Lanthanum-pyBOX complexes as catalysts for the enantioselective conjugate addition of malonate esters to beta-gamma-unsaturated alfa-ketimino esters

"This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Coordination Chemistry on 2018, available online: https://doi.org/10.1080/00958972.2018.1437422."[EN] In this paper, we report the application of chiral complexes of La(III) with pyBOX ligands as Lewis acid catalysts in the conjugate addition of malonic esters to N-tosyl imines derived from ß,gamma-unsaturated alfa-keto esters to give the corresponding chiral alfa,ß-dehydroamino esters. pyBOX complexes with La(III), Yb(III), Sc(III), and In(III) triflates were assessed in this reaction but only La(III) showed good activity and enantioselectivity, while Yb(III) provided the expected product with low yield and stereoselectivity, and the Sc(III) and In(III) complexes were completely inactive. The complex of La(OTf)3 with the diphenyl-pyBOX ligand prepared in situ provided the best results and allowed obtaining chiral ¿,ß-dehydroamino esters 3 with excellent yields, E:Z diastereomeric ratios (29:71-99:1) and high enantiomeric excesses (20-95%). The reaction could be applied to imines having a substituted aromatic ring or a heterocycle attached to the double bond, although the presence of electron-withdrawing groups on the aromatic ring was detrimental for stereoselectivity. The reaction products were obtained with the S configuration at the stereogenic center and the Z configuration at the enamine double bond as determined by NOESY experiments and X-ray analysis. Based on the experimental results a stereochemical model involving a nine-coordinate La(III) species has been proposed.This work was supported by the Ministerio de Economia y Competitividad (MINECO-Gobierno de Espana) [grant number CTQ2013-47494-P].Espinosa, M.; Blay, G.; Cardona, L.; Fernández, I.; Muñoz Roca, MDC.; Pedro, J. (2018). Lanthanum-pyBOX complexes as catalysts for the enantioselective conjugate addition of malonate esters to beta-gamma-unsaturated alfa-ketimino esters. Journal of Coordination Chemistry. 71(6):864-873. https://doi.org/10.1080/00958972.2018.1437422S864873716Yukawa, T., Seelig, B., Xu, Y., Morimoto, H., Matsunaga, S., Berkessel, A., & Shibasaki, M. (2010). Catalytic Asymmetric Aza-Morita−Baylis−Hillman Reaction of Methyl Acrylate: Role of a Bifunctional La(O-iPr)3/Linked-BINOL Complex. Journal of the American Chemical Society, 132(34), 11988-11992. doi:10.1021/ja103294aKodama, H., Ito, J., Hori, K., Ohta, T., & Furukawa, I. (2000). Lanthanide-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrones to alkenes using 3,3′-bis(2-oxazolyl)-1,1′-bi-2-naphthol (BINOL-Box) ligands. Journal of Organometallic Chemistry, 603(1), 6-12. doi:10.1016/s0022-328x(00)00024-3De Bettencourt-Dias, A., Barber, P. S., & Bauer, S. (2012). A Water-Soluble Pybox Derivative and Its Highly Luminescent Lanthanide Ion Complexes. Journal of the American Chemical Society, 134(16), 6987-6994. doi:10.1021/ja209572mComelles, J., Pericas, À., Moreno-Mañas, M., Vallribera, A., Drudis-Solé, G., Lledos, A., … Roces-Fernández, L. (2007). Highly Enantioselective Electrophilic Amination and Michael Addition of Cyclic β-Ketoesters Induced by Lanthanides and (S,S)-ip-pybox:  The Mechanism⊥. The Journal of Organic Chemistry, 72(6), 2077-2087. doi:10.1021/jo0622678Sanchez-Blanco, A. I., Gothelf, K. V., & Jørgensen, K. A. (1997). Lanthanide-catalyzed endo- and enantioselective 1,3-dipolar cycloaddition reactions of nitrones with alkenes. Tetrahedron Letters, 38(45), 7923-7926. doi:10.1016/s0040-4039(97)10048-xDesimoni, G., Faita, G., Guala, M., & Pratelli, C. (2003). Different Lanthanide Ions and the Pybox Substituents Induce the Reverse of the Sense of Induction in the Enantioselective Diels−Alder Reaction between Acryloyloxazolidinone and Cyclopentadiene. The Journal of Organic Chemistry, 68(20), 7862-7866. doi:10.1021/jo034215dDesimoni, G., Faita, G., Filippone, S., Mella, M., Zampori, M. G., & Zema, M. (2001). A new and highly efficient catalyst for the enantioselective Mukaiyama–Michael reaction between ( E )-3-crotonoyl-1,3-oxazolidin-2-one and 2-trimethylsilyloxyfuran. Tetrahedron, 57(51), 10203-10212. doi:10.1016/s0040-4020(01)01055-9Sammis, G. M., Danjo, H., & Jacobsen, E. N. (2004). Cooperative Dual Catalysis:  Application to the Highly Enantioselective Conjugate Cyanation of Unsaturated Imides. Journal of the American Chemical Society, 126(32), 9928-9929. doi:10.1021/ja046653nJiang, J., Ma, Z., & Castle, S. L. (2015). Bulky α,β-dehydroamino acids: their occurrence in nature, synthesis, and applications. Tetrahedron, 71(34), 5431-5451. doi:10.1016/j.tet.2015.06.001Li, B., Cooper, L. E., & van der Donk, W. A. (2009). Chapter 21 In Vitro Studies of Lantibiotic Biosynthesis. Methods in Enzymology, 533-558. doi:10.1016/s0076-6879(09)04821-6M.A. Blaskovich. In Handbook on Syntheses of Amino Acids. General Route to Amino Acids, p. 225, ACS and Oxford University Press, New York (2010).Espinosa, M., García-Ortiz, A., Blay, G., Cardona, L., Muñoz, M. C., & Pedro, J. R. (2016). E,Z-Stereodivergent synthesis of N-tosyl α,β-dehydroamino esters via a Mukaiyama–Michael addition. RSC Advances, 6(19), 15655-15659. doi:10.1039/c5ra27354dEspinosa, M., Blay, G., Cardona, L., & Pedro, J. R. (2013). Corrigendum: Asymmetric Conjugate Addition of Malonate Esters to α,β-UnsaturatedN-Sulfonyl Imines: An Expeditious Route to Chiral δ-Aminoesters and Piperidones. Chemistry - A European Journal, 19(52), 17632-17632. doi:10.1002/chem.201304285X-ray data for compound 3bl: crystallized from hexane-EtOAc; C25H29SN1O8; Mr = 503.55; triclinic; space group = P1; a = 6.2550(2), b = 10.2870(4), c = 11.1380(5) Å; α = 69.333(2), β = 78.688(2), γ = 82.555(2)°; V = 656.11(5) Å3; Z = 1; ρcalcd = 1.274 Mg m−3; μ = 0.170 mm−1; F(0 0 0) = 266. A colorless crystal of 0.04 × 0.08 × 0.08 mm3 was used; 5797 [R(int) = 0.0682] total reflections were collected on a Enraf Nonius Kappa CCD equipped with a graphite monochromator and Mo Kα (λ = 0.71073 Å) radiation. The structures were solved by using direct methods with SHELXS-2014 and refined by using full matrix least squares on F2 with SHELXL-2014 [16]. Non-hydrogen atoms were refined anisotropically and hydrogens were obtained or placed in calculated positions refined by using idealized geometries (riding model) and assigned fixed isotropic displacement parameters. Final values were R = 0.0469 and ωR = 0.1054. CCDC-1581116 contains the supplementary crystallographic data for this compound. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.Parsons, S., Flack, H. D., & Wagner, T. (2013). Use of intensity quotients and differences in absolute structure refinement. Acta Crystallographica Section B Structural Science Crystal Engineering and Materials, 69(3), 249-259. doi:10.1107/s205251921301001

Resurgence of vaccine-preventable diseases in Venezuela as a regional public health threat in the Americas

Venezuela’s tumbling economy and authoritarian rule have precipitated an unprecedented humanitarian crisis. Hyperinflation rates now exceed 45,000%, and Venezuela’s health system is in free fall. The country is experiencing a massive exodus of biomedical scientists and qualified healthcare professionals. Reemergence of arthropod-borne and vaccine-preventable diseases has sparked serious epidemics that also affect neighboring countries. In this article, we discuss the ongoing epidemics of measles and diphtheria in Venezuela and their disproportionate impact on indigenous populations. We also discuss the potential for reemergence of poliomyelitis and conclude that action to halt the spread of vaccine-preventable diseases within Venezuela is a matter of urgency for the country and the region. We further provide specific recommendations for addressing this crisis. © 2019 Centers for Disease Control and Prevention (CDC). All rights reserved

Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage

Antimicrobial resistance (AMR) is a serious threat to global public health, but obtaining representative data on AMR for healthy human populations is difficult. Here, we use meta-genomic analysis of untreated sewage to characterize the bacterial resistome from 79 sites in 60 countries. We find systematic differences in abundance and diversity of AMR genes between Europe/North-America/Oceania and Africa/Asia/South-America. Antimicrobial use data and bacterial taxonomy only explains a minor part of the AMR variation that we observe. We find no evidence for cross-selection between antimicrobial classes, or for effect of air travel between sites. However, AMR gene abundance strongly correlates with socio-economic, health and environmental factors, which we use to predict AMR gene abundances in all countries in the world. Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR. We propose metagenomic analysis of sewage as an ethically acceptable and economically feasible approach for continuous global surveillance and prediction of AMR.Peer reviewe