Showing papers on "Enone published in 2011"

Organocatalytic functionalization of carboxylic acids: isothiourea-catalyzed asymmetric intra- and intermolecular Michael addition--lactonizations.

Abstract: Tetramisole promotes the catalytic asymmetric intramolecular Michael addition−lactonization of a variety of enone acids, giving carbo- and heterocyclic products with high diastereo- and enantiocontrol (up to 99:1 dr, up to 99% ee) that are readily derivatized to afford functionalized indene and dihydrobenzofuran carboxylates. Chiral isothioureas also promote the catalytic asymmetric intermolecular Michael addition−lactonization of arylacetic acids and α-keto-β,γ-unsaturated esters, giving anti-dihydropyranones with high diastereo- and enantiocontrol (up to 98:2 dr, up to 99% ee).

Photocatalytic Reductive Cyclizations of Enones: Divergent Reactivity of Photogenerated Radical and Radical Anion Intermediates

Abstract: Photocatalytic reactions of enones using metal polypyridyl complexes proceed by very different reaction manifolds in the presence of either Lewis or Bronsted acid additives. Previous work from our lab demonstrated that photocatalytic [2 + 2] cycloadditions of enones required the presence of a Lewis acidic co-catalyst, presumably to activate the enone and stabilize the key radical anion intermediate. On the other hand, Bronsted acid activators alter this reactivity and instead promote reductive cyclization reactions of a variety of aryl and aliphatic enonesvia a neutral radical intermediate. These two distinct reactive intermediates give rise to transformations differing in the connectivity, stereochemistry, and oxidation state of their products. In addition, this reductive coupling method introduces a novel approach to the tin-free generation of β-ketoradicals that react with high diastereoselectivity and with the high functional group compatibility typical of radical cyclization reactions.

Palladium‐Mediated Annulation of Vinyl Aziridines with Michael Acceptors: Stereocontrolled Synthesis of Substituted Pyrrolidines and Its Application in a Formal Synthesis of (−)‐α‐Kainic Acid

Abstract: route to vinyl epoxides and vinyl aziridines via chiral sulfur ylides, we were keen to develop their potential in synthesis further. It had been reported that palladium-catalyzed reactions of vinyl epoxides and aziridines with doubly activated Michael acceptors gave tetrahydrofurans and pyrrolidines in good yield but usually with poor stereocontrol. However, related reactions with singly activated Michael acceptors were not effective. Nevertheless, we recognized that if we could find a way of coercing vinyl aziridines to react with singly activated enones/acrylates, and we were able to control stereochemistry in the annulation process, then we could potentially utilize this methodology in synthesis. Herein, we describe our success in simultaneously meeting these two significant challenges and also describe its application in a formal synthesis of ( )-a-kainic acid 1. Our initial efforts at promoting reaction between vinyl aziridine 2a and methyl vinyl ketone (MVK, A) using [Pd2(dba)3·CHCl3], (p-FC6H5)3P in THF (conditions employed by Yamamoto), however, were fruitless—we only observed decomposition. Using trimethylsilyl-substituted trans vinyl aziridine 2e, we now observed isomerization to a mixture of trans/cis aziridines (1:20). With this substrate, clearly the Pd was performing its role in generating the p-allyl palladium complex as this resulted in isomerization of the vinyl aziridine. However, the amide anion that was generated did not react with the enone. This result reinforced the observations by Yamamoto and Knight that doubly activated Michael acceptors were required to capture the relatively unreactive amide anion. We reasoned that ion pairing of the amide anion with the cationic Pd complex might compromise its reactivity, and that increased nucleophilicity should therefore be possible with an anionic Pd complex instead (Scheme 2).

Asymmetric inverse-electron-demand hetero-Diels-Alder reaction of six-membered cyclic ketones: an enamine/metal Lewis acid bifunctional approach.

Abstract: The combination of organocatalysis with metal catalysis has emerged as a potentially powerful tool in organic synthesis. This new concept aims to achieve organic transformations that cannot be accessed by organocatalysis or metal catalysis alone. In our effort to combine organo-enamine catalysis with metal Lewis acid catalysis, we have developed a new class of bifunctional enamine/metal Lewis acid catalysts. These bifunctional catalysts displayed unusually high activity and high stereoselectivity in asymmetric direct aldol reactions. The challenge in the development of Lewis acid/Lewis base catalytic systems lies in the acid-base quenching reaction that leads to catalyst inactivation. A common and elegant approach to solving this problem is the use of a soft acid along with a hard base, or vice versa. Based on this approach, organo-enamine catalysis has been successfully combined with Cu, Ag, Pd, and Au. We use a different strategy to solve the acid-base problem. This new strategy complements the mixed soft/hard approach. In our system, the Lewis base (primary or secondary amine) is tethered to a chelating ligand, which serves as a “trap” for the incoming metal. In this way, the base and the metal Lewis acid are brought into close proximity in one molecule without interacting with each other (Figure 1). The bifunctional enamine/metal Lewis acid catalysts have two unique advantages. First, a large number of metals can be introduced. The Lewis acidity can be easily tuned by simply using a different metal, thereby offering great flexibility to this system. For example, stronger Lewis acids, such as La, can be used to activate the enamine acceptor more strongly. Second, the bifunctional catalysts can potentially convert an intermolecular reaction into a much more efficient intramolecular reaction. In addition, the intramolecular bifunctional nature of the catalysts would also enhance the stereoselectivity of the reaction. With these catalysts, we intend to develop new carbon–carbon or carbon–heteroatom bond-forming reactions involving difficult organic transformations. Herein, we report the first example of a highly chemoand enantioselective inverse-electron-demand hetero-Diels–Alder (HDA) reaction of cyclic ketones with b,g-unsaturated-a-ketoesters catalyzed by primary-amine-based enamine/metal Lewis acid bifunctional catalysts. Asymmetric inverse-electron-demand hetero-Diels– Alder (IED/HDA) reactions of electron-rich alkenes with an electron-deficient a,b-unsaturated ketone offers a valuable synthetic entry into dihydropyran derivatives, which are chemically and biologically of significant importance, allowing the construction of up to three stereogenic centers in one operation. In most of the inverse-electron-demand HDA reactions, enol ethers derived from aldehydes act as the electron-rich alkenes (dienophiles). Very recently, enaminebased organocatalytic asymmetric inverse-electron-demand HDA reactions, in which an in situ formed enamine from a chiral pyrolidine and an aldehyde serves as the dienophile, have been made possible. Ketones are much less reactive compared to aldehydes because of electronic and steric reasons. Asymmetric HDA reactions of ketones, in particular cyclic ketones, have remained a long-standing challenge. We are interested in developing a catalytic asymmetric enamine-based IED/HDA reaction of simple ketones with enones, as it would greatly generalize this method, and open it up to much wider exploitation. To achieve this we believe that the activation of enones should extend beyond hydrogen-bond methods, 8] for example, by using a strong metal Lewis acid. In contrast, the formation of a less congested enamine intermediate using a primary amine catalyst may also contribute to or facilitate this transformation. The primary-amine-based enamine/metal Lewis acid bifunctional catalysts developed in our laboratory appear to be ideal candidates to tackle this difficult problem. We envision that the primary amine/metal Lewis acid bifunctional catalyst would engage enone 3 and the cyclic ketone 2 intramolecularly (Scheme 1). The primary amine would form an enamine in situ with the ketone (A) and the Figure 1. Illustration of primary amine/metal Lewis acid bifunctional catalysts.

A Highly Regio‐ and Stereoselective Cascade Annulation of Enals and Benzodi(enone)s Catalyzed by N‐Heterocyclic Carbenes

Abstract: A new asymmetric annulation of bis-enone derivatives of type (I) is achieved in the presence of a NHC-catalyst.

Transition States and Energetics of Nucleophilic Additions of Thiols to Substituted α,β-Unsaturated Ketones: Substituent Effects Involve Enone Stabilization, Product Branching, and Solvation

Abstract: CBS-QB3 enthalpies of reaction have been computed for the conjugate additions of MeSH to six α,β-unsaturated ketones. Compared with addition to methyl vinyl ketone, the reaction becomes 1–3 kcal mol–1 less exothermic when an α-Me, β-Me, or β-Ph substituent is present on the C═C bond. The lower exothermicity for the substituted enones occurs because the substituted reactant is stabilized more by hyperconjugation or conjugation than the product is stabilized by branching. Substituent effects on the activation energies for the rate-determining step of the thiol addition (reaction of the enone with MeS–) were also computed. Loss of reactant stabilization, and not steric hindrance, is the main factor responsible for controlling the relative activation energies in the gas phase. The substituent effects are further magnified in solution; in water (simulated by CPCM calculations), the addition of MeS– to an enone is disfavored by 2–6 kcal mol–1 when one or two methyl groups are present on the C═C bond (ΔΔG⧧). The...

Asymmetric Iodoamination of Chalcones and 4‐Aryl‐4‐oxobutenoates Catalyzed by a Complex Based on Scandium(III) and a N,N′‐Dioxide Ligand

Abstract: Highly diastereo- and enantioselective iodoamination of chalcones, 4-aryl-4-oxobutenoates, and a trifluoro-substituted enone has been accomplished in the presence of a chiral N,N'-dioxide/[Sc(OTf)(3)] complex (0.5-2 mol%), delivering the desired vicinal anti-α-iodo-β-amino carbonyl compounds regioselectively in high yields (up to 97%) and with excellent diastereoselectivities (>99:1 d.r.) and enantioselectivities (up to 99% ee). Enantiopure syn-α-iodo-β-amino products could also be obtained from the isomerization of particular iodo compounds. TsNHX species (X=Cl, Br, I), generated from the reactions between the halo sources and TsNH(2), were further confirmed as the active species in the haloamination reactions involved in the formation of the key halonium ion intermediates. A typical haloamination dependency was observed, with reactivity decreasing in the order NBS>NIS≫NCS.

Enantioselective synthesis of β-substituted cyclic ketones via cobalt-catalyzed asymmetric reductive coupling of alkynes with alkenes.

Abstract: A CoI2/(R)-BINAP, Zn, ZnI2, H2O system efficiently catalyzes the intermolecular asymmetric reductive coupling of alkynes with cyclic enones to afford highly regio- and enantioselective β-alkenyl cyclic ketones. A possible mechanism that involves the formation of a cobaltacyclopentene intermediate from the alkyne and cyclic enone is proposed.

Gold-Catalyzed Approach to Multisubstituted Fulvenes via Cycloisomerization of Furan/Ynes

Abstract: A new approach to functionalized fulvenes with an enone or enal moiety has been developed through gold-catalyzed intramolecular cycloisomerization of furan/ynes with a two-carbon tether in between the furan and the triple bond. The reaction proceeds with complete regioselectivity via a 6-endo-cyclization and high stereoselectivity. Moreover, the E- or Z-stereochemistry of the double bond in fulvene products can be easily controlled by performing the reaction in different solvents.

Asymmetric Organocatalytic Intramolecular Aza-Michael Addition of Enone Carbamates: Catalytic Enantioselective Access to Functionalized 2-Substituted Piperidines

Abstract: The synthetically useful functionalized 2-substituted piperidines containing a lateral ketone group have been strategically accessed via an organocatalytic enantioselective intramolecular aza-Michael addition of enone carbamates, in which a novel internal substrate combination of the enone moiety as Michael acceptor and the carbamate moiety as Michael donor was revealed in asymmetric bifunctional organocatalysis This heteroatom conjugate addition, which was realized by using a catalytic chiral Cinchona-based primary-tertiary diamine and an achiral Bronsted acid, mostly proceeded in high yield and good to excellent stereocontrol (up to 99% ee) This reaction provides an alternative catalytic asymmetric method for installing the stereogenic nitrogen-containing carbon center in functionalized 2-substituted piperidines, leading to the development of a straightforward and expeditious synthesis of some naturally occurring bioactive 2-substituted piperidine alkaloids

Old Yellow Enzyme-Catalyzed Dehydrogenation of Saturated Ketones

Abstract: Enzymes from extremophiles have always been of great interest for biotechnology because of their ruggedness against various stress factors. We have isolated, cloned, heterologously expressed and characterized a thermostable old yellow enzyme (OYE) from Geobacillus kaustophilus. In addition to the expected 'enone' reduction, GkOYE also catalyzes the reverse reaction, i.e., the desaturation of C—C bonds adjacent to a carbonyl to give the corresponding α,β-unsaturated ketone. The reaction proceeds at the expense of molecular oxygen without the need for a nicotinamide cofactor and represents an environmentally benign alternative to known chemical dehydrogenation methods.

Exploiting the facile release of trifluoroacetate for the α-methylenation of the sterically hindered carbonyl groups on (+)-sclareolide and (-)-eburnamonine.

Abstract: An efficient method for the α-methylenation of carbonyl groups is reported, and this transformation is accomplished by a facile elimination of trifluoroacetate during the formation of the olefin. This method represents an improvement beyond existing protocol in cases of steric hindrance, and we have demonstrated the utility of the process across a series of ketones, lactams, and lactones. Additionally, we have applied this method to produce semisynthetic derivatives of the natural products (+)-sclareolide and (−)-eburnamonine, in which the carbonyl group is proximal to bulky functional groups. Mechanistic insight is also provided from a time course of 19F NMR. Biological evaluation of the natural-product-derived enones led to the identification of a derivative of (−)-eburnamonine with significant cytotoxicity (LC50 = 14.12 μM) in drug-resistant MDA-MB-231 breast cancer cells.

Stereoselective heterocycle synthesis through a reversible allylic alcohol transposition and nucleophilic addition sequence

Abstract: The abilities of Re2O7 to promote non-stereoselective allylic alcohol transposition reactions and acetal ionization or enone activation have been coupled for a heterocycle synthesis in which thermodynamics dictate stereochemical outcomes. The stabilities of intermediate allylic cation and oxocarbenium ion intermediates dictate the efficiency of product equilibration. Long range stereoinduction can be observed in the synthesis of spiroketals and spirotricycles through this protocol.

Phosphine-Free Palladium Catalytic System for the Selective Direct Arylation of Furans or Thiophenes bearing Alkenes and Inhibition of Heck-Type Reaction

Abstract: Palladium acetate associated to potassium carbonate as catalytic system has been found to efficiently catalyse the direct 5-arylation of furans or thiophenes bearing enal, enone or acrylate functions at carbon C-2, and to inhibit the Heck-type reaction. The nature of the base is crucial to control the selectivity of the arylation. In the presence of electron-deficient aryl bromides and potassium carbonate as the base, the direct arylation is favoured, whereas the use of potassium fluoride gave selectively the Heck-type product, and tri-n-butylamine the reductive addition product.

A Ligand Structure–Activity Study of DNA‐Based Catalytic Asymmetric Hydration and Diels–Alder Reactions.

Abstract: A structure-activity relationship study of the first generation ligands for the DNA-based asymmetric hydration of enones and Diels-Alder reaction in water is reported. The design of the ligand was optimized resulting in a maximum ee of 83% in the hydration reaction and 75% in the Diels-Alder reaction, and some guidelines for ligand design were formulated. A comparison between these two reaction classes using salmon testes DNA/Cu(2+)-L catalysts, showed that the enantioselectivity in the hydration reaction was not the result of selective shielding of one pi face of the enone. In contrast, the structure of the ligand was suggested to be crucial to position and orient the substrate bound Cu(2+) complex optimally with respect to the structured first hydration layer of the DNA. Likely, the DNA activates and directs the H(2)O nucleophile for attack to one preferred pi face of the enone.

Alkyne–Aldehyde Reductive C–C Coupling through Ruthenium-Catalyzed Transfer Hydrogenation: Direct Regio- and Stereoselective Carbonyl Vinylation to Form Trisubstituted Allylic Alcohols in the Absence of Premetallated Reagents

Abstract: Nonsymmetric 1,2-disubstituted alkynes engage in reductive coupling to a variety of aldehydes under the conditions of ruthenium-catalyzed transfer hydrogenation by employing formic acid as the terminal reductant and delivering the products of carbonyl vinylation with good to excellent levels of regioselectivity and with complete control of olefin stereochemistry. As revealed in an assessment of the ruthenium counterion, iodide plays an essential role in directing the regioselectivity of C–C bond formation. Isotopic labeling studies corroborate reversible catalytic propargyl C–H oxidative addition in advance of the C–C coupling, and demonstrate that the C–C coupling products do not experience reversible dehydrogenation by way of enone intermediates. This transfer hydrogenation protocol enables carbonyl vinylation in the absence of stoichiometric metallic reagents.