Beta-unsaturated Esters Research Articles

Zinc and Nickel-Salophen Catalysts in Mediated Electrohydrocyclization Reactions

Electrohydrocyclization (EHC) refers to those processes which undergo an electrochemically promoted reductive cyclization leading to the formation of a new sigma bond between the beta-carbons of alpha, beta-unsaturated esters or nitriles. Moens, Baizer, and Little reported the use of an EHC reaction as the key step in the total synthesis of the natural product 1-sterpurene.1 Nickel-salen compounds have been shown as effective electron transfer agents in mediated electrohydrocyclization reactions.2 Experimental and computational methods have provided evidence that electron transfer occurs primarily through an inner-sphere process, implying the existence of a ligand-centered radical anion as the electron transfer agent.3 Our current study has focused upon changing the identity of the metal and changing the structure of the ligand in hopes of stabilizing the radical anion intermediate, resulting in a more efficient inner sphere electron transfer. The compounds we studied are shown in Figure 1. Figure 2 cyclic voltammetry showed that Zn-salophen 1 gives an irreversible wave at -1.70 V (vs Ag/AgCl) and Ni-salophen 2 gives a reversible wave at -1.60 V (vs Ag/AgCl). The cyclic voltammograms were run using a glassy carbon working electrode, platinum wire counter electrode, and a Ag/AgCl reference electrode. The experiment was run in dimethylformamide (DMF) solvent using 0.1 M tetrabutylammonium hexafluorophosphate as the supporting electrolyte at a scan rate of 0.2 V/sec. Both compounds 1 and 2 exhibited catalytic activity towards mediated EHC (Scheme 1). Controlled potential electrolysis using 5 mol % mediator, dimethyl malonate as proton donor, 0.1 M tetrabutylammonium hexafluorophosphate as supporting electrolyte in dimethylformamide gave cyclized products cis (4) and trans (5). The reactions proceeded with >95% product conversion after 2 hours and yielded similar cis:trans ratios for both catalysts. The cis: trans ratio using Zinc-salophen (1) was 35:65 and for Nickel-salophen (2) was 32:68. These results showed an improvement over previous metal-salen mediated EHC reactions with higher yields and faster reaction times. Future work includes the investigation of other metal-salophens (different metals and varying the ligand structure) to further stabilize the radical anion intermediate. We also wish to develop a solid-phase version of mediated EHC using polymer supported metal-salen catalysts that utilize Merrifield resin or possibly zeolite frameworks for heterogeneous catalysis. References L. Moens, M.M. Baizer, and R.D. Little. J. Org. Chem., 51, 4497 (1986).J. A. Miranda, C.J. Wade, and R.D. Little. J. Org. Chem., 70, 8017 (2005).J.M. Yates, J.S. Fell, J.A. Miranda, B.F. Gherman. J. Electrochem. Soc., 160, G3080 (2013). Acknowledgments We gratefully acknowledge Sacramento State University for their support of this research through the Instructionally Related Activities Grant (ASI), Russell-Forkey Summer Research Award (Chemistry Department), and Faculty Endowment for Student Scholarship Award. We also thank the Sacramento State College of Natural Science and Mathematics for funding this research. Figure 1

ChemInform Abstract: Organocatalytically Enantioselective Approach to Polysubstituted Tetrahydropyridines and Piperidines.

A convenient and highly enantioselective method for assembly of functionalized 1,2,3,4,5-pentasubstituted tetrahydropyridines and piperidines was developed. This method relies on preparing the required enantiopure cyclic semi-acetals via an organocatalyzed Michael addition/cyclization cascade reaction of aldehydes and alpha-keto-alpha,beta-unsaturated esters, and subsequent reductive amination/condensation with primary amines.

Organocatalytically Enantioselective Approach to Polysubstituted Tetrahydropyridines and Piperidines

AbstractA convenient and highly enantioselective method for assembly of functionalized 1,2,3,4,5‐pentasubstituted tetrahydropyridines and piperidines was developed. This method relies on preparing the required enantiopure cyclic semi‐acetals via an organocatalyzed Michael addition/cyclization cascade reaction of aldehydes and α‐keto‐α,β‐unsaturated esters, and subsequent reductive amination/condensation with primary amines.

ChemInform Abstract: A Radical Cyclization Route to Pyrrolidines Based on Conjugate Addition to Electron Deficient Phenylselenenylalkenes.

alpha-Phenylselenenyl-alpha,beta-unsaturated esters, amides, ketones, nitriles and sulfones were prepared by zinc chloride promoted chloroselenation/dehydrochlorination of the corresponding alpha,beta-unsaturated compounds. After Michael addition of allyl

ChemInform Abstract: Development of Highly Stereoselective Reactions Utilizing Heteroatoms. New Approach to the Stereoselective Horner-Wadsworth-Emmons Reaction

This article reviews a new approach to stereoselective Horner-Wadsworth-Emmons (HWE) reactions. The HWE reaction is one of the most efficient methods for the preparation of alpha,beta-unsaturated esters, which play an important role in the synthesis of biologically active compounds. The reactions of aldehydes with phosphonates bearing alpha-substituents which stabilize the carbanion, preferentially furnish the corresponding E-alkenes. However, the stereoselectivity of the HWE reactions with ketones has never been investigated in detail because of their low reactivity and low stereoselectivity. The conventional HWE reactions of aryl alkyl ketones with ethyl diethylphosphonoacetate in the presence of sodium hydride gave the corresponding alpha,beta-unsaturated esters with modest E-selectivity. On the other hand, the treatment of aryl alkyl ketones with ethyl diethylphosphonoacetate in the presence of Sn(OSO2CF3)2 and N-ethylpiperidine afforded alpha,beta-unsaturated esters in a highly Z-selective fashion. A significant improvement in the selectivity and yield was found when the Still's reagent, methyl bis(trifluoroethyl)phosphonoacetate, was used under Sn(II)-mediated conditions. On the basis of the experimental results, the high Z-selectivity in the Sn(II)-mediated HWE reactions of aryl alkyl ketones with these phosphonates can be rationalized in terms of six-membered transition state involving Sn(II) chelation. Similarly, the HWE reactions of aryl alkyl ketones with ethyl 2-fluoro-2-diethylphosphonoacetate in the presence of Sn(OSO2CF3)2 and N-ethylpiperidine gave the corresponding alpha-fluoro-alpha,beta-unsaturated esters in a highly E-selective manner. Finally, the Sn(II)-mediated asymmetric HWE reactions of isopropyl 2-fluoro-2-diethylphosphonoacetate with 4-tert-butylcyclohexanone in the presence of a chiral diamine is described.

Iron-Catalyzed Regio- and Stereoselective Substitution of γ,δ-Epoxy-α,β-unsaturated Esters and Amides with Grignard Reagents

When gamma,delta-epoxy-alpha,beta-unsaturated esters or amides were treated with 2 equiv of Grignard reagents in the presence of 10-24 mol % FeCl(2), regio- and stereoselective substitution of the epoxide moiety with the Grignard reagent occurred to give exclusively delta-hydroxy-gamma-alkyl or aryl-alpha,beta-unsaturated esters or amides in good yields.

Enantioselective Syntheses of Pachastrissamine and Jaspine AviaHydroxylactonization of a Chiral Epoxy Ester

A new enantioselective total synthesis of pachastrissamine (jaspine B) was achieved from a known alpha,beta-unsaturated aldehyde by utilizing Córdova's asymmetric epoxidation as the chirality-inducing step. The 2,3-cis stereochemistry of pachastrissamine was established via intramolecular epoxide ring opening of a gamma,delta-epoxy-alpha,beta-unsaturated ester intermediate coupled with oxy-Michael cyclization. Treatment of pachastrissamine with tetrahydro-2-furanol under acidic conditions led to smooth oxazolidine ring formation, furnishing jaspine A in a high yield.

Synthesis of Substituted Benzenes and Phenols by Ring‐Closing Olefin Metathesis

New synthetic approaches to substituted aromatic compounds are reported. Ring-closing olefin metathesis (RCM)/dehydration and RCM/tautomerization are the key processes in the synthesis of substituted benzenes 3 and phenols 6, respectively. Readily accessible 1,5,7-trien-4-ols 7, which are the precursors of benzenes, were prepared from beta-halo-alpha,beta-unsaturated aldehydes 11 or beta-halo-alpha,beta-unsaturated esters 19 by utilizing reliable transformations in which cross-coupling with vinylic metal reagents 12 and allylation with allylic metal reagents 13 were employed as carbon-carbon bond forming reactions. RCM of 7, followed by dehydration, afforded a wide variety of substituted benzenes 3. In addition, RCM of 1,5,7-trien-4-ones 9, which were prepared by oxidation of 7, furnished various substituted phenols 6 by automatic tautomerization.

Enantioselective Synthesis of a Mealybug Pheromone with an Irregular Monoterpenoid Skeleton

The first enantioselective synthesis of a mealybug sex pheromone with an unprecedented monoterpenoid skeleton has been accomplished by using a highly diastereoselective conjugate addition of an organocopper reagent to a gamma-alkyl-alpha,beta-unsaturated ester intermediate as the key step.

Single-Isomer Trisubstituted Olefins from a Novel Reaction of (E)-β-Chloro-α-iodo-α,β-unsaturated Esters and Amides

(E)-beta-chloro-alpha-iodo-alpha,beta-unsaturated esters are converted to single isomer trisubstituted olefins bearing three different carbon substituents by cross-coupling under reflux. Mechanistic investigations suggest that this process transfers a hydrogen from the boronic acid to the alpha-position of the substrate and then introduces an aryl group to the beta-position of the intermediate template while replacing chloride. The reaction is highly stereoselective, showing preference for the E-isomer. The process proceeds through (E)-beta-chloro-alpha-aryl-alpha,beta-unsaturated esters that are transformed efficiently into the corresponding E-products through stereoselective Suzuki-type reactions giving single isomers. The observed stereochemistry is apparently enabled by the intermediacy of a palladium allenoate. The reaction involves a catalytic cycle in which Pd(II) is reduced to Pd(0) through the formation of biaryl-coupled products.

Enantioselective Assembly of Substituted Dihydropyrones via Organocatalytic Reaction in Water Media

The diarylprolinol ether/HOAc-catalyzed cascade Michael addition and cyclization of aldehydes and alpha-keto-alpha,beta-unsaturated esters proceeds smoothly in water to afford cyclic hemiacetals, which are oxidized to furnish highly functionalized 3,4,5,6-tetrasubstituted dihydropyrones with excellent enantioselectivities.

Asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine, jaspine B (pachastrissamine), 2-epi-jaspine B, and deoxoprosophylline via lithium amide conjugate addition

The highly diastereoselective anti-aminohydroxylation of (E)-gamma-tri-iso-propylsilyloxy-alpha,beta-unsaturated esters, via conjugate addition of lithium (S)-N-benzyl-N-(alpha-methylbenzyl)amide and subsequent in situ enolate oxidation with (+)-(camphorsulfonyl)oxaziridine, has been used as the key step in the asymmetric synthesis of N,O,O,O-tetra-acetyl d-lyxo-phytosphingosine (20% yield over 7 steps), the anhydrophytosphingosine jaspine B (10% yield over 9 steps), 2-epi-jaspine B (14% yield over 9 steps), and the Prosopis alkaloid deoxoprosophylline (26% yield over 7 steps).

Efficient synthesis of (+)-1,8,8a-tri-epi-swainsonine, (+)-1,2-di-epi-lentiginosine, (+)-9a-epi-homocastanospermine and (−)-9-deoxy-9a-epi-homocastanospermine from a d-glucose-derived aziridine carboxylate, and study of their glycosidase inhibitory activities

The utility of a D-glucose-derived aziridine carboxylate was demonstrated for the synthesis of polyhydroxylated quinolizidine and indolizidine alkaloids. The chemoselective reduction of 1 followed by two-carbon homologation by the Wittig reaction afforded gamma,delta-aziridino-alpha,beta-unsaturated ester 9, which on regioselective nucleophilic aziridine ring opening either by using water as a nucleophile or hydrogenation afforded delta-lactams 11/16--true synthons for the synthesis of four structurally different iminosugars, namely quinolizidine alkaloids 5b/5c, swainsonine 6b and lentiginosine 7b analogues. Glycosidase inhibitory activities of these iminosugars were investigated.

Organocatalytic Sequential α-Amination−Horner−Wadsworth−Emmons Olefination of Aldehydes: Enantioselective Synthesis of γ-Amino-α,β-Unsaturated Esters

A novel and highly enantioselective method for the synthesis of gamma-amino-alpha,beta-unsaturated esters via tandem alpha-amination-Horner-Wadsworth-Emmons (HWE) olefination of aldehydes is described. The one-pot assembly has been demonstrated for the construction of functionalized chiral 2-pyrrolidones, subunits present in several alkaloids. [structure: see text]

Synthesis of beta-phenylchalcogeno-alpha, beta-unsaturated esters, ketones and nitriles using microwave and solvent-free conditions

A simple, clean and efficient solvent-free protocol was developed for hydrochalcogenation of alkynes containing a Michael acceptor (ester, ketone and nitrile) with phenylchalcogenolate anions generated in situ from the respective diphenyl dichalcogenide (Se, Te, S), using alumina supported sodium borohydride. This efficient and improved method is general and furnishes the respective (Z)-beta-phenylchalcogeno-<FONT FACE=Symbol>a,b</FONT>-unsaturated esters, ketones and nitriles, in good yield and higher selectivity, compared with those that use organic solvent and inert atmosphere. The use of microwave (MW) irradiation facilitates the procedure and accelerates the reaction.

A Novel Synthesis of Succinic Acid Type Gemini Surfactant by the Functional Group Interconversion of Corynomicolic Acid

2,3-Bis(undecyl)succinic acid, succinic acid type Gemini surfactant, was successfully synthesized from Corynomicolic acid by the functional interconversion of OH of Corynomicolic acid to COOH via (1) mesylation of OH of syn-isomer, (2) elimination of methanesulfonate group using base to E-alpha,beta-unsaturated ester, (3) Michael addition of CN(-) with 18-crown-6 and (4) hydrolysis. In most hydrolysis conditions, a mixture of syn- and anti-2,3-bis(undecyl)succinic acid was obtained, but hydrolysis in 75% H(2)SO(4) gave only anti-2,3-bis(undecyl)succinic anhydride. After converting a mixture of syn- and anti-2,3-bis(undecyl)succinic acids to corresponding acid anhydrides, syn- and anti-anhydride isomers were separated by column chromatography, and by following hydrolysis syn- and anti-2,3-bis(undecyl)succinic acid was selectively prepared. Based on the surface tension measurement, the effect of stereochemistry on surface tension isotherms was discussed in terms of the hydrophobic interaction between two alkyl groups and the electrostatic repulsion between two hydrophilic COO(-) groups.

Lewis Base Activation of Grignard Reagents with N-Heterocyclic Carbenes. Cu-Free Catalytic Enantioselective Additions to γ-Chloro-α,β-Unsaturated Esters

Direct activation of alkylmagnesium halides with a chiral bidentate N-hetrocyclic carbene (NHC), formed in situ from the imidazolinium chloride precursor, is reported. The Cu-free catalytic asymmetric allylic alkylation (AAA) of alpha-alkyl-gamma-chloro-alpha,beta-unsaturated esters with alkyl-based Grignard reagents is promoted in the presence of 5-10 mol % of the chiral imidazolinium salt to afford synthetically versatile beta,gamma-unsaturated esters. Products bear all-carbon quaternary sterogenic centers generated in 3.5-13.3:1 regioselectivity, 63-98% ee, and in up to 80% isolated yield of the SN2' product. The in-situ-generated chiral NHC promotes enantioselectivity while altering the reactivity of the Grignard reagents: there is only approximately 30% conversion and <2% allylic alkylation in the absence of chiral carbene.

Stereocontrolled Synthesis of Functionalized cis-Cyclopentapyrazolidines by 1,3-Dipolar Cycloaddition Reactions of Azomethine Imines

The reaction of alkene-tethered alpha-ketocarboxylic acid derivatives with monosubstituted hydrazines allows highly substituted cis-cyclopentapyrazolidine ring systems to be constructed rapidly. Successful cyclocondensations are realized under thermal reaction conditions; in some cases, protic or Lewis acids accelerate these reactions. alpha-Methoxy-alpha,beta-unsaturated esters are suitable alkene components, as are alkenes having either electron-withdrawing or electron-donating substituents at the terminal alkene carbon. alpha-Ketoesters, alpha-ketoamides, and alpha-ketothioesters can be employed. Various hydrazines substituted with N-acyl, N-carboalkoxy, or N-carbamothioyl protecting groups are tolerated in these transformations. The rate of intramolecular cycloaddition is found to reflect not only the reactivity and equilibrium concentration of the azomethine imine intermediate, but, also in some cases, the rate at which hydrazone stereoisomers interconvert under the reaction conditions.

Enantioselective Synthesis of Vinylcyclopropanes and Vinylepoxides Mediated by Camphor-Derived Sulfur Ylides: Rationale of Enantioselectivity, Scope, and Limitation

By a sidearm approach, camphor-derived sulfur ylides 1 were designed and synthesized for the cyclopropanation of electron-deficient alkenes and epoxidation of aldehydes. Under the optimal conditions, the exo-type sulfonium salts 4a and 4b reacted with beta-aryl-alpha,beta-unsaturated esters, amides, ketones, and nitriles to give 1,3-disubstituted-2-vinylcyclopropanes with high diastereoselectivities and enantioselectivities. When the endo-type sulfonium salts 5a and 5b were used, the diastereoselectivities were not changed, whereas the absolute configurations of the products became the opposite to those of the reactions of 4a and 4b. An ylide cyclopropanation of chalcone derivatives with phenylvinyl bromide in the presence of catalytic amount of chiral sulfonium salts 4b and 5b has been developed. The sidearmed hydroxyl group was found to play a key role in the control of enantioselectivity and diastereoselectivity. The origins of the high diastereoselectivity and enantioselectivity were also studied by density functional theory calculations, which reveal the importance of the hydrogen-bonding between the sidearmed hydroxyl group and the substrate in determining the diastereoselectivity and enantioselectivity. The ylides 1 were also successfully applied for the epoxidation of aromatic aldehydes.

Single-Isomer Tetrasubstituted Olefins from Regioselective and Stereospecific Palladium-Catalyzed Coupling of β-Chloro-α-iodo-α,β-unsaturated Esters

The efficient regioselective and stereospecific synthesis of tetrasubstituted olefins using a mild and convenient method is disclosed. 2-Alkynyl esters are selectively converted to E-beta-chloro-alpha-iodo-alpha,beta-unsaturated esters by exposure to Bu4NI in refluxing dichloroethane. These products are produced cleanly, regio- and stereoselectively, and in high yields. Single-isomer tetrasubstituted olefins bearing four different carbon substituents are then synthesized by sequential palladium-catalyzed coupling reactions. Selectivity results from reactivity differences in the intermediate substrates.