Síntesi i reactivitat de derivats del triciclo[3.3.0.0/3,7]octà

[cat] Els compostos policíclics d'elevada simetria, a més del seu gran atractiu estètic i interès estructural, són substrats valuosos per a estudis mecanístics o bé com a intermedis en la síntesi de molècules orgàniques més complexes. Des de fa més de vint anys el grup d'investigació del Prof. Pelayo Camps del Departament de Famacologia i Química Terapèutica de la Universitat de Barcelona treballa en la síntesi i en la reactivitat de compostos policíclics. Concretament, en la present Tesi Doctoral s'ha dut a terme l'obtenció de l'1,3,5,7-tetraiodotriciclo[3.3.0.0/3,7]octà, un derivat bisnoradamantànic polisubstituït en les posicions cap de pont, com a precursor del compost triciclo[3.3.0.0/3,7]octa-1(5),3(7)-diè, que contindria dos dobles enllaços altament piramidalitzats perpendiculars entre si, com a un intermedi sintètic per a la preparació de compostos policíclics més complexes. Malauradament, tots els intents duts a terme per a obtenir aquest intermedi tant inestable van resultar infructuosos, degut probablement a la formació d'un enllaç intern a la molècula conduint a la formació d'un derivat [2.2.1]propel·lànic contingut dins l'esquelet de bisnoradamantà, extremadament reactiu, que conté dos àtoms de carboni amb geometria invertida. Per a verificar la formació d'aquest intermedi propel·lànic, es va dur a terme l'obtenció del (±)-1,3-diiodotriciclo[3.3.0.0/3,7]octà, un derivat bisnoradamantànic 1,3-disubstituït en les posicions cap de pont, a partir del qual mitjançant reaccions amb diferents agents reductors s'ha generat l'1,3-deshidrobisnoradamantà, un [2.2.1]propel·là amb un pont metilènic entre les posicions 2 i 5, altament reactiu, que en les condicions de les reaccions realitzades evolucionaria cap a diversos productes, molts dels quals han estat aïllats i plenament caracteritzats. Els càlculs teòrics DFT realitzats suggereixen també la formació d'aquest intermedi. Paral·lelament, s'ha sintetitzat una petita col·lecció de derivats bisnoradamantànics enantiopurs di- i tetrasubstituïts en les posicions cap de pont utilitzat l'(R)-N-fenilpantolactama, un auxiliar quiral desenvolupat en el nostre grup d'investigació. Aquests compostos són els primers exemples descrits de bisnoradamantans quirals enantiopurs que tenen la seva quiralitat a la diferent substitució en les posicions cap de pont. La puresa enantiomèrica dels compostos obtinguts s'ha determinat utilitzat CG quiral/EM en alguns d'aquests compostos.[eng] Polycyclic cage compounds are a unique class of organic compounds. They are useful substrates for mechanistic studies as well as intermediates in the synthesis of more complex organic molecules. For more than twenty years Prof. Pelayo Camps' research group at the Departament de Farmacologia i Química Terapèutica of the Universitat de Barcelona has been working on the synthesis and reactivity of polycyclic compunds. Specifically, in this Thesis the syntheses of 1,3,5,7-tetraiodotricyclo[3.3.0.0/3,7]octane was carried out, a bridgehead tetrasubstituted bisnoradamantane derivative, as a potential precursor of the tricyclo[3.3.0.0/3,7]oct-1(5),3(7)-diene. This compound, that features two highly pyramidalized carbon-carbon double bonds, may be useful as an intermediate in the syntheses of more complex polycyclic compounds. Unfortunately, we have no evidences in favor of the formation of this intermediate, probably because a very reactive [2.2.1]propellane derivative is generated. This intermediate has two carbon atoms with inverted geometries. To verify the formation of this propellane intermediate, the synthesis of (±)-1,3-diiodotricyclo[3.3.0.0/3,7]octane was carried out, a bridgehead 1,3-disubstituted bisnoradamantane derivative. From the reaction of this compound with different reductors evidences for the generation of 1,3-dehydrobisnoradamantane, a bridged, highly distorted and very reactive [2.2.1]propellane were found. Theoretical calculations also support the intermediacy of this derivative. On the other hand, a series of enantiomeric bridgehead di- and tetrasubstituted bisnoradamantane derivatives have been prepared by using (R)-N-phenylpantolactam, a chiral auxiliary developed by our research group. Although several bridgehead substituted chiral bisnoradamantane were known, efforts directed towards their preparation as single enantiomers had not been previously described. The enantiopurity of these compounds was established by chiral GC/MS

Synthesis and catalytic applications of C3-symmetric tris(triazolyl)methanol ligands and derivatives

Recently introduced tris(1,2,3-triazol-4-yl)methanols and derivatives (TTM ligands) have become a valuable subclass of C3-symmetric tripodal ligands for transition metal-mediated reactions. TTM-based ligand architectures are modularly constructed through regioselective, one-pot triple [3+2] cycloaddition of azides and alkynes. Applications of homogeneous systems of this type and of heterogenized (polystyrene- and magnetic nanoparticle-supported) TTM ligands in synthesis and catalysis are compiled in this Feature Article.</p

A Polystyrene-Supported 9-amino(9-deoxy)epi Quinine Derivative for Continuous Flow Asymmetric Michael Reactions

A polystyrene (PS)-supported 9-amino(9-deoxy)epi quinine derivative catalyzes Michael reactions affording excellent levels of conversion and enantioselectivity using different nucleophiles and structurally diverse enones. The highly recyclable, immobilized catalyst has been used to implement a single-pass, continuous flow process (residence time: 40 min) that can be operated for 21 hours without significant decrease in conversion and with improved enantioselectivity with respect to batch operation. The flow process has also been used for the sequential preparation of a small library of enantioenriched Michael adducts</p

Continuous Flow Enantioselective Three-Component anti-Mannich Reactions Catalyzed by a Polymer-Supported Threonine Derivative

A series of primary amino acid-derived polystyrene-supported organocatalysts was tested in anti-selective Mannich reactions. The polystyrene-immobilized threonine derivative showed the best performance in three-component (hydroxyacetone, anilines and aldehydes) Mannich reactions to provide anti-b-amino-a-hydroxycarbonyl compounds (11 examples; up to 95% ee) and its use could be extended to dihydroxyacetone and protected hydroxyacetones (7 examples; up to 90% ee). The high activity depicted by the catalyst has allowed its implementation in continuous flow. Under this operation mode, the supported threonine catalyst produces anti-Mannich adducts with generally higher diastereo- and enantioselectivity than in batch. A family of five different enantioenriched anti-Mannich adducts has been sequentially prepared in flow by passing different combinations of anilines and aromatic aldehydes over the same sample of catalyst. This confirms the suitability of this methodology for the rapid access to small libraries of enantioenriched compounds.</p

Conversion of oxiranes and CO2 to organic cyclic carbonates using a recyclable, bifunctional polystyrene-supported organocatalyst

The development of a heterogeneous one-component bifunctional catalyst system able to catalyse the conversion of carbon dioxide and oxiranes to organic cyclic carbonates at low temperature (45 °C) is reported. The bifunctional system can be easily recycled and reactivated when required. When compared with other heterogeneous organocatalysts for the same transformation, the reported catalyst is active at much milder temperatures, thus emphasising the optimal sustainability profile of the new catalyst system

A Highly Active Polymer-Supported Catalyst for Asymmetric Robinson Annulations in Continuous Flow

The preparation through Robinson annulation of enantiopure building blocks with both academic and industrial relevance, such as the Wieland–Miescher and Hajos–Parrish ketones, has suffered from important drawbacks, such as the need for high catalyst loading or extremely long reaction times. Here we report a heterogenized organocatalyst based on Luo’s diamine for fast and broad-scope enantioselective Robinson annulation reactions. The polystyrene-supported diamine <b>19a</b> enables the high-yield, highly enantioselective preparation of a wide range of chiral bicyclic enones under mild conditions, with reaction times as short as 60 min (batch) or residence times of 10 min (flow). In contrast with its homogeneous counterpart <b>19b</b>, the catalytic resin <b>19a</b> experiences a notable increase in catalytic activity with temperature in 2-MeTHF (a 10-fold decrease in reaction times without erosion in enantioselectivity is observed from room temperature to 55 °C). The scope of the transformation in batch mode has been illustrated with 14 examples, including examples only reported in poorly enantioenriched (<b>22n</b>) or in racemic form (<b>22k</b>). Enantiopure <b>22k</b> has been used as the starting material for a straightforward formal synthesis of the antibiotic and antifeedant sesquiterpene (−)-isovelleral (<b>24</b>). The heterogenized catalyst <b>19a</b> admits extended recycling (10 cycles) and has been used to develop the first asymmetric Robinson annulations in continuous flow. The potential of the flow process is illustrated by the large-scale preparation of the Wieland–Miescher ketone (65 mmol in 24 h of operation, TON of 117) and by a sequential flow experiment leading to a library of eight enantioenriched diketone compounds

Continuous Flow Enantioselective Three-Component <i>anti</i>-Mannich Reactions Catalyzed by a Polymer-Supported Threonine Derivative

A series of primary amino acid-derived polystyrene-supported organocatalysts was tested in <i>anti</i>-selective Mannich reactions. The polystyrene-immobilized threonine derivative showed the best performance in three-component (hydroxyacetone, anilines, and aldehydes) Mannich reactions to provide <i>anti</i>-β-amino-α-hydroxycarbonyl compounds (11 examples; up to 95% ee), and its use could be extended to dihydroxyacetone and protected hydroxyacetones (7 examples; up to 90% ee). The high activity depicted by the catalyst has allowed its implementation in continuous flow. Under this operation mode, the supported threonine catalyst produces <i>anti</i>-Mannich adducts with generally higher diastereo- and enantioselectivity than in batch. A family of five different enantioenriched <i>anti</i>-Mannich adducts has been sequentially prepared in flow by passing different combinations of anilines and aromatic aldehydes over the same sample of catalyst. This confirms the suitability of this methodology for the rapid access to small libraries of enantioenriched compounds

A fully recyclable heterogenized Cu catalyst for the general carbene transfer reaction in batch and flow

A polystyrene-linked tris(triazolyl)methanecopper(I) cationic catalyst operates under heterogeneous conditions for the reaction of ethyl diazoacetate (EDA) with an array of substrates. Carbon–hydrogen as well as X–H (X ¼ O, N) functionalization derived from the formal transfer of the carbene moiety (:CHCO2Et) from the copper center and subsequent insertion have been achieved, the reactions permitting repeated catalyst recycling and reuse. The addition of the same carbene unit to benzene leading to a cycloheptatriene derivative (B¨uchner reaction) or to phenylacetylene (cyclopropenation) took place at similar rates to the insertion processes and with the same catalyst recyclability. The use of this heterogenized cationic Cu catalyst in continuous flow has also been implemented. Key characteristics of the flow process are its high and constant turnover frequency (TOF) (residence times of 1 min still lead to full conversion in the reaction with ethanol after 48 h operation) and its suitability for the sequential performance of different types of carbene transfer reactions with a simple and affordable experimental setup.This work was funded by MINECO (grants CTQ2011-28942-C02-01 and CTQ2012-38594-C02-01), DEC-Generalitat de Catalunya (Grant 2014SGR827), Junta de Andalucia (P10-FQM-06292) and ICIQ Foundation. The ICIQ team also thanks MINECO for support through Severo Ochoa Excellence Accreditation 2014-2018 (SEV-2013-0319). L. M. thanks MECD for a FPU fellowship. E. O. thanks ICIQ for a postdoctoral fellowship. C. A. thanks MINECO for a Juan de la Cierva posdoctoral fellowship

Epidemiology, Risk Factors, and Prognosis of Candida parapsilosis Bloodstream Infections: Case-Control Population-Based Surveillance Study of Patients in Barcelona, Spain, from 2002 to 2003

Candida parapsilosis has emerged as an important yeast species causing fungemia. We describe the incidence and epidemiology of C. parapsilosis fungemia. Data from active population-based surveillance in Barcelona, Spain, from January 2002 to December 2003 were analyzed. We focused on 78 episodes of C. parapsilosis fungemia, and we compared them with 175 Candida albicans controls. C. parapsilosis accounted for 23% of all fungemias. The annual incidences were 1 episode per 10(5) patients, 1.2 episodes per 10(4) discharges, and 1.7 episodes per 10(5) patient days. All isolates but one (99%) were fluconazole susceptible. Seventy-two isolates (92%) were inpatient candidemias. Forty-two episodes (51%) were considered catheter-related fungemia, 35 (45%) were considered primary fungemia, and 3 (4%) were considered secondary fungemia. Risk factors for candidemia were vascular catheterization (97%), prior antibiotic therapy (91%), parenteral nutrition (54%), prior surgery (46%), prior immunosuppressive therapy (38%), malignancy (27%), prior antifungal infection (26%), transplant recipient (16%), neutropenia (12%), and prior colonization (11%). Multivariate analysis of the differential characteristics showed that the factors that independently predicted the presence of C. parapsilosis fungemia were neonate patients (odds ratio [OR], 7.5; 95% confidence interval [CI], 2.1 to 26.8; P = 0.002), transplant recipients (OR, 9.2; 95% CI, 1.9 to 43.3; P = 0.005), patients with a history of prior antifungal therapy (OR, 5.4; 95% CI, 1.8 to 15.9; P = 0.002), and patients who received parenteral nutrition (OR, 2.2; 95% CI, 1.09 to 4.6; P = 0.028). The overall mortality rate was lower than that associated with C. albicans candidemia (23% versus 43%; P < 0.01). In summary, C. parapsilosis was responsible for 23% of all candidemias and was more frequent in neonates, in transplant recipients, and in patients who received parenteral nutrition or previous antifungal therapy, mainly fluconazole. The mortality rate was lower than that associated with C. albicans fungemia