Cyclic Epoxides Research Articles

Position 123 of halohydrin dehalogenase HheG plays an important role in stability, activity, and enantioselectivity

HheG from Ilumatobacter coccineus is a halohydrin dehalogenase with synthetically useful activity in the ring opening of cyclic epoxides with various small anionic nucleophiles. This enzyme provides access to chiral β-substituted alcohols that serve as building blocks in the pharmaceutical industry. Wild-type HheG suffers from low thermostability, which poses a significant drawback for potential applications. In an attempt to thermostabilize HheG by protein engineering, several single mutants at position 123 were identified which displayed up to 14 °C increased apparent melting temperatures and up to three-fold higher activity. Aromatic amino acids at position 123 resulted even in a slightly higher enantioselectivity. Crystal structures of variants T123W and T123G revealed a flexible loop opposite to amino acid 123. In variant T123G, this loop adopted two different positions resulting in an open or partially closed active site. Classical molecular dynamics simulations confirmed a high mobility of this loop. Moreover, in variant T123G this loop adopted a position much closer to residue 123 resulting in denser packing and increased buried surface area. Our results indicate an important role for position 123 in HheG and give first structural and mechanistic insight into the thermostabilizing effect of mutations T123W and T123G.

Synthesis and catalytic testing of Lewis acidic nano zeolite Beta for epoxide ring opening with alcohols

Lewis acidic zeolites are robust catalytic materials that are capable of a range of important chemistry for fine chemical production, including the epoxide ring opening with alcohols. The crystalline structure imposes diffusion limitations for large molecules that are overcome through reducing the particle size to produce nano zeolite beta substituted with Lewis acidic tin (nSnBeta). nSnBeta is characterized using standard methods to demonstrate that tin is efficiently incorporated into the zeolite framework with open and closed sites similar to the micron-sized conventional Sn-Beta (cSnBeta). While nSnBeta exhibits comparable catalytic activity to cSnBeta for reactions involving small substrates such as epichlorohydrin and methanol, an improvement in catalytic performance is observed for nSnBeta relative to cSnBeta when using large substrates such as 1,2-epoxyoctane and ethanol. nSnBeta and cSnBeta convert a cyclic epoxide too large to enter the pores to similar extents, indicating that the improved performance is not associated with an increased number of catalytic sites on the external surface. Catalyst reuse experiments demonstrate that organic accumulation on the material reduces catalytic activity that can be partially restored through calcination. Overall, the results demonstrate that nano zeolite beta can be synthesized with small particle sizes (i.e., 150 nm) to help overcome diffusion limitations for bulky substrates for the alcohol ring opening of epoxides.

Solventless synthesis of cyclic carbonates by direct utilization of CO2 using nanocrystalline lithium promoted magnesia

Cyclic carbonates are industrially important chemicals. In this work, an efficient synthesis of cyclic carbonate was achieved by cyclization of epoxide with CO2 using nanocrystalline lithium promoted magnesia (Li-MgO), without using any co-catalyst or solvent. A series of Li-MgO were prepared by gel combustion method and well characterized. Li-MgO forms active F-centers (crystallographic defect) due to the difference in valence state of lithium (Li+) and magnesium (Mg2+) and acts as an active site for CO2 activation. In the synthesis of 4-(chloromethyl)-1,3-dioxolan-2-one from epichlorohydrin, 0.75% (w/w) Li-MgO was the most active catalyst for CO2 fixation into cyclic carbonate with excellent conversion (∼98%) and selectivity (100%), at 130 °C and 3 MPa of CO2 pressure. The catalyst showed structural stability and was reused for three cycles without loss of activity. The current synthesis protocol is 100% atom-efficient and thus was extended to a variety of substrates. Langmuir- Hinshelwood-Hougen-Watson (LHHW) type of mechanism was proposed and kinetics studied. Both reactants are strongly adsorbed making the overall reaction zero order with an apparent activation energy of 15.14 kcal/mol.

Alternating copolymerization of epoxides with carbon dioxide or cyclic anhydrides using bimetallic nickel and cobalt catalysts: Preparation of hydrophilic nanofibers from functionalized polyesters

A series of di-nuclear metal acetate complexes 1–6 incorporated by nitrogen heterocycle-containing salen-type ligands have been synthesized, structurally characterized and performed as catalysts to prepare biodegradable polycarbonates and polyesters. Their catalytic performances for copolymerization of carbon dioxide-epoxides or cyclic anhydride-epoxides were systematically examined. Bimetallic nickel(II) complexes 1, 2 and 5 were active catalysts for the alternating copolymerization of cyclohexene oxide (CHO) with CO2; di-nickel complex 1 was shown to be the most effective and selective, leading to obtaining poly(cyclohexene carbonate)s with the best efficiency among them. Moreover, complex 1 was also found to be versatile for the ring-opening copolymerization of CO2 with different cyclic epoxides to give the corresponding polycarbonates. Additionally, di-cobalt(II) analogs 3, 4 and 6 were efficient catalysts for the alternating copolymerization of CHO and phthalic anhydride (PA) under mild conditions. Based on the results of catalytic studies, complex 3 was demonstrated to be the most active one CHO-PA copolymerization, producing the polymeric products with a “controlled” manner involving controllable molecular weights and narrow polydispersity. Interestingly, Co complex 3 was also able to catalyze the copolymerization of PA with 4-vinyl-1,2-cyclohexene oxide to obtain the associated polyester with the vinyl functionality on the side chains, which was further functionalized with tertiary amine moieties via thiol-ene click functionalization and converted to nanofibers through electrospinning. Due to the incorporation of polar groups, the resulting tertiary amine-modified polyester nanofibers that exhibit an improved hydrophilic property relative to their un-modified counterpart have been considered to have high potential to be utilized as a new functional fiber material.

HheG, a Halohydrin Dehalogenase with Activity on Cyclic Epoxides

Halohydrin dehalogenases (HHDHs) are of biotechnological interest due to their promiscuous epoxide ring-opening activity with a set of negatively charged nucleophiles, enabling the formation of C–C, C–N, or C–O bonds. The recent discovery of HHDH-specific sequence motifs aided the identification of a large number of halohydrin dehalogenases from public sequence databases, enlarging the biocatalytic toolbox substantially. During the characterization of 17 representatives of these phylogenetically diverse enzymes, one HHDH, namely HheG from Ilumatobacter coccineus, was identified to convert cyclic epoxide substrates. The enzyme exhibits significant activity in the azidolysis of cyclohexene oxide and limonene oxide with turnover numbers of 7.8 and 44 s–1, respectively. As observed for other HHDHs, the cyanide-mediated epoxide ring-opening proceeded with lower rates. Wild-type HheG displays modest enantioselectivity, as the resulting azido- and cyanoalcohols of cyclohexene oxide ring-opening were obtained in ...

Substrate-Triggered Stereoselective Preparation of Highly Substituted Organic Carbonates

Trisubstituted cyclic organic carbonates with multiple though well-defined stereochemical configurations are difficult to prepare. Here we present a conceptual design toward these CO2-based synthons using hydroxyl-substituted cyclic epoxide precursors and their catalytic conversion, to afford these challenging target compounds with fused ring sizes of up to eight under excellent stereocontrol. The observed stereochemistry of the organic carbonates combined with various control experiments revealed that these compounds are formed through a mechanistic manifold that involves a depolymerization reaction within an oligomeric carbonate induced by a pendant hydroxyl nucleophile. This manifold therefore provides an alternative approach toward CO2 valorization into functional cyclic carbonate scaffolds of use in synthetic chemistry.

Copolymerization of Carbon Dioxide with Epoxides Catalyzed by Structurally Well-Characterized Dinickel Bis(benzotriazole iminophenolate) Complexes: Influence of Carboxylate Ligands on the Catalytic Performance.

A series of structurally well-defined dinickel carboxylate complexes based on the RBiIBTP derivatives [RBiIBTP = bis(benzotriazole iminophenolate), where R = 3C for the propyl-bridged backbone and 5C for the 2,2-dimethyl-1,3-propyl-bridged backbone] were synthesized and developed for copolymerization of CO2 and epoxides. The one-pot reactions of nickel perchlorate with the RBiIBTP-H2 proligands and an appropriate amount of carboxylic acid derivatives (CF3COOH or 4-X-C6H4CO2H; X = H, CF3, OMe) upon the addition of triethylamine in refluxing methanol (MeOH) afforded dinuclear nickel dicarboxylate complexes, which could be formulated as either [(RBiIBTP)Ni2(O2CCF3)2] (1 and 2) or [(RBiIBTP)Ni2(O2CC6H4-4-X)2] (3-7). The dinickel monobenzoate complexes [(RBiIBTP)Ni2(O2CPh)(ClO4)(H2O)] [R = 3C (8) and 5C (9)] were prepared by using a similar synthetic route in tetrahydrofuran under reflux with a ligand precursor to metal salt to benzoic acid ratio of 1:2:1 in the presence of NEt3. Recrystallization of neutral nickel perchlorate complex 8 in a saturated MeOH or ethanol (EtOH) solution gave ionic and alcohol-solvated monobenzoate bimetallic analogues [(3CBiIBTP)Ni2(O2CPh)(S)2]ClO4, where S = MeOH (10) and EtOH (11). Single-crystal X-ray crystallography of dinickel analogues 1-11 indicates that the BiIBTP scaffold performs as a N,O,N,N,O,N-hexadentate ligand to chelate two Ni atoms, and the ancillary carboxylate group adopts a bridging bidentate bonding mode. Catalysis for copolymerization of carbon dioxide (CO2) with cyclohexene oxide (CHO) by complexes 1-9 was systematically investigated, and the influence of carboxylate ligands on the catalytic behavior was also studied. Trifluoroacetate-ligated dinickel complex 1 efficiently catalyzed CO2 and CHO with a high turnover frequency (>430 h-1) in a controlled fashion, generating perfectly alternating poly(cyclohexenecarbonate) with large molecular weight (Mn > 50000 g/mol). In addition to CO2/CHO copolymerization, bimetallic complex 1 was found to effectively copolymerize CO2 with 4-vinyl-1,2-cyclohexene oxide (VCHO) or cyclopentene oxide, producing the high carbonate contents of poly(VCHC-co-VCHO)s and highly alternating poly(cyclopentene carbonate)s, respectively. This study also enabled us to compare the catalytic efficiency of using cyclic epoxides with different ring strains or functional groups as comonomers by the dinickel catalyst 1.

Total Syntheses of Sesterterpenoid Ansellones A and B, and Phorbadione.

Ansellane-type sesterterpenoids including, ansellones A-G and (+)-phorbadione are structurally novel marine secondary metabolites which exhibit anticancer and anti-HIV activity. The first, asymmetric total syntheses of three structurally representative members, (-)-ansellones A and B and (+)-phorbadione, were accomplished in 16-23 steps from (+)-sclareolide. The route features the first regioselective cyclization of vinyl epoxides with internal alcohol nucleophiles in a 1,4-addition manner (SN 2'). Additionally, the allylic C-H oxidation was exploited at a late stage of the synthesis of (-)-ansellone A and (+)-phorbadione. This strategy is expected to be applicable to the synthesis of other ansellane sesterterpenoids.

Total Syntheses of Sesterterpenoid Ansellones A and B, and Phorbadione

AbstractAnsellane‐type sesterterpenoids including, ansellones A‐G and (+)‐phorbadione are structurally novel marine secondary metabolites which exhibit anticancer and anti‐HIV activity. The first, asymmetric total syntheses of three structurally representative members, (−)‐ansellones A and B and (+)‐phorbadione, were accomplished in 16–23 steps from (+)‐sclareolide. The route features the first regioselective cyclization of vinyl epoxides with internal alcohol nucleophiles in a 1,4‐addition manner (SN2′). Additionally, the allylic C−H oxidation was exploited at a late stage of the synthesis of (−)‐ansellone A and (+)‐phorbadione. This strategy is expected to be applicable to the synthesis of other ansellane sesterterpenoids.

Synthesis of 4-Chloro-5,6-dihydro-2H-pyran Derivatives by NbCl5 Mediated Cyclization of Epoxides with Homopropargylic Alcohols

Synthesis of 4-Chloro-5,6-dihydro-2H-pyran Derivatives by NbCl5 Mediated Cyclization of Epoxides with Homopropargylic Alcohols

Total Synthesis of Lingzhiol and its Analogues through the Wittig Reaction of an Oxocyclopentane Carboxylate

AbstractThe biosynthesis of polycyclic natural product lingzhiol (1) through an intramolecular Friedel–Crafts alkylation reaction of an aryl‐substituted cyclopentane epoxide (22) was attempted. The synthesis of this endocyclic epoxide involved the alkylation of cyclopentane carboxylate 14 with alkyl iodide 25 to afford ketoester 26. Subsequent Wittig olefination led to exocyclic alkene exo‐15 in good yield. Epoxidation, opening of the epoxide to generate allyl alcohol 29, and a second epoxidation reaction afforded compounds 22 and 31. However, presumably owing to stereoelectronic effects, the cyclization of these substrates into polycycles 17 and 32, respectively, was unsuccessful. Nevertheless, the Wittig reaction to afford exo‐15 allowed us to converge with the previously reported route of Qin et al., which featured the cyclization of spiro epoxide 16. Thus, lingzhiol is now available in only nine steps. Various analogues of lingzhiol were also prepared, including desoxy derivative 37, quinone 38, mono‐methoxy‐deoxy derivative 39, and ketone 40.

Salts of 1-(Chloromethyl)-DABCO: A Highly Efficient Organocatalyst for the Alcoholysis of Epoxides

Background: Epoxides are useful and important intermediates in pharmaceutical and agrochemical industries. In particular, the opening of epoxides with alcohols is an important transformation for the synthesis of β-alkoxy alcohols which are considered as valuable organic solvents, versatile synthons and intermediates. We have synthesized simple, highly efficient and environment benign catalyst and applied for the ring opening of epoxides with alcohols at room temperature. Methods: All the chemicals were purchased from commercial sources. Solvents used for the chemical synthesis were acquired from commercial sources, were of analytical grade and used without further purification. Thin layer chromatography (Merck Kiesel 60 F254, 0.2 mm thickness) was used to monitor the progress of the reactions and the compounds were purified by silica gel (60-120 mesh) column chromatography. Determination of the purity of the substrate and reaction monitoring were accomplished by GC analysis (Shimadzu GC-2010 Plus) using N2 as a carrier gas and Rtx-5 column (30 m x 0.25 mm x 0.25 mm, Restek, USA). 1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on Jeol ECX FT-NMR instrument using CDCl3 as solvent and TMS as internal reference. The chemical shift values were expressed on δ scale and the coupling constant (J) in Hz. Results: The quaternary salts of 1-(chloromethyl)-DABCO was synthesised from 1-(chloromethyl)-4- aza-1-azonia-bicyclo[2.2.2]octane tetrafluoroborate and different acids in acetone at 25 °C temperature. These salts were exhibits high catalytic activity for the ring opening of epoxides and gave corresponding β-alkoxy alcohols in good to excellent yields. Styrene oxide and phenyl glycidyl ether gave completely regioselective β-alkoxy alcohol. Conclusion: We have synthesized simple, convenient, highly efficient salts of 1-(chloromethyl)- DABCO and applied as organocatalysts (0.127 mol%) for the regioselective ring opening of epoxides with methanol. Ring opening of styrene oxide with different alcohols to afforded β-alkoxy alcohols in good to excellent yields. The cyclic epoxides gave trans-2-methoxy-cyclic alcohols in excellent yields. The catalyst also catalyzed the less reactive epoxide like glycidyl ethers, epichlorohydrin required a high loading of organocatalyst 3 (2 mol%) to complete the reaction. Keywords: Alcoholysis, epoxides, salt of DABCO, alkoxy ethers, ring opening of epoxides.

A Green, Solvent‐Free, Microwave‐Assisted, High‐Yielding YbCl3 Catalyzed Deprotection of THP/MOM/Ac/Ts Ethers of Chalcone Epoxide and 2′‐Aminochalcone and Their Sequel Cyclization

Under microwave and solvent‐free conditions, YbCl3 efficiently catalyzed the deprotection of tetrahydropyran‐2‐yl, methoxymethyl (MOM), acetyl, and tosyl groups and sequel cyclization of chalcone epoxide to 2‐hydroxyindanone and 2′‐aminochalcone to aza‐flavanone. The reaction afforded the products in excellent yield (78–99%) at 850 W microwave heating within 1–5 min under eco‐friendly conditions. The merits of the presented protocol include high yield, use of microwave irradiation, solvent‐free condition, catalyst reusability, and no need for purification with column chromatography. The present method is very much milder but more advanced than those reported earlier.

ChemInform Abstract: Nazarov Cyclization of Divinyl and Arylvinyl Epoxides: Application in the Synthesis of Resveratrol‐Based Natural Products.

AbstractA novel variant of the Nazarov cyclization of divinyl epoxides and arylvinyl epoxides, generated in solution from the corresponding ketones and ethyl bromoacetate or trimethylsulfonium iodide is developed.

ChemInform Abstract: Enantioselective Cross‐Coupling of meso‐Epoxides with Aryl Halides.

AbstractThe enantioselective reaction of a variety of cyclic epoxides with aryl bromides or cyclohexenyl triflate is studied in the presence of NiCl2 and a chiral menthyl substituted titanocene as catalysts.

Nazarov cyclization of divinyl and arylvinyl epoxides: application in the synthesis of resveratrol-based natural products.

New variation in the Nazarov cyclization has been developed by preparing divinyl and arylvinyl epoxides as pentadienyl cation precursors for the first time. Highly substituted cyclopentadienes, hydrindienes, and indenes were synthesized to demonstrate the compatibility of this reaction with substrates bearing a variety of substitutions and having different types of epoxides. Application of this method in the synthesis of resveratrol-based natural products was also demonstrated.

ChemInform Abstract: Carbon Dioxide as a Protecting Group: Highly Efficient and Selective Catalytic Access to Cyclic cis‐Diol Scaffolds.

AbstractEfficient procedures are described for the reaction of cyclic epoxides with carbon dioxide to give cyclic carbonates generally with exclusive or high cis‐diastereoselectivity.

New iron pyridylamino-bis(phenolate) catalyst for converting CO2 into cyclic carbonates and cross-linked polycarbonates.

The atom-efficient reaction of CO2 with a variety of epoxides has been efficiently achieved employing iron pyridylamino-bis(phenolate) complexes as bifunctional catalysts. The addition of a Lewis base co-catalyst allowed significant reduction in the amount of iron complex needed to achieve high epoxide conversions. The possibility of controlling the selectivity of the reaction towards either cyclic carbonate or polycarbonate was evaluated. An efficient switch in selectivity could be achieved when cyclic epoxides such as cyclohexene oxide and the seldom explored 1,2-epoxy-4-vinylcyclohexane were used as substrates. The obtained poly(vinylcyclohexene carbonate) presents pending vinyl groups, which allowed post-synthetic cross-linking by reaction with 1,3-propanedithiol. The cross-linked polycarbonate displayed a substantial increase in the glass transition temperature and chemical resistance, thus opening new opportunities for the application of these green polymers.

β-Cyclodextrin in water: highly facile biomimetic one pot deprotection of phenolic THP/MOM/Ac/Ts ethers and concomitant regioselective cyclization of chalcone epoxides and 2′-aminochalcones

A “green” and mild catalytic method for the deprotection of THP/MOM/Ac/Ts ethers and the concomitant cyclizations of epoxy chalcone to 2-hydroxyindanone or 2′-aminochalcone to aza-flavanone are reported.

ChemInform Abstract: Ring Opening of Epoxides with Alcohols Using Fe(Cp)2BF4 as Catalyst.

Abstract Fe(Cp) 2 BF 4 is an efficient catalyst for the alcoholysis of aromatic, aliphatic, and cyclic epoxides giving excellent yields of the corresponding β-alkoxy alcohols under ambient conditions. The methanolysis of styrene oxide using Fe(Cp) 2 BF 4 as a catalyst (5 mol %) gave excellent yield of 2-methoxy-2-phenylethanol with complete regio-selectivity. The ring opening of cyclic epoxides gave 77–97% yields of trans -β-methoxy alcohols, in 0.5–6 h. The use of 1,2-epoxyhexane and 1,2-epoxydodecane as substrates gave both regioisomers in excellent yields. The first order rate of reaction with respect to catalyst was observed for the kinetics of ring opening of 1,2-epoxyhexane with methanol.