Complejos de rutenio con ligandos fosfina-fosfito. Síntesis, caracterización y aplicación en catálisis asimétrica

En nuestro grupo se inició hace algunos años una línea de investigación dedicada al estudio de complejos de rutenio con ligandos fosfina-fosfito (P-OP). Esta elección se realizó en base a la diversa reactividad catalítica de los complejos de rutenio con ligandos fosforados, junto con la elevada modularidad de los ligandos P-OP preparados en nuestro laboratorio, que facilitan el proceso de optimización de un catalizador. Además, con anterioridad a nuestro trabajo no se habían descrito complejos de Ru con ligandos de esta clase. En una fase inicial, el trabajo se dedicó a la síntesis y la caracterización estructural de una serie de bis-alil complejos de rutenio de formulación [Ru(¿3-2-MeC3H4)2(P-OP)]. La elección de estos derivados se debe a que los complejos análogos que incorporan ligandos difosfina [Ru(¿3-2-MeC3H4)2(P-P)] (P-P = difosfina) son activos en distintas reacciones catalíticas. Además, estos derivados resultan adecuados como precursores sintéticos de otros complejos activos en distintos procesos catalíticos homogéneos. Como continuación de estas investigaciones, en el primer capítulo de esta Tesis Doctoral se ha abordado el estudio de la reactividad de los derivados [Ru(¿3-2-MeC3H4)2(P-OP)], así como su aplicación en un par de reacciones catalíticas seleccionadas. Concretamente la hidrogenación enantioselectiva de ácidos carboxílicos ¿¿¿-insaturados y la polimerización del 1-norborneno mediante metátesis con apertura de anillo (ROMP) En el segundo capítulo del trabajo se recogen los estudios dirigidos al descubrimiento de nuevos complejos de formulación RuCl2(P-OP)(N-N) (P-OP = ligando fosfina-fosfito; N-N = ligando nitrogenado quelatante) apropiados para la hidrogenación de N-aril iminas. Los resultados más importantes de este trabajo se recogen a continuación: 1.- Los alil complejos de formulación [Ru(¿3-2-MeC3H4)2(P-OP)] reaccionan fácilmente con reactivos próticos. En particular, la reacción con el pentaclorofenol produce la abstracción de un ligando alilo y la formación del alil-complejo [Ru(¿2-O,Cl-OC6Cl5)(¿3-2-MeC3H4)(2j)] (3j) Por el contrario, la reacción con el ácido tíglico permite desplazar los dos ligandos alilo, y da lugar a los correspondientes tiglatos [Ru(¿2-O2CC(Me)=CHMe)2(P-OP)] (4a y 4j). 2.- Los alil complejos [Ru(¿3-2-MeC3H4)2(P-OP)] conducen a catalizadores activos en la hidrogenación enantioselectiva de ácidos ¿¿¿¿insaturados. Para esta transformación se ha observado una influencia significativa de la temperatura y el disolvente en la actividad catalítica y en la enantioselectividad del catalizador. En el caso del ácido tíglico, la optimización de la estructura del ligando fosfina-fosfito ha conducido a un catalizador que produce un exceso enantiomérico del 87%. Este valor aumenta hasta el 89 % de exceso enantiomérico en el caso del ácido 2-metil-1-pentenoico. 3.- Los alil-complejos [Ru(¿3-2-MeC3H4)2(P-OP)] catalizan la polimerización del 2-norborneno mediante un proceso de metátesis con apertura del anillo (ROMP) con rendimientos de hasta el 74%, para un valor de 100 de la relación sustrato/catalizador. El análisis de los pesos moleculares y de las polidispersidades de los polímeros obtenidos muestra que el proceso de activación del catalizador es considerablemente más lento que el de crecimiento de la cadena. 4.- Se ha llevado a cabo la síntesis de una familia de complejos de formulación RuCl2(P-OP)(N-N). Las estructuras de estos derivados se han estudiado en profundidad mediante técnicas de RMN y de difracción de rayos X. En particular, los derivados de formulación RuCl2(P-OP)(DPEN) muestran configuraciones en las que los átomos de cloro se encuentran dispuestos en posiciones mutuamente cis o trans según la naturaleza del ligando fosfina-fosfito y la configuración de la diamina. 5.- Los estudios sobre la aplicación de los complejos RuCl2(P-OP)(N-N) en la hidrogenación enantioselectiva de la acetofenona revelan que estos complejos conducen, en presencia de tBuOK, a catalizadores que operan con valores bajos o moderados de actividad catalítica y enantioselectividad. En las reacciones llevadas a cabo en iPrOH, se ha observado que la reducción de la cetona mediante un proceso de transferencia de hidrógeno desde el disolvente es un proceso competitivo con la hidrogenación directa. La presencia de ambos procesos dificulta notablemente la consecución de valores elevados de enantioselectividad. 6.- Los complejos RuCl2(P-OP)(N-N) en presencia de tBuOK conducen a catalizadores eficientes en la hidrogenación enantioselectiva de N-aril iminas, que operan en condiciones suaves de reacción (temperatura ambiente y 4 atm de H2) y niveles de enantioselectividad elevados. El curso estereoquímico de la reacción puede explicarse mediante la participación de un dihidruro de formulación cis-RuH2(P-OP)(N-N). 7. La optimización del ligando P-OP en las reacciones de hidrogenación de iminas con los complejos RuCl2(P-OP)(N-N) ha permitido localizar un catalizador basado en un ligando P-OP aquiral. Este catalizador tiene un rango de aplicación amplio que permite preparar una amplia variedad de N-aril aminas con elevados niveles de exceso enantiomérico. 8.- Los estudios preliminares realizados con el complejo 7j indican que los complejos de formulación RuCl2(P-OP)(N-N) son capaces de efectuar la reducción de iminas mediante el empleo de aductos amina-borano. Sin embargo, debido a la complejidad del sistema, el desarrollo de un proceso catalítico que curse con valores de enantioselectividad y conversiones satisfactorios requerirá estudios adicionales a los realizados que contemplen diferentes condiciones de reacción y catalizadores alternativos

Simplified statistical image reconstruction for X-ray CT with beam-hardening artifact compensation

CT images are often affected by beam-hardening artifacts due to the polychromatic nature of the X-ray spectra. These artifacts appear in the image as cupping in homogeneous areas and as dark bands between dense regions, such as bones. This paper proposes a simplified statistical reconstruction method for X-ray CT based on Poisson statistics that accounts for the non-linearities caused by beam hardening. The main advantages of the proposed method over previous algorithms is that it avoids the preliminary segmentation step, which can be tricky, especially for low-dose scans, and it does not require knowledge of the whole source spectrum, which is often unknown. Each voxel attenuation is modeled as a mixture of bone and soft tissue by defining density-dependent tissue fractions, maintaining one unknown per voxel. We approximate the energy-dependent attenuation corresponding to different combinations of bone and soft tissue, so called beam-hardening function, with the 1D function corresponding to water plus two parameters that can be tuned empirically. Results on both simulated data with Poisson sinogram noise and two rodent studies acquired with the ARGUSCT system showed a beam hardening reduction (both cupping and dark bands) similar to analytical reconstruction followed by post-processing techniques, but with reduced noise and streaks in cases with low number of projections, as expected for statistical image reconstruction.This work was partially funded by NIH grants R01-HL-098686 and U01 EB018753, by Spanish Ministerio de Economia y Competitividad (projects TEC2013-47270-R and RTC-2014-3028-1) and the Spanish Ministerio de Economia, Industria y Competitividad (projects DPI2016-79075-R AEI/FEDER, UE - Agencia Estatal de Investigación and DTS17/00122 Instituto de Salud Carlos III - FIS), and co-financed by ERDF (FEDER) Funds from the European Commission, “A way of making Europe”. The CNIC is supported by the Spanish Ministerio de Economia, Industria y Competitividad and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505).En prens

Hydrogenation of imines catalysed by ruthenium(ii) complexes based on lutidine-derived CNC pincer ligands

The preparation of new Ru(ii) complexes incorporating fac-coordinated lutidine-derived CNC ligands is reported. These derivatives are selectively deprotonated by tBuOK at one of the methylene arms of the pincer, leading to catalytically active species in the hydrogenation of imines.Ministerio de Economía y Competitividad CTQ2009-11867, CSD2007-00006Junta de Andalucía 2008/FQM-3830, 2009/FQM-483

Investigation of Different Sparsity Transforms for the PICCS Algorithm in Small- Animal Respiratory Gated CT

Data Availability Statement: All relevant data are available from the Zenodo database, under the DOI: http://dx.doi.org/10.5281/zenodo.15685.Respiratory gating helps to overcome the problem of breathing motion in cardiothoracic small-animal imaging by acquiring multiple images for each projection angle and then assigning projections to different phases. When this approach is used with a dose similar to that of a static acquisition, a low number of noisy projections are available for the reconstruction of each respiratory phase, thus leading to streak artifacts in the reconstructed images. This problem can be alleviated using a prior image constrained compressed sensing (PICCS) algorithm, which enables accurate reconstruction of highly undersampled data when a prior image is available. We compared variants of the PICCS algorithm with different transforms in the prior penalty function: gradient, unitary, and wavelet transform. In all cases the problem was solved using the Split Bregman approach, which is efficient for convex constrained optimization. The algorithms were evaluated using simulations generated from data previously acquired on a micro-CT scanner following a high-dose protocol (four times the dose of a standard static protocol). The resulting data were used to simulate scenarios with different dose levels and numbers of projections. All compressed sensing methods performed very similarly in terms of noise, spatiotemporal resolution, and streak reduction, and filtered back-projection was greatly improved. Nevertheless, the wavelet domain was found to be less prone to patchy cartoon-like artifacts than the commonly used gradient domain.This work was partially funded by the RICRETIC network (RD12/0042/0057) from the Ministerio de Economía y Competitividad (www.mineco.gob.es/) and projects TEC2010-21619-C04-01 and PI11/00616 from Ministerio de Ciencia e Innovación (www.micinn.es/). The research leading to these results was supported by funding from the Innovative Medicines Initiative (www.imi.europa.eu) Joint Undertaking under grant agreement n°115337, the resources of which comprise financial contributions from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies ("in kind contribution"). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Expanding the dynamic range of flat-panel detectors used in small-animal cone-beam CT: an automated dual-exponsure technique

[Poster] 4th European Molecular Imaging Meeting, Barcelona, Spain, May 27 - 30, 2009This work is supported in part by Ministerio de Ciencia e Innovación (TEC2008-06715 and TEC2007-64731), EU-FP7 project FMTXCT-201792 and CD-TEAM project (CENIT program).Publicad

Corrección empírica de primer y segundo orden del artefacto de endurecimiento de haz en imágenes de micro-TAC

Actas de: XXIX Congreso Anual de la Sociedad Espñaola de Ingeniería Biomédica (CASEIB 2011). Cáceres, 16-18 Noviembre 2011.Los artefactos más comunes producidos por el fenómeno físico de endurecimiento de haz en imágenes obtenidas en un tomógrafo de rayos X son: "cupping", en volúmenes homogéneos y bandas oscuras, en presencia de objetos densos. Este trabajo presenta un esquema de corrección completa para ambos artefactos: un primer paso implementa una corrección de "cupping" por medio de un método de corrección de primer orden: linealización sobre los datos de proyección; en un segundo paso, se aplica un algoritmo de corrección de segundo orden sobre la imagen ya reconstruida para eliminar las bandas oscuras. En todo el proceso se elimina la necesidad de conocer el espectro de la fuente de rayos X. Ambos métodos han sido validados en maniquíes homogéneos y heterogéneos compuestos por dos materiales distintos, además de estudios de pequeño animal (ratas y ratones de laboratorio) adquiridos en un tomógrafo de rayos X para pequeños animales (micro-TAC) diseñado en el laboratorio. Los resultados demuestran la validez del esquema de corrección.Este trabajo ha sido financiado por el Ministerio de Ciencia e Innovación (proyectos CENIT AMIT, TEC 2008-06715-C02-1, RD07/0014/2009, TRA2009 0175 y Red RECAVA) y por la Comunidad de Madrid y Fondos FEDER (programa ARTEMIS S2009DPI-1802).Publicad

Effects of sinogram filtering in the quality of PET reconstructions: preliminary results

Proceeding of: 2006 IEEE Nuclear Science Symposium Conference Record, San Diego, CA, Oct. 29 - Nov. 1, 2006Low-pass filtering sinograms prior to reconstruction is a general practice to reduce noise. Sinograms are generally filtered in the radial direction, although other filtering schemes have been proposed. It is known that the Fourier transform of a sinogram shows a particular shape of the spectral energy distribution (“bow-tie”). In this work, this property has been exploited to perform an adapted filter, whose performance has been compared with previously reported methods: angular, axial and stackgram domain filtering. Stackgram and angular filtering degraded resolution (~16 and ~5.7 % respectively) while no significant enhancement in contrast to noise ratio (CNR) was achieved. Angular filtering resulted in a circle blurring artifact dependant on the distance to the center of the FOV. Bow-tie filtering showed the best results (enhancement of ~26% in resolution and of ~12% in CNR). Axial filtering degraded resolution but enhanced CNR (~14 %), appearing as a good strategy to reduce radial filtering. Experiments on rodent images showed a noticeable image quality enhancement achieved when using bow-tie filtering combined with radial and axial filters.This work was supported in part by from Ministerio de Educación y Ciencia (FIS-PI052583 and TEC2004-07052-C02), Ministerio de Industria (CD-TEAM, CENIT program) and Comunidad de Madrid (GR/SAL/024104)

Automatic Monte-Carlo Based Scatter correction for X-ray Cone Beam CT using General Purpose Graphic Processing Units (GP-GPU): a Feasibility study

Proceedings of: 2011 IEEE Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC). Valencia, Spain, 23-29 October 2011Scattered photons highly degrade the quality of X-ray images and their effect has become more important due to the increasing interest in cone-beam geometry for the acquisition of CT (CBCT) and micro-CT data. The random nature of scatter events and the great influence of the sample suggest that the most accurate methods for their estimation are Monte Carlo (MC) techniques, but their use is usually hampered by the large computation time required to obtain an acceptable estimation of the scattered radiation. We present an approach for scatter correction in CBCT by MC estimation, speeding up the computation by means of general purpose graphic processing units (GPGPU) and developing a framework for the automatic correction and reconstruction of projection data. The method consists of five stages: FDK reconstruction of the original data; histogram based automatic segmentation of the volume assigning a material and density to each voxel; fast MC estimation of the scatter signal; denoising of the independent scatter components and subtraction from original data; and FDK reconstruction of the corrected data. Every stage runs in a GPGPU using Nvidia CUD A. The MC stage is based on the MC-GPU code. To simulate polychromatic X-ray beams, the Spektr model is used to generate the source spectrum. Photon scattering is forced in order to reduce the number of events needed to obtain an acceptable scatter image weighting the photon histories to assure the correctness of the result. Further reduction in the variance is obtained by split the photon in several virtual photons which are forced point to the detector and are transported with no further interaction to the detector's surface. Furthermore, the divergence of the execution path of GPGPU kernels has been minimized. These techniques achieve a reduction of the variance of the scatter signal of two orders of magnitude and the final efficiency is improved by a factor of ~30.This work has been partially funded by the Spain Ministry of Education, FPU program; Spain Ministry of Science and Innovation, projects TEC2008-06715 and TEC2007-64731; CDTI under the CENIT Programme (AMIT Project); Comunidad de Madrid (ARTEMIS S2009/DPI-1802); and EU-FP7, FMTXCT-201792Publicad

Simulation of mechanical misalignments in a cone-beam micro-CT system

Proceeding of: 2008 IEEE Nuclear Science Symposium Conference Record (NSS '08), Dresden, Germany, 19-25 October 2008X-ray CT images usually show artefacts due not only to physical effects -e.g., beam hardening-, but also to misalignments that remain after mechanical calibration. These artefacts become particularly noticeable in the case of high spatial resolution systems and in hybrid systems, such as PETCT, SPECT-CT scanners, which rely on a correct registration of emission and CT data. Hence, slight mechanical misalignments affect the quality of the CT images and any attenuation correction methods or further quantification based on them. We implemented a computer simulator of these artefacts on a conebeam, flat-panel based micro-CT scanner. Using this simulator, we studied the effect of these different misalignments (pitch and roll tilts, skew and shifts) on reconstructed images.This work is partially funded by the CD-TEAM Project, CENIT Program, Spanish Ministerio de Industria, and with grants from the Ministerio de Educaci6n y Ciencia, projects TEC200764731 and TEC2008-06715-C02-01

Accuracy of CT-based attenuation correction in bone imaging with PET/CT

Proceeding of: 2007 IEEE Nuclear Science Symposium Conference Record (NSS'07), Honolulu, Hawaii, USA, Oct. 27 - Nov. 3, 2007PET/CT has become the most comprehensive diagnostic tool in oncology imaging providing improved lesion identification and localization. Bone is a common site of metastasis and the quantitative accuracy of PET images in bone tissue is important for assessing response to therapy. The use of CT images for attenuation correction is becoming a standard procedure in these scanners. However the impact of CT-based attenuation correction (CTAC) on the accuracy of PET tracer uptake values measured in bone has not been carefully evaluated, having only been carefully studied in soft tissue. We investigated the accuracy of CTAC on PET bone images by comparing the attenuation coefficients with PET transmission scans. For this, we imaged frozen bovine femur segments in a 20x20 cm cylindrical phantom. Different regions of the bones in both images were segmented by using thresholding and erosion methods to get equivalent volume masks. Differences in linear attenuation coefficients between the two images were then calculated. We repeated this analysis using patient images from the same patient imaged on the GE Advance PET scanner and the GE Discovery STE PET/CT scanner. The impact of the errors in the linear attenuation coefficients on PET SUV measurements was evaluated by simulations using the patent images with known bone disease and elevated levels of FDG uptake in bone (e.g. SUV = 5) at disease sites. The impact of the errors in the linear attenuation coefficients was then estimated by forward projection and reconstruction, after including the effects of attenuation and attenuation correction.This work was supported in kart by Agencia Antidroga de la Comunidad de Madrid (S-SAL2007), Ministerio de Sanidad y Consumo (CIBER CB06/01/0079), and Ministerio de Industria (Programa CENIT). It was also supported in part by NIH grants R01- CA124573 and R01-CA115870