Stereoselective synthesis of α-amino-C-phosphinic acids and derivatives

α-Amino-C-phosphinic acids and derivatives are an important group of compounds of synthetic and medicinal interest and particular attention has been dedicated to their stereoselective synthesis in recent years. Among these, phosphinic pseudopeptides have acquired pharmacological importance in influencing physiologic and pathologic processes, primarily acting as inhibitors for proteolytic enzymes where molecular stereochemistry has proven to be critical. This review summarizes the latest developments in the asymmetric synthesis of acyclic and phosphacyclic α-amino-C-phosphinic acids and derivatives, following in the first case an order according to the strategy used, whereas for cyclic compounds the nitrogen embedding in the heterocyclic core is considered. In addition selected examples of pharmacological implications of title compounds are also disclosed.The authors gratefully acknowledge the CONACYT (grant 181816, 248868) and PRODEP (project UAEMOR-PTC-379) of Mexico, Ministerio de Economía y Competitividad (grant CTQ2013-40855-R) and Gobierno de Aragón-FSE (research group E40) for their financial support.We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI)

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

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

Practical access to the proline analogs (S,S,S)- and (R,R,R)-2- methyloctahydroindole-2-carboxylic acids by HPLC enantioseparation

An efficient methodology for the preparation of the α- tetrasubstituted proline analog (S,S,S)-2-methyloctahydroindole-2-carboxylic acid, (S,S,S)-(αMe)Oic, and its enantiomer, (R,R,R)-(αMe)Oic, has been developed. Starting from easily available substrates and through simple transformations, a racemic precursor has been synthesized in excellent yield and further subjected to HPLC resolution using a cellulose-derived chiral stationary phase. Specifically, a semipreparative (250 mm × 20 mm ID) Chiralpak® IC column has allowed the efficient resolution of more than 4 g of racemate using a mixture of n-hexane/tert-butyl methyl ether/2-propanol as the eluent. Multigram quantities of the target amino acids have been isolated in enantiomerically pure form and suitably protected for incorporation into peptides. © 2011 Wiley-Liss, Inc.Contract grant sponsors: Ministerio de Ciencia e Innovación–FEDER, Gobierno de Aragón; Contract grant numbers: CTQ2007-62245, CTQ2010- 17436, PIP206/2005 and research group E40.Peer Reviewe

Organocatalyzed Michael addition reaction by novel (2R,3aS,7aS)-octa-hydroindole-2-carboxylic acid, a new fused proline

We present here the results obtained in our study on organocatalytic enantioselective Michael addition reaction of acetone to different nitroolefines using (2R,3aS,7aS)-octahydroindole-2-carboxylic acid [(R,S,S)-Oic] as a new and suitable catalyst for this process. Computational calculations support the results obtained with (R,S,S)-Oic versus its diastereomeric form (S,S,S)-Oic. The final products are obtained in good yields and moderate enantioselectivities (up to 58% ee). © Georg Thieme Verlag Stuttgart.We thank the Spanish National Research Council (CSIC. Project PIE-200880I260), the Ministry of Science and Innovation (MICINN, Madrid; Projects CTQ2009-09028, CTQ2010-19606, and CTQ2010-17436) and the Government of Aragón (Zaragoza; Project PI064/09 and Research Groups E-10 and E-40) for financial support of our research. R.P.H. thanks the Aragón I + D Foundation for her permanent contract.Peer Reviewe

Synthesis of quaternary α-aminophosphonic acids

This work was carried out with the financial support of CONACYT of Mexico (project 62271), FOSISS-10-ST-564, Ministerio de Educación y Ciencia-FEDER (project CTQ2010-17436), Gobierno de Aragón (group E40) and bilateral proyect CONACYT-CSIC (project J000.400/2009 and 2008MX0044).Peer Reviewe

Access to the cis-fused stereoisomers of proline analogues containing an octahydroindole core

El pdf del artículo es la versión post-print.An overview of the synthetic methods developed to build all the cis-fused stereoisomers of octahydroindole-2-carboxylic acid and its α-methylated derivative in enantiomerically pure form is presented. Both asymmetric synthetic strategies(auxiliary- or substrate-controlled processes) and procedures based on the resolution of racemic compounds (chemical, enzymatic, and chromatographic processes) are summarized. Special emphasis has been placed on those strategies able to provide multigram quantities of enantiopure compounds, a prerequisite to make downstream biological applications feasible.Financial support from the Ministerio de Ciencia e Innovación (projects CTQ2007-62245 and CTQ2010-17436; predoctoral fellowship for P. L.) and the Gobierno de Aragón (project PIP206/ 2005 and research group E40) is gratefully acknowledged.Peer Reviewe

Quantum-chemical predictions of redox potentials of carbamates in methanol

Redox potentials for two stepwise anodic oxidations of a series of carbamates in methanolic solution have been calculated using ab initio and DFT quantum mechanical methods. Hartree-Fock method and Density Functional Theory at the B3LYP level, together with 6-31G(d), 6-31G(d,p) and 6-311++G(2df,2p) basis sets have been used for the calculation. The Polarizable Continuum Model (PCM) is used to describe the solute-solvent interactions of carbamates, and those of their radical-cations and cations. Linear relationships were observed between the theoretically predicted redox potential values and the corresponding anodic peak potentials obtained by cyclic voltammetry or the corresponding calculated energies of the Highest Occupied Molecular Orbital (HOMO) of these carbamates. This journal is © the Owner Societies.Financial support from the Spanish Ministry of Science and Innovation—FEDER (grants CTQ2010-17436 and CTQ2009- 14629-C02-02) and the Regional Government of Aragón (research group E40 and E52) is gratefully acknowledged.Peer Reviewe

Efficient access to N-protected derivatives of (R,R,R)- and (S,S,S)-octahydroindole-2-carboxylic acid by HPLC resolution

The preparation of the proline analogue (2S,3aS,7aS)-octahydroindole-2-carboxylic acid (Oic) and its enantiomer, (2R,3aR,7aR)-Oic, is described. A racemic precursor has been synthesized in good yield and subjected to HPLC resolution on a chiral column. The high efficiency of both the synthetic and chromatographic procedures has allowed the isolation of multigram quantities of each amino acid in enantiomerically pure form and suitably protected for use in peptide synthesis.Financial support from the Ministerio de Educación y Ciencia–FEDER (Project CTQ2004-5358) and Gobierno de Aragón (Project PIP206/2005 and research group E40) is gratefully acknowledged. The authors thank Ana Lidia Bernad for technical assistance with HPLC. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number NO1-CO-12400. The content of this publication does not necessarily reflect the view of the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.Peer reviewe

An improved synthesis of the antibiotic dehydrophos

Within this work an efficient procedure for the synthesis of the vinyl phosphonate tripeptide dehydrophos is described. This procedure constitutes a significant improvement over previously described strategies, since critical transformations in the synthesis of dehydrophos were carried out in only two synthetic steps, with higher yields and under smooth conditions. Thus, the dehydrophosphoalanine residue was generated by means of the Horner–Wadsworth–Emmons reaction of formaldehyde with a peptide bearing an aminomethylbis(phosphonate) moiety, whereas deprotection of the N‐terminal position of the thus‐obtained dehydrophosphonopeptide and partial hydrolysis of the dimethyl phosphonate residue took place simultaneously. In addition, we confirmed that the chiral integrity of the leucine residue was preserved throughout these transformations.This work was supported by the Ministerio de Economía y Competitividad (grant CTQ2013‐40855‐R) and the Gobierno de Aragón‐FEDER (Research group E19_17R) M. M. J.‐A. thanks the Gobierno de Aragón‐FSE for a predoctoral grant.Peer reviewe