Allylic Hydroperoxides Research Articles

The role of the 12-carboxylic acid group in the spontaneous autoxidation of dihydroartemisinic acid

Three of the four steps in the slow spontaneous autoxidation of dihydroartemisinic acid to artemisinin (‘ene-type’ reaction of molecular oxygen with the Δ 4,5 double bond, Hock cleavage of the resulting tertiary allylic hydroperoxide, oxygenation of the enol product from Hock cleavage and cyclization of the resulting vicinal hydroperoxyl-aldehyde to the 1,2,4-trioxane system of artemisinin) are shown to be assisted by the proximity of the 12-carboxylic acid functional group in dihydroartemisinic acid to the functional groups participating in these reactions.

The mechanism of the spontaneous autoxidation of dihydroartemisinic acid

Dihydroartemisinic acid undergoes slow spontaneous autoxidation to artemisinin and other natural products, which have been reported from the medicinal plant Artemisia annua. The mechanism of this complex transformation is shown to involve four steps: (i) initial reaction of the Δ 4,5-double bond of dihydroartemisinic acid with molecular oxygen, (ii) Hock cleavage of the resulting tertiary allylic hydroperoxide; (iii) oxygenation of the enol product from Hock cleavage; and (iv) cyclization of the resulting vicinal hydroperoxyl-aldehyde to the 1,2,4-trioxane system of artemisinin.

Comparisons of Hydroperoxide Isomerase and Monooxygenase Activities of Cytochrome P450 for Conversions of Allylic Hydroperoxides and Alcohols to Epoxyalcohols and Diols: Probing Substrate Reorientation in the Active Site

Ferric cytochrome P450 (P450) catalyzes intramolecular rearrangements of hydroperoxides to diols by heterolytic scission of the O-O bond and insertion of the terminal oxygen atom into the resulting alcohol. The goals of this work were to further characterize the regio- and stereochemistry of P450 isomerase activity using allylic hydroperoxides and to compare these reactions with NADPH-supported monooxygenations of the corresponding alcohols. Microsomes from phenobarbital-treated rats or purified P450 2B1 catalyzed the conversions of several peroxyquinols, including 2-tert-butyl-4-hydroperoxy-4-methylcyclohexa-2,5-dien-1-one (BMPOOH) and its 2,6-dimethyl derivative (TMPOOH), to diols and to alpha,beta-epoxyquinols by predominant (>93%) cis addition of oxygen to the least hindered double bond. Monooxygenation of the 4-hydroxy analogues (quinols) yielded identical cis-epoxyquinols, and both isomerization and monooxygenation reactions exhibited similar enantioselectivities (32-74% enantiomer excess). Regioselectivities were similar for BMPOOH and BMPOH (epoxyquinol:diol ratios of 5.8-7.6), but quite different for TMPOOH and TMPOH (ratios of 0.6 and 6.4, respectively). Bulky peroxyquinols and quinols derived from the A-rings of 17beta-estradiol and estrone were utilized to further compare these reactions. Both estradiol derivatives underwent approximately equal amounts of 6beta-hydroxylation and 1,2-epoxidation. The estrone derivatives also underwent 6beta-hydroxylation, but only estrone quinol yielded a second product consistent with hydroxylation at position 16. The results support several conclusions. (i) Allylic hydroperoxides may be isomerized to alpha,beta-epoxyalcohols by a heterolytic O-O cleavage mechanism with high stereoselectivity. (ii) Hydroperoxide isomerization is an efficient process relative to monooxygenation. (iii) Isomerase substrates remain in proximity to the P450 oxoferryl intermediate and are rapidly captured by the oxidant. Monooxygenase substrates, on the other hand, may bind to ferric P450 in multiple orientations and undergo more extensive substrate reorientation prior to oxidative attack.

Photoinitiated catalysis in Nafion membranes containing palladium(II) meso-tetrakis(N-methyl-4-pyridyl)porphyrin and iron(III) meso-tetrakis-(2,6-dichlorophenyl)porphyrin for O2-mediated oxidations of alkenes.

Immobilisation of both palladium(II) meso-tetrakis(N-methyl-4-pyridyl)porphyrin (PdTMPyP4+) and iron(III) meso-tetrakis(2,6-dichlorophenyl)porphyrin (FeTDCPP+) in the same membrane of Nafion creates a new composite system, in which the photoexcited palladium complex induces the O2-mediated oxidation of cyclohexene to the corresponding allylic hydroperoxide and the iron porphyrin works as a catalyst for specific oxygenations of cyclohexene and cyclooctene. The role of PdTMPyP4+ is to induce the photoactivation of O2 with visible light (lambda > 500 nm) to generate singlet oxygen (1O2) by means of energy transfer from the excited triplet state. Consequently, the 1O2-mediated oxidation of cyclohexene to cyclohexenyl hydroperoxide can be realised with a selectivity greater than 90%. Spectroscopic and photophysical investigations show that the tetracationic palladium porphyrin is mainly fixed to the external part of the Nafion membrane, it is characterised by a triplet-state lifetime significantly higher than that in the solution phase. The monocationic FeTDCPP+ is able to diffuse into the anionic cavities of Nafion, where it works as a catalyst for O2-mediated autooxidation processes that are initiated by the photogenerated hydroperoxides. These processes continue in the dark for many hours giving cyclohex-2-en-1-ol and trans-cyclohexane-1,2-diol monoethyl ether as main oxidation products. The presence of this ether, indirectly, reveals the formation of cyclohexene epoxide which undergoes a nucleophilic attack by ethanol and epoxide opening because of the strong acidic environment inside Nafion. The good photocatalytic efficiency of the oxidation process is demonstrated by an overall quantum yield of 1.1, as well as by a turnover value of 4.7 x 10(3) with respect to the iron porphyrin. When cyclooctene is present as co-substrate, it also undergoes oxygenation. In contrast to what was observed for cyclohexene, cyclooctene epoxide can be accumulated in a significant amount. As far as the stability of the system is concerned, FeTDCPP+ undergoes about 1% degradation during the process, while the Nafion matrix can be utilised several times without observable modification.

Chemoselective hydroperoxidation of alkenylarenes within thionin-supported zeolite Na-Y

Photooxidation of several 1-aryl-2-methylpropenes within the thionin-supported zeolite Na-Y affords the ene type allylic hydroperoxides in a highly chemoselective manner. This is in contrast to their photooxygenation reaction in solution, where the ene pathway is less favorable compared to the [4+2] or [2+2] pathways. Cation-π interactions are likely to be responsible for this selectivity.

Reaction of Tri- and Tetrasubstituted Alkenes with the Low-Temperature Oxidizing System Aluminum tert-Butylate-tert-Butyl Hydroperoxide

The system consisting of aluminum tert-butylate and tert-butyl hydroperoxide under mild conditions (20°C) oxidizes tri- and tetrasubstituted ethylenes containing at least one α-methyl group. The reaction proceeds via formation of tertiary allylic hydroperoxides and their subsequent transformations into unsaturated alcohols and epoxy alcohols, and also into carbonyl compounds. The presence of the latter products suggests degradation of the carbon skeleton of alkenes.

Biomimetic synthesis of arteannuin h and the 3,2-rearrangement of allylic hydroperoxides

The acyl endoperoxide arteannuin H, recently reported as a novel natural product from Artemtsia annua, has been obtained in two steps from the photooxidation of dihydroartemisinic acid, thereby confirming biogenetic speculation regarding its derivation from a secondary allylic hydroperoxide. The little studied 3,2-rearrangement reaction of such allylic hydroperoxides is also discussed.

Autoxidation of 4-amorphen-11-ol and the biogenesis of nor- and seco-amorphane sesquiterpenes from fabiana imbricata

Photooxidation of 4-amorphen-11-ol ( 1), recently reported as one of the major sesquiterpene natural products from the medicinal plant Fabiana imbricata, results in three allylic hydroperoxides 6, 9 and 10, which are expected from the “ene-type” reaction of molecular oxygen with the tri-substituted double bond in 1. The tertiary allylic hydroperoxide 6 undergoes carbon-carbon bond cleavage and a second autoxidation reaction to yield the more highly oxygenated seco-amorphane 11 under very mild conditions. In acid, this compound may then undergo either a second carbon-carbon bond cleavage reaction to yield nor-sesquiterpenes 2 and 3 (reported as bona fide natural products from F. imbricata, or cyclize to the sesquiterpene peroxofabianane ( 5), which is a presumed precursor to the natural product fabianane ( 4). Some mechanistic investigations concerning the two chemical processes: viz:- carbon-carbon bond cleavage and autoxidation which would account for the formation of natural products 2, 3 and 4 from 1 are reported. Tertiary allylic hydroperoxide 32, which lacks the 11-hydroxyl functional group present in 1 undergoes only C-4/C-5 carbon-carbon bond cleavage under more forcing conditions, suggesting a role for this functional group in assisting the autoxidation reactions of 4-amorphen-11-ol.

Autoxidation of allohimachalol

The tri-substituted (2,3)-double bond in allohimachalol ( 1) undergoes autoxidation in the presence of singlet molecular oxygen, resulting in tertiary and secondary allylic hydroperoxides 6 and 7. These autoxidation products may then participate in complex rearrangement reactions to yield seco-allohimachalanes, which have undergone carbon-carbon bond cleavage at the 2,3- or 3,4-positions. The observed autoxidation/rearrangement reactions of 1 in vitro would account for the biogenesis of several allohimachalanes recently reported from the medicinal plant Illicium tsangii as natural products.

Oxidation of Chiral 1,4-Cyclohexadienes: A Comparison of Chemically and Photochemically Generated Singlet Oxygen1O2(1Δg)

Chiral alkyl-substituted 2,5-cyclohexadiene-l-carboxyIic acids la-c have been oxidized in water and in methanol with singlet oxygen, 1O2 (1Δg), generated either photochemically or chemically from the catalytic system hydrogen peroxide/sodium molybdate. These methods were compared in terms of chemo-, regio- and diastereoselec-tivities and the chemical (kT) and physical (kq) quenching rate constants of 1O2 were determined. The ratio of the cis and trans isomers of the hydroperoxides 2a-c is not influenced by the source of 1O2 but, on the other hand, it depends slightly on the solvent and greatly on the steric hindrance of the substituents linked to the chiral carbon. The results may be interpreted on the basis of the successive formation of an exciplex and a perepoxide that evolves either by giving the final allylic hydroperoxide or by dissociating into the starting substrate and singlet or triplet oxygen.

Photooxygenation of chiral dienol ethers: asymmetric synthesis of alkoxydioxines

The addition of 1O 2 to chiral dienol ethers provides a new route to alkoxydioxines (alkoxyendoperoxides). Depending upon substitution and geometry, the [4+2] cycloaddition is accompanied or even supplanted by [2+2] cycloaddition leading to alkene cleavage and/or ene-like reaction leading to allylic hydroperoxides. The diastereoselectivity of cycloaddition is ultimately limited by the conformational freedom of the dienol ether substrates.

Halogenated oxo- and peroxotitanium porphyrinates as sensitizers for the photooxygenation of olefinic compounds

A series of porphines, oxotitanium(IV) and peroxotitanium(IV) porphyrinates were tested as photosensitizers of the singlet oxygen ene reaction with cyclohexene and cis-cyclooctene. The relative order of activity is: H 2(P)>OTi(P)≥Ti(O 2)P. Best stability is obtained for porphines or porphyrinate complexes with fluorine substituents. Oxotitanium(IV) porphyrinates are active in the decomposition of allylic hydroperoxides. The (photo)catalytic epoxidation occurs less readily than the thermal reaction at 82°C. Attempts of photocatalytic hydrogen peroxide activations lead to fast destruction of OTi(P).

Novel seco-cycloartanes from Kadsura coccinea and the assisted autoxidation of a tri-substituted alkene

Eight novel seco-cycloartanes ( 1–8) have been isolated from the medicinal plant Kadsura coccinea. The major component of the extract, coccinetane A ( 1), undergoes extremely facile autoxidation to yield tertiary and secondary allylic hydroperoxides 2 and 3. Evidence is presented that such autoxidation of the Δ 24-tri-substituted double bond is assisted by the presence of the 3-carboxylic acid group or its methyl ester.

An organic sensitizer within Ti-zeolites as photocatalyst for the selective oxidation of olefins using oxygen and water as reagents

A new positive photocatalytic system comprising an organic dye within the micropores of a titanium zeolite is able to effect the catalytic dihydroxylation of alkenes using water and molecular oxygen as reagents; the dye acts as an antenna to absorb the energy of visible light, generating hydroxyl radicals from water; subsequently, the OH· radicals react with olefins in the presence of oxygen to form allylic hydroperoxides that in the presence of the Ti atoms of the zeolite promote the epoxidation of the alkene.

Photooxygenation of 2,4-Dimethyl-1,3-pentadiene: Solvent Dependence of the Chemical (Ene Reaction and [4 + 2] Cycloaddition) and Physical Quenching of Singlet Oxygen

The photooxygenation of 2,4-dimethyl-1,3-pentadiene (1) was investigated in seven polar and nonpolar solvents by oxygen-uptake measurements. The overall deactivation rate ko ( = kr + kq) was additionally measured in chloroform solutions by singlet-oxygen (1Δg) phosphorescence quenching which showed excellent agreement with the data from the detailed steady-state kinetics. The difference in solvent-polarity effects on the [4 + 2] cycloaddition (major path, leading to the endoperoxide 2) and ene reaction (minor path, leading to the allylic hydroperoxide 3) are explained by competition between a concerted and a perepoxide mechanism. In all solvents the physical quenching of singlet oxygen by 1 is at least as efficient as the chemical quenching. The reaction of the endoperoxide 2 and 3,3,6,6-tetramethyl-1,2-dioxene 9 with carbonyl compounds in the presence of TMSOTf resulting in the dihydrofuran 8 and the 1,2,4-trioxane 10, was also studied.

ChemInform Abstract: A Novel Endoperoxide and Related Sesquiterpenes from Artemisia annua Which Are Possibly Derived from Allylic Hydroperoxides.

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A Study of Photooxygenation of Cycloalkenes under 2,4,6-Triphenylpyrylium Tetrafluoroborate Sensitization

Abstract 2,4,6-Triphenylpyrylium tetrafluoroborate sensitized oxygenation of cycloalkenes to allylic hydroperoxides is described. This reaction appears to involve unusual electron transfer mechanism in the formation of observed products.

A novel endoperoxide and related sesquiterpenes from Artemisia annua which are possibly derived from allylic hydroperoxides

Seven novel cadinane sesquiterpenes, including the seven-membered endoperoxide lactone arteannuin H ( 1), two six-membered lactones arteannuins I ( 4) and J ( 5), three five-membered lactones arteannuins K-M ( 6–8) and a keto acid arteannuin N ( 9) have been isolated from the dried leaves of Artemisia annua in addition to the known compounds dihydroartemisinic acid ( 27), dihydroarteannuin B ( 24) and dihydro- epi-deoxyarteannuin B ( 22). It is proposed that these novel sesquiterpenes are biogenetically related to dihydroartemisinic acid via intermediate secondary and tertiary allylic hydroperoxides.

Preparation of an Unsymmetrically Labeled Allylic Hydroperoxide and Study of Its Allylic Peroxyl Radical Rearrangement

Preparation of an Unsymmetrically Labeled Allylic Hydroperoxide and Study of Its Allylic Peroxyl Radical Rearrangement

Skin sensitization to linalyl hydroperoxide: support for radical intermediates.

In order to better understand the skin sensitization mechanism of allylic hydroperoxides, linalyl hydroperoxide (1) and several of its potential rearrangement products-epoxylinalool (2), epoxynerol (3), epoxygeraniol (4), and furan (5) and pyran (6) derivatives-were synthesized. The sensitizing properties of these molecules have been screened on mice using the local lymph node assay (LLNA) and further evaluated on guinea pigs using the Freund's complete adjuvant test (FCAT). Linalyl hydroperoxide (1) and linalyl epoxide (2) were found to be sensitizers, while the other compounds were classified as mild sensitizers or nonsensitizers. In the guinea pigs, no cross-reactions were observed between skin sensitizers 1 and 2. Radical-trapping experiments were carried out on linalyl hydroperoxide (1) using TTBP as trapping agent and Fe(3+)-TPP as radical inducer. The major reaction taking place is the formation of a furan ring by intramolecular reaction of the oxygen-centered radical with the isoprenyl double bond with the formation of a tertiary radical. Reaction of this intermediate with radicals derived from TTBP gave compounds 10a,b in 25% yield. The second important reaction, accounting for 14%, is taking place on the allylic double bond with the formation of a less stable primary radical which is not trapped by a TTBP-derived radical but by a hydroxy radical to give a mixture of epoxides 3 and 4. These results are in favor of the formation of a carbon-centered reactive radical as intermediate in the skin sensitization to linalyl hydroperoxide.