Biomimetic total synthesis of litseaverticillols B, E, I, and J and structural reassignment of litseaverticillol E

[reaction: see text] The first total synthesis of litseaverticillols B (1), E (2), I (4), and J (5) as well as the structural reassignment of litseaverticillol E (2) have been achieved by means of a biomimetic sequence of transformations during which a [4 + 2]-initiated reaction cascade and an ene reaction, both involving singlet oxygen ((1)O(2)), formed key steps. The reassignment of the structure of litseaverticillol E (3) to include an allylic hydroperoxide provides strong support for our biogenetic hypothesis.     

Spiroperoxy lactones from furans in one pot: synthesis of (+)-premnalane a

A [4+2]-cycloaddition between singlet oxygen and a furan, followed by an ene reaction and ketalization, in one synthetic operation, was used for the synthesis of (+)-premnalane A. The first example of a singlet oxygen ene reaction that furnishes exclusively a Z-double bond is noted.     

Calcium peroxide diperoxohydrate as a storable chemical generator of singlet oxygen for organic synthesis

Calcium peroxide diperoxohydrate (CaO(2).2H(2)O(2)) is an environmentally friendly generator of singlet oxygen ((1)O(2), (1)Delta(g)) that can be used in organic synthesis as an alternative to the regular photochemical method. This compound produces (1)O(2) in various solvents and can be easily recovered by filtration for further regeneration. Both monitoring of (1)O(2) luminescence at 1270 nm and specific trapping have shown that CaO(2).2H(2)O(2) can be stored for several days at -80 degrees C and that the yield of (1)O(2) is equal to 25%. Oxidation of typical organic substrates in methanol or THF through [4 + 2] or [2 + 2] cycloaddition and ene reaction have been carried out on a preparative scale with total conversion and selectivity.     

Control of the mode selectivity (ene reaction versus [2 + 2] cycloaddition) in the photooxygenation of ene carbamates: directing effect of an alkenylic nitrogen functionality

The geometry of the double bond in oxazolidinone-substituted ene carbamates controls the mode selectivity (ene reaction versus [2+2] cycloaddition) of singlet oxygen through stereoelectronic effects, whereas the chiral auxiliary provides high diastereoselectivity through steric shielding.     

Total syntheses of four stereoisomers of 4alpha-hydroxy-1beta,7beta-peroxy- 10betaH-guaia-5-ene

[reaction: see text]. The first total syntheses of four stereoisomers of 4alpha-hydroxy-1beta,7beta-peroxy-10betaH-guaia-5-ene are reported starting from the readily available (+)-dihydrocarvone. These compounds have been synthesized from dienes (-)-isoguaiene and (-)-10-epi-isoguaiene by tandem ene hydroperoxylation-[4 + 2] cycloaddition with O(2) followed by selective reduction. The structure of the natural 4alpha-hydroxy-1beta,7beta-peroxy-10betaH-guaia-5-ene isolated from Liabum floribundum has been confirmed.     

Stereocontrolled Photooxygenations–A Valuable Synthetic Tool§

The stereochemical course of the singlet-oxygen ene reaction with acyclic olefins may be controlled if in the substrate conformational fixation (1,3-allylic strain) an allyl-ic substituent for interaction with the attacking oxygen enophile aligns. Various substrates were chosen to elucidate the features of the olefin that are necessary to control the sense (threo versus erythro) and the extent of the ii-facial preference of the singlet-oxygen attack. Depending on the electronic properties of the double bond and the nature of the allylic substituent, threo or erythro selectivity may be imposed through hydrogen bonding, electrostatic and steric effects and stereoelectronic alignment. Such directing properties, especially that of the hydroxy group, were also confirmed in the other reaction modes of singlet oxygen, namely the [4+2] cycloaddition to chiral naphthylenic alcohols and the [2+2] cycloaddition to an adamantylidene-substituted allylic alcohol. The syntheses of the natural products Merucathin and Iso-dihydromahubanolide B are two examples in which such stereocontrolled photooxygenations have been used as key steps to build up the required chirality diastereose-lectively.     

A novel pathway in the photooxygenation of cyclic allenes

[equation--see text] The photooxidation of cyclic allenes gives rise to cyclic 1,2, 3-trione hydrates. The formation of these compounds points to a novel photooxidation mechanism involving both singlet and triplet oxygen. Upon placement of a methyl group on the allene, the mechanism shifts to predominantly an "ene" reaction. The corresponding cycloadditions with 4-methyl-1,3,4-triazoline-3, 5-dione (MTAD) with cyclic allenes involve 2 equiv of MTAD. The dipolar intermediates are trapped with H(2)O to give alpha-urazole-substituted 2-cycloalkenones.     

Enecarbamates as selective substrates in oxidations: chiral-auxiliary-controlled mode selectivity and diastereoselectivity in the [2+2] cycloaddition and ene reaction of singlet oxygen and in the epoxidation by DMD and mCPBA

The stereochemical course of the oxidation of chiral oxazolidinone-substituted enecarbamates has been studied for singlet oxygen ((1)O(2)), dimethyldioxirane (DMD), and m-chloroperbenzoic acid (mCPBA) by examining of the special structural and stereoelectronic features of the enecarbamates. Valuable mechanistic insight into these selective oxidations is gained. Whereas the R(1) substituent on the chiral auxiliary is responsible for the steric shielding of the double bond and determines the sense of the pi-facial diastereoselectivity, structural characteristic such as the Z/E configuration and the nature of the R(2) group on the double bond are responsible for the extent of the diastereoselectivity. Stereoelectronic steering by the vinylic nitrogen functionality controls the mode selectivity (ene reaction vs [2+2] cycloaddition) in the case of (1)O(2).     

Visible‐Light‐Mediated 1,2‐Acyl Migration: The Reaction of Secondary Enamino Ketones with Singlet Oxygen

Secondary enaminones were oxidized by photochemically generated singlet oxygen, followed by nucleophilic addition of alcohol and an unexpected 1,2‐acyl migration to afford quaternary amino acid derivatives. An ene‐type reaction pathway is proposed. It is distinctively different from the typical [2+2] addition of singlet oxygen to a C?C bond pathway.     

Enantioselective intramolecular [2+2] photocycloaddition reactions of 4-substituted coumarins catalyzed by a chiral Lewis acid

Eight coumarins, which carry a terminal alkene tethered by a CH(2)XCH(2) group to their 4-position (X = CH(2), CMe(2), O, S, NBoc, NZ, NTs, NBn), were synthesized in overall yields of 51-80?%. Starting materials for the syntheses were either commercially available 4-hydroxycoumarin or 4-formylcoumarin. The intramolecular [2+2] photocycloaddition of these coumarins gave diastereoselectively products with a tetracyclic 3,3a,4,4a-tetrahydro-1H-cyclopenta[2,3]cyclobuta[1,2-c]chromen-5(2H)-one skeleton. Direct irradiation at λ = 300?nm in dichloromethane (c = 10?mM) led to product formation in good yields for most substrates, presumably via a singlet excited state intermediate. Due to the low coumarin absorption at λ >350?nm the photocycloaddition was slow upon irradiation at λ = 366?nm. Addition of a chiral oxazaborolidine-based Lewis acid (50?mol?%) increased the reaction rate at λ = 366?nm and induced a significant enantioselectivity in the [2+2] photocycloaddition. Six out of eight coumarin substrates (X = CH(2), CMe(2), O, NBoc, NZ, NTs) gave the respective products in yields of 72-96?% and with 74-90?% enantiomeric excess (ee) upon irradiation in dichloromethane (c = 20?mM) at -75?°C. The Lewis acid presumably acts by coordination to the coumarin carbonyl oxygen atom, which leads to a bathochromic shift (redshift) of the UV absorption and which increases the singlet state lifetime. A second electrostatic interaction of the hydrogen atom at C3 with the oxygen atom of the oxazaborolidine is likely.     

On the origin of regio- and stereoselectivity in singlet oxygen addition to enecarbamates

The reactions of excited state singlet molecular oxygen ((1)Δ(g),(1)O(2)) continue to witness interesting new developments. In the most recent manifestation, (1)O(2) is tamed to react with enecarbamates in a stereoselective manner, which is remarkable, in view of its inherently high reactivity (Acc. Chem. Res. 2008, 41, 387). Herein, we employed the CAS-MP2(8,7)/6-31G* as well as the CAS-MP2(10,8)/6-31G* computations to unravel the origin of (i) diastereoselectivities in dioxetane or hydroperoxide formation and (ii) regioselectivity leading to a [2 + 2] cycloadduct or an ene product when (1)O(2) reacts with an oxazolidinone tethered 2-phenyl-1-propenyl system. The computed Gibbs free energy profiles for E- and Z-isomers when (1)O(2) approaches through the hindered and nonhindered diastereotopic faces (by virtue of chiral oxazolidinone) of the enecarbamates exhibit distinct differences. In the case of E-isomer, the relative energies of the transition structures responsible for hydroperoxide (ene product) are lower than that for dioxetane formation. On the other hand, the ene pathway is predicted to involve higher barriers as compared to the corresponding dioxetane pathway for Z-isomer. The energy difference between the rate-determining diastereomeric transition structures involved in the most favored ene reaction for E-enecarbamate suggests high diastereoselectivity. In contrast, the corresponding energy difference for Z-enecarbamate in the ene pathway is found to be diminishingly close, implying low diastereoselectivity. However, the dioxetane formation from Z-enecarbamate is predicted to exhibit high diastereoselectivity. The application of activation strain model as well as the differences in stereoelectronic effects in the stereocontrolling transition structures is found to be effective toward rationalizing the origin of selectivities reported herein. These predictions are found to be in excellent agreement with the experimental observations.     

Chemistry of trans-resveratrol with singlet oxygen: [2+2] addition, [4+2] addition, and formation of the phytoalexin moracin M

Resveratrol (1) reacts with singlet oxygen by two major pathways: A [2+2] cycloaddition forming a transient dioxetane that cleaves into the corresponding aldehydes and a [4+2] cycloaddition forming an endoperoxide that, upon heating, undergoes a rearrangement to moracin M. The rate constant by which singlet oxygen is removed by 1 (k(T)) was determined by time-resolved infrared luminescence spectroscopy to be 1.5 × 10(6) M(-1) sec(-1) in CD(3)OD, smaller than previously reported values. Chemical reaction accounts for ca. 25% of k(T).     

Singlet Oxygen Generation by Cyclometalated Complexes and Applications

While cyclometalated complexes have been extensively studied for optoelectronic applications, these compounds also represent a relatively new class of photosensitizers for the production of singlet oxygen. Thus far, singlet oxygen generation from cyclometalated Ir and Pt complexes has been studied in detail. In this review, photophysical data for singlet oxygen generation from these complexes are presented, and the mechanism of ¹O₂ generation is discussed, including evidence for singlet oxygen generation via an electron‐transfer mechanism for some of cyclometalated Ir complexes. The period from the first report of singlet oxygen generation by a cyclometalated Ir complex in 2002 through August 2013 is covered in this review. This new class of singlet oxygen photosensitizers may prove to be rather versatile due to the ease of substitution of ancillary ligands without loss of activity. Several cyclometalated complexes have been tethered to zeolites, polystyrene, or quantum dots. Applications for photooxygenation of organic molecules, including “traditional” singlet oxygen reactions (ene reaction, [4 + 2] and [2 + 2] cycloadditions) as well as oxidative coupling of amines are presented. Potential biomedical applications are also reviewed.     

Cycloaddition reactions of allenylphosphonates and related allenes with dialkyl acetylenedicarboxylates, 1,3-diphenylisobenzofuran, and anthracene

Cycloaddition reactions of allenylphosphonates [(RO)(2)P(O)[(R(1))C═C═CR(2)(2)] with dialkyl acetylenedicarboxylates, 1,3-diphenylisobenzofuran, and anthracene have been investigated and compared with those of allenoates [(EtO(2)C)RC═C═CH(2)] and allenylphosphine oxides [Ph(2)P(O)(R(1))C═C═CR(2)(2)] in selected cases. Allenylphosphonates (RO)(2)P(O)(Ar)C═C═CH(2) with an α-aryl group preferentially undergo [4 + 2] cycloaddition with DMAD/DEAD under thermal activation, but in addition to the expected 1:1 (allene: DMAD) product, the reaction also leads to 1:2 as well as 2:1 products that were not reported before. When an extra vinyl group is present at the γ-carbon of allenylphosphonate [e.g., (OCH(2)CMe(2)CH(2)O)P(O)(Ph)C═C═CH(C═CHMe)], [4 + 2] cycloaddition takes place utilizing either the vinylic or the aryl end, but additionally a novel cyclization wherein complete opening of the [β,γ] carbon-carbon double bond of the allene is realized. In contrast to these, the reaction of allenylphosphonate (OCH(2)CMe(2)CH(2)O)P(O)(H)C═C═CMe(2) possessing a terminal ═CMe(2) group with DMAD occurs by both [2 + 2] cycloaddition and ene reaction. While the reaction of ═CH(2) terminal allenylphosphonates as well as allenylphosphine oxides with 1,3-diphenylisobenzofuran afforded preferentially endo-[4 + 2] cycloaddition products via [α,β] attack, the analogous allenoates [(EtO(2)C)RC═C═CH(2)] underwent exo-[4 + 2] cyclization. Under similar conditions, allenylphosphonates with a terminal ═CR(2) group gave only [β,γ]-cycloaddition products. An unusual ring-opening of a [4 + 2] cycloaddition product followed by ring-closing via [4 + 4] cycloaddition, as revealed by (31)P NMR spectroscopy, is reported. Anthracene reacted in a manner similar to 1,3-diphenylisobenzofuran, albeit with lower reactivity. Key products, including a set of exo- and endo- [4 + 2] cycloaddition products, have been characterized by single crystal X-ray crystallography.     

PSORALEN-OLEFIN PHOTOPRODUCI'S: FIRST OBSERVATION OF A PHOTO-ENE REACTION

Abstract Methyl-substituted psoralens (4'-(hydroxymethyl)-4,5',8-trimethylpsoralen and 4,5',8-trimethylpsoralen) are found to yield an ene product as well as the expected [2+2] cycloaddition product from photochemical reaction with simple olefins. As determined by absorbance, liquid chromatography-mass spectrometry and nuclear magnetic resonance, both products are formed at the pyrone side of the respective psoralen. The product distribution is dependent on olefin concentration as well as the nature of the olefin. In deoxygenated solutions, cyclic olefins form as much as 50% ene product, while unsubstituted straight-chain olefins form as little as 3%. In oxygenated solutions, the product distribution is strongly affected by singlet oxygen.     

Efficient pi-facial control in the ene reaction of nitrosoarene,triazolinedione, and singlet oxygen with tiglic amides of the bornane-derived sultam as chiral auxiliary: an economical synthesis of enantiomerically pure nitrogen- and oxygen-functionalized acrylic acid derivatives

The ene reaction of 4-nitronitrosobenzene (ArNO), N-phenyl-1,2,4-triazoline-3,5-dione (PTAD), and singlet oxygen (1O2) with the optically active tiglic-acid derivatives of Oppolzer's bornane-derived sultam affords the respective ene products regioselectively in excellent diastereoselectivity (de up to 99%) and in good yield (55-90%). The enophiles ArNO and PTAD give with the methyl-substituted substrate exclusively the like-configured ene adduct, while 1O2 leads to an 83:17 diastereomeric mixture. With the sterically more demanding isopropyl-substituted derivative even the smallest enophile 1O2 forms exclusively the like diastereomer. The high diastereoselectivity is rationalized in terms of the proper conformational alignment of the substrate and a preferred enophilic attack from the C(beta)-re face of the double bond. This concept offers an efficient synthetic route to enantiomerically pure nitrogen- and oxygen-functionalized acrylic acid derivatives.     

Reaction mechanism and chemoselectivity of intermolecular cycloaddition reactions between phenyl-substituted cyclopropenone ketal and methyl vinyl ketone

In this paper, the mechanisms of the intermolecular [3+2] and [1+2] cycloaddition reactions of 1,1/1,3-dipolar π-delocalized singlet vinylcarbenes, which is obtained from cyclopropenone, with an electron-deficient C═O or C═C dipolarophile, to generate five-membered ring products are first disclosed by the density functional theory (DFT). Four reaction pathways, including two concerted [3+2] cycloaddition reaction pathways and two stepwise reaction pathways (an initial [1+2] cycloaddition and then a rearrangement from the [1+2] cycloadducts to the final [3+2] cycloadducts), are investigated at the B3LYP/6-31G(d,p) level of theory. The calculated results reveal that, in contrast to the concerted C═O [3+2] cycloaddition reaction pathway, which is 7.1 kcal/mol more energetically preferred compared with its stepwise reaction pathway, the C═C dipolarophile favors undergoing [1+2] cycloaddition rather than concerted [3+2] cycloaddition (difference of 5.3 kcal/mol). The lowest free energy barrier of the C═O concerted [3+2] cycloaddition reaction pathway shows that it predominates all other reaction pathways. This observation is consistent with the finding that the C═O [3 + 2] cycloadduct is the main product under experimental conditions. In addition, natural bond orbital second-order perturbation charge analyses are carried out to explain the preferred chemoselectivity of C═O to the C═C dipolarophile and the origins of cis-stereoselectivity for C═C [1+2] cycloaddition. Solvent effects are further considered at the B3LYP/6-31G(d,p) level in the solvents CH(3)CN, DMF, THF, CH(2)Cl(2), toluene, and benzene using the PCM model. The results indicate that the relative reaction trends and the main products are insensitive to the polarity of the reaction solvent.     

An experimental and computational study on the reactivity and regioselectivity for the nitrosoarene ene reaction: comparison with triazolinedione and singlet oxygen

The regioselectivities and the reactivities (relative rates) for the ene reaction of the enophile 4-nitronitrosobenzene (ArNO) with an extensive set of regiochemically defined acyclic and cyclic olefins have been determined. These experimental data establish that the ArNO enophile attacks the olefinic substrate along the novel skew trajectory, with preferred hydrogen abstraction at the corner (twix regioselectivity). This is in contrast to the isoelectronic species singlet oxygen ((1)O(2)), which abstracts at the higher substituted side of the double-bond (cis effect), and triazolindione (TAD), which undergoes the ene reaction at the more crowded end (gem effect). Ab initio computations (B3LYP/6-31+g) for the ene reaction of the ArNO with 2-methyl-2-butene reveal that the steric effects between the aryl group of the enophile and the substituents of the olefin dictate the skew trajectory. These computations identify the aziridine N-oxide (AI) as a bona fide intermediate in this ene reaction, whose formation is usually rate-determining and, thus, irreversible along the skew trajectory (twix selectivity). The reversible generation of the AI becomes feasible when conformational constraints outweigh steric effects, as manifested by enhanced twin regioselectivity.     

Effect of structural modification on photodynamic activity of hypocrellins

Aluminum ion complexed 5,8-di-Br-hypocrellin B is a new water-soluble perylenequinonoid derivative with enhanced absorption over hypocrellin B (HB) in the phototherapeutic window (600-900 nm). Electron paramagnetic resonance and 9,10-diphenyl-anthracene bleaching methods were used to investigate the photosensitizing activity of [AL2(5,8-di-Br-HB)Cl4]n in the presence of oxygen. Singlet oxygen, superoxide anion radical and hydroxyl radical can be generated by [AL2(5,8-di-Br-HB)CL4]n photosensitization. Singlet oxygen (1O2) is formed via energy transfer from triplet-state [AL2(5,8-di-Br-HB)CL4]n to ground-state molecular oxygen. 1O2 participates in the generation of a portion of superoxide anion radical (O2.-). Besides superoxide anion radical (O2.-) may originate from the electron transfer between the triplet-state [AL2(5,8-di-Br-HB)CL4]n and the ground-state molecular oxygen. OH is formed through the Fenton-Haber-Weiss reaction and the decomposition of DMPO-1O2 adduct. Compared with HB [AL2(5,8-di-Br-HB)CL4]n primarily remains and enhances the generation efficiency of superoxide anion radical and hydroxyl radical but that of singlet oxygen decreases.     

Ene reaction of singlet oxygen,triazolinedione, and nitrosoarene with chiral deuterium-labeled allylic alcohols: the interdependence of diastereoselectivity and regioselectivity discloses mechanistic insights into the hydroxy-group directivity

The ene reaction of singlet oxygen ((1)O(2)), triazolinedione (TAD), and nitrosoarene, specifically 4-nitronitrosobenzene (ArNO), with the tetrasubstituted 1,3-allylically strained, chiral allylic alcohol 3,4-dimethylpent-3-en-2-ol (2) leads to the threo-configured ene products in high diastereoselectivity, a consequence of the hydroxy-group directivity. Hydrogen bonding favors formation of the threo-configured encounter complex threo-EC in the early stage of ene reaction. For the analogous twix deuterium-labeled allylic alcohol Z-2-d(3), a hitherto unrecognized dichotomy between (1)O(2) and the ArNO and TAD enophiles is disclosed in the regioselectivity of the tetrasubstituted alcohol: Whereas for ArNO and TAD, hydrogen bonding with the allylic hydroxy group dictates the regioselectivity (twix selectivity), for (1)O(2), the cis effect dominates (twin/trix selectivity). From the interdependence between the twix/twin regioselectivity and the threo/erythro diastereoselectivity, it has been recognized that the enophile also attacks the allylic alcohol from the erythro pi face without assistance by hydrogen bonding with the allylic hydroxy functionality.