Showing papers on "Enone published in 2004"

Enantioselective tandem O-nitroso Aldol/Michael reaction.

Abstract: This communication presents studies that illustrated nitroso Diels−Alder adduct has been obtained in uniformly high enantioselectivity via a tandem nitroso aldol/Michael reaction using an amine catalyst. The regiochemical outcome of this construction is documented to be the opposite to that of the normal nitroso aldol reaction, which has been determined by X-ray analysis. The reaction of the enone with silver−BINAP catalyst has also been investigated in conjunction with the control of regiochemistry in a stepwise process.

Direct organocatalytic asymmetric heterodomino reactions: the Knoevenagel/Diels-Alder/epimerization sequence for the highly diastereoselective synthesis of symmetrical and nonsymmetrical synthons of benzoannelated centropolyquinanes.

Abstract: Amino acids and amines have been used to catalyze three component hetero-domino Knoevenagel/Diels−Alder/epimerization reactions of readily available various precursor enones (1a−l), aldehydes (2a−p), and 1,3-indandione (3). The reaction provided excellent yields of highly substituted, symmetrical and nonsymmetrical spiro[cyclohexane-1,2‘-indan]-1‘,3‘,4-triones (5) in a highly diastereoselective fashion with low to moderate enantioselectivity. The Knoevenagel condensation of arylaldehydes (2a−p) and 1,3-indandione (3) under organocatalysis provided arylidene-1,3-indandiones (17) in very good yields. We demonstrate for the first time amino acid- and amine-catalyzed epimerization reactions of trans-spiranes (6) to cis-spiranes (5). The mechanism of conversion of trans-spiranes (6) to cis-spiranes 5 was shown to proceed through a retro-Michael/Michael reaction rather than deprotonation/reprotonation by isolation of the morpholine enamine intermediate of cis-spirane (22). Prochiral cis-spiranes (5ab) and trans...

Copper-Catalyzed Tandem Conjugate Addition-Electrophilic Trapping: Ketones, Esters, and Nitriles as Terminal Electrophiles

Abstract: Exposure of enone substrates 1a-18a, which possess appendant ketone, ester, and nitrile moieties, to Et2Zn in the presence of catalytic Cu(OTf)2/P(OEt)3 provides the cyclized products in good to excellent yields and diastereoselectivities. These results represent the first use of ketones, esters, and nitriles as terminal electrophiles in Cu-catalyzed conjugate addition-electrophilic trapping.

Catalytic Enantioselective Conjugate Addition of Carbamates

Abstract: Catalytic, asymmetric conjugate addition of carbamates to enoyl systems has been realized for the first time, providing a two-step access to virtually enantiopure N-protected β-amino acids.

Desymmetrization of enone-diones via rhodium-catalyzed diastereo- and enantioselective tandem conjugate addition-aldol cyclization.

Abstract: Catalytic tandem conjugate addition-enolate trapping represents an effective strategy for the design of catalytic transformations that enable formation of multiple C—C bonds. Recently, using enantioselective rhodium-catalyzed conjugate addition methodology, we developed a catalytic tandem conjugate addition-aldol cyclization of keto-enones. Here, we report related desymmetrizations and parallel kinetic resolutions involving the use of diones as terminal electrophiles. The Rh-enolate generated on enone carbometallation effectively discriminates among four diastereotopic π-faces of the appendant dione, ultimately providing products that embody four contiguous stereocenters, including two adjacent quaternary centers, with quantitative diastereoselection and high levels of enantiomeric excess. This methodology allows concise entry to optically enriched seco-B ring steroids possessing a 14-hydroxy cis-fused C-D ring junction, as found in naturally occurring cardiotonic steroids derived from digitalis.

Phosphine Catalyzed α-Arylation of Enones and Enals Using Hypervalent Bismuth Reagents: Regiospecific Enolate Arylation via Nucleophilic Catalysis

Abstract: Exposure of enones and enals to 20 mol % tributylphosphine in the presence of triarylbismuth(V) dichlorides results in regiospecific aryl transfer to the α-position of the enone or enal pronucleophile. These results represent the first examples of enolate arylation under the conditions of nucleophilic catalysis.

Can simple enones be useful partners for the catalytic stereoselective alkylation of indoles

Abstract: A new catalytic system for the first example of enantioselective Friedel−Crafts-type (FC) addition of indoles to simple enones is described. The use of an equimolar amount of chiral [Al(salen)Cl] and 2,6-lutidine (10 mol %) was found to be effective in promoting the conjugate addition of indoles to (E)-arylcrotyl ketones, furnishing the corresponding β-indolyl ketones in excellent yield and high enantioselectivity (ee up to 89%). The role of the base was investigated through spectroscopic as well as computational analyses, which suggested that in situ formation of a new chiral (base·[Al(salen)]) complex was operating under our reaction conditions. In particular, a stable cationic [Al(salen)] hexacoordinate trans complex with the additive base and the enone is suggested as being responsible for the stereocontrolled reaction. Finally, detailed monitoring of the reaction course was carried out showing that a conventional FC pathway induced by [Al(salen)Cl] acting as a Lewis acid is operating.

Chemically induced anion radical cycloadditions: intramolecular cyclobutanation of bis(enones) via homogeneous electron transfer.

Abstract: The first examples of anion radical cycloaddition induced by homogeneous electron transfer from chemical agents are described. Specifically, upon exposure to chrysene anion radical, bis(enone) substrates are found to engage in stereoselective intramolecular [2 + 2] cycloaddition. These studies, along with the corresponding electrochemically initiated reactions, provide insight into this fundamentally new pattern of reactivity and support the feasibility of expanding this novel reaction type.

A Mild and Efficient Synthesis of Oxindoles: Progress Towards the Synthesis of Welwitindolinone A Isonitrile

Abstract: The complete carbon skeleton of welwitindolinone A isonitrile has been prepared by using a [2+2] cycloaddition to establish the bicyclo[4.2.0]octane core and a SmI2-mediated intramolecular reductive cyclization between an enone and an aryl isocyanate to stereoselectively install the spiro-oxindole (see scheme; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene).

Natural product based inhibitors of the thioredoxin–thioredoxin reductase system

Abstract: Spiroketal naphthodecalins are readily assembled by Barton's base mediated Ullmann binaphthyl ether coupling, Dakin reactions and hypervalent iodine spirocyclization. The core structures can be further diversified by enone addition and Stille coupling reactions. Nanomolar inhibitors for the Trx/TrxR redox control system were prepared by this approach and compared to series of natural product isolates. Cytotoxicity in MCF-7 cell assays ranged from an IC50 of 1.6 to >100 µM.

Pd(0)-Catalyzed Conjugate Addition of Benzylzinc Chlorides to α,β-Enones in an Atmosphere of Carbon Monoxide: Preparation of 1,4-Diketones

Abstract: Pd(0)-catalyzed conjugate addition of benzylzinc chloride to methyl vinyl ketone in the presence of chlorotrimethylsilane and lithium chloride in an atmosphere of carbon monoxide at room temperature afforded 1-phenyl-2,5-hexanedione monosilyl enol ether. In this catalytic carbonylation, four components are connected in one reaction. Successive acidic workup generated a variety of 1,4-diketones from substituted benzylzinc chlorides or related compounds and α,β-enones. Some products were converted to cyclopentenones or five-membered heterocyclic compounds containing an N, O, or S atom.

PuPHOS: A Synthetically Useful Chiral Bidentate Ligand for the Intermolecular Pauson−Khand Reaction

Abstract: Here we describe the synthesis and use of the Pulegone-derived bidentate P,S ligands PuPHOS and CyPuPHOS in the intermolecular Pauson−Khand reaction. Ligand exchange reaction of hexacarbonyldicobalt−alkyne complexes with PuPHOS provides a diasteromeric mixture of complexes (up to 4.5:1) from which the major isomers can be conveniently separated by simple crystallization. An isomerization−crystallization sequence of the original mixture results in a dynamic resolution that allows the preparation of the pure major Co2(μ-TMSC2H)(CO)4−PuPHOS (15a) in a multigram scale. Pauson−Khand reaction of 15a with norbornadiene provided, for the first time, the corresponding enone 18 with up to 93% yield and 97% ee. The use of (+)-18 as a surrogate of chiral cyclopentadienone is also demonstrated. Copper-catalyzed Michael addition of a Grignard reagent followed by removal of the TMS group with TBAF were the most reliable methods to transform (+)-18 into valuable starting materials 20a−e for the enantioselective synthesis...

On the Role of PIII Ligands in the Conjugate Addition of Diorganozinc Derivatives to Enones

Abstract: A mechanistic study on the conjugate addition of diethylzinc to cyclohexenone catalyzed by various chiral PIII ligands, provides new insights into its mechanism. Complete in situ conversion of the catalytic amount of Cu(OTf)2 into CuI species by excess ZnEt2 is demonstrated by EPR spectroscopy. Experimental evidence is presented in favor of a critical ternary 1:1:1 complex between enone, Et2Zn and catalyst, supporting a rate-limiting reductive elimination or carbocupration from a preformed mixed Cu/Zn cluster carrying one- or two-ligand molecules. A crystal structure has been obtained for a CuIL2 complex, which shows catalytic turnover on addition of reagent and substrate. NMR spectroscopic analyses and VT experiments reveal that steric hindrance may prevent complexation of a second ligand molecule on the CuI cation, leading to extremely fast precatalysts based on CuX.L species.

Synthesis and biological activity of enantiomers of antitumor irofulven.

Abstract: Stereoselective synthesis of (-)-irofulven has been achieved by cycloaddition of (R)-5-chloro-5-methyl-2-cyclopentenone to the 1,3-dipolar intermediate from 1-acetyl-1-(diazoacetyl)cyclopropane. The enantiomer, (+)-irofulven, was prepared in a similar way starting with (S)-5-chloro-5-methyl-2-cyclopentenone. (+)-Irofulven was 5 to 6 times less toxic than (-)-irofulven to adenocarcinoma (MV 522) cells.

Enone Olefin [2 + 2] Photochemical Cycloadditions

Abstract: The photochemical [2 + 2] cycloaddition reaction of alkenes to enones, the light-induced cycloaddition of an excited state enone to a ground state alkene to produce a cyclobutane, is a highly useful reaction in organic synthesis since two new carbon–carbon bonds are formed and a maximum of four new stereogenic centers are introduced into the molecule in the process. The first [2 + 2] photocycloaddition reaction was reported by Ciamician in 1908 when he observed the formation of carvone camphor on exposure of carvone to sunlight for one year. After confirmation of this finding in the late 1950s numerous investigators immediately recognized the value of the reaction for the rapid construction of complex molecular frameworks. The photocycloaddition of a series of Diels–Alder adducts of various dienes and benzoquinones to efficiently produce complex caged structures was subsequently carried out. This included the cycloaddition of a diketone to form a diketone. Meanwhile, a similar photochemical cycloaddition of an enone was utilized in a synthesis of the platonic solid cubane. Shortly thereafter investigations of the intermolecular reaction were initiated through a study of the dimerization of cyclopentenone and the photocycloaddition of cyclopentenone to cyclopentene. Further investigation of the various synthetic and mechanistic aspects of the photocycloaddition resulted in several total syntheses, including caryophyllene and bourbonene, as well as a proposed mechanistic rationale for the reaction. As a result of this pioneering work, largely by Eaton, Corey, and De Mayo, numerous natural and nonnatural products have been prepared by synthetic routes which have a [2 + 2] photocycloaddition as a crucial step in their synthesis. Through further refining over the last 15–20 years, the photocycloaddition reaction has become recognized as an important transformation in the repertoire of the synthetic organic chemist. Both the intermolecular and intramolecular versions of the reaction have been extensively studied. The intramolecular photocycloaddition, like the intramolecular variation of many reactions, has been the subject of much recent work. It is generally thought to be more predictable with regard to regiochemical and stereochemical control, but as will be seen from many of the examples in this chapter, the intermolecular reaction can be highly selective and predictable if the proper reaction participants and conditions are chosen. This chapter reviews the literature on the enone olefin [2 + 2] photocycloaddition since its discovery. Because of the volume of work in the field, there will undoubtedly be some omissions. Examples of all the major types of enone alkene photocycloadditions have been included so that the reader can get a sense of the historical evolution and the current state of the art. Both the intermolecular and the intramolecular variants of this reaction are treated in this chapter. The reader is also referred to a number of excellent reviews on the intermolecular reaction, the intramolecular reaction, and complete treatments which have appeared. Keywords: enone olefin; photochemical cycloadditions; intramolecular additions; intermolecular additions; regioselectivity; stereoselectivity; competing reactions; scope; limitation; experimental procedures; alkenes; acetylenes; cyclohexenones; benzoquinones; pyrimidines; azaenones; cyclopentanones; bridged bicyclic dienes; benzopyranones; hexadienes; nitrogen; oxygen

Gas-phase hydrogen transfer reduction of α,β-unsaturated ketones on Mg-based catalysts

Abstract: The gas-phase regioselective reduction of mesityl oxide to the allyl alcohol using 2-propanol as a hydrogen donor was studied at 523 K on basic MgO, MgAl0.33Ox and Cu0.05MgAl0.65Ox oxides. Catalysts were characterized using a variety of physical and spectroscopic techniques. The effect of contact time on the product distribution was determined in order to identify primary and secondary reaction pathways. Main reaction products from mesityl oxide conversion were the two allyl alcohol isomers (UOL, 4-methyl-3-penten-2-ol and 4-methyl-4-penten-2-ol), isomesityl oxide, methyl isobutyl ketone (MIBK), methyl isobutyl carbinol and C9 aldol condensation products. Bifunctional Cu0.05MgAl0.65Ox did not produce alcohols. Metallic Cu atoms readily decomposed 2-propanol forming acetone and mobile surface H atoms that selectively reduced the C C bond of mesityl oxide giving mainly MIBK. UOL formed on MgO at unusually high yields for a gas-phase reaction (40% at 523 K, 2-propanol/mesityl oxide = 5 and HLSV = 14 cm3/(h g)). UOL formation on MgO proceeds via a hydrogen transfer Meerwein–Ponndorf–Verley (MPV) mechanism without participation of surface H atoms from 2-propanol dissociation. Weak acid–strong base Mg2+ O2− surface pairs efficiently promote formation of the six-atom cyclic intermediate required in the MPV mechanism for selectively reducing the C O bond of an unsaturated ketone to the corresponding allyl alcohol. In contrast, UOL yield on MgAl0.33Ox was always lower than 5%. UOL formation is hindered on MgAl0.33Ox because surface Al3+ sites decrease by dilution the density of Mg2+ O2− pairs and concomitantly favor the adsorption of mesityl oxide via the C C bond, thereby promoting the selective formation of MIBK.

Synthesis of (±)-Hamigeran B, (−)-Hamigeran B, and (±)-1-epi-Hamigeran B: Use of Bulky Silyl Groups to Protect a Benzylic Carbon−Oxygen Bond from Hydrogenolysis

Abstract: Enone 42 was converted into diene 56, which was then subjected to hydrogenation. Use of the tert-butyldimethylsiloxy groups enforces facial selectivity and protects the C(5) oxygen from hydrogenolysis. The resulting product (55) is easily converted into hamigeran B (1), a marine natural product with powerful activity against herpes and polio viruses. Optically pure enone 73 was made by use of a Meyers' auxiliary and converted into (-)-hamigeran B with the natural absolute configuration.

A total synthesis of estrone based on a novel cascade of radical cyclizations

Abstract: Two conceptually different and novel radical-mediated cascade reactions leading to a total synthesis of the steroid (±)-estrone 1 and to a synthesis of 14-epiestrone 40 are described. Treatment of the iododienynone 23 with Bu3SnH/2,2′-azobis(isobutyronitrile) (AIBN) triggers a 13-endo-dig radical macrocyclization followed by two sequential radical transannulation reactions leading to the crystalline estrane 24 in 50% yield. The x-ray crystal structure of 24 established its trans, syn, stereochemistry. Transposition of the enone functionality in 24 next led to 38, which was then converted into 39 by reductive methylation. Deprotection of the methyl ether 39 finally gave 14-epiestone 40. When the substituted iodovinylcyclopropane 55 was treated similarly with Bu3SnH/AIBN, the resulting radical center underwent a different sequence of cascade macrocyclization-transannulation reactions producing the trans, anti, trans estrane 56 in 12% overall yield. Oxidation of 56, using CrO3-H2SO4 next led to the cyclopentanone 57, which, on deprotection using BBr3 gave (±)-estrone 1. A number of alternative substituted iodopolyenynones and iodovinylcyclopropanes, i.e., 8a, 8b, 33, 49a, and 49b, underwent similar radical-mediated cascade cyclizations leading to other estranes, i.e., 21a, 21b, 35, and 50, and, in one case, to the 6,6,5,6-tetracycle 51, in variable overall yields. The structures and stereochemistries of several estranes were established by using x-ray crystal structure measurements in combination with analysis of their NMR spectroscopic data and correlation with literature precedent.