Nitrones 1-pyrroline 1-oxides

In alieyclic systems, more emphasis has been placed on oxidation of nitrones. At least one aldonitrone of the pyrroline series (62) undergoes autoxidation to the hydroxamic acid (63). This is probably a... 

Recendy, PEN, a-4-pyridyl-oxide-N-t-butyl nitrone (POEN) or 5-5,dimethyl-1, pyrroline-N-oxide (DMPO) were evaluated in models of experimental shock (endo-toxic, traumatic and mesenteric artery occlusion in rats). All three nitrones, when given prior to the insult intraperitoneally, were protective. When the nitrone s spin trapping ability was inactivated by exposure to solar light and air, they were no longer efficacious (Novelli, 1992). 

The enantiomerically pure indolizidine (—)-422 has been synthesized starting from L-malic acid diethyl ester 407. The hydroxyl function of L-malic acid diethyl ester 407 has been protected as dihydropyranyl ether 408 with 2/7-dihydropyran and Amberlyst 15 in pentane at room temperature. The diethyl ester 408 was then reduced with lithium aluminium hydride in diethyl ether under reflux and the newly generated hydroxyl functions then protected with mesyl chloride in the presence of triethylamine in dichloromethane at 0°C. This was converted into newly protected pyrroline nitrone 409 in 44% overall yield through a well-established method (Scheme 90). The regio-isomeric 5-pyrroline-iV-oxide 410 formed in 4% overall yield was easily separated by column chromatography <20000L2475>. 

The pyrroline-iV-oxide 411 lost enantiomeric purity in the deprotection step. The THP protecting group could be deprotected under very mild conditions using Amberlyst 15 in methanol. However, the mixture was obtained in low yield accompanied by partial or total racemization as indicated by variation of specific rotation. Racemization also occurred during purification by silica gel chromatography or recrystallization. The lack of configurational stability of the nitrone 411 may be explained with the occurrence of a fast (not detectable by NMR), nitrone-hydroxyenamine tautomerism (Scheme 91). 

Substituted 3-hydroxy-2-pyrrolidinones were synthesised via 1,3-DC reactions of furfuryl nitrones with acrylates and subsequent intramolecular cyclisation after N-0 bond reduction. Addition of iV-acryloyl-(2/()-bomane-10,2-sultam to Z-nitrone 83 gave the endo/exo cycloadducts in 85 15 ratio with complete stereoface discrimination <00JOC1590>. The 1,3-DC of pyrroline A-oxide to chiral pentenoates using (-)-/rans-2-phenylcyclohexanol and (-)-8-phenylmenthol as chiral auxiliaries occurred with moderate stereocontrol (39% de and 57% de, respectively) and opposite sense of diastereoselectivity <00EJO3595>. The... 

Mild reaction conditions make it possible for DMD to be used in the formation of optically active nitrones such as (S)-5- hydroxymethyl -1-pyrroline TV-oxide... 

Intramolecular variations of a series of bifunctional derivatives lead to the formation of cyclic nitrones. Many pyrroline /V-oxide derivatives were obtained in the course of intramolecular interaction in situ between carbonyl and hydrox-ylamine groups, resulting from the reduction of a y-nitro group (Scheme 2.31) (Fig. 2.8) (238-253). 

Photoisomerization of nonconjugated nitrones, in particular derivatives of 3-imidazoline-3-oxide and pyrroline-N -oxide, appears to be irreversible (Scheme 2.83) (10, 452). 

Addition of the Grignard reagent, generated in situ from (375), to nitrone (373) or to 2,5-dimethyl-l-pyrroline-A-oxide, affords biradical (379) or nitrone containing monoradical (380). Furthermore, (380) can be transformed into biradical (381) and triradical (382) (Scheme 2.165) (620). 

For example, the reaction of nitronates (123) with a zinc copper pair in ethanol followed by treatment of the intermediate with aqueous ammonium chloride a to give an equilibrium mixture of ketoximes (124) and their cyclic esters 125. Heating of this mixture b affords pyocoles (126). Successive treatment of nitronates (123) with boron trifluoride etherate and water c affords 1,4-diketones (127). Catalytic hydrogenation of acyl nitronates (123) over platinum dioxide d or 5% rhodium on aluminum oxide e gives a-hydroxypyrrolidines (128) or pyrrolidines 129, respectively. Finally, smooth dehydration of a-hydroxypyrrolidines (128) into pyrrolines (130f) can be performed. 

Japanese researchers varied aryl substituent at C-4 in nitronate (147), LA, and the reaction conditions, they used successfully diastereomerically pure nitronates (147) (Scheme 3.121) for the synthesis of various fused-ring systems, such as benzofuro-[3,2-d]-l,2-oxazines (322), furo-[3,4-d]-isoxazoles (323—326), indolo-[2,3-b]-l-pyrroline 1-oxides (327), 4//-1,2-benzoxazines (328), benzofuro-[2,3-c]-tetrahydropyrans (329), and monocyclic 1,2-oxazines (330). 

The use of nitrone scavengers was precedented by the work of Iwamura and Inamoto (1967), who had used esr spectroscopy to detect the nitroxide formed by addition of cyanopropyl radicals to the cyclic nitrone, 5,5-dimethyl-pyrroline-N-oxide (DMPO) [2], and had actually isolated the cyanopropyl radical adduct of the nitrone [3]. 

Perhydropyrrolo[l,2-fc]isoxazoles result from 1,3-dipolar cycloaddition of cyclic nitrones with alkenes. The high regio- and stereoselectivity of this cycloaddition has been used to control the stereochemistry in the synthesis of natural products. As one example, pyrroline N-oxide (70) and 3,4-dimethoxystyrene gave a diastereomeric mixture of pyrroloisoxazoles (71) and (72), in nearly quantitative yield with preferential formation of (71). 

Simple nonconjugated nitrones have a strong absorption maximum in the UV at around 230 nm. Acyclic nitrones are, in general, photo-chemically cyclized to the corresponding oxaziridines.148 The cyclic nitrone, 5,5-dimethyl-l-pyrroline 1-oxide (164) is similarly converted into the oxaziridine (165) by photolysis in ethanol/cyclohexane solution,146 and several 2-substituted 1-pyrroline 1-oxides were subsequently found to undergo the same cyclization in cyclohexane solution.147... 

Tufariello has reviewed his strategy for the synthesis of alkaloids (including necine bases) using the 1,3-dipolar cycloaddition of nitrones to alkenes.5 This work began with the synthesis of ( )-supinidine (7) from 1-pyrroline 1-oxide (see these Reports, Vol. 2, Ch. 4). A related approach has been used by Iwashita et al. in their synthesis of ( )-isoretronecanol (5).6 The stereochemistry of the exo-product (8), formed by regiospecific 1,3-dipolar cycloaddition of 1-pyrroline 1-oxide to dihydrofuran (Scheme 2), was confirmed by its conversion into... 

The seco-phenanthroindolizidine alkaloid septicine has been synthesized by a nitrone route. A cycloaddition of 1-pyrroline 1-oxide with 2,3-bis-(3,4-dimethoxyphenyl)butadiene gives two stereoisomeric isoxazolidines, one of which is converted into ( ) septicine.10 ( )-Tylophorine and 5-coniceine have been prepared by a new route that makes use of an intramolecular imino-Diels-Alder reaction.11 A stereoselective synthesis of 3,5-dialkyl-indolizidines has been applied to the synthesis of a stereoisomer of the trail pheromone of the Pharaoh ant and to a stereoisomer of gephyrotoxin 223.12 A stereoselective total synthesis of ( )-perhydrogephyrotoxin (21)13 and a simple synthesis of ( )-gephyran14 have been reported. 

The reaction of cyclic nitrones with free radicals takes place as in Scheme 8.21 with 5,5-dimethyl-l-pyrroline IV-oxide (DMPO) as an example.119,120 The resulting stable nitroxide spin adducts can be detected and quantified by ESR. 

The selectivity of the trap towards hydroxyl radicals was demonstrated by several control experiments using different radicals, showing that the formation of the respective hydroxylation product, 5-hydroxy-6-0-zso-propyl-y-tocopherol (57), was caused exclusively by hydroxyl radicals, but not by hydroperoxyl, alkylperoxyl, alkoxyl, nitroxyl, or superoxide anion radicals. These radicals caused the formation of spin adducts from standard nitrone-and pyrroline-based spin traps, whereas a chemical change of spin trap 56 was only observed in the case of hydroxyl radicals. This result was independent of the use of monophasic, biphasic, or micellar reaction systems in all OH radical generating test systems, the trapping product 57 was found. For quantitation, compound 57 was extracted with petrol ether, separated by adsorption onto basic alumina and subsequently oxidized in a quantitative reaction to a-tocored, the deeply red-colored 5,6-tocopheryldione, which was subsequently determined by UV spectrophotometry (Scheme 23). 

Similar reactions have been carried out with variously substituted pyrroline 1-oxides, imidazole 1-oxides, isoxazoline N-oxides (nitronic esters) and 3,4-diazacyclopentadienone AT-oxides in combination with a large variety of alkenic and alkynic dipolarophiles, aryl isocyanates, aryl isothiocyanates and N- sulfinylamines, leading to pyrrolidinoisoxazoles, pyrrolo[l,2-6][l,2,4]oxadiazoles, pyrrolo[2,l-d][l,2,3,5]oxathiadiazoles, isoxazolo[2,3-b ]isoxazoles and isoxazolo[l, 2-6 ]pyrazoles. 

Deoxygenation of a nitrone. Some years ago Todd and co-workers noted that 1-pyrroline-1-oxides can be obtained by reductive cyclization of a y-nitro ketone. This reaction was used recently in a synthesis of chlonns related to vitamin B,. Thus the nitro ketone 1 on reduction with zinc and acetic acid gives the pyrroline N-oxide 2 in high yield. The N-oxide is stable to triphenylphosphiue or trimethyl phosphite, but is reduced to the imine 3 in high yield by TiCl,. 

Many aliphatic and alicyclic nitrones have been reported to give dimers thus 2,4,4-trimethyl-1-pyrroline-l-oxide dimerized, on standing, to 88 by the nucleophilic addition of a 2-methyl group of the monomer across the C=N bond of another molecule (the chemistry of nitrones has been reviewed by Delpierre and Lamchen110). Oxidation of 1-hydroxypiperidine does not give the expected cyclic nitrone but a product to which the dimeric structure 89 has been assigned.111... 

Dipolar cycloadditions. Nitrones such as 1 combine with alkenes to form isoxazolidines. Tufariello has employed these 1,3-dipolar cycloadditionS as key steps in the synthesis of several alkaloids. Monosubstituted olefins react with nitrones regioselectively to afford 5-substituted iSoxazolidines thus addition of 2 to 1-pyrroline-l-oxide produces the cycioadduct 3, which serves as an intermediate in a total synthesis of elaeocarpine (4). ... 

Insoluble polymer-supported dipolarophiles such as 92 were used to mask the nitrone moiety of the chiral pyrroline A-oxide 91 to prevent racemization at the vicinal stereogenic center by temporary formation of the resin linked isoxazolidines 93. A thermally induced 1,3-dipolar cycloreversion was used to cleave the product from the resin and restore the 1,3-dipole functionality which underwent intramolecolar 1,3-DC to afford the enantiomerically pure tricyclic isoxazolidine 95 <03SL1889>. 

With cyclic nitrones, where ( /Z) isomerization is not possible, the exo transition state is usually steri-cally preferred (equation 19-21). When steric factors in the endo and exo transition states are nearly the same, however, the existence of bonding secondary orbital interactions in the endo transition state can tip the balance in its favor this appears to be the case for the reaction of methyl crotonate and l-pyrroline 1-oxide (equation 22). ... 

Examples of photorearrangement in nitrones and heteroaromatic N-oxides have again been described, and the subject has been critically reviewed. The hydroxyoxaziridines (81) have been prepared by irradiation of the corresponding 1-pyrroline 1-oxides (82), ° whereas photorearrangement of the dinitrone (83) gave the oxaziridines (84) and (85) and the lactam (86) oxaziridines (84), (85), and (86) were converted into the piperazine-2,5-dione (87) by further irradiation. ... 

Bicyclic A(0-Mti-homonucleoside analogues such as 591 were synthesized through 1,3-dipolar cycloaddition of an enantiopure 3-hydroxy-l-pyrroline A -oxide and protected allyl alcohol and subsequent introduction of thymine by a Mitsunobu reaction <2003T5231>. Furthermore, isoxazole, isoxazoline, and isoxazolidine analogues of (7-nucleo-sides such as 592-594 were synthesized by 1,3-dipolar cycloaddition of nitrile oxides and nitrones derived from uracil-5-carbaldehydes with suitable dipolarophiles <2003T4733, 2006T1494>. 

A new nitrone, 5-methyl-5-phosphono-l-pyrroline N-oxide (DHPMPO), has... 

The oxidation of thioketene (245) by nitrones (246) of the 1-pyrroline 1-oxide type furnishes a-thiolactones (thiiranones) (247) (Equation (40)) <77AG(E)722>. But the oxidation of thioketene S-oxide gives thioketone S-oxide via thiiranone S-oxide (Scheme 87). 

N-methylen-tert-butylamin-N-oxid 7991a> and 5,5-dime thyl-A1 -pyrrolin-N-oxid T892 have been employed as spin traps, but a variety of other nitrones is also suitable93. While ESR data from adducts to 81 c give relatively little information on fine structure of the radicals88, in the spectra of adducts from 79 and 78 more such information is recognizable926 d 94 ... 

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