Recent Development in Palladium-Catalyzed Domino Reactions: Access to Materials and Biologically Important Carbo- and Heterocycles

The chemistry of palladium complexes has no limits. Many domino processes (even multicomponent) are continuously appearing in the literature. Carbocyclic and heterocyclic molecules are efficiently prepared under the atom-economy principle using the smallest amount of the catalyst. The importance of the applications in many scientific areas of all of these cyclic skeletons made this general methodology much more attractive.We gratefully acknowledge financial support from the Spanish Ministerio de Economía y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI), and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat Valenciana (PROMETEOII/2014/017), University of Alicante and Mersin University (Project. MEU-2017-COL-01007-M150D)

Stereoselective Synthesis of Densely Substituted Pyrrolidines via a [3 + 2] Cycloaddition Reaction between Chiral N-tert-Butanesulfinylazadienes and Azomethine Ylides

The N-tert-butanesulfinylimine group behaves as a suitable electron-withdrawing group in 1-azadienes, allowing the diastereoselective synthesis of densely substituted pyrrolidines by 1,3-dipolar cycloadditions (1,3-DCs) with azomethylene ylides. The use of Ag2CO3 as catalyst has allowed one to obtain a wide variety of proline derivatives with high regio- and diastereoselectivities. Subsequent efficient transformations provide valuable proline derivatives, some of which can be used as organocatalysts. The influence of the N-tert-butanesulfinyl group on the diastereoselectivity was studied by computational methods.We gratefully acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (project RED2018-102387-T), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2017-82935-P and PID2019-107268GB-I00), the Generalitat Valenciana (IDIFEDER/2021/013, GVA-COVID19/2021/079, CIDEGENT/2020/058, CIAPOT/2022/11, and APOTIP/2021/020), Medalchemy S. L. (Medalchemy-18T), and the University of Alicante (VIGROB-068, UAUSTI21-05)

Synthesis of Bicyclic Hemiacetals Catalyzed by Unnatural Densely Substituted γ-Dipeptides

The asymmetric synthesis of bicyclic highly substituted tetrahydropyrans is described. The reaction is catalyzed by unnatural γ-dipeptides based on densely substituted l- and d-proline derivatives. This organocatalytic one-pot reaction takes place among a ketone, a nitroalkene, and an aldehyde to yield an octahydro-2H-chromene scaffold. Monomeric species, from which the corresponding γ-dipeptides are synthesized, cannot catalyze the reaction, thus confirming the emergent nature of the catalytic behavior of these dimeric species.Financial support for this work was provided by the Spanish Ministerio de Ciencia, Innovación y Universidades (MICINNFEDER, Grants PID2019-104772GB-I00 and RED2018-102387-T) and the Gobierno Vasco/Eusko Jaurlaritza (GV/EJ, Grant IT-1553-22). M.d.G.R. thanks the DIPC and UPV/EHU for her postdoctoral contract. M.A. thanks the Gobierno Vasco/Eusko Jaurlaritza for her Ph.D. grant. J.Z. thanks the China Scholarship Council for his Ph.D. grant (CSC 201908390051). The authors also thank the SGI/IZO-SGIker of the UPV/EHU and the DIPC for the generous allocation of analytical and computational resources

Current Trends towards the Synthesis of Bioactive Heterocycles and Natural Products Using 1,3-Dipolar Cycloadditions (1,3-DC) with Azomethine Ylides

This review summarizes the trends in the formation of complex or not so complex heterocyclic structures through 1,3-dipolar cy­cloadditions of azomethine ylides. Diastereo- and enantioselective processes as well as non-asymmetric cycloadditions constitute very important synthetic tools for achieving these compounds. This review covers the literature from 2015 through 2016 and organizes the research in terms of biologically important heterocycles and natural products from cascade 1,3-dipolar cycloadditions of azomethine ylides to the simpler forms of 1,3-dipolar cycloaddition.We thank Mersin University (Project no. BAP 2015-AP2-1342), and Universities of Seville and Alicante for their support. We also thank funding by the Spanish Ministerio de Ciencia e Innovación (MICINN) (Consolider INGENIO 2010 CSD2007-00006, CTQ2004-00808/BQU, CTQ2007-62771/BQU, CTQ2010-20387 and the Hispano-Brazilian project PHB2008-0037-PC), the Spanish Ministerio de Economía y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat Valenciana (PROMETEO 2009/039 and PROMETEOII/2014/017). M.G.R. thanks Junta de Andalucía (Grant 2012/FQM 1078 and a postdoctoral fellowship)

Additive and Emergent Catalytic Properties of Dimeric Unnatural Amino Acid Derivatives: Aldol and Conjugate Additions

Different densely substituted L- and D-proline esters were prepared by asymmetric (3+2) cycloaddition reactions catalyzed by conveniently selected EhuPhos chiral ligands. The γ-nitro-2-alkoxycarbonyl pyrrolidines thus obtained in either their endo or exo forms were functionalized and coupled to yield the corresponding γ-dipeptides. The catalytic properties of these latter dimers were examined using aldol and conjugate additions as case studies. When aldol reactions were analyzed, an additive behavior in terms of stereocontrol was observed on going from the monomers to the dimers. In contrast, in the case of the conjugate additions between ketones and nitroalkenes, the monomers did not catalyze this reaction, whereas the different γ-dipeptides promoted the formation of the corresponding Michael adducts. Therefore, in this latter case emergent catalytic properties were observed for these novel γ-dipeptides based on unnatural proline derivatives. Under certain conditions stoichiometric amounts of ketone, acid and nitroalkene), formation of N-acyloxy-2-oxooctahydro-1H-indoles was observed.Financial support for this work was provided by the Spanish Ministerio de Ciencia e Innovación (MICINN-FEDER, Grants PID2019-104772GB-100 and RED2018-102387-T) and the Gobierno Vasco/Eusko Jaurlaritza (GV/EJ, Grant IT-1346-19). A.R.-O. thanks the Ministerio de Ciencia, Innovación y Universidades for her Ph.D. grant. M.d.G.R thanks the DIPC and UPV/EHU for her postdoctoral contract

Enantioselective 1,3-Dipolar Cycloaddition Using (Z)-α-Amidonitroalkenes as a Key Step to the Access to Chiral cis-3,4-Diaminopyrrolidines

The enantioselective 1,3-dipolar cycloaddition between imino esters and (Z)-nitroalkenes bearing a masked amino group in the β-position was studied using several chiral ligands and silver salts. The optimized reaction conditions were directly applied to the study of the scope of the reaction. The determination of the absolute configuration was evaluated using NMR experiments and electronic circular dichroism (ECD). The reduction and hydrolysis of both groups was performed to generate in an excellent enantiomeric ratio the corresponding cis-2,3-diaminoprolinate.We gratefully acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (project RED2018-102387-T) the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P, CTQ2016-80375-P, CTQ2017-82935-P and PID2019-107268GB-I00), the Generalitat Valenciana (IDIFEDER/2021/013, CIDEGENT/2020/058 and APOTIP/2020/002), Medalchemy S. L. (Medalchemy-18T) and the University of Alicante (VIGROB-068, UAUSTI21-05)

Diastereoselective deacylative aldol reaction of 3-acetyl-3-fluorooxindoles with aldehydes

The deacetylative aldol reaction of N-methyl-3-acetyl-3-fluoro-2-oxindole is optimized with benzaldehyde and the most appropriate conditions are used for the survey of the scope of this transformation with different aldehydes. The relative configuration of the resulting compounds is also confirmed. The reaction is diastereoselective and affords the syn-stereoisomer in good yields. DFT calculations are used for the explanation of this diastereoselectivity through a traditional chair-like transition state.We gratefully acknowledge financial support from the Spanish Ministerio de Ciencia, Innovación y Universidades (project RED2018-102387-T) the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P, CTQ2016-80375-P, CTQ2017-82935-P, PID2019-104090RB-100 and PID2019-107268GB-I00), the Generalitat Valenciana (IDIFEDER/2021/013, CIDEGENT/2020/058 and APOTIP/2020/002), Medalchemy S. L. (Medalchemy-18T) and the University of Alicante (VIGROB-068, UAUSTI21-05). P.M. thanks the Regional Government of Aragon (Grupos 17R-34 and a pre-doctoral contract to M.P.) for financial support. The authors thankfully acknowledge the resources from the super-computers "Memento" and “Cierzo”, technical expertise and assistance provided by BIFI-ZCAM (Universidad de Zaragoza, Spain)

Stereoselective Synthesis of Biheterocycles Containing Indole and 5,6-Dihydropyridin-2(1H)-one or α-Methylene-β-butyrolactam Scaffolds

Indium-mediated allylation of N-tert-butanesulfinyl imines derived from indole-2 and 3-carbaldehydes 3 and 5 with allylic bromides 6, proceed with high diastereoselectivity. Homoallylic amide derivatives 13 and 14 are transformed into dihydropyridinones 15 and 16, upon successive desulfinylation, N-acylation with acryloyl chloride and ring-closing-metathesis. Desulfinylation of amine ester derivatives 17 and 18, obtained when ethyl 2-(bromomethyl)acrylate (6 b) is used as the allylating reagent, lead to the corresponding α-methylene-γ-butyrolactams 19 and 20, in modest yields.We thank the continuous financial support from the Spanish Ministerio de Economía y Competitividad (MINECO; project CTQ2016-81797-REDC, CTQ2017-85093-P), Ministerio de Ciencia, Innovación y Universidades (RED2018-102387-T, PID2019-107268GB-100), FEDER, the Generalitat Valenciana (IDIFEDER/2021/013, CIDEGENT/2020/058, APOTIP/2021/020), the University of Alicante (VIGROB-068), and the Ministère de l’Enseignement Supérieur et de la Recherche Scientifique Algérienne; Direction de la Coopération et des Echanges Interuniversitaires; Programme de Formation Résidentielle à l’Étranger au titre de l’année universitaire 2019/2020: Programme National Exceptionnel (PNE)

Dual chiral silver catalyst in the synthetic approach to the core of hepatitis C virus inhibitor GSK 625433 using enantioselective 1,3-dipolar cycloaddition of azomethine ylides and electrophilic alkenes

The asymmetric 1,3-dipolar cycloaddition of an imino ester 5 with tert-butyl acrylate is catalyzed by a dual chiral silver(I) complex formed from a chiral phosphoramidite 14 and the chiral silver(I) binolphosphate (R)-17. This reaction is selected to achieve the synthesis of enantiomerically enriched key structures to access the third generation of GSK HCV inhibitors. The scope of this dual chiral catalytic system is analyzed by employing different imino esters and dipolarophiles, and also compared with the same cycloaddition reactions performed with the chiral phosphoramidite 14·AgClO4 complex.Financial support was provided by the Spanish Ministerio de Ciencia e Innovación (MICINN) (projects CTQ2010-20387, and Consolider Ingenio 2010, CSD2007-00006), the Spanish Ministerio de Economía y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat Valenciana (PROMETEO 2009/039 and PROMETEOII/2014/017), and the University of Alicante

Remote Substituent Effects on the Stereoselectivity and Organocatalytic Activity of Densely Substituted Unnatural Proline Esters in Aldol Reactions

The organocatalytic activities of highly substituted proline esters obtained through asymmetric [3+2] cycloadditions of azomethine ylides derived from glycine iminoesters have been analyzed by 19F NMR and through kinetic isotope effects. Kinetic rate constants have been determined for unnatural proline esters incorporating different substituents. It has been found that exo-L and endo-L unnatural proline methyl esters yield opposite enantiomers in aldol reactions between cyclic ketones and aromatic aldehydes. The combined results reported in this study show subtle and remote effects that determine the organocatalytic behavior of these synthetic but readily available amino acid derivatives. These data can be used as design criteria for the development of new pyrrolidine-based organocatalysts.Financial support was provided by the Spanish Ministerio de Economía y Competitividad (MINECO) and the Fondo Europeo de Desarrollo Regional (FEDER) (projects CTQ2010-16959/BQU, CTQ2012-35535, CTQ2013-40855-R, CTQ2007-62771/BQU, CTQ2010-20387, CTQ2010-17436, and Consolider-Ingenio CSD2007-00006), the University of the Basque Country (UPV/EHU, UFI11/22 QOSYC), the Basque Government (GV/EJ, grant IT-324-07), the Generalitat Valenciana-FEDER (PROMETEO/2009/039), the Gobierno de Aragón-FSE (research group E40), and the University of Alicante. M. d. G. R. thanks the Donostia International Physics Center (DIPC) for a postdoctoral contract. M. S. and L. C. gratefully thank MINECO for a contract funding their PhD projects