Organocatalytic Lewis base functionalisation of carboxylic acids, esters and anhydrides via C1-ammonium or azolium enolates

This tutorial review highlights the organocatalytic Lewis base functionalisation of carboxylic acids, esters and anhydrides via C1-ammonium/azolium enolates. The generation and synthetic utility of these powerful intermediates is highlighted through their application in various methodologies including aldol-lactonisations, Michael-lactonisations/lactamisations and [2,3]-rearrangements.Publisher PDFPeer reviewe

Hydrazones as Singular Reagents in Asymmetric Organocatalysis

This Minireview summarizes strategies and developments regarding the use of hydrazones as reagents in asymmetric organocatalysis, their distinct roles in nucleophile–electrophile, cycloaddition, and cyclization reactions. The key structural elements governing the reactivity of these reagents in a preferred pathway will be discussed, as well as their different interactions with organocatalysts, leading to diverse activation modes. Along these studies, the synthetic equivalence of N-monoalkyl, N,N-dialkyl, and N-acyl hydrazones with several synthons is also highlighted. Emphasis is also put on the mechanistic studies performed to understand the observed reactivities. Finally, the functional group transformations performed from the available products has also been analyzed, highlighting the synthetic value of these methodologies, which served to access numerous families of valuable multifunctional compounds and nitrogen-containing heterocycles.Ministerio de Economía y Competitividad CTQ2013-48164-C2-1-P, CTQ201348164-C2-2-PEuropean FEDER fundsJunta de Andalucía 2012/FQM 107

Catalytic enantioselective synthesis of quaternary carbon stereocentres.

Quaternary carbon stereocentres-carbon atoms to which four distinct carbon substituents are attached-are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials

Stereodivergent, Diels-Alder-initiated organocascades employing α,β-unsaturated acylammonium salts: scope, mechanism, and application.

Chiral α,β-unsaturated acylammonium salts are novel dienophiles enabling enantioselective Diels-Alder-lactonization (DAL) organocascades leading to cis- and trans-fused, bicyclic γ- and δ-lactones from readily prepared dienes, commodity acid chlorides, and a chiral isothiourea organocatalyst under mild conditions. We describe extensions of stereodivergent DAL organocascades to other racemic dienes bearing pendant secondary and tertiary alcohols, and application to a formal synthesis of (+)-dihydrocompactin is described. A combined experimental and computational investigation of unsaturated acylammonium salt formation and the entire DAL organocascade pathway provide a rationalization of the effect of Brønsted base additives and enabled a controllable, diastereodivergent DAL process leading to a full complement of possible stereoisomeric products. Evaluation of free energy and enthalpy barriers in conjunction with experimentally observed temperature effects revealed that the DAL is a rare case of an entropy-controlled diastereoselective process. NMR analysis of diene alcohol-Brønsted base interactions and computational studies provide a plausible explanation of observed stabilization of exo transition-state structures through hydrogen-bonding effects

Organocatalysis in total synthesis

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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

Synthesis of Simplified Azasordarin Analogs as Potential Antifungal Agents

A new series of simplified azasordarin analogs was synthesized using as key steps a Diels–Alder reaction to generate a highly substituted bicyclo[2.2.1]heptane core, followed by a subsequent nitrile alkylation. Several additional strategies were investigated for the generation of the key tertiary nitrile or aldehyde thought to be required for inhibition at the fungal protein eukaryotic elongation factor 2. This new series also features a morpholino glycone previously reported in semisynthetic sordarin derivatives with broad spectrum antifungal activity. Despite a lack of activity against Candida albicans for these early de novo analogs, the synthetic route reported here permits more comprehensive modifications of the bicyclic core and structure–activity relationship studies that were not heretofore possible

Step economy in the stereoselective synthesis of functionalized oxindoles via organocatalytic domino/one-pot reactions

Oxindoles are an important class of heterocyclic scaffolds widely present in natural products and bioactive compounds. For this reason, a plethora of methodologies for the stereoselective synthesis of enantioenriched oxindoles has been studied over the years. Among all the reported synthetic strategies, organocatalysis has proven to be a powerful tool for the asymmetric synthesis of this class of compounds being a step- and atom-economical, environmentally friendly, and non-toxic approach. This review will outline the application of asymmetric organocatalysis in the synthesis of chiral oxindole-based structures, relying on domino/one-pot reaction sequences in a step-economical fashion

Asymmetric organocatalytic cascade reactions

302 p. : gráf.[ES]En la presente memoria se recoge el trabajo de investigación enmarcado en elempleo de aminas secundarias quirales como organocatalizadores para el diseño dereacciones en cascada con el fin de obtener compuestos de interés con elevadorendimiento y control estereoquímico. De esta manera, en primer lugar se ha puestoa punto una metodología para la síntesis de furanos mediante una reacción encascada aminocatalítica oxa-Michael/reacción aldólica/hemiacetalización entrealdehídos , -insaturados y dihidroxiacetona combinando los modos de activacióniminio y enamina. Asimismo, se ha demostrado la posibilidad de llevar a cabotransformaciones eficientes de manera selectiva sobre los aductos obtenidospermitiendo obtener un amplio abanico de compuestos, lo que pone de manifiesto elpotencial de esta metodología para la síntesis enantioselectiva de diversos buildingblocks quirales de interés en síntesis orgánica. La extensión de dicha estrategia aluso de -aminoacetofenona ha permitido obtener distintas -lactamasenantioenriquecidas con excelentes rendimientos.En segundo lugar, se ha puesto a punto una metodología enfocada a lasíntesis asimétrica de ciclobutanos sustituidos mediante una reacción formal decicloadición [2+2] entre aldehídos , -insaturados enolizables y nitroalquenos -hidroximetil susutituidos. En este caso, se ha empleado un sistema catalíticocompuesto por un derivado de difenilprolinol y una tiourea aquiral, haciendo así usode la aminocatálisis y la catálisis por formación de enlaces de hidrógeno. De estemodo, se ha demostrado que la cooperación de ambos modos de activación permiteel desarrollo de dicha transformación sintética con elevados rendimientos yexcelente estereocontrol[EN]AbstractIn this dissertation, our work on the study of chiral secondary amines aspromoters in enantioselective organocatalytic cascade reactions towards theasymmetric synthesis of different substituted hetero- and carbocycles is presented.In this sense, we have developed an efficient methodology for theconstruction of hexahydrofuro[3,4-c]furans containing four stereocenters by meansof an amine catalyzed oxa-Michael/aldol/hemiacetalization cascade reaction byreacting different , -unsaturated aldehydes with dihydroxyacetone underiminium/enamine catalysis. Remarkably, a high pKa oxygen pro-nucleophile hasbeen employed as functionalized Michael donor to initiate the conjugate process,which represents an important feature of this transformation. This methodology hasled to the formation of polysubstituted furofuranes in excellent yields and diastereoandenantioselectivities. Moreover, different related compounds can be accessedthrough the selective manipulation of the functionalities present within the obtainedadducts emphasising the potential of this methodology for the synthesis of usefulchiral building blocks. Additionally, this strategy has been extended to the use of Nprotected--aminoacetophenone for the synthesis of -lactams through aMichael/hemiaminalization cascade sequence.On the other hand, we have set up an enantioselective formal [2+2]cycloaddition reaction between enolizable , -unsaturated aldehydes andnitroalkenes towards the synthesis of highly substituted cyclobutanes. In thisparticular case, the combination of an , -diphenylprolinol derivative and anachiral thiourea was employed as the catalytic system, which was shown as apowerful activation strategy for the development of this reaction, affording productsin high yields and with excellent stereocontrol[EU]LaburpenaDoktorego tesi honetan, estrategia organokatalitikoak aukeratu dira zenbaitinteres handiko konposatuen sintesi asimetrikoa aurrera eramateko. Zentzu honetan,kaskada erreakzioetan oinarritutako prozesuak diseinatu dira aminokatalizatzaileekeskaintzen duten aktibazio modu ezberdinak erabiliz etekin eta kontrolestereokimiko altuak lortuz.Lehenik, enantioaberastutako furofurano poliordezkatuak lortzeko sintesiaminokatalitikoa ikertu da dihidroxiazetona eta aldehido , -asegabetuak erabiliz.Kasu honetan, iminio eta enamina aktibazio motak konbinatu egin dira oxa-Michael/aldolika erreakzioa/hemiazetalizazioa kaskada prozesu enantioselektibo etaeraginkor bat aurrera eramanez. Era berean, lortutako produktuen aldakortasunsintetikoak zenbait eraldaketa kimiko burutzea ahalbidetu du metodologia honengarrantzi sintetikoa erakutsiz. Halaber, garatutako estrategia aminokatalitikoazabaltzeko asmoz, -aminoazetofenonaren erabilera frogatu da -laktamaezberdinak lortuz. Aldi berean, sintetizatutako heteroziklo hauek konposatu 1,4-dikarboniliko enantioaberats ezberdinetan eraldatu egin dira.Bestalde, [2+2] zikloadizio organokatalitiko formala aztertu da katalisikobalente eta ez kobalentea erabiliz. Horretarako, aminokatalizatzaile eta tioureazosatutako sistema katalitikoa aukeratu da, bi aktibazio modu hauen kooperazioaketekin eta kontrol estereokimiko altuak lortzea ahalbideratzen duela frogatuz.Gobierno Vasco: beca y subvención a Grupos IT-328-10. UPV-EHU (UFI QOSYC 11/22 y Subvención,9/UPV00041.310-15835/2004) y al MICINN (CTQ2008-00136/BQU y CTQ2011-22790). Petronor S.A. por donación de hexano

Enantioselective organocatalyzed synthesis of 2-amino-3-cyano-4H-chromene derivatives

The structural motif that results from the fusion of a benzene ring to a heterocyclic pyran ring, known as chromene, is broadly found in nature and it has been reported to be associated with a wide range of biological activity. Moreover, asymmetric organocatalysis is a discipline in expansion that is already recognized as a well-established tool for obtaining enantiomerically enriched compounds. This review covers the particular case of the asymmetric synthesis of 2-amino-3-cyano-4H-chromenes using organocatalysis. Herein, we show the most illustrative examples of the methods developed by diverse research groups, following a classification based on these five different approaches: (1) addition of naphthol compounds to substituted a, a-dicyanoolefins; (2) addition of malononitrile to substituted o-vinylphenols; (3) addition of malononitrile to N-protected o-iminophenols; (4) Michael addition of nucleophiles to 2-iminochromene derivatives; and (5) organocatalyzed formal 4+2] cycloaddition reaction. In most cases, chiral thioureas have been found to be effective catalysts to promote the synthetic processes, and generally a bifunctional mode of action has been envisioned for them. In addition, squaramides and cinchona derivatives have been occasionally used as suitable catalysts for the substrates activation