Double Bond Isomerization Research Articles

Non‐canonical C16 Homoterpene Biosynthesis Widespread in Actinobacteria

A novel biosynthetic pathway towards the rare and underexplored non‐canonical family of homoterpenes was discovered in actinobacteria through targeted genome mining and enzymatic in vitro reconstitution. The pathway comprises initial methylation‐induced double bond isomerization of farnesyl diphosphate (FPP) to (2E,7E)‐6‐methyl‐farnesyl diphosphate, catalyzed by a novel family of methyltransferases with unique dual function. The resulting linear C16 double bond isomer of FPP constitutes the specific substrate for a distinct family of type I terpene cyclases, catalyzing diverse cyclization reactions. Functional characterization of nine enzyme pairs led to discovery of five unprecedented homoterpene natural products. The enzymological novelty enable the development of novel biocatalytic and genetically programmable synthetic strategies towards methylated terpenoids with potentially unique properties (“magic methyl effect”).

Non-canonical C16 Homoterpene Biosynthesis Widespread in Actinobacteria.

A novel biosynthetic pathway towards the rare and underexplored non-canonical family of homoterpenes was discovered in actinobacteria through targeted genome mining and enzymatic in vitro reconstitution. The pathway comprises initial methylation-induced double bond isomerization of farnesyl diphosphate (FPP) to (2E,7E)-6-methyl-farnesyl diphosphate, catalyzed by a novel family of methyltransferases with unique dual function. The resulting linear C16 double bond isomer of FPP constitutes the specific substrate for a distinct family of type I terpene cyclases, catalyzing diverse cyclization reactions. Functional characterization of nine enzyme pairs led to discovery of five unprecedented homoterpene natural products. The enzymological novelty enable the development of novel biocatalytic and genetically programmable synthetic strategies towards methylated terpenoids with potentially unique properties ("magic methyl effect").

Synthesis of Thiazole‐Fused Diosgenin Derivatives as Potential Therapeutic Agents

AbstractDiosgenin, a hydrolyzed product of phytosteroid saponin, has widely been studied for its medicinal properties. In an effort to find bioactive molecules, 25 novel thiazole‐fused diosgenin molecules have been synthesized by an efficient reaction protocol. The chemistry involves the Oppenauer oxidation followed by double bond isomerization in a one‐pot reaction, epoxidation, and the reaction of urea derivatives with the epoxyketone to synthesize the target compounds. These novel chimeric compounds were tested for their potential antimicrobial and cytotoxic properties. Antimicrobial studies against a panel of Gram‐positive and Gram‐negative led to the discovery of some of these molecules as narrow‐spectrum antimicrobial agents against Bacillus subtilis bacteria. In preliminary cytotoxicity studies, 2‐fluorophenyl derivative (10) inhibited the growth of several cell lines of the NCI‐60 cell line panels including >93 % inhibition of UO‐31 cell line. Furthermore, the hit antibacterial compounds are non‐toxic to human cancer cell lines, and the cytotoxic compound is not active against the bacterial strains, showing the selective therapeutic potential of the chimeric compounds.

Merging of a Supramolecular Ligand with a Switchable Luminophore - Light-Responsiveness, Photophysics and Bioimaging.

In this contribution we report on a novel approach towards luminescent light-responsive ligands. To this end, cyanostilbene- guanidiniocarbonyl-pyrrole hybrids were designed and investigated. Merging of a luminophore with a supramolecular bioactive ligand bears numerous advantages by overcoming the typical drawbacks of drug-labelling, influencing the overall performance of the active species by attachment of a large luminophore. Here we were able to establish a simple and easily accessible synthesis route to different cyanostyryl-guanidininiocarbonyl-pyrrole (CGCP) derivatives. These compounds were investigated regarding their light-responsive double bond isomerisation, their molecular structures in single crystals by means of X-ray diffractometry, their emission properties by state of the art photophysical characterisation as well as bioimaging and assessment of cell toxicity.

KOtBu Assisted Regio‐ and Stereo‐Selective Alkoxy‐Isomerization of Ortho‐Alkynyl Allylic Alcohols: Synthesis of Alkylidene Dihydroisobenzofurans and Indenones

AbstractA transition metal‐free synthesis of alkylidene dihydroisobenzofurans from the ortho‐alkynyl allylic alcohols is reported herein. Notably, a simple base tBuOK is utilized for the 5‐exo‐dig cyclization and double bond isomerization of ortho‐alkynyl allylic alcohols to furnish alkylidene dihydrobenzofurans with Z‐stereoselectivity under shorter reaction times. In addition, the geometry of the double bonds was confirmed by 1D Selective Gradient NOESY and 2D NMR (NOESY) analysis. Furthermore, the effectuality of the ortho‐alkynyl allylic alcohols has been shown by extending to the one‐pot synthesis of indanones via aqueous acid‐mediated hydrolysis (ring‐opening) of in‐situ formed dihydroisobenzofurans followed by intramolecular condensation reaction under acidic conditions

Photoisomerization pathway of the microbial rhodopsin chromophore in solution

Photoisomerization is a key photochemical reaction in microbial and animal rhodopsins. It is well established that such photoisomerization is highly selective; all-trans to 13-cis, and 11-cis to all-trans forms in microbial and animal rhodopsins, respectively. Nevertheless, unusual photoisomerization pathways have been discovered recently in microbial rhodopsins. In an enzymerhodopsin NeoR, the all-trans chromophore is isomerized into the 7-cis form exclusively, which is stable at room temperature. Although, the 7-cis form is produced by illumination of retinal, formation of the 7-cis form was never reported for a protonated Schiff base of all-trans retinal in solution. Present HPLC analysis of retinal oximes prepared by hydroxylamine reaction revealed that all-trans and 7-cis forms cannot be separated from the syn peaks under the standard HPLC conditions, while it is possible by the analysis of the anti-peaks. Consequently, we found formation of the 7-cis form by the photoreaction of all-trans chromophore in solution, regardless of the protonation state of the Schiff base. Upon light absorption of all-trans protonated retinal Schiff base in solution, excited-state relaxation accompanies double-bond isomerization, producing 7-cis, 9-cis, 11-cis, or 13-cis form. In contrast, specific chromophore-protein interaction enforces selective isomerization into the 13-cis form in many microbial rhodopsins, but into 7-cis in NeoR.Graphical

Energy-efficient frontal polymerization of poly(DCPD-co-TCPD) with improving thermomechanical properties and chemical resistance

Polydicyclopentadiene (PDCPD) was attractive in marine, automotive and new energy fields, but limited by its lower rigidity. Herein, poly(dicyclopentadiene-co-tricyclopentadiene) (poly(DCPD-co-TCPD)), was prepared by rapid and energy-efficient frontal polymerization (FP). The flexural properties of copolymers prepared via FP were comparable to those prepared by long-term oven curing. Furthermore, the study explored the cis-trans isomerization of double bond, molecular weight between cross-links, density, swelling degree and monomer conversion to systematically analyze the influence of tricyclopentadiene (TCPD) incorporation. Notably, the selected comonomer TCPD was relatively simple in synthesis, and its incorporation resulted in remarkable enhancement of the thermomechanical properties and acid-base resistance of neat PDCPD. At an 80 wt% TCPD incorporation, the flexural modulus increased significantly from 1865 MPa to 2703 MPa, and the Tg elevated from 147 ℃ to 210 ℃. Compared to other widely used thermosets, poly(DCPD-co-TCPD) exhibited significant advantages in terms of being lightweight and heat-resistant. The resulting thermosets demonstrated considerable potential for applications as high-performance thermosets and in composites with adjustable thermomechanical properties.

Synthesis of Styrylbenzazole Photoswitches and Evaluation of their Photochemical Properties.

Styrylbenzazoles form a promising yet under-represented class of photoswitches that can perform a light-driven E-Z isomerization of the central alkene double bond without undergoing irreversible photocyclization, typical of the parent stilbene. In this work, we report the synthesis and photochemical study of 23 styrylbenzazole photoswitches. Their thermal stabilities, quantum yields, maximum absorption wavelengths and photostationary state (PSS) distributions can be tuned by changing the benzazole heterocycle and the substitution pattern on the aryl ring. In particular, we found that push-pull systems show large redshifts of the maximum absorption wavelengths and the highest quantum yields, whereas ortho-substituted styrylbenzazole photoswitches exhibit the most favorable PSS ratios. Taking advantage of both design principles, we produced 2,6-dimethyl-4-(dimethylamino)-styrylbenzothiazole, a thermally stable and efficient P-type photoswitch which displays negative photochromism upon irradiation with visible light up to 470 nm to obtain a near-quantitative isomerization with a very high quantum yield of 59 %. Furthermore, 4-hydroxystyrylbenzoxazole was demonstrated to be a pH-sensitive switch which exhibits a 100 nm redshift upon deprotonation. Ortho-methylation of its benzothiazole analogue improved the obtained PSS ratio in its deprotonated state from E : Z=53 : 47 to E : Z=18 : 82. We anticipate that this relatively unexplored class of photoswitches will form a valuable expansion of the current family of photoswitches.

Construction of 3-Methyl-2-Substituted Benzo[b]furans and 3-Methyl-2-Substituted Benzo[b]thiophenes Using Solid Calcium Carbide as a Substitute for Gaseous Acetylene.

A concise method for the facile construction of 3-methyl-2-substituted benzo[b]furans and 3-methyl-2-substituted benzo[b]thiophenes using low-cost, abundant, and easy-to-use solid calcium carbide instead of flammable and explosive gaseous acetylene as an original alkyne source, o-bromophenyl ethers or o-bromophenyl thioethers as substrates through an intramolecular carbanion-yne cyclization in a 5-exo-dig manner, and subsequent double-bond isomerization is described. The simultaneous formation of two C-C bonds is realized in a one-step route. The wide substrate scope, high yield, and simple workup manipulations are also merits of this method. The synthetic strategy can also be suitable for the gram scale.

"Inverted" Cyclic(Alkyl)(Amino)Carbene (CAAC) Ruthenium Complex Catalyzed Isomerization Metathesis (ISOMET) of Long Chain Olefins to Propylene at Low Ethylene Pressure.

Isomerization Metathesis (ISOMET) reaction is an emerging tool for "open loop" chemical recycling of polyethylene to propylene. Novel, latent N-Alkyl substituted Cyclic(Alkyl)(Amino)Carbene (CAAC)-ruthenium catalysts (5a-Ru, 3b-Ru - 6c-Ru) are developed rendering "inverted" chemical structure while showing enhanced ISOMET activity in combination with (RuHCl)(CO)(PPh3)3(RuH) double bond isomerization co-catalyst. Systematic investigations reveal that the steric hindrance of the substituents on nitrogen and carbon atom adjacent to carbene moiety in the CAAC ligand have significantly improved the catalytic activity and robustness. In contrast to the NHC-Ru and CAAC-Ru catalyst systems known so far, these systems show higher isomerization metathesis (ISOMET) activity (TON: 7400) on the model compound 1-octadecene at as low as 3.0bar optimized pressure, using technical grade (3.0) ethylene. The propylene content formed in the gas phase can reach up to 20% by volume.

Acceptorless Dehydrogenation of Primary and Secondary Alcohols Catalysed by Phosphine‐free C, C Chelated Ir (III) NHC Complexes

AbstractHerein, an efficient, atom‐economic, environmentally benign catalytic protocol has been developed for synthesising ketones and aldehydes by acceptorless dehydrogenation of alcohols. The protocol employs C, C chelated Ir (III) NHC complexes to promote acceptorless dehydrogenation of both secondary and primary alcohols. Notably, oxidation of primary alcohol selectively yields the corresponding aldehyde where forming ester byproducts is possible. Using C, C chelated Ir (III) NHC complexes (0.1 mol%), and a catalytic amount of base tBuONa (5 mol%), several aliphatic and aromatic aldehydes and ketones including more challenging carbonyl compounds bearing heterocyclic rings were obtained in moderate to high yields. Moreover, the protocol is also efficient for synthesising industrially important molecules like heliotropin and 3,4,5‐trimethoxy acetophenone in moderate yields. Remarkably, the catalytic system allows the straightforward synthesis of the potentially bio‐active compound cholest‐4‐en‐3‐one through acceptorless dehydrogenation followed by double bond isomerisation under the reaction conditions. Low catalyst loading, mild reaction conditions, high selectivity, short reaction time, and broad‐substrate scopes are a few interesting characteristics of the catalytic protocol described herein.

β-Alkenylation of Saturated N-Heterocycles via a C(sp3)-O Bond Wittig-like Olefination.

Although the C-Hα functionalization of N-heterocycles is, in fact, an easy chemical transformation, the C-Hβ functionalization is, on the contrary, a quite difficult chemical process. Here, we present a two-step protocol that allows the ready conversion of pyrrolidines, piperidines, and an azepane into their corresponding 3-exo-alkenyl lactams via the transient formation of 3-alkoxyamino lactams followed by a Wittig-like C(sp3)-O bond olefination with stabilized ylides from phosphonium salts mediated by t-BuOK. Additionally, as a proof of the synthetic effectiveness of this novel methodology, the first synthesis of the natural product callylactam A was achieved through a TiCl4-catalyzed double bond isomerization of a 3-exo-alkenyl 2-piperidone to its endo-isomer.

Access to CF3-benzofulvenes via palladium-catalyzed cascade arylation/Trost-Oppolzer cyclization/double-bond isomerization.

Herein, we demonstrated a Pd-catalyzed cascade reaction that involves arylation, Trost-Oppolzer type Alder ene reaction, and double bond isomerization using the 4-(2-alkynylphenyl)-allylcarbonates and aryl boronic acids. This cascade process delivers a wide array of distinctive functionalized CF3-benzofulvenes in good yields with high stereoselectivity (E). A single palladium catalyst orchestrates the two individual reactions in a single operation. Trost-Oppolzer type Alder ene reaction is the key in this transformation, also called a rare acid-free iso-Nazarov type cyclization.

Multiplicity-driven photochromism controls three-state fulgimide photoswitches.

Fulgimide photoswitches display three-state photoswitching between isomeric forms Z, E and C. Fulgimides have therefore access to both large steric change of double bond isomerization and the large spectral change induced by electrocyclization. By controlling the multiplicity and photoisomerization conditions, we achieved precise and near-quantitative control over both isomerization modes.

Stereocontrolled and time-honored access to piperidine- and pyrrolidine-fused 3-methylenetetrahydropyrans using lactam-tethered alkenols.

Polycyclic oxygen-heterocycles bearing the 3-methylenetetrahydropyran (i.e., 3-MeTHP) motif are resident in bioactive molecules such as hodgsonox and iridoid. Meanwhile, the δ- and γ-lactam topologies as well as their reduced variants (i.e., piperidines and pyrrolidines) are at the core of several pharmaceuticals and fragrances. A stereocontrolled, time-honored, and cost-effective strategy that merges a 3-MeTHP motif with the aforementioned azaheterocyclic scaffolds could exponentially expand the 3D-structural space for the discovery of new small molecules with medicinal value. In these studies, readily affordable lactam-tethered alkenols have been interrogated in two complementary cascade approaches, leading to the regioselective and stereocontrolled synthesis of lactam-fused 3-MeTHPs. The first approach hinges on regioselective 6-endo-trig bromoetherification of the alkenols and concomitant elimination to arrive at the desired 3-MeTHPs. The methylene portion of the 3-MeTHP is unveiled at a late stage, which is noteworthy since all existing approaches to 3-MeTHPs rely on early-stage introduction of the methylene group. The second strategy involves transition metal-catalyzed alkoxylation of the tethered alkenol followed by base-induced double bond isomerization. The lactam-fused 3-MeTHPs are obtained in high site- and diastereo-selectivities. Post-modification of the bicycles has led to the construction of 3-MeTHP-fused saturated piperidines and pyrrolidines as well as 3-MeTHPs bearing four contiguous stereocenters.

Design and Investigation of a Side-Chain Liquid Crystalline Polysiloxane with a Ntb-Phase-Forming Side Chain

A new mesogenic non-symmetric dimeric monomer with a terminal olefin function, forming a twist bend nematic (Ntb) as well as a nematic (N) phase, was synthesized, using an enhanced synthetic methodology, which avoids isomerization of the terminal double bond in the preparation of the dimer. This monomer was attached to a pentamethyldisiloxane group, resulting in the SmA LC phase behavior of the ensuing material. Linking the monomer to a siloxane main chain resulted in nematic phase behavior. Detailed studies with the Ntb phase forming dimer DTC5C7 show full miscibility of the dimer and the new LC polymer in the LC state, suggesting that the side-chain LC polymer forms a Ntb phase as the low-temperature nematic phase. Copolymerizing the monomer with a cyanobiphenyl-based monomer allows us to tune the glass transition and phase behavior further.

Multi-responsive Electropolymer Surface Coatings Based on Azo Molecular Switches and Carbazoles: Light, pH, and Electrochemical Control of Z→E Isomerization in Thin Films.

Light-responsive surfaces are attracting increasing interest, not least because their physicochemical properties can be selectively and temporally controlled by a non-invasive stimulus. Most existing immobilization strategies involve the chemical attachment of light-responsive moieties to the surface, although this approach often suffers from a low surface concentration of active species or a high inhomogeneity of applied coatings. Herein, electropolymerization of carbazoles as a facile and rapid approach for preparing light-responsive azo-based surface coatings is presented. The electrochemical oxidative polymerization of bis-carbazole containing azo-monomers yields stable films, in which the photochemical properties and specific pH sensitivity of azo molecular switches are retained. Moreover, the molecular design enables electrocatalytic control over Z→E azo double bond isomerization facilitated by the conductive polycarbazole backbone. Ultimately, the high degree of control over macromolecular properties yields conductive surface coatings responsive to a range of stimuli, showing great promise as a strategy for versatile application in organic electronics.

Pd-Catalyzed Tandem Pathway for Stereoselective Synthesis of (E)-1,3-Enyne from β-Nitroalkenes by Using a Sacrificial Directing Group.

The involvement of nitroalkenes instead of minimal one alkyne motif for (E)-1,3-enynes synthesis through a palladium catalyzed stereoselective bond forming pathway at room temperature is presented. Implication of nitro group as a sacrificial directing group, formation of magical alkyne on a newly developed Csp 3 -Csp 3 bond with initial palladium-MBH adduct make this methodology distinctive. This protocol features an unprecedented sequential acetate addition, carbon-carbon bond formation, isomerization of double bond and nitromethane degradation in a tandem catalytic walk via dancing hybridization. Mechanistic understanding through identification of intermediates and computational calculations furnishes complete insight into the tandem catalytic pathway. Broad substrates scope and functional groups tolerance make this synthetic methodology magnificent and dynamic. This represents the first example of stereoselective 1,3-enyne synthesis exclusively from alkene substrates by introducing the concept of sacrificial directing group.

Expanding the Diversity of Azepino [3,2,1‐hi] Indoles via Transition Metal‐based Strategies such as Cross‐coupling Reaction and Ring Closing Metathesis

AbstractHere we report several useful synthetic strategies to azepino hi‐indoles, that are structural units in natural products by using commercially available indole derivatives such as 7‐bromo indole and 7‐formylindole via palladium catalyzed cross‐coupling reaction, ring closing olefin metathesis (RCM) as key steps. Later, we extended this strategy to seven‐membered fused indoles containing dioxano and dioxocano derivatives via allylation, double bond isomerization and RCM sequence as key step. Additionally, azepino indole having diene moiety was obtained by enyne metathesis and shown to be useful for Diels−Alder strategy. Along similar lines, we also report eight‐membered fused azocino indole using Grignard reaction and RCM as key steps and we demonstrated that the product obtained is useful for Fischer indolization to obtain bis‐indole derivative. Here several synthetically useful transformations were performed to generate diversity in the fused indole derivatives. All the compounds synthesized here are well characterized by NMR and HRMS data.Introduction

Geometrical isomerization of arachidonic acid during lipid peroxidation interferes with ferroptosis.

Geometrical mono-trans isomers of arachidonic acid (mtAA) are endogenous products of free radical-induced cis-trans double bond isomerization occurring to natural fatty acids during cell metabolism, including lipid peroxidation (LPO). Very little is known about the functional roles of mtAA and in general on the effects of mono-trans isomers of polyunsaturated fatty acids (mtPUFA) in various types of programmed cell death, including ferroptosis. Using HT1080 and MEF cell cultures, supplemented with 20μM PUFA (i.e., AA, EPA or DHA) and their mtPUFA congeners, ferroptosis occurred in the presence of RSL3 (a direct inhibitor of glutathione peroxidase 4) only with the PUFA in their natural cis configuration, whereas mtPUFA showed an anti-ferroptotic effect. By performing the fatty acid-based membrane lipidome analyses, substantial differences emerged in the membrane fatty acid remodeling of the two different cell fates. In particular, during ferroptosis mtPUFA formation and their incorporation, together with the enrichment of SFA, occurred. This opens new perspectives in the role of the membrane composition for a ferroptotic outcome. While pre-treatment with AA promoted cell death for treatment with H2O2 and RSL3, mtAA did not. Cell death by AA supplementation was suppressed also in the presence of either ferroptosis inhibitors, such as the lipophilic antioxidant ferrostatin-1, or NADPH oxidase (NOX) inhibitors, including diphenyleneiodonium chloride and apocynin. Our results confirm a more complex scenario for ferroptosis than actually believed. While LPO processes are active, the importance of environmental lipid levels, balance among SFA, MUFA and PUFA in lipid pools and formation of mtPUFA influence the membrane phospholipid turnover, with crucial effects in the occurrence of cell death by ferroptosis.