Alquinilación conjugada enantioselectiva de compuestos carbonílicos a,b-insaturados

En los últimos años se ha dedicado un considerable esfuerzo hacia el desarrollo de reacciones de adición conjugada catalítica enantioselectiva de alquinos terminales a compuestos electrofílicos proquirales. Estos procedimientos proporcionan una forma sencilla de sintetizar compuestos con un centro estereogénico propargílico. Existen numerosos ejemplos de reacciones de alquinilación a compuestos carbonílicos e iminas, obteniendo alcoholes y aminas propargílicas respectivamente. Sin embargo, la alquinilación de compuestos carbonílicos α,β-insaturados ha sido menos estudiada. En los capítulos introductorios de la presente tesis se encuentra un estudio detallado de la bibliografía más relevante relacionada con este tema. En este contexto, en la presente tesis se describe el desarrollo de nuevos procedimientos catalíticos enantioselectivos para la adición conjugada de alquinos terminales a distintos compuestos carbonílicos α,β-insaturados catalizada por complejos de Zn(II) y Cu(I). En el capítulo 4.1, se describe la adición conjugada de alquinos terminales a 2-ariliden-1,3-dicetonas en presencia de dietilcinc y (R)-VANOL. Los productos de alquinilación se obtuvieron con buenos rendimientos y excesos enantioméricos de hasta el 93%. Los mejores resultados se obtuvieron con enonas con grupos R1 = Me y R2 = aromático o heteroaromático, y con alquinos sustituidos con grupos R3= aromático o heteroaromático. Este es el primer ejemplo de alquinilación conjugada mediada por cinc en el que se emplean cantidades catalíticas de material quiral. Se demostró el potencial sintético de los productos resultantes mediante varias transformaciones. En el capítulo 4.2, se describe la adición conjugada de alquinos terminales a 3-alcoxicarbonilcumarinas. La reacción se llevó a cabo con un sistema catalítico novedoso basado en ligandos de tipo bis-hidroxiamidas de simetría C2 derivados del ácido isoftálico y amino alcoholes quirales, y dietilcinc. Las correspondientes trans 3-alcoxicrabonildihidrocumarinas 4-alquinil sustituidas se obtuvieron con buenos rendimientos y excesos enantioméricos (60-94%). Estos compuestos son intermedios sintéticos de cromanos y tetrahidrofuro[2,3-b]benzofuranos. En el capítulo 4.3, se describe la alquinilación conjugada enantioselectiva de 1,1-difluoro-1-(fenilsulfonil)-3-en-2-onas catalizada por el complejo [Cu(CH3CN)4]BF4-MeOBIPHEP. Los correspondientes productos de alquinilación se obtuvieron con rendimientos elevados y enantioselectividades excelentes (92-99% ee) para un amplio rango de enonas aromáticas y heteroaromáticas. Este es el primer ejemplo en el que las 1,1-difluoro-1-(fenilsulfonil)-3-en-2-onas se emplean como sustratos en catálisis asimétrica. También se mostró que la agrupación difluoro(fenilsulfonil)metilo puede ser transformados en las agrupaciones CF2H y CF3. Además los compuestos de alquinilación pueden ser considerados como equivalentes sintéticos de ésteres y amidas en catálisis asimétrica. En el capítulo 4.4, se describe la alquinilación conjugada enantioselectiva de 1,1,1-trifluorometil-3-en-2-onas catalizada por complejos de MeOBIPHEP-Cu(I). Con respecto al capítulo 4.3 este procedimiento requiere menores cantidades de catalizador (2,5% mol), alquino (1,3 equiv.) y base (0,1 equiv.). Los productos de alquinilación se obtuvieron con enantioselectividades excelentes (90-98% ee) empleando enonas con grupos R1 aromático o heteroaromático en la posición β del doble enlace. Los compuestos de alquinilación son precursores sintéticos de furanos quirales con un centro estereogénico trifluorometilado. En el capítulo 4.5, se describe el primer procedimiento enantioselectivo para la adición conjugada de 1,3-diinos a dobles enlaces electrofílicos empleando condiciones similares a las descritas en el capítulo 4.4. Este es el primer ejemplo en catálisis asimétrica en el que no se requiere premetalación del diino terminal con cantidades estequiométricas o superiores de reactivos de dialquilcinc. Los correspondientes de alquinilación se obtuvieron con excelentes excesos enantioméricos (84-95% ee) para un amplio rango de enonas y diinos. En el capítulo 4.6, se describe el primer ejemplo de alquinilación conjugada enantioselectiva de β-trifluorometil α,β-enonas empleando complejos de [Cu(CH3CN)4]BF4-taniaphos como catalizador. Se obtuvieron las correspondientes cetonas con un centro estereogénico propargílico trifluorometilado con rendimientos buenos y excesos enantioméricos (70-99%) para enonas con un grupo aromático o heteroaromático unido al grupo carbonilo. Estos compuestos son productos de partida para la síntesis de heterociclos quirales trifluorometilados como 4-trifluorometil-4H-piranos mediante ciclación con iodo. En el capítulo 4.7, se describe la alquinilación conjugada enantioselectiva de β-trifluorometil α,β-enonas β-sustituidas para dar los correspondientes productos con un centro estereogénico propargílico tetracarbosustituido. La reacción se llevó a cabo en presencia de dietilcinc y cantidades catalíticas de derivados del BINOL. Los productos de alquinilación se obtuvieron con excesos enantioméricos moderados (40-90% ee) aunque estos pudieron ser enriquecidos enantioméricamente mediante cristalización. Este es el primer ejemplo de alquinilación conjugada enantioselectiva de enonas β,β-disustitutidas. Los productos pudieron ser transformados en 4-trifluorometil-4H-piranos mediante ciclación con iodo.The development of catalytic enantioselective reactions involving nucleophilic addition of alkynes to prochiral electrophiles has received considerable attention in recent years. These procedures provide a straightforward way to synthesize internal alkynes bearing a propargylic stereogenic center. Considerable success has been obtainedin the alkynylation reaction of carbonyl compounds and imines to give propargylic alcohols and amines. However, the conjugate alkynylation of ,β-unsaturated carbonyl compounds has been studied in less extension. A survey of the most relevant literature related with this topic is provided in the introductory chapters of the thesis. In this context, the objectives of this thesis have focused in the development of new enantioselective procedures for the conjugate addition of terminal alkynes to several α,β-unsaturated carbonyl compounds catalyzed by Zn(II) and Cu(I) complexes. In chapter 4.1, the conjugate addition of terminal alkynes 2 to 2-aryliden-1,3-diketones 1 in the presence of diethylzinc and (R)-VANOL (L9) is described. The alkynylated diketones 3 were obtained with good yields and enantiomeric excesses up to 93%. The best result were obtained with enones 1 with R1 = Me and R2 = aromatic or heteroaromatic, and with alkynes substituted with R3 aromatic or heteroaromatic groups. This is the first example of conjugate alkynylation of enones mediated by zinc employing catalytic amounts of chiral inducer. The potential synthetic applicability of the resulting products was shown by diverse transformations. In chapter 4.2, the conjugate addition of terminal alkynes 2 to 3-alcoxycarbonyl coumarins 14 is reported. The reaction is carried out with a novel catalytic system that uses C2-symmetrical bis-hydroxyamides derived from isophtalic acid and chiral amino alcohols, and diethylzinc. The corresponding trans 4-alkynyl-substituted 3-(alkoxycarbonyl)dihydrocumarins 19 were obtained with good yields and enantiomeric excesses (60-94%). Compounds 19 were shown to be synthetic intermediates for chromanes and tetrahydrofuro[2,3-b]benzofurans. Chapter 4.3 describes a highly enantioselective conjugate alkynylation of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones 27 catalyzed by the [Cu(CH3CN)4]BF4-MeOBIPHEP (L31) complex. The corresponding alkynylated compounds 28 were obtained with good yields and excellent enantioselectivities (92-99% ee) for a wide range of -aryl- and -heteroaryl- substituted enones 27. This is the first example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones 27 as substrates in asymmetric catalysis. It has also been shown that the difluoro(phenylsulfonyl)methyl moiety can be transformed into a CF2H or CF3 group. Furthermore, it has been shown that compounds 27 can be considered as surrogates for esters and amides in asymmetric catalysis. In chapter 4.4, a highly enantioselective conjugate alkynylation of 1,1,1-trifluoromethyl-3-en-2-ones 35 catalyzed by the MeOBIPHEP-Cu(I) complex is reported. The procedure requires reduced amounts of catalyst (2.5 mol %), alkyne (1.3 equiv) and base (0.1 equiv) with respect to the reaction described in chapter 4.3. Compounds 33 were obtained with excellent enantioselectivities (90-98% ee) from trifluoromethyl enones 35 bearing R1 aromatic or heteroaromatic groups at the β position of the double bond. Compounds 33 have been shown to be synthetic precursors for chiral furans bearing a quaternary trifluoromethylated stereogenic center. In chapter 4.5, the first enantioselective procedure for the conjugate addition of 1,3-diynes to electron deficient alkenes is reported under similar reaction conditions to those used for the addition of alkynes in chapter 4.4. This is the first example on the use of terminal 1,3-diynes in asymmetric catalysis which does not requires premetalation with stoichiometric or higher amounts of dialkylzinc reagent. Compounds 40 were obtained with excellent enantiomeric excesses (84-95%) for a wide range of trifluoromethyl enones bearing R1 aromatic, heteroaromatic or aliphatic substituents and for a wide range of diynes. In chapter 4.6, the first enantioselective conjugate addition of terminal alkynes to β-trifluoromethyl α,β-enones 45 using the [Cu(CH3CN)4]BF4-taniaphos (L29) complex as catalyst is described. Ketones 46 bearing a trifluoromethylated propargylic stereogenic center were obtained with good yields and enantiomeric excesses (70-99%) from enones 45 having an aromatic or heteroaromatic substituent attached to the carbonyl group. These compounds have been shown to be building blocks for the synthesis of chiral trifluoromethylated heterocycles such as 4-trifluoromethyl-4H-pyrans upon iodocyclization. In chapter 4.7, the catalytic enantioselective conjugate addition of terminal alkynes to β-trifluoromethyl-β-substituted α,β-unsaturated enones 52, to give ketones 53 bearing a quaternary trifluoromethylated propargylic stereogenic center has been studied. The reaction is carried out in the presence of diethylzinc and a catalytic amount of a BINOL derivative L32. Compounds 53 were obtained with moderated enantioselectivities (40-90% ee) although they can be enantiomerically enriched upon crystallization. This is the first example of enantioselective conjugate alkynylation of β,β-disubstituted enones. Products 53 could be transformed into 4-trifluoromethyl-4H-pyrans bearing a quaternary stereocenter upon iodocyclization

Conjugate alkynylation of electrophilic double bonds. From regioselectivity to enantioselectivity

This review surveys the historical efforts addressed toward the development of the conjugate alkynylation reaction. The regio- and enantioselective conjugate alkynylation of electron-deficient double bonds, most commonly unsaturated carbonyl compounds, has been an elusive reaction for a long time. Intensive research during the last decades has resulted in the identification of a number of effective reagents and catalysts to perform this reaction. Non-stereoselective conjugate alkynylation of unsaturated carbonyl compounds was first achieved by using preformed alkynyl organometallics and later with terminal alkynes under catalytic conditions. These methods paved the way for the development of enantioselective procedures. After initial methods requiring stoichiometric amounts of chiral material, the findings by Corey on Ni-catalyzed addition of alkynylalanes and, particularly, by Carreira on Cu-catalyzed addition of terminal alkynes boosted the research on the development other asymmetric procedures catalyzed by Cu, Zn, Rh, Co, Ru and Pd complexes. The alkynylation of electrophilic alkenes conjugated with groups other than carbonyl and the alkynylation of extended conjugated systems are also discussed in the last part of this review

Asymmetric Organocatalytic Synthesis of aza-Spirocyclic Compounds from Isothiocyanates and Isocyanides

The spirocyclic motif is present in natural products, chiral ligands, and compounds of pharmacological interest. Isothiocyanates as well as isocyanides bearing electron-withdrawing groups in the α-position can be deprotonated and react as formal dipoles on account of the presence of a nucleophilic carbanion and an electrophilic atom in the isothiocyanate or isocyanide functional groups. In the last years a number of procedures involving the formal [3+2] cycloaddition reaction of isothiocyanates or isocyanides with cyclic compounds bearing electrophilic exocyclic double bonds have been developed for the enantioselective synthesis of aza-spirocyclic compounds. Among them, organocatalysis has played a predominant role in the development of asymmetric versions for these reactions. The synthesis of spirooxindoles by using this methodology has received especial attention, although other spirocyclic scaffolds are available depending on the structure of the dipolarophiles and the formal isothiocyanate and isocyanide dipoles

Enantioselective zinc-mediated conjugate alkynylation of saccharin-derived 1-aza-butadienes

The enantioselective 1,4-alkynylation of conjugated imines derived from saccharin with aryl- and alkyl-substituted terminal alkynes has been achieved. The reaction mediated by diethylzinc in the presence of a catalytic amount of a bis(hydroxy)malonamide chiral ligand provides the corresponding imines bearing a propargylic stereocenter with moderate yields and fair to excellent enantioselectivities

An Expedient Method for the Umpolung Coupling of Enols with Heteronucleophiles

[EN] In this paper, we present an unprecedented and general umpolung protocol that allows the functionalization of silyl enol ethers and of 1,3-dicarbonyl compounds with a large range of heteroatom nucleophiles, including carboxylic acids, alcohols, primary and secondary amines, azide, thiols, and also anionic carbamates derived from CO2. The scope of the reaction also extends to carbon-based nucleophiles. The reaction relies on the use of 1-bromo-3,3-dimethyl-1,3-dihydro-1 lambda(3)[d][1,2]iodaoxole, which provides a key alpha-brominated carbonyl intermediate. The reaction mechanism has been studied experimentally and by DFT, and we propose formation of an unusual enolonium intermediate with a halogen-bonded bromide.The authors are grateful for support from the Swedish Research Council through Vetenskapsradet, and from the Goran Gustafsson Foundation. This project was also funded by the European Union's Horizon 2020 research and innovation programme under Grant Agreement 721223 and NordForsk through NordCO2 (85378)

ZnO/ZnS heterostructures for hydrogen production by photoelectrochemical water splitting

This work studies the photoelectrochemical behavior of novel ZnO/ZnS heterostructures obtained by means of anodization in water and glycerol/water/NH4F electrolytes with different Na2S additions under controlled hydrodynamic conditions. For this purpose different techniques such as Field Emission Scanning Electronic Microscopy (FE-SEM) with EDX, Raman spectroscopy and photoelectrochemical water splitting tests under standard AM 1.5 conditions have been carried out. The obtained results showed that the hydrodynamic conditions promoted an ordered nanotubular morphology which facilitates electron-hole separation and consequently, the photoelectrochemical activity for water splitting is enhanced. Additionally, the effect of glycerol in the anodization solutions seems to be beneficial for increasing the dark current photostability

Cathodoluminescence characterization of ZnO/ZnS nanostructures anodized under hydrodynamic conditions

ZnO/ZnS nanostructures were successfully synthesized by a simple electrochemical anodization of zinc in a glycerol based electrolyte containing sulfide-ammonium fluoride. The influence of different hydrodynamic conditions and anodization potentials during anodization on the morphological and electronic properties of the obtained ZnO/ZnS nanostructures was studied. The anodized samples were characterized using confocal Raman microscopy, X-Ray Diffraction (XRD), Field Emission Scanning Electronic Microscopy (FE-SEM), cathodoluminescence (CL), and photoelectrochemical water splitting tests under standard AM 1.5 conditions. The results showed that hydrodynamic conditions and higher potentials promoted the formation of ZnO/ZnS nanotubes with both higher sulphur content and crystalline defect density, which reduces the near band edge transition value of the materials and improves the photoelectrochemical activity for water splitting. Additionally, the higher photocurrent densities for water splitting were obtained for the samples anodized at the highest anodization potential and under hydrodynamic conditions, increasing in a 71% for the nanostructures anodized at 1000 rpm when the anodization potential changes from 20 to 40 V

Asymmetric Addition and Cycloaddition Reactions with Ylidene-Five-Membered Heterocycles

Five-membered heterocycles bearing an exocyclic double bond have been successfully used as substrates in asymmetric addition and cycloaddition reactions. Ylidene-heterocycles are attractive substrates due to their high functionalization and the presence of an electrophilic conjugated exocyclic double bound that can participate in nucleophilic addition reactions as well as cycloaddition reactions, which may be triggered by the formation of aromatic intermediates or products in many cases. During the last decades, catalytic methodologies have been developed using ylidene-heterocycles as substrates in order to synthesize useful optically active heterocyclic derivatives. 4-Ylidene-pyrazol-5-ones, isoxazolin-5-ones, 2,3-dioxopyrrolidines, rhodanines, oxazolidindiones, Erlenmeyer-Ploch azlactones and 5-ylidene-thiazolones have been successfully used as substrates in asymmetric reactions. This review collects the powerful research in asymmetric addition and cycloaddition reactions where ylidene-five-membered heterocycles have been used

Organocatalytic enantioselective Mannich reaction of isoxazol-5(4H)-ones to isatin-derived ketimines

An efficient organocatalytic asymmetric Mannich reaction between isoxazol-5(4H)-ones and isatin-derived ketimines has been developed. A bifunctional squaramide/Brønsted base organocatalyst catalyzed the enantioselective Mannich addition to afford chiral 3-aminooxindoles bearing a tetrasubstituted stereocenter at C3 decorated with an isoxazole moiety in good yields and with excellent enantioselectivities. Additionally, several synthetic transformations were described showing the versatility of the prepared compounds

Enantioselective Synthesis of Functionalized Diazaspirocycles from 4-Benzylideneisoxazol-5(4H)-one derivatives and Isocyanoacetate Esters

Enantioenriched spirocyclic compounds bearing three contiguous stereocenters and high functionalization were obtained through a formal [3+2] cycloaddition reaction catalyzed by a cooperative system. The spiro compounds were synthesized from 4-arylideneisoxazol-5-ones and isocyanoacetate esters using a bifunctional squaramide/Brønsted base organocatalyst derived from a Cinchona alkaloid and silver oxide as Lewis acid. This method afforded two out of the four possible diastereomers with good yields and high enantiomeric excess for both diastereomers