Ene Product Research Articles

Surface-Doped Graphitic Carbon Nitride Catalyzed Photooxidation of Olefins and Dienes: Chemical Evidence for Electron Transfer and Singlet Oxygen Mechanisms

A new photocatalytic reactivity of carbon-nanodot-doped graphitic carbon nitride (CD-C3N4) with alkenes and dienes, has been disclosed. We have shown that CD-C3N4 photosensitizes the oxidation of unsaturated substrates in a variety of solvents according to two competing mechanisms: the energy transfer via singlet oxygen (1O2) and/or the electron transfer via superoxide (O·−2). The singlet oxygen, derived by the CD-C3N4 photosensitized process, reacts with alkenes to form allylic hydroperoxides (ene products) whereas with dienes, endoperoxides. When the electron transfer mechanism operates, cleavage products are formed, derived from the corresponding dioxetanes. Which of the two mechanisms will prevail depends on solvent polarity and the particular substrate. The photocatalyst remains stable under the photooxidation conditions, unlike the most conventional photosensitizers, while the heterogeneous nature of CD-C3N4 overcomes usual solubility problems.

Highly stereoselective trifluoropyruvate-ene reaction with Δ20(22)-steroidal olefin by chiral Pd2+-catalyst: New type of VDR antagonist for osteocalcin, Δ20(21)-ene product without (dehydro)lactone and lactam motifs

The highly stereoselective trifluoropyruvate-ene reaction with steroidal 1,1-disubstituted Δ20(22)-side chain olefin was achieved by the dicationic BINAP-Pd complex as an effective chiral Lewis acid catalyst to give the Δ20(21)-steroidal ene-product in high yield and enantioselectivity. The ene product itself without (dehydro)lactone and lactam structures exhibited remarkably high antagonist activity for human osteocalcin even in low binding affinity for human vitamin D hormone receptor.

Two Useful Directing Modes in Singlet Oxygen Reactivity: Electrostatic Effects in the Ene Reaction with Allylic Alcoholates and a Chemoselectivity Change with α‐Alkoxy Michael Esters

AbstractThe singlet oxygen reaction with trisubstituted E‐allylic alcohols resulted in the unselective formation of regioisomeric secondary and tertiary allylic hydroperoxides. Increasing the steric demand at the allylic hydroxymethyl group leads to a moderate large‐group effect that can be strongly enhanced by deprotonation of a dimethylated allylic alcohol and even more pronounced by cation complexation. The presence of alkoxide groups did additionally alter the diastereoselectivity of the singlet oxygen ene reactions with chiral allylic alcohols. The molecular combination of Michael ester and enol ether in α‐alkoxy ester substrates made possible the design of chemoselective substrates for singlet oxygen ene versus [2+2] cycloaddition, e. g. a 3,3‐dimethylated Michael ester as a selective substrate for the ene reaction and an adamantyl analogue as a selective 2+2 substrate. The Z/E‐monomethylated substrates as probes for cis regioselectivity revealed that there is no site preference for Z‐alkoxy hydrogen transfer on the way to the corresponding ene product.

Catalytic Asymmetric Hetero-ene Reaction for Direct Customizable Allylic Functionalization

In a recent publication in Nature , Tambar and coworkers have reported a Lewis-acid-assisted Bronsted-acid-catalyzed asymmetric hetero-ene reaction that proceeds from internal alkenes with excellent enantio-, regio-, and E -olefin selectivity. Key to the success is the use of a sulfurimide enophile. Derivatization of the ene products affords various allylic compounds.

Solvent-free, uncatalyzed asymmetric "ene" reactions of N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines: a general approach to enantiomerically pure α-(trifluoromethyl)tryptamines.

A novel approach to regioselectively substituted and stereoselectively α-trifluoromethylated tryptamines is reported based on the ene reaction of Boc-protected 3-methyleneindolines with optically pure (R)- or (S)-tert-butanesulfinyltrifluoroacetaldimine. Boc- and sulfinylamido-protected α-trifluoromethyltryptamines are obtained in 60-70% yield and 85/15 dr by just heating equimolar amounts of the two reaction partners at 80-90 °C for 2-3 h without a solvent. The absolute configuration of the amino α-carbon has been assigned based on the vibrational circular dichroism (VCD) spectral analysis. The two protecting group can be chemoselectively removed allowing further regio- and stereoselective elaboration of the ene products to various biologically interesting compounds.

ChemInform Abstract: Intramolecular Carbonyl‐Ene Reactions in the Synthesis of peri‐Oxygenated Hydroaromatics.

Abstract2‐Methallyl aromatic aldehydes, obtained by Suzuki coupling of 2‐formylphenylboronic acids with methallyl bromide, are shown to provide cycloalkylidene ene products under acidic conditions.

Intramolecular carbonyl-ene reactions in the synthesis of peri-oxygenated hydroaromatics

2-Methallyl aromatic aldehydes, synthesized by Suzuki coupling of 2-formylphenylboronic acids, are shown to provide cycloalkylidene ene products under acidic conditions. Susceptibility of the products to aromatization is manoeuvred by varying the reaction conditions and catalysts including binol-derived Brønsted acid catalysts. A peri-effect is identified as a controlling factor for the aromatizations. Several oxidative transformations of an ene product are carried out as model studies of hydroaromatic polyketide natural products.

An Experimental and Computational Approach to Understanding the Reactions of Acyl Nitroso Compounds in [4 + 2] Cycloadditions.

Catalytic aerobic oxidation of phenyl hydroxycarbamate 1 and 1-hydroxy-3-phenylurea 2 using CuCl2 and 2-ethyl-2-oxazoline in methanol gave acyl nitroso species in situ, which were trapped in nitroso-Diels-Alder (NDA) reactions with various dienes to afford the corresponding cycloadducts in high yields (90-98%). Competing ene products were also present for dienes containing both alkene π-bonds and allylic σ-bonds, and the ene yields are higher with 1 than with 2. The use of the chiral hydroxamic acid, (R)-1-hydroxy-3-(1-phenylethylurea) 3 (same conditions) gave NDA cycloadducts in high yields (97-99%) with no ene product from 2,3-dimethyl-1,3-butadiene. NDA cycloadducts were not obtained from other hydroxamic acid analogues [RCONHOH (R = PhCH2 4; Ph(CH2)2 5; Ph(CH2)3 6; Ph(CH2)4 7; Ph 8; 2-pyridyl 9; 3-pyridyl 10] with various dienes using copper-oxidation but rather were obtained using sodium periodate, resulting in variable NDA yields (13-51%) from hydroxamic acids 1-10 with cyclohexa-1,3-diene and 2,3-dimethyl-1,3-butadiene (several cycloadducts characterized by X-ray crystallography). The NDA and nitroso-ene reaction pathways of nitroso intermediates with dienes were mapped by DFT computations (B3LYP/6-31G*), which showed that the acyl nitroso species are super-reactive and that activation energies in the NDA processes are lower than the isomerization barriers between some cis- and trans-butadienes.

Chiral Pd-catalyzed trifluoropyruvate-ene reactions with steroidal side chains for late-stage fluoromethyl-functionalization: remarkably high agonist activities of ene products even in low VDR binding affinity

The highly enantioselective trifluoropyruvate-ene reactions of chiral steroid side chain olefins were achieved by dicationic palladium complexes as chiral Lewis acid catalysts to give steroidal ene-products in high diastereoselectivity. The ene products exhibited remarkably high agonist activities for human osteocalcin even in low vitamin D receptor binding affinity for human vitamin D hormone receptor.

Catalytic asymmetric carbon–carbon bond forming reactions catalyzed by tetrahydroisoquinoline (TIQ) N,N′-dioxide ligands

The use of TIQ-N,N′-dioxide ligands in asymmetric C–C bond forming reactions is described. In the Michael addition of cyclohexane-1,3-dione and malonates to β,γ-unsaturated α-ketoesters, excellent yields (up to 93%) and moderate to good enantioselectivities (70–89% ee) were obtained. The catalytic hetero-ene reaction of 2-methoxypropene with phenylglyoxal gave the ene product in excellent yield (95%) with moderate enantioselectivity (77% ee). The catalyst system performed well at temperatures ranging from 0 to 30°C and relatively low catalyst loading (0.2–5mol%) with dichloromethane being the preferred solvent for all reactions.

Pathologies of axonal transport in neurodegenerative diseases

Gene products such as organelles, proteins and RNAs are actively transported to synaptic terminals for the remodeling of pre-existing neuronal connections and formation of new ones. Proteins described as molecular motors mediate this transport and utilize specialized cytoskeletal proteins that function as molecular tracks for the motor based transport of cargos. Molecular motors such as kinesins and dynein's move along microtubule tracks formed by tubulins whereas myosin motors utilize tracks formed by actin. Deficits in active transport of gene products have been implicated in a number of neurological disorders. We describe such disorders collectively as "transportopathies". Here we review current knowledge of critical components of active transport and their relevance to neurodegenerative diseases.

Organic Dye‐Photocatalyzed Acylnitroso Ene Reaction

AbstractRose bengal, an inexpensive and readily available organic dye, is demonstrated to be a photoredox catalyst for the formation of transient acylnitroso intermediates under visible light irradiation. This method is operationally simple and uses air as the terminal oxidant. Reactions of acylnitroso with a range of functionalized alkenes give intermolecular acylnitroso ene products in moderate to good yields. This is an environmentally friendly allylic amination methodology that avoids the use of metal catalysts and stoichiometric amount of oxidants. A plausible reaction mechanism is proposed on the basis of singlet oxygen and fluorescence quenching studies.

Cobalt- versus Ruthenium-Catalyzed Alder–Ene Reaction for the Synthesis of Credneramide A and B

The first synthesis of the natural products credneramide A and B was accomplished by utilizing Alder-ene reactions between a terminal alkene and an internal alkyne to generate the rather uncommon 1,4-diene substructure of these compounds. Moreover, two different short linear sequences toward these targets are evaluated using either a cobalt-catalyzed Alder-ene reaction of 1-chloropent-1-yne or a ruthenium-catalyzed Alder-ene reaction of 1-trimethylsilyl-1-pentyne with 5-hexenoic acid derivatives in the key step transformation. In addition, saponification of the primary Alder-ene product derived from the cobalt-catalyzed Alder-ene reaction led to credneric acid, the biological precursor of both natural products.

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.

Selective Molecular Sequestration with Concurrent Natural Product Functionalization and Derivatization: From Crude Natural Product Extracts to a Single Natural Product Derivative in One Step

A resin-bound nitroso compound sequestered a single unexpected component from crude plant seed extracts. Several plants, including Piper nigrum, Eugenia caryophyllata, and Pimenta dioica, were extracted with organic solvent in the presence of a nitroso-containing resin. The nitroso resin selectively sequestered a single compound, β-caryophyllene, via a chemo- and regioselective ene reaction. The ene product was released from the resin, and proper selection of the solid-phase linker and cleavage cocktail allowed concomitant further transformation of the primary ene product to a novel functionalized polycycle. Preliminary studies indicate that the new hydroxylamine-containing natural product derivatives have antibiotic activity.

Palladium‐Catalyzed Enantioselective Ene and Aldol Reactions with Isatins, Keto Esters, and Diketones: Reliable Approach to Chiral Tertiary Alcohols

AbstractChiral dicationic Pd‐complex‐catalyzed enantioselective ene and aldol reactions with various isatin derivatives are shown to produce the corresponding 3‐hydroxy‐2‐oxindole products in good yields with high enantioselectivities. These catalytic processes are effective not only with isatins but also with keto esters and diketones derivatives. Even with unprotected isatin, high yields and enantioselectivities were obtained to produce convolutamydine A as a naturally occurring compound. Sequentially, α‐oxidation by m‐CPBA and α‐fluorination by selectfluor of the ene product could be achieved to give the corresponding α‐hydroxy and α‐fluoro ketones, respectively.

On the Reaction of N-Formylbenzotriazole and Norbornene with NAlkylacetonitrilium Salts

Reaction of N-methyl/isopropylacetonitrilium hexachloroantimonate 1a, b with N-formylbenzotriazole 2 afforded the corresponding iminium salts 4a, b; of which 4a reacts with the oxime derivatives 5a-d to give the corresponding N-oxyiminium salts 6a-d in a good yield (60-92 %). Reaction of N-methylacetonitrilium hexachloroantimonate 1a with norbornene (7) furnished the new ring system 1,4,4a,5,6,7,8,8a-octahydro-5,8-methano-4(2-norbornyl)-naphthridinium hexachloroantimonate 10 in 85 % yield. The Treatment of 10 with DDQ oxidized the two bridged protons and afforded 1,4,5,6,7,8-hexahydro-5,8-methano-4(2-norbornyl)-naphthrdinium hexachloroantimonate 11 in 80% yield. Keywords: Nitrilium salts, N-formylbenzotriazole, norbornene, Ene product, iminium salts, octahydro-5, 8-methanonaphthridinium salts, salts, 8-methanonaphthridinium, Alkylacetonitrilium Salts, DDQ, Benzotriazole, amide group, IR spectra, oximes, 1H NMR spectra, ClCH2CH2Cl, Crystallization

ChemInform Abstract: Novel Base-Promoted Addition-Elimination Reaction of Electron- Deficient Benzylidene Derivatives with N-Phenyl-1,2,4-triazole-3,5- dione (PTAD).

The reaction of electron-deficient benzylidene derivatives with PTAD afforded the double Diels–Alder product and the Diels–Alder ene product; the latter underwent novel base-induced elimination of phenyl urazole via a stable carbanion.

ChemInform Abstract: Base-Induced Addition-Elimination Reactions of Electron-Deficient Vinylarenes Containing a Carbonyl or Ester Group Utilizing 4-Phenyl-3H- 1,2,4-triazole-3,5(4H)-dione (PTAD).

The reaction of electron-deficient vinylarenes such as styrylketones and cinnamate with PTAD afforded double Diels–Alder products and Diels–Alder ene products; the latter underwent novel base-induced elimination of 4-phenyl-1,2,4-triazolidine-3,5-dione via a stable carbanion.

ChemInform Abstract: Chiral Titanium Complex Catalyzed Carbonyl-Ene Reaction with Glyoxylate: Remarkable Positive Nonlinear Effect.

Abstract The enantioselective glyoxylate-ene reaction catalyzed by chiral titanium complex derived from partially resolved binaphthol (BINOL) is shown to exhibit a remarkable level of asymmetric amplification (positive nonlinear effect). Thus, the optical yield of the ene product significantly exceeds the enantio-purity of the chiral ligand (BINOL).