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α’-Oxy Enones for Construction of All-Carbon Quaternary Stereogenic Centers: Azlactones as Pronucleophiles

Studies in our group have shown that α’-oxy enones react in the presence of Brønsted base catalysts with 3-substituted oxindoles, cyanoesters, 5H-oxazol-4-ones, 1H-imidazol-4-(5H)-ones and azlactones to give the corresponding 1,5-dicarbonyl Michael adducts with a fully substituted carbon center in high enantioselectivity. For example, the reaction between azlactones 2 and enone 1 is efficiently promoted by catalyst C1 to led, after desilylation, to the corresponding products 3 with good yields and ee’s. In each case, reactions proceed with high site selectivity and no products from reaction at the C2-possition of the azlactone ring are observed. Besides their utility for the installation of aldehyde and ketone functionality, α’-oxy enones, through simple oxidative cleavage of the ketol moiety in the resulting adducts, act as α-β-unsaturated carboxylic acid surrogates for which successful methodologies are notably deficient.

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A more efficient entry to phenanthridinone

The presence of the phenanthridinone core in natural products and biologically active compounds has encouraged research on more efficient approaches to such valuable tricyclic framework.[1] Due to the lack of transmetallating agents and the atom-economy implied, palladium-catalyzed direct arylation is an appealing alternative for the ring closure step. However, the relative high amount of the catalyst employed may become a serious drawback from a practical view.[2] In this context, we wish to present the application of a palladacyclic complex to this reaction and the significant reduction of the catalytic amount achieved (0.05 mol%) in the successful preparation of a series of phenanthridinone derivatives.

[1] Bhakuni, B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J. A.; Konar, S.; Kumar, S. Org. Lett. 2012, 14, 2838-2841.

[2] Rousseaux, S.; Gorelsky, S. I.; Chung, B. K. W.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 10692-10705.

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Brønsted acid catalyzed enantioselective inter and intramolecular α-amidoalkylation reactions in the synthesis of isoquinoline derivatives

The a-amidoalkylation reaction of aromatic systems using N-acyliminium ions as electrophiles is one of the most attractive methods for C-C bond formation in heterocyclic chemistry and has found widespread application in natural products synthesis.[1] A significant progress in the application of enantioselective versions of a-amidoalkylation reactions has been marked by the development of chiral Brønsted acids (mainly BINOL derived phosphoric acids) and hydrogen bond donors (mainly ureas and thioureas). In this context, we have shown that BINOL-derived chiral Brønsted acids catalyze the intermolecular a-amidoalkylation of a bicyclic a-hydroxylactams, obtained by Parham cyclyzation of the corresponding N-phnethylimides, with indole derivatives. Thus, a convenient enantioselective synthesis of 12b-substituted isoindoloisoquinolines (ee up to 95 %) has been achieved.[2]

[1] Martínez-Estibalez, U.; Gómez-SanJuan, A.; García-Calvo, O.; Lete, E.; Sotomayor, N. Eur. J. Org. Chem. 2011, 3610

[2] Aranzamendi, E.; Sotomayor, N; Lete,. E. J. Org. Chem. 2012, 77, 2986.

 

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Enantioselective Synthesis of Chiral Proline Derivatives

The pyrrolidine framework is present as key structure in many natural products with interesting biological and pharmaceutical activities.[1] It is also used in organic chemistry playing different roles such as ligand, organocatalyst or building block in chiral pool synthesis.[2] Furthermore, these properties are very often influenced by the configuration of the stereogenic center present in the molecule. For this reason, new and efficient routes are required to synthesize chiral proline derivatives in a stereocontrolled way. With this in mind, our group has established a good approach to this scaffold employing as key steps an organocatalytic cascade process based on a Michael addition/imine formation sequence and a novel base-promoted rearrangement reaction (Scheme 1). Therefore, the reaction between enones and aminomalonates has been studied using a chiral primary amine as catalyst, due to the known ability of the latter to activate α,β-unsaturated ketones as Michael acceptors under iminium ion formation.[3] A sequential diastereoselective reduction leads to enantiopure 1,3-disubstituted pyrrolidines in good yield and enantioselectivity, which are transformed into the desired trisubstituted proline derivatives through a base-promoted rearrangement/deprotection reactions under mild conditions.

[1] For selected reviews, see: (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247; (b) Hanessian, S. ChemMedChem 2006, 1, 1300; (c) Pyne, S. G.; Tang, M.-Y. Curr. Org. Chem. 2005, 9, 1393; (d) Liddell, J. R. Nat. Prod. Rep. 2002, 19, 773; (e) Sardina, F. J.; Rapoport, H. Chem. Rev. 1996, 96, 1825.

[2] For selected reviews, see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471; (b) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416; (c) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005.

[3] For recent reviews, see: (a) Melchiorre, P. Angew. Chem. Int. Ed. 2012, 51, 9748; (b) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807; (c) Chen, Y.-C. Synlett 2008, 13, 1919.

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Catalytic Enantioselective Quick Entry to Aldol-Tethered 1,6- and 1,7-Enynes and Their Synthetic Application

Herein we present an effective asymmetric route to functionalized 1,6- and 1,7- enynes based on a direct cross-aldol reaction between ω-unsaturated aldehydes and propargylic aldehydes (α,β-ynals) promoted by combined α,α-dialkylprolinol ether/Brønsted acid catalysis. This synergistic activation strategy is a key to access the corresponding aldol adducts with high enantio- and diastereoselectivity.[1] The aldol reaction also proceeds well with propargylic ketones (α,β-ynones) thus enabling a stereocontrolled access to the corresponding tertiary alcohols. The utility of these adducts, which are difficult to prepare through standard methodology, is demonstrated by their transformation into trisubstituted bicyclic enones using standard Pauson-Khand conditions.

 [1]. E. Gomez-Bengoa, J. M. García. S. Jimenez, I. Lapuerta, A. Mielgo, J. M. Odriozola, M. Oiarbide, I. Otazo, I. Urruzuno, S. Vera, C. Palomo. Chem. Sci. 2013, 4, 3198-3204.

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New Methods For Stereocontrolled Cycloaddition/Dearomatization Reactions Under Catalytic Conditions

Our group has previously developed ferrocenyl-proline ligands that incorporate planar and central chirality. This feature makes them suitable for a particularly efficient simultaneously chiral induction. In fact, they have shown excellent diastereo- and enantioselectivity in [3+2] cycloaddition reactions between azomethine ylides and electron deficient alkenes.[1]

Büchner[2] discovered in 1885 a route for the functionalization of benzene employing diazo compounds to provide a carbene moiety. Since then, the use of diazo compounds has been the most developed method for the metal mediated carbene transfer to C-C double bonds.[3] This reaction provides a very useful method for the convergent formation of cyclopropanes. These [2+1] cycloadducts constitute attractive target molecules in natural products and bioorganic chemistry.[4] In the present work stereoselective [2+1] reactions between fused hetero polyaromatic rings and different diazo compounds are described, in which ligands LP-1 to LP-5 constitute the source of chirality.

[1] Conde, E.; Bello, D.; de Cozár, A.; Sanchez, M.; Vazquez, M. A.; Cossío, F. P. Chem. Sci. 2012, 3, 1486-1491.

[2] Büchner, E.; T. Ber. Dtsch. Chem. Ges. 1885, 18, 2377.

[3] Maas, G. Chem. Soc. Rev., 2004, 33, 183-190.

[4] (a) Kirkland, T.A; Colucci, J.; Geraci, L. S.; Marx, M.A.; Schneider, M.; Kaelin, D.E; Martin, S.F. J. Am. Chem. Soc., 2001, 123, 12432-12433; (b) Chen, D. Y. K.; Pouwer, R. H.; Richard, J. A. Chem.Soc.Rev., 2012, 41, 4631-4642; (c) Özüduru G.; Schubach, T.; Boysen M. M. K. Org, Lett., 2012, 14 (19), 4990-4993.

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Searching for new applications of the hypervalent iodine reagents in the construction of nitrogen containing compounds

The search for novel applications of the hypervalent iodine reagents in organic synthesis has witnessed a huge development in the last years due to the fact that most of them shows activity in the presence of almost all types of functional groups.[1] Their high stability and ease of use make these reagents ideal candidates to be included in many synthetic designs. The two main aspects of the reactivity of this kind of reagents are (i) the high electrophility at the iodine atom, and (ii) the extremely high ability of iodobenzene (the resulting by-product of several of the most commonly used hypervalent iodine chemicals) to act as a “super-leaving group”. Continuing our interest in this field, we are facing at the moment a new challenge.[2] The ability of some I(III) reagents, such as diaryliodonium salts 4, to transfer one of their groups to the nucleophilic position of different substrates[3] has been employed, for example, in the metal-free arylation of malonates 1.[4] The required conditions to accomplish this task (enolate formation under basic conditions) are similar to the ones required to perform a subsequent construction of a barbituric acid of type 3 in the presence of ureas 5.[5] In other words, it is the aim of this project to perform the two-step synthesis of 5-aryl substituted barbituric acids 3 in a one-pot procedure (without isolation of 2) or even in a multicomponent approach.

[1] See, for example, (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299. (b) Varvoglis, A. The Organic Chemistry of Polycoordinated Iodine, VCH, Weinheim, 1992. (c) Hypervalent Iodine Chemistry, in Top. Curr. Chem. 224, Wirth, T. Ed., Springer, Berlin, 2003. (d) Pouységu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010, 66, 2235. (e) Varvoglis, A. Tetrahedron 1997, 53, 1179.

[2] For a review of a summary of our contributions, see: Tellitu, I.; Domínguez, E. Synlett 2012, 2165, and references cited therein.

[3] Merritt, E. A.; Olofsson, B. Angew. Chem. Int. Ed. 2009, 48, 9052.

[4] Oh, C. H.; Kim, J. S.; Jung, H. H. J. Org. Chem. 1999, 64, 1338.

[5] Dickey, J. B.; Gray, A. R. Org. Synth. 1943, Coll. Vol. 2, 60.

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  • 23 Reads
Intramolecular Palladium-catalyzed C-H activation reactions: Synthesis of substituted quinolones

In the last years, the Palladium-catalyzed direct alkenylation of Csp2-H bonds, an oxidative variant of the Heck reaction known as Fujiwara-Moritani reaction, has emerged as an efficient, atom-economical, and environmentally friendly synthetic tool for the preparation of highly functionalized aromatic molecules. In connection with our work in catalytic C-H activation chemistry,[1] we decided to apply this procedure to the synthesis of polysubstituted quinolone scaffolds, an important structural motif embedded in a wide variety of bioactive natural products and pharmaceuticals. An efficient approach to the synthesis of biologically active 3-alkenyl-4-substituted quinolin-2(1H)-ones that involves two sequential C-H alkenylation reactions has been developed. First, a Pd(II) catalyzed selective 6-endo intramolecular C-H alkenylation of N-phenylacrylamides has allowed the construction of the quinolone core, which could be further functionalized in C-3 through a second intermolecular C-H alkenylation reaction. This method is a significant advance over the existing procedures that require preactivatated reaction partners. Furthermore, these reactions can also be carried out in aqueous media at room temperature, using a 2% aqueous solution of PTS, or even in water, in good yields. Details of these transformations will be given.

[1]. (a) Lage, S.; Martínez Estíbalez, U. Sotomayor, N. Lete, E. Adv. Synth. Catal.. 2009, 351, 2460. (b) Coya, E.; Sotomayor, N. Lete, E. Adv. Synth. Catal. 2014, 356, 1853.

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  • 26 Reads
Favouring Trienamine Activation through Unconjugated Dienals

The possibility for primary or secondary amines to activate enolizable aldehydes or ketones towards a variety of reactions opened the way for their α-functionalization in a catalytic and enantioselective fashion. In the same line, the β-functionalization of enones and enals is possible through the catalytic formation of an α,β-unsaturated iminium ion. More recently, the combination of these two activation manifolds along with the principle of vinylogy has opened the possibility for the remote functionalization of unsaturated aldehydes and ketones, allowing the γ- and δ-functionalization through dienamine catalysis and vinylogous iminium ion activation respectively. Much more recently, it has also been shown that even a more remote ε-functionalization is also possible by the formation of trienamine intermediates1 which, if conformationally locked, also allow the selective installation of ε-stereocenters with high level of stereochemical control. The implementation of a reaction through dienamine or trienamine intermediates entails that the conjugation level of the starting material has to increase from a simple aldehyde or ketone to an α,β-unsaturated or α,β,γ,δ-polyunsaturated aldehyde or ketone respectively and this involves a progressive depletion of its reactivity towards condensation with the aminocatalyst.          

In this work, unconjugated 2,5-dienals are proposed to constitute more reactive substrates than the corresponding fully conjugated α,β,γ,δ-unsaturated aldehydes towards organocatalytic activation through trienamine intermediates. This has been demonstrated in the Diels-Alder reaction with nitroalkenes,2 which proceeds with clean β,ε-selectivity to afford the final products in high yields and stereoselectivities, while the related polyconjugated 2,4-dienals were found to be completely unreactive.

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New catalytic systems for oxygen-mediated oxidative processes

The oxidation of alcohols to the corresponding carbonyl compounds is a current transformation in laboratory and industrial chemistry. Traditionally this reaction involves oxidants used in stoichiometric or overstoichiometric amounts so that relatively large quantities of waste are generated. Molecular oxygen is the ideal oxidant (readily available, safe, environmentally friendly, water as waste, etc.), but the need of metal catalysts to control the reaction outcome in relatively high amounts can become a serious drawback.[1],[2] We wish to present two pallacyclic systems with remarkable catalytic properties in the aerobic oxidation of a number of alcohols.

[1] Sheldon, R.A.; Arends, I.W.C.E.; ten Brink, G.J.; Dijksman, A. Acc. Chem. Res. 2002, 35, 774-778.

[2] Verho, O., Dilenstam, M.D.V.; Kärkäs, M.D., Johnston, E.V.; Åkermark, T.; Bäckvall, J.E.; Åkermark, B. Chem. Eur. J. 2012, 18, 16947-16954.

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