Higher-Order Electrocyclizations in Biological and Synthetic Processes

In general, electrocyclizations follow the Woodward-Hoffmann's rules of conservation of orbital symmetry. These rules have been extensively verified in low-order processes, both in thermal and photochemical reactions, up to eight π-electrons. However, when the number of π-electrons in the system increases, some deviations of that general rules can be found. This focused review highlights the main features of reported higher-order electrocyclizations involving 10, 12, 14, 16 and 18 π-electrons. Some of these examples constitute useful intermediates in the synthesis of biologically active compounds. When computational studies were not included in the reported examples, DFT calculations have been performed to be included in this review. Analysis of the respective pericyclic topologies shows the importance of computational tools for understanding the selectivity observed experimentally.Financial support for this work was provided by the Spanish Ministerio de Ciencia, Innovación y Universidades (MICIN/AEI/PID2019-104772GB-I00 and MCIN/AEI/RED2022-134287-T) and the Gobierno Vasco/Eusko Jaurlaritza (GV(EJ, Grant IT-1553-22). The authors thank SGI/IZO-SGIker of the UPV/EHU and the DIPC for the generous allocation of computational resources

Radiationless mechanism of UV deactivation by cuticle phenolics in plants

[EN] Hydroxycinnamic acids present in plant cuticles, the interphase and the main protective barrier between the plant and the environment, exhibit singular photochemical properties that could allow them to act as a UV shield. Here, we employ transient absorption spectroscopy on isolated cuticles and leaf epidermises to study in situ the photodynamics of these molecules in the excited state. Based on quantum chemical calculations on p-coumaric acid, the main phenolic acid present in the cuticle, we propose a model in which cuticle phenolics display a photoprotective mechanism based in an ultrafast and non-radiative excited state deactivation combined with fluorescence emission. As such, the cuticle can be regarded as the first and foremost protective barrier against UV radiation. This photostable and photodynamic mechanism seems to be universal in land plants giving a special role and function to the presence of different aromatic domains in plant cuticles and epidermises.This work has been supported by grants RTI2018-094277-B/AEI/10.13039/501100011033, PID2020-119636GB-I00 and RED2018-102331-T from Agencia Estatal de Investigación, Ministerio de Ciencia e Innovación, Spain co-financed by the European Regional Development Fund (ERDF) and SBPLY/17/180501/000189 from UCLM Junta de Comunidades de Castilla-La Mancha (JCCM-FEDER). Computational resources, technical and human support provided by IZO-SGI, SGIker (UPV/EHU, MICINN, GV/EJ, ERDF and ESF) and DIPC (Donostia International Physics Centre) are gratefully acknowledged. Ana González Moreno is the recipient of a Formación Personal Universitario fellowship FPU17/01771. The authors thank Dr. Jessica Román, Dr. José Luis Zafra and Dr. Cristina Capel for their technical work and Dr. Victoria Gómez, Universidad de Castilla-La Mancha, for the NMR assignments

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

Nature of Alkali- and Coinage-Metal Bonds Versus Hydrogen Bonds

We have quantum chemically studied the structure and nature of alkali- and coinage-metal bonds (M-bonds) versus that of hydrogen bonds between A-M and B- in archetypal [A-M center dot center dot center dot B](-) model systems (A, B=F, Cl and M=H, Li, Na, Cu, Ag, Au), using relativistic density functional theory at ZORA-BP86-D3/TZ2P. We find that coinage-metal bonds are stronger than alkali-metal bonds which are stronger than the corresponding hydrogen bonds. Our main purpose is to understand how and why the structure, stability and nature of such bonds are affected if the monovalent central atom H of hydrogen bonds is replaced by an isoelectronic alkali- or coinage-metal atom. To this end, we have analyzed the bonds between A-M and B- using the activation strain model, quantitative Kohn-Sham molecular orbital (MO) theory, energy decomposition analysis (EDA), and Voronoi deformation density (VDD) analysis of the charge distribution.O.L. gratefully acknowledges the UPV/EHU for her postdoctoral grant. This work was supported by funding provided by the Spanish Ministry of Economy and Competitiveness (MINECO CTQ2013-45415P and CTQ2016-80375P), the Gobierno Vasco-Eusko Jaurlaritza (Grant IT673-13) and the Netherlands Organization for Scientific Research (NWO). We also thank SURFsara for the support in using the Lisa Computer Cluster, and DIPC and SGI-IZO-SGIker (UPV/EHU) for generous allocation of computational resource

syn-Selective Michael reaction of α-branched aryl acetaldehydes with nitroolefins promoted by squaric amino acid derived bifunctional Brønsted bases

[EN] Here we describe a direct access to 2,2,3-trisubstituted syn γ-nitroaldehydes by addition of α-branched aryl acetaldehydes to nitroolefins promoted by a cinchona based squaric acid-derived amino acid peptide. Different α-methyl arylacetaldehydes react with β-aromatic and β-alkyl nitroolefins to afford the Michael adducts in high enantioselectivity and syn-selectivity. NMR experiments and DFT calculations predict the reaction to occur through the intermediacy of E-enolate. The interaction between the substrates and the catalyst follows Pápai’s model, wherein an intramolecular H-bond interaction in the catalyst between the NH group of one of the tert-leucines and the squaramide oxygen seems to be key for discrimination of the corresponding reaction transition states.Support has been provided by the University of the Basque Country UPV/EHU (UFI QOSYC 11/22), Basque Government (GV grant IT1236-19), and Ministerio de Ciencia e Innovación (grant PID2019-109633GB-C21), Spain. A. G. and T. E. thank Basque Government and MINECO respectively for fellowships. We would like to express our gratitude to the students I. Gonzalez-Mujika and M. Campo for their participation in conducting some experiments of the reaction scope. We also thank SGIker (UPV/EHU) for providing NMR, HRMS. X-Ray and computational resources

Role of imine isomerization in the stereocontrol of the Staudinger reaction between ketenes and imines

Computational–experimental analysis has allowed determining that the stereochemistry of the Staudinger reaction between ketenes and imines is strongly associated with the nature of the imine, which affects the two steps of the reaction. The first step, namely the nucleophilic attack of the sp2-hybridized nitrogen atom of the imine on the sp-hybridized carbon atom of the ketene, is affected by the energetically accessible in situ isomerization patterns of the imine. The second step consists of a conrotatory electrocyclization of the zwitterionic intermediate formed in the previous step. This latter pericyclic step depends on the inward/outward torquoelectronic effects generated by the substituents of the imine. The impact of these factors on the stereochemistry of this reaction has been analyzed kinetically by numerical methods. The results of these simulations are compatible with the experimental results and support these conclusions

Efficient Diastereo- and Enantioselective Synthesis of exo-Nitroprolinates by 1,3-Dipolar Cycloadditions Catalyzed by Chiral Phosphoramidite⋅Silver(I) Complexes

Chiral complexes formed by privileged phosphoramidites and silver triflate or silver benzoate are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides generated from α-amino acid-derived imino esters and nitroalkenes affording with high dr the exo-cycloadducts 4,5-trans-2,5-cis-4-nitroprolinates in high ee at room temperature. In general, better results are obtained using silver rather than copper(II) complexes. In many cases the exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. The mechanism and the justification of the experimentally observed stereodiscrimination of the process are supported by DFT calculations. These enantiomerically enriched exo-nitroprolinates can be used as reagents for the synthesis of nitropiperidines, by ester reduction and ring expansion, which are inhibitors of farnesyltransferase.This work has been supported by the Spanish Ministerio de Ciencia e Innovación (MICINN) (Consolider INGENIO 2010 CSD2007-00006, CTQ2010-20387), FEDER, Generalitat Valenciana (PROMETEO/2009/039abd PROMETEOII/2014/017), and by the University of Alicante. L. M. C. thanks the MICINN for an FPI fellowship. Financial support was provided by the MICINN and FEDER (projects CTQ2010-16959/BQU, 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 authors thank the SGI/IZO-SGIker UPV/EHU and the DIPC for generous allocation of computational resources

Enantioselective Synthesis of exo-4-Nitroprolinates from Nitro­alkenes and Azomethine Ylides Catalyzed by Chiral Phosphor­amidite·Silver(I) or Copper(II) Complexes

Chiral complexes formed by privileged phosphoramidites derived from chiral binol and optically pure Davies’ amines, and copper(II) triflate, silver(I) triflate or silver(I) benzoate are excellent catalysts for the general 1,3-dipolar cycloaddition between nitroalkenes and azomethine ylides generated from α-amino acid derived imino esters. These three methods can be conducted at room temperature to afford the exo-cycloadducts (4,5-trans-2,5-cis-4-nitroprolinates) with high diastereoselectivity and high enantioselectivity. In general, the three procedures are complementary but silver catalysts are more versatile and less sensitive to sterically congested starting materials.This work has been supported by the Spanish Ministerio de Ciencia e Innovación (MICINN) (Consolider INGENIO 2010 CSD2007-00006, CTQ2010-20387) and Ministerio de Economía y Competitvidad (MINECO) (CTQ2013-43446P, CTQ2014-51912-REDC), FEDER, Generalitat Valenciana (PROMETEO/2009/039 and 2014/017), and by the University of Alicante. L.M.C. thanks the MICINN for a FPI fellowship. Financial support was also provided by the MICINN and FEDER (projects CTQ2010-16959/BQU), the University of the Basque Country (UPV/EHU, UFI11/22QOSYC) and the Basque Government (GV/EJ, grant IT-324-07)

Phosphoramidite-Cu(OTf)2 complexes as chiral catalysts for 1,3-dipolar cycloaddition of iminoesters and nitroalkenes

Chiral complexes formed by phosphoramidites such as (Sa,R,R)-9 and Cu(OTf)2 are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted proline esters mainly as exo-cycloadducts in high er at room temperature. The exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. DFT calculations support the stereochemical results.This work has been supported by the Spanish Ministerio de Economía y Competitividad (MINECO) (Consolider INGENIO 2010 CSD2007-00006, CTQ2010-20387), FEDER, Generalitat Valenciana (PROMETEO/2009/039), and the University of Alicante. L.M.C. thanks the MINECO for an FPI fellowship