and as analytical reagents for the identification of HO2* and other such transient species. In this work, the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) and PCM/mPW1K/6-31+G(d,p) density functional theory (DFT) methods were employed to predict the reactivity of HO2* with various functionalized nitrones as spin traps. The calculated second-order rate constants and free energies of reaction at both levels of theory were in the range of 100-103 M-1 s-1 and 1 to -12 kcal mol-1, respectively, and the rate constants for some nitrones are on the same order of magnitude as those observed experimentally. The trend in HO2* reactivity to nitrones could not be explained solely on the basis of the relationship of the theoretical positive charge densities on the nitronyl-C, with their respective ionization potentials, electron affinities, rate constants, or free energies of reaction. However, various modes of intramolecular H-bonding interaction were observed at the transition state (TS) structures of HO2* addition to nitrones. The presence of intramolecular H-bonding interactions in the transition states were predicted and may play a significant role toward a facile addition of HO2* to nitrones. In general, HO2* addition to ethoxycarbonyl- and spirolactam-substituted nitrones, as well as those nitrones without electron-withdrawing substituents, such as 5,5-dimethyl-pyrroline N-oxide (DMPO) and 5-spirocyclopentyl-pyrroline N-oxide (CPPO), are most preferred compared to the methylcarbamoyl-substituted nitrones. This study suggests that the use of specific spin traps for efficient trapping of HO2* could pave the way toward improved radical detection and antioxidant protection.     

N-benzyl aspartate nitrones: unprecedented single-step synthesis and [3 + 2] cycloaddition reactions with alkenes

N-benzyl aspartate nitrones 2, prepared by addition of N-benzylhydroxylamine to dialkyl acetylenedicarboxylates 1, underwent [3 + 2] thermal cycloaddition with a wide range of alkenes to afford isoxazolidines 4 bearing a polyfunctionalized quaternary center. Under these uncatalyzed conditions, the trans stereocontrol observed with vinyl ethers is higher than that obtained with all acyclic activated nitrones reported to date. The first asymmetric access to a type-4 pure adduct was achieved starting from the chiral aspartate nitrone derived from (S)-alpha-methylbenzylhydroxylamine.     

Efficient entry to highly functionalized beta-lactams by regio- and stereoselective 1,3-dipolar cycloaddition reaction of 2-azetidinone-tethered nitrones. Synthetic applications

Racemic as well as optically pure 2-azetidinone-tethered nitrones, both cyclic and acyclic, were smoothly prepared from 4-oxoazetidine-2-carbaldehydes. The regio- and diastereoselectivities of the intermolecular 1,3-dipolar cycloaddition reactions of 2-azetidinone-tethered nitrones with substituted alkenes and alkynes were investigated. 2-Azetidinone-tethered nitrones on reacting with various dipolarophiles yielded isoxazolinyl-, isoxazolidinyl-, or fused polycyclic-beta-lactams, exhibiting good regio- and facial stereoselectivity in the most of the cases. In addition, some interesting transformations of these cycloadducts were performed, yielding aziridinyl beta-lactams or functionalized beta-alkoxycarbonyl gamma-lactams (derivatives of the aza analogue of paraconic acid).     

Diastereoselective addition of alkynylalanes to carbohydrate-derived nitrones

Propargylic N-hydroxypyrrolidines were prepared by diastereoselective addition of pre-formed alkynylalanes to various highly functionalized carbohydrate-derived endocyclic nitrones. Excellent diastereoisomeric excesses were obtained using dimethyl-2-phenylethynylalane. Addition of other alkynylalane derivatives to such type of nitrones is also reported.     

New chiral nitrones as precursors of α,α-disubstituted amino-acids,according to the SRS principle

The preparation of new enantiopure cyclic nitrones based on the 1-oxy-2,3-dihydro-imidazol-4-one ring is described. The addition of arylmagnesium or alkynylzinc reagents to these nitrones can be achieved with total enantio- and diastereoselectivity, leading to α,α-disubstituted amino-acid precursors.     

Nitrone—XI Isoxazolidin-verbindungen—VIII : N-substituierte 5-isoxazolidinone durch reformatzky-reaktion mit nitronen

The two step procedure of the Reformatzky reaction with nitrones enables the synthesis of 2-alkyl 3-aryl 5-isoxazolidinones from α-bromo esters and such nitrones, which are too basic for the one step procedure, Diethyl α-bromo methylmalonate is especially suited for the Reformatzky reaction with nitrones, yielding the E-isomer of the corresponding isoxazolidinone. Reaction of ethyl α-bromo butyrate yields chiefly the Z-isomer, from which result conclusions are drawn concerning the transition state of the primary addition step.     

Approach to Fully Substituted Cyclic Nitrones from N‐Hydroxylactam Derivatives: Development and Application to the Total Synthesis of Cylindricine C

An approach to cyclic nitrones from N‐hydroxylactam derivatives is documented. The nucleophilic addition of an organolithium reagent to an N‐OSEM [SEM=2‐(trimethylsilyl)ethoxymethyl] lactam forms a five‐membered chelated intermediate, which undergoes both elimination and deprotection to give a fully substituted nitrone in a one‐pot process. When combined with the N‐oxidation of easily available chiral lactams, this method becomes especially useful for the quick synthesis of chiral nitrones in enantio‐pure form, enabling the concise total synthesis of cylindricine C.     

1,3-dipolar cycloaddition on solid supports: nitrone approach towards isoxazolidines and isoxazolines and subsequent transformations

1,3-dipolar cycloaddition reactions of nitrones with alkenes and alkynes are well-studied reactions in solution-phase organic chemistry. However, the number of studies concerned with their application in solid-phase organic synthesis is rather low compared to other 1,3-dipoles, e.g. azides or nitrile oxides. This tutorial review aims to summarise the main approaches towards the application of nitrones in 1,3-dipolar cycloaddition reactions on solid supports in addition to subsequent transformations with polymer-bound isoxazolidines and reactions using polymer-bound catalysts.     

Nucleophilic additions of lithiated allylphenylsulfone to nitrones: experimental and theoretical investigations

The nucleophilic addition of lithiated allylphenylsulfone to nitrones at −80 °C proceeds exclusively α to the phenylsulfonyl group affording anti adducts in high yield. At 0 °C isoxazolidines are obtained with complete all-trans selectivity. The formation of these compounds involves isomerization of the allylsulphonyl moiety to give a transient vinylsulfone that then undergoes a subsequent intramolecular Michael addition. The addition to several nitrones has been studied and theoretical calculations have been refined to accurately explain the selectivity of the allylation reaction.     

Alpha-(trifluoromethyl)amine derivatives via nucleophilic trifluoromethylation of nitrones

(Trifluoromethyl)trimethylsilane (TMSCF(3)) reacts with nitrones to afford alpha-(trifluoromethyl)hydroxylamines protected as O-trimethylsilyl ethers. Potassium t-butoxide initiates the nucleophilic trifluoromethylation. The reaction works best with alpha,N-diaryl nitrones, and the conditions are compatible with a range of substituents on the aryl groups. Acidic deprotection of the nitrone/TMSCF(3) adducts generates alpha-(trifluoromethyl)hydroxylamines. Catalytic hydrogenation of the adducts produces alpha-(trifluoromethyl)amines. Nitrone/TMSCF(3) adducts with strong electron-withdrawing groups on the alpha-aryl ring or heterocyclic alpha-aryl groups undergo an elimination/addition sequence to generate alpha,alpha-bis(trifluoromethyl)amines. Nitrones with alkyl groups bound directly to the 1,3-dipolar moiety fail to react with TMSCF(3), but trifluoromethylation of beta,gamma-unsaturated nitrones followed by reduction of the double bond can circumvent this limitation.     

Radical addition of nitrones to acrylates mediated by SmI2: asymmetric synthesis of gamma-amino acids employing carbohydrate-based chiral auxiliaries

Alkyl nitrones possessing N-substituted sugars as chiral auxiliaries were found to effectively undergo an SmI(2)-mediated radical addition to n-butyl acrylate affording gamma-amino acid derivatives with high diastereomeric control.     

Oxazolinyloxiranyllithium-mediated synthesis of highly strained heterocyclic compounds

The addition reaction of α-lithiated oxazolinyloxiranes to nitrones has been investigated. 1,5,9-Trioxa-8,10-diazadispiro[2.0.4.3]undecanes formed in a completely diastereoselective manner upon treatment of α-lithiated oxiranes with nitrones. The lithiation of optically active trans and cis-oxazolinyloxiranes followed by the addition of a nitrone resulted in the formation of the same dispirocyclic compound. An explanation for the observed stereoselectivity is provided.     

Synthesis of chiral cyclic nitrones by asymmetric addition of β-ketosulfones to nitroalkenes followed by reductive cyclization

The first organocatalytic addition of β-ketosulfones to nitroalkenes catalyzed by thiourea cinchona alkaloids is presented. The readily obtained addition products were selectively transformed into chiral nitrones by reduction of the nitro group and in situ cyclization (up to 99:1 e.r. and >98:2 d.r.). Moreover, the utility of this method has additionally been demonstrated by the further transformation to functionalized N-hydroxypyrrolidines that possess a quaternary center by addition of trimethylsilyl cyanide (TMSCN) to the C=N bond of the cyclic nitrones in the presence of a Lewis acid.     

Diversity-oriented synthesis of 1,2,3,5-tetrahydrobenzo[e][1,2,4]oxadiazepines and 2,3-dihydro-1H-benzo[e][1,2,4]triazepines by base-induced [4 + 3] annulation reactions

The base-induced formal [4 + 3] annulation reactions of N-(ortho-chloromethyl)aryl amides with nitrones or hydrazonoyl chlorides have been reported. When nitrones are used as the 1,3-dipole, the corresponding reaction afforded a series of 1,2,3,5-tetrahydrobenzo[e][1,2,4]oxadiazepine derivatives. Highly functionalized 2,3-dihydro-1H-benzo[e][1,2,4]triazepine derivatives were also synthesized via an unprecedented tandem aza-Michael addition/rearrangement aromatization between N-(ortho-chloromethyl)aryl amides and hydrazonoyl chlorides.     

Zinc triflate catalyzed aerobic cross-dehydrogenative coupling (CDC) of alkynes with nitrones: a new entry to isoxazoles

A mild, operationally simple cross-dehydrogenative coupling between nitrones and terminal alkynes is described by using cheap, readily available 3,3',5,5'-tetra-tert-butyldipheno-quinone and dioxygen as oxidants. These cross-couplings can be performed on various nitrones and alkynes with good to excellent yields. Product nitrones are readily transformed to pharmaceutically important 3,5-disubstituted isoxazoles.