Olefin Geometry Research Articles

Linear and Nonlinear Optical Properties of All-cis and All-trans Poly(p-phenylenevinylene).

Poly(p-phenylenevinylene) (PPV) is a staple of the family of conjugated polymers with desirable optoelectronic properties for applications including light-emitting diodes (LEDs) and photovoltaic devices. Although the significant impact of olefin geometry on the steady-state optical properties of PPVs has been extensively studied, PPVs with precise stereochemistry have yet to be investigated using nonlinear optical spectroscopy for quantum sensing, as well as light harvesting for biological applications. Herein, we report our investigation of the influence of olefin stereochemistry on both linear and nonlinear optical properties through the synthesis of all-cis and all-trans PPV copolymers. We performed two-photon absorption (TPA) using a classical and entangled light source and compared both classical TPA and entangled two-photon absorption (ETPA) cross sections of these stereodefined PPVs. Whereas the TPA cross section of the all-trans PPV was expectedly higher than that of all-cis PPV, presumably because of the larger transition dipole moment, the opposite trend was measured via ETPA, with the all-cis PPV exhibiting the highest ETPA cross section. DFT calculations suggest that this difference might stem from the interaction of entangled photons with lower-lying electronic states in the all-cis PPV variant. Additionally, we explored the photoinduced processes for both cis and trans PPVs through time-resolved fluorescence upconversion and femtosecond transient absorption techniques. This study revealed that the sensitivity of PPVs in two-photon absorption varies with classical versus quantum light and can be modulated through the control of the geometry of the repeating alkenes, which is a key stepping stone toward their use in quantum sensing, bioimaging, and the design of polymer-based light-harvesting systems.

Organocatalytic Enantio‐ and Diastereoselective Diels‐Alder Reaction between 2,4‐Dienals and α,β‐Unsaturated Esters

AbstractDespite advances in the development of catalytic asymmetric Diels‐Alder reactions, introducing α,β‐unsaturated esters as dienophiles remains challenging owing to their low reactivity. Herein, we report that a chiral aminocatalyst in conjunction with a chiral isothiourea catalyst or a Brønsted acid can promote enantio‐ and diastereoselective Diels‐Alder reactions between 2,4‐dienals and α,β‐unsaturated esters. This method proceeds through the formation of chiral trienamine intermediates for the exo‐cycloaddition with activated dienophiles, α,β‐unsaturated acylammonium species or protonated N‐heteroaryl‐substituted alkenes. Through synergistic activation of both dienes and ester dienophiles, densely functionalized cyclohexenes bearing multiple stereocenters can be afforded with up to >25:1 dr and >99% ee. Moreover, we show that variation of the configurations of the chiral catalysts and the olefin geometry allows the stereodivergent preparation of four stereoisomers of the enantiopure exo‐products.

Design, Synthesis, In Vitro, and In Silico Insights of 5-(Substituted benzylidene)-2-phenylthiazol-4(5H)-one Derivatives: A Novel Class of Anti-Melanogenic Compounds.

(Z)-5-Benzylidene-2-phenylthiazol-4(5H)-one ((Z)-BPT) derivatives were designed by combining the structural characteristics of two tyrosinase inhibitors. The double-bond geometry of trisubstituted alkenes, (Z)-BPTs 1-14, was determined based on the 3JC,Hβ coupling constant of 1H-coupled 13C NMR spectra. Three (Z)-BPT derivatives (1-3) showed stronger tyrosinase inhibitory activities than kojic acid; in particular, 2 was to be 189-fold more potent than kojic acid. Kinetic analysis using mushroom tyrosinase indicated that 1 and 2 were competitive inhibitors, whereas 3 was a mixed-type inhibitor. The in silico results revealed that 1-3 could strongly bind to the active sites of mushroom and human tyrosinases, supporting the kinetic results. Derivatives 1 and 2 decreased the intracellular melanin contents in a concentration-dependent manner in B16F10 cells, and their anti-melanogenic efficacy exceeded that of kojic acid. The anti-tyrosinase activity of 1 and 2 in B16F10 cells was similar to their anti-melanogenic effects, suggesting that their anti-melanogenic effects were primarily owing to their anti-tyrosinase activity. Western blotting of B16F10 cells revealed that the derivatives 1 and 2 inhibited tyrosinase expression, which partially contributes to their anti-melanogenic ability. Several derivatives, including 2 and 3, exhibited potent antioxidant activities against ABTS cation radicals, DPPH radicals, ROS, and peroxynitrite. These results suggest that (Z)-BPT derivatives 1 and 2 have promising potential as novel anti-melanogenic agents.

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles.

We have developed a catalytic aza-Nazarov reaction of N-acyliminium salts generated in situ from the reaction of a variety of cyclic and acyclic imines with α,β-unsaturated acyl chlorides to afford substituted α-methylene-γ-lactam heterocycles. The reactions proceed effectively in the presence of catalytic (20 mol %) amounts of AgOTf as an anion exchange agent or hydrogen-bond donors such as squaramides and thioureas as anion-binding organocatalysts. The aza-Nazarov cyclization of 3,4-dihydroisoquinolines with α,β-unsaturated acyl chlorides gives tricyclic lactam products 7 in up to 79% yield with full diastereocontrol (dr = >99:1). The use of acyclic imines in a similar catalytic aza-Nazarov reaction with 20 mol % of AgOTf results in the formation of α-methylene-γ-lactam heterocycles 19 in up to 76% yield and with good to high diastereoselectivities (4.3:1 to 16:1). We have demonstrated the scalability of the reaction with a gram-scale example. The relative stereochemistry of the α-methylene-γ-lactam products 19 has been determined via the single-crystal X-ray analysis of lactam 19l. In order to shed light on the details of the reaction mechanism, we have performed carefully designed mechanistic studies which consist of experiments on the effect of β-silicon stabilization, the alkene geometry of the α,β-unsaturated acyl chloride reactants, and adventitious water on the success of the catalytic aza-Nazarov reaction.

Access to Substituted Indenol Ethers via a Regioselective Intermolecular Carbopalladation Cascade.

Alkyne carbopalladation reactions can rapidly generate multiple new C-C bonds; however, regioselectivity is challenging for intermolecular variants. Using ynol ethers, we observe complete regiocontrol of migratory insertion followed by a second migratory insertion with a pendant alkene to turn-over the catalytic cycle. The resulting products are oligosubstituted 1-indenol ethers with defined stereochemistry based on the initial alkene geometry. Blocking β-hydride elimination allowed for C-H and C-C reductive elimination steps for catalyst turnover.

Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes towards Chiral Allylated Triazoles and Tetrazoles

A general Rh-catalyzed addition reaction of nitrogen containing heterocycles to internal allenes is reported. Starting from racemic internal allenes a dynamic kinetic resolution (DKR) provides N-allylated triazoles and tetrazoles. Simultaneous control of N1/Nx-position selectivity, enantioselectivity and olefin geometry gives access to important building blocks of target-oriented synthesis. The synthetic utility is demonstrated by a gram-scale reaction and a broad substrate scope tolerating multiple functional groups. Deuterium labeling experiments and experiments with enantioenriched allenes as starting material support a plausible reaction mechanism.

Chemo- and Stereoselective Synthesis of Substituted Thiazoles from tert-Alcohols Bearing Alkene and Alkyne Groups with Alkaline Earth Catalysts.

We report here that thioamides can distinguish C–C double bonds and C–C triple bonds chemoselectively when subjected to a reaction with pent-1-en-4-yn-3-ol derivatives in the presence of Ca(OTf)2. This protocol offers a fast, efficient, and high-yielding synthesis of functionalized thiazoles. Interestingly, this reaction offers a time-dependent formation of kinetic and thermodynamic products. The products showed stereoselectivity concerning the alkene geometry. Further, we extended this protocol to synthesize oxazoles from propargyl alcohols and ibuprofen (NSAID) was converted into amide and then subjected to oxazole formation with tert-propargyl alcohols.

E/Z Photoisomerization of Olefins as an Emergent Strategy for the Control of Stereodivergence in Catalysis

AbstractThe stereoselective photoisomerization of olefins via Energy Transfer (EnT) sensitization bears significant potential in the context of rational design of catalytic stereodivergent methodologies. Whereas approaches for controlling the access to E‐ and Z‐ isomers depend highly on the nature of the catalyst – and therefore are not easily implemented as a general strategy – EnT catalysis has emerged in recent years as an increasingly powerful tool for olefin geometry control in a nearly perfect step‐economic fashion. Moreover, this approach presents both high functional group tolerance and, most notably, has demonstrated ample multicatalytic compatibility. This feature has enabled the development of tandem stereodivergent catalytic strategies, which are the focus of this Review.magnified image

Diastereoselective Addition of Prochiral Nucleophilic Alkenes to α-Chiral N-Sulfonyl Imines.

The Lewis-acid-promoted addition of prochiral E- and Z-allyl nucleophiles to chiral α-alkoxy N-tosyl imines is described. Alkene geometry is selectively transferred to the newly formed carbon-carbon bond, resulting in stereochemical control of C1, C2, and C3 of the resulting 2-alkoxy-3-N-tosyl-4-alkyl-5-hexene products. A computational analysis to elucidate the high selectivity is also presented. This methodology was employed in the synthesis of two naturally occurring isomers of clausenamide.

Triflic Acid-Catalyzed Synthesis of Indole-Substituted Indane Derivatives via In Situ Formed Acetal-Facilitated Nucleophilic Addition and 4π-Electron-5-Carbon Electrocyclization Sequence.

An efficient protocol for the synthesis of indole-substituted indanes from o-alkenylbenzaldehydes under acetalization conditions has been presented. The cyclization occurs via a nucleophilic addition of indole on the oxacarbenium ion generated from acetal formed under the reaction condition followed by a conrotatory 4π-electrocyclization reaction, which takes care of the exclusive diastereoselectivity observed during the cyclization step. Olefin geometry of o-alkenylbenzaldehyde and the amount of indole play a decisive role in the success of this cyclization process.

Density Functional Theory-Inspired Design of Ir/P,S-Catalysts for Asymmetric Hydrogenation of Olefins

In silico-based optimization of Ir/P,S-catalysts for the asymmetric hydrogenation of unfunctionalized olefins using (E)-1-(but-2-en-2-yl)-4-methoxybenzene as a benchmark olefin has been carried out. DFT calculations revealed that the thioether group has a major role in directing the olefin coordination. This, together with the configuration of the biphenyl phosphite group, has an impact in maximizing the energy gap between the most stable transition states leading to opposite enantiomers. As a result, the optimized catalyst proved to be efficient in the hydrogenation of a range of alkenes with the same substitution pattern and olefin geometry as the benchmark olefin, regardless of the presence of functional groups with different coordination abilities (ee values up to 97%). Appealingly, further modifications at the thioether groups and at the biaryl phosphite moiety allowed the highly enantioselective hydrogenation of olefins with different substitution patterns (e.g., α,β-unsaturated lactones and lactams, 1,1′-disubstituted enol phosphinates, and cyclic β-enamides; ee values up to >99%).

Dihydroquinolines, Dihydronaphthyridines and Quinolones by Domino Reactions of Morita-Baylis-Hillman Acetates.

An efficient synthetic route to highly substituted dihydroquinolines and dihydronaphthyridines has been developed using a domino reaction of Morita-Baylis-Hillman (MBH) acetates with primary aliphatic and aromatic amines in DMF at 50–90 °C. The MBH substrates incorporate a side chain acetate positioned adjacent to an acrylate or acrylonitrile aza-Michael acceptor as well as an aromatic ring activated toward SNAr ring closure. A control experiment established that the initial reaction was an SN2′-type displacement of the side chain acetate by the amine to generate the alkene product with the added nitrogen nucleophile positioned trans to the SNAr aromatic ring acceptor. Thus, equilibration of the initial alkene geometry is required prior to cyclization. A further double bond migration was observed for several reactions targeting dihydronaphthyridines from substrates with a side chain acrylonitrile moiety. MBH acetates incorporating a 2,5-difluorophenyl moiety were found to have dual reactivity in these annulations. In the absence of O2, the expected dihydroquinolines were formed, while in the presence of O2, quinolones were produced. All of the products were isolated in good to excellent yields (72–93%). Numerous cases (42) are reported, and mechanisms are discussed.

Stereoselective Synthesis and Structural Confirmation of the Specialized Pro-Resolving Mediator Resolvin E4.

Herein, we report the stereoselective and convergent synthesis of resolvin E4, a newly identified specialized pro-resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV–Vis and LC–MS/MS) data of synthetic resolvin E4 matched those obtained from biologically produced material.

Coumarins by Direct Annulation: β-Borylacrylates as Ambiphilic C3 -Synthons.

Modular β‐borylacrylates have been validated as programmable, ambiphilic C3‐synthons in the cascade annulation of 2‐halo‐phenol derivatives to generate structurally and electronically diverse coumarins. Key to this [3+3] disconnection is the BPin unit which serves a dual purpose as both a traceless linker for C(sp2)–C(sp2) coupling, and as a chromophore extension to enable inversion of the alkene geometry via selective energy transfer catalysis. Mild isomerisation is a pre‐condition to access 3‐substituted coumarins and provides a handle for divergence. The method is showcased in the synthesis of representative natural products that contain this venerable chemotype. Facile entry into π‐expanded estrone derivatives modified at the A‐ring is disclosed to demonstrate the potential of the method in bioassay development or in drug repurposing.

Coumarins by Direct Annulation: β‐Borylacrylates as Ambiphilic C3‐Synthons

AbstractModular β‐borylacrylates have been validated as programmable, ambiphilic C3‐synthons in the cascade annulation of 2‐halo‐phenol derivatives to generate structurally and electronically diverse coumarins. Key to this [3+3] disconnection is the BPin unit which serves a dual purpose as both a traceless linker for C(sp2)–C(sp2) coupling, and as a chromophore extension to enable inversion of the alkene geometry via selective energy transfer catalysis. Mild isomerisation is a pre‐condition to access 3‐substituted coumarins and provides a handle for divergence. The method is showcased in the synthesis of representative natural products that contain this venerable chemotype. Facile entry into π‐expanded estrone derivatives modified at the A‐ring is disclosed to demonstrate the potential of the method in bioassay development or in drug repurposing.

Naphthalenes and Quinolines by Domino Reactions of Morita-Baylis-Hillman Acetates.

An efficient synthetic route to highly functionalized naphthalenes and quinolines has been developed using domino reactions between Morita–Baylis–Hillman (MBH) acetates and active methylene compounds (AMCs) promoted by anhydrous K2CO3 in dry N,N-dimethylformamide (DMF) at 23 °C. The substrates incorporate allylic acetates positioned adjacent to a Michael acceptor as well as an aromatic ring activated toward a SNAr ring closure. A control experiment indicated that the initial reaction was an SN2’-type displacement of a side chain acetoxy by the AMC anion to afford the alkene product bearing the added nucleophile trans to the SNAr aromatic ring acceptor. Thus, equilibration of the alkene geometry of the initial product was required prior to cyclization. Products were isolated in good to excellent yields. Numerous cases (24) are reported, and several mechanistic possibilities are discussed.

Substrate-dependent stereospecificity in samarium-mediated allylic benzoate reductions

Abstract A series of experiments were performed to determine if SmI2(H2O)n reductions of allylic benzoates was stereospecific to alkene geometry. The results indicate that for alkyl-substituted alkenes, the reaction is stereospecific (i.e. the cis- and trans-isomers select for the opposite major diastereomer). However, the introduction of a phenyl substituent causes the reaction to become non-stereospecific, both cis- and trans-isomers converging to the same major diastereomer. A potential rationale is presented based on stabilization of a proposed organosamarium intermediate by the phenyl group that allows for isomerization of alkene geometry to a sterically preferred trans-configuration at the transition state. The data provide further insights into the mechanism of this reaction, the nature of allylic organosamarium complexes, and the unique reactivity of benzene rings in samarium-mediated transformations.

Rhodium-catalyzed cycloisomerization of ester-tethered 1,6-diynes with cyclopropanol moiety leading to tetralone/exocyclic diene hybrid molecules.

The rhodium-catalyzed cycloisomerization of ester-tethered 1,6-diynes bearing a cyclopropanol moiety produced tetralone/exocyclic diene hybrid molecules with thermodynamically unfavorable alkene geometry. The results of control experiments and density functional theory calculations suggest that the ester tether plays an important role in the efficiency of E/Z isomerization processes.

Stereoselective Syntheses of γ,δ-Bifunctionalized Homoallylic Alcohols and Ethers via Chemoselective Allyl Addition to Aldehydes.

Stereoselective synthesis of γ,δ-bifunctionalized homoallylic alcohols and ethers via chemoselective allylation is reported. Pd-catalyzed 1,2-diboration of allenylsilane provided a novel 1,1,2-trifunctional allylation reagent. Allylboration of aldehydes with the reagent followed by in situ protection gave TES-protected homoallylic alcohols with excellent Z-selectivities. Chemoselective allylsilation with the same reagent delivered γ,δ-bifunctionalized homoallylic ethers with high E-selectivities. The bifunctionalized alkene group in the products underwent various transformations without erosion of the olefin geometry.

Stereocontrolled Total Synthesis of (+)-Isolaurenidificin and (-)-Bromlaurenidificin.

We report the first total syntheses of (+)-isolaurenidificin (1) and (-)-bromlaurenidificin (2), the latest acetogenins of the 2,6-dioxabicyclo[3.3.0]octane class. The synthesis features a completely stereoselective one-pot epimerization-ring contraction to establish the cis configuration with respect to C10-H and C12-H of the tetrahydrofuran ring. Six stereogenic centers and an olefin geometry were constructed in a highly stereoselective manner. Absolute configurations of the natural products were deduced by the comparison of NMR data and specific rotations.