RESUMEN
Two new families of enantiomerically pure carbocyclic nucleoside analogues based on a cyclohexane moiety with five chiral centers and a fused cyclopropyl ring have been synthesized. A highly regio- and stereoselective synthetic approach for the modular construction of the functionalized bicyclo[4.1.0]heptyl azide intermediate 6 has been established. Key steps to achieve this asymmetric synthesis involved highly diastereoselective allylic oxidation and hydroboration reactions. The first family of compounds, 1a,b and 2, presents different natural nucleobases, whereas the second one 3a-e bears functionalized 1,2,3-triazoles. These derivatives have been tested as antiviral agents, and compound 3d has shown to display moderate activity against coxsackie B4 virus.
Asunto(s)
Heptanos , Nucleósidos , Nucleósidos/farmacología , Antivirales/farmacología , Estereoisomerismo , TriazolesRESUMEN
Allyloxymethyloxymethyl and 4-pentenoyloxymethyl substituents have been used as tethering groups to study the intramolecular [2 + 2] photocycloaddition of chiral 5-substituted 2(5 H)-furanones. The photoreactions proceed in good yield and provide the expected regio- and diastereoselective tricyclic compounds with complementary regioselectivity, which depends on whether the vinyl chain is attached to the furanone by an acetal or an ester linkage. Computational simulations agree with experimental observations and indicate that the origin of the different observed regioselectivity in the intramolecular photochemical reaction of lactones 5 and 6 arises from the relative stability of the initial conformers. The synthetic potential of the enantiomerically pure photoadducts is illustrated by preparing an all- cis 1,2,3-trisubstituted cyclobutane bearing fully orthogonally protected hydroxyl groups.
RESUMEN
A new strategy for the stereoselective synthesis of alkaloids with perhydro-9b-azaphenalene skeleton has been developed. The starting material is the substituted glutarimide derivative 1, readily available in either enantiomeric form through the palladium-catalyzed asymmetric allylic alkylation of glutarimide. The strategy relies on an iterative methodology encompassing two nucleophilic allylations and two ring closing metathesis processes. The approach has been used in the first synthesis of (-)-9a- epi-hippocasine.
Asunto(s)
Alcaloides/síntesis química , Alcaloides/química , Catálisis , Técnicas de Química Sintética , Modelos Moleculares , Conformación Molecular , Paladio/química , EstereoisomerismoRESUMEN
The α-arylation of carbonyl compounds is generally accomplished under basic conditions, both under metal catalysis and via aryl transfer from the diaryl λ(3)-iodanes. Here, we describe an alternative metal-free α-arylation using ArI(O2CCF3)2 as the source of a 2-iodoaryl group. The reaction is applicable to activated ketones, such as α-cyanoketones, and works with substituted aryliodanes. This formal C-H functionalization reaction is thought to proceed through a [3,3] rearrangement of an iodonium enolate. The final α-(2-iodoaryl)ketones are versatile synthetic building blocks.
RESUMEN
In the title compound, C(36)H(28)P(2)S(2), the dihedral angle between the central benzene rings is 66.95â (13)°. In the crystal, molecules are linked via C(ar)-Hâ¯π and π-π inter-actions [shortest centroid-centroid distance between benzene rings = 3.897â (2)â Å].
RESUMEN
The high conformational flexibility of peptoids can generate problems in biomolecular selectivity as a result of undesired off-target interactions. This drawback can be counterbalanced by restricting the original flexibility to a certain extent, thus leading to new peptidomimetics. By starting from the structure of an active peptoid as an apoptosis inhibitor, we designed two families of peptidomimetics that bear either 7-substituted perhydro-1,4-diazepine-2,5-dione 2 or 3-substituted 1,4-piperazine-2,5-dione 3 moieties. We report an efficient, solid-phase-based synthesis for both peptidomimetic families 2 and 3 from a common intermediate. An NMR spectroscopic study of 2a,b and 3a,b showed two species in solution in different solvents that interconvert slowly on the NMR timescale. The cis/trans isomerization around the exocyclic tertiary amide bond is responsible for this conformational behavior. The cis isomers are more favored in nonpolar environments, and this preference is higher for the six-membered-ring derivative 3a,b. We propose that the hydrogen-bonding pattern could play an important role in the cis/trans equilibrium process. These hydrogen bonds were characterized in solution, in the solid state (i.e., by using X-ray studies), and by molecular modeling of simplified systems. A comparative study of a model peptoid 10 containing the isolated tertiary amide bond under study outlined the importance of the heterocyclic moiety for the prevalence of the cis configuration in 2a and 3a. The kinetics of the cis/trans interconversion in 2a, 3a, and 10 was also studied by variable-temperature NMR spectroscopic analysis. The full line-shape analysis of the NMR spectra of 10 revealed negligible entropic contribution to the energetic barrier in this conformational process. A theoretical analysis of 10 supported the results observed by NMR spectroscopic analysis. Overall, these results are relevant for the study of the peptidomimetic/biological-target interactions.
Asunto(s)
Peptidomiméticos/química , Peptoides/química , Conformación Proteica , Amidas/química , Cristalografía por Rayos X , Diseño de Fármacos , Enlace de Hidrógeno , Isomerismo , Espectroscopía de Resonancia Magnética , Estructura Molecular , Peptidomiméticos/síntesis química , Peptoides/síntesis químicaRESUMEN
The photochemical [2 + 2] cycloaddition of chiral 3-chloro and 3-fluoro-5-hydroxymethyl-2(5H)-furanone to ethylene and acetylene has been studied. The effect of the halogen atom on the chemical yield and facial diastereoselectivity of the cycloaddition process has been evaluated. From the major anti cycloadducts, practical syntheses of several purine cyclobutane and cyclobutene-fused nucleosides containing a halogen atom have been developed. The anti-HIV activity of the new nucleoside analogues has been evaluated.
Asunto(s)
Compuestos Bicíclicos con Puentes/química , Cicloheptanos/química , Nucleósidos/síntesis química , Purinas/síntesis química , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Nucleósidos/química , Purinas/química , EstereoisomerismoRESUMEN
Metal chelation is considered a rational therapeutic approach for interdicting Alzheimer's amyloid pathogenesis. At present, enhancing the targeting and efficacy of metal-ion chelating agents through ligand design is a main strategy in the development of the next generation of metal chelators. Inspired by the traditional dye Thioflavin-T, we have designed new multifunctional molecules that contain both amyloid binding and metal chelating properties. In silico techniques have enabled us to identify commercial compounds that enclose the designed molecular framework (M1), include potential antioxidant properties, facilitate the formation of iodine-labeled derivatives, and can be permeable through the blood-brain barrier. Iodination reactions of the selected compounds, 2-(2-hydroxyphenyl)benzoxazole (HBX), 2-(2-hydroxyphenyl)benzothiazole (HBT), and 2-(2-aminophenyl)-1H-benzimidazole (BM), have led to the corresponding iodinated derivatives HBXI, HBTI, and BMI, which have been characterized by X-ray diffraction. The chelating properties of the latter compounds toward Cu(II) and Zn(II) have been examined in the solid phase and in solution. The acidity constants of HBXI, HBTI, and BMI and the formation constants of the corresponding ML and ML2 complexes [M = Cu(II), Zn(II)] have been determined by UV-vis pH titrations. The calculated values for the overall formation constants for the ML2 complexes indicate the suitability of the HBXI, HBTI, and BMI ligands for sequestering Cu(II) and Zn(II) metal ions present in freshly prepared solutions of beta-amyloid (Abeta) peptide. This was confirmed by Abeta aggregation studies showing that these compounds are able to arrest the metal-promoted increase in amyloid fibril buildup. The fluorescence features of HBX, HBT, BM, and the corresponding iodinated derivatives, together with fluorescence microscopy studies on two types of pregrown fibrils, have shown that HBX and HBT compounds could behave as potential markers for the presence of amyloid fibrils, whereas HBXI and HBTI may be especially suitable for radioisotopic detection of Abeta deposits. Taken together, the results reported in this work show the potential of new multifunctional thioflavin-based chelating agents as Alzheimer's disease therapeutics.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/antagonistas & inhibidores , Quelantes/síntesis química , Quelantes/farmacología , Diseño de Fármacos , Tiazoles/química , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Benzotiazoles , Quelantes/química , Cobre/química , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Yodo/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura Molecular , Fragmentos de Péptidos/metabolismo , Zinc/químicaRESUMEN
The title compound, C(10)H(11)NTe, is the first organyl ethynyl telluride, R-Te-C C-H, to be structurally characterized. In the L-shaped mol-ecule, the aryl moiety, viz. Me(2)NC(6)H(4)Te, is almost perpendicular to the Te-C C-H fragment. The Te-Csp(2) bond [2.115â (3)â Å] is significantly longer than the Te-Csp bond [2.041â (4)â Å]. The Te-C C group is approximately linear [Te-C-C = 178.5â (4)° and C C = 1.161â (5)â Å], while the coordination at the Te atom is angular [C-Te-C = 95.92â (14)°]. In the crystal structure, there are Csp-Hâ¯N hydrogen bonds which are perpendicular to the CNMe(2) group; the N atom displays some degree of pyramidalization. Centrosymmetrically related pairs of mol-ecules are linked by Teâ¯π(ar-yl) inter-actions, with Teâ¯Cg = 3.683â (4)â Å and Csp-Teâ¯Cg = 159.1â (2)° (Cg is the centroid of the benzene ring). These inter-actions lead to the formation of zigzag ribbons which run along c and are approximately parallel to (110).
RESUMEN
An improved procedure for the synthesis of 3-amino-9-arylsubstituted-thieno[3,2-b]benzothiazine S,S-dioxide 2-decarboxylated is reported. Thieno-[3,2-b]benzothiazine S,S-dioxide derivatives were investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their efficacy in rodent Plasmodium berghei. Compounds 5j-o were the most promising as inhibitors of hemoglobin hydrolysis, however, the compounds are not as efficient as chloroquine. A structure-activity relationship (SAR) study was carried out in this series. Our results allow us to determine the minimal structural requirements to produce the biological response.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Benceno/química , Óxidos/química , Tiazinas/síntesis química , Tiazinas/farmacología , Animales , Antimaláricos/química , Cristalografía por Rayos X , Globinas/metabolismo , Hemoproteínas/biosíntesis , Ratones , Modelos Moleculares , Estructura Molecular , Plasmodium berghei/efectos de los fármacos , Electricidad Estática , Relación Estructura-Actividad , Tiazinas/químicaRESUMEN
Green crystals of the title compound, C(14)H(14)I(2)O(2)Te x 0.5 C(2)H(6)OS, space group P3(2), show twinning by merohedry (class II). The asymmetric unit contains two organotellurium molecules and one dimethyl sulfoxide (DMSO) molecule. The crystal structure displays secondary Te...I and Te...O(DMSO) bonds that lead to [(4-MeOC(6)H(4))(2)TeI(2)](2) x DMSO supramolecular units in which the two independent organotellurium molecules are bridged by the DMSO O atom. In addition to these secondary bonds, I...I interactions link translationally equivalent organotellurium molecules to form nearly linear ...I-Te-I...I-Te-I... chains. These chains are crosslinked, forming two-dimensional arrays parallel to (001). The crystal packing consists of a stacking of these sheets, which are related by the 3(2) axis. This study describes an unusual dimeric arrangement of X-Te-X groups.
RESUMEN
[structure: see text]. A stereselective synthesis of 3-oxabicyclo[3.2.0]heptane nucleoside analogues, which were designed as conformational mimics of the anti-HIV agents 2',3'-didehydro-2',3'-dideoxythimidine (stavudine, d4T) and 2',3'-didehydro-2',3'-dideoxyadenosine (d4A), is described. The target compounds were prepared by condensation of a common intermediate bicyclic acetate, derived from a homochiral 2(5H)-furanone, with pyrimidine and purine bases under modified Vorbrüggen conditions. The conformational behavior of the synthesized nucleoside analogues was studied by NMR spectroscopy and X-ray crystallography.
Asunto(s)
Fármacos Anti-VIH/química , Ciclobutanos/química , Ciclobutanos/síntesis química , Nucleósidos/química , Nucleósidos/síntesis química , Estavudina/química , Fármacos Anti-VIH/farmacología , Cristalografía por Rayos X , Conformación Molecular , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Estavudina/farmacologíaRESUMEN
Ligand 2-diphenylphosphinothiophenol (Hsarp) reacted with Pt(PPh3)4 to yield trans-[PtH(sarp)(PPh3)], which undergoes fast exchange with free PPh3 on the NMR time scale and very slowly and reversibly formed some cis-[PtH(sarp)(PPh3)] over time in solution (11%, 24 h). Reaction of trans-[PtH(sarp)(PPh3)] with Hsarp in boiling toluene gave cis- and trans-[Pt(sarp)2]; the cis isomer being more stable. These complexes were characterized by (1)H and (31)P NMR and also analyzed by XRD in the case of trans-[PtH(sarp)(PPh3)], trans-[Pt(sarp)2], and cis-[Pt(sarp)2]. trans-[PtH(sarp)(PPh3)] was evaluated as a preformed, tin-free hydroformylation catalyst on styrene and found active at 100 °C, at pressures over 75 bar, yielding phenylpropanal (regioselectivities up to 83% in 2-phenylpropanal), with total conversions to aldehydes up to 100% at styrene/platinum ratios from 400/1 to 1000/1 and minimal hydrogenation products.
RESUMEN
The lithium perchlorate-induced ring opening of (S)-triphenylethylene oxide (3) with secondary amines (piperidine (a), N-methylpiperazine (b), N-phenylpiperazine (c) and morpholine (d)) takes place in a stereospecific and completely regioselective manner to afford (R)-2-(dialkylamino)-1,1,2-triphenylethanols (4a-d). These amino alcohols catalytically induce the addition of diethylzinc to benzaldehyde with high enantioselectivity at 0 degrees C and at room temperature. Ligand 4a, which provides the highest enantioselectivity at 0 degrees C, has been studied in the addition of Et(2)Zn to a family of 20 representative aliphatic and aromatic aldehydes 5a-t. For a 17-membered set of alpha-substituted substrates (5a-m,q-t), including ortho-, meta-, and para-substituted benzaldehydes, the naphthaldehydes, alpha,beta-unsaturated and aliphatic (cyclic and acyclic) aldehydes, the mean enantiomeric excess of the resulting alcohols 6a-m,q-t is 97%, whereas for three alpha-unsubstituted specimens (5n-p) the addition takes place with an enantioselectivity of 92-93%.
RESUMEN
Three isoxazoline tetracycles were obtained enantiomerically pure by intramolecular 1,3-dipolar cycloaddition. The characterization of the new compounds was performed by high-resolution 1H and 13C NMR spectroscopy. The relative configuration of the new chiral centers was determined by NOESY experiments and confirmed by single-crystal X-ray structural analysis.
Asunto(s)
Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Isoxazoles/síntesis química , Cristalografía por Rayos X , Compuestos Heterocíclicos de 4 o más Anillos/química , Isoxazoles/química , Resonancia Magnética Nuclear Biomolecular , EstereoisomerismoRESUMEN
Combining X-ray data on thioflavin-T and theoretical calculations on its binding to a peptide model for Abeta(1-42) fibrils gives evidence of main stabilizing interactions, which influence the dihedral angle between the two moieties of thioflavin-T and thereby its fluorescence properties; these results shed new light on possible strategies for the design of dyes to bind amyloid fibrils more specifically.
Asunto(s)
Péptidos beta-Amiloides/química , Fragmentos de Péptidos/química , Tiazoles/química , Benzotiazoles , Sitios de Unión , Cristalografía por Rayos X , Colorantes Fluorescentes/química , Conformación Molecular , Unión Proteica , Estructura Secundaria de ProteínaRESUMEN
A series of phenylsubstituted pyrazolo and pyrimido benzothiazine dioxide derivatives were synthesized and investigated for their abilities to inhibit beta-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Compounds 3-amino-7-chloro-9-(2'-methylphenyl)-1,9-dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2b and 2,4-diamino-8-chloro-10H-phenyl-pyrimido-[5,4-b]benzothiazine 5,5-dioxide 3a were the most promising as inhibitors of hemoglobin hydrolysis, however, their effect as inhibitors of beta-hematin formation was marginal, except for compound 3-amino-7-chloro-9-(3'-chlorophenyl)-1,9dihydro-pyrazolo-[4,3-b]benzothiazine 4,4-dioxide 2g. The most active compound to emerge from the in vitro and in vivo murine studies was 2b, suggesting an antimalarial activity via inhibition of hemoglobin hydrolysis, however, not as efficient as chloroquine.
Asunto(s)
Antimaláricos/síntesis química , Antimaláricos/farmacología , Plasmodium berghei/efectos de los fármacos , Tiazinas/síntesis química , Tiazinas/farmacología , Animales , Antimaláricos/química , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Espectrofotometría Infrarroja , Tiazinas/químicaRESUMEN
[Chemical reaction: See text] Several derivatives of (+)- and (-)-2-aminocyclobutane-1-carboxylic acid, 1, have been prepared through enantiodivergent synthetic sequences. The stereoselective synthesis of free amino acid (+)-1 has been achieved, and this product has been fully characterized for the first time. Stereocontrolled alternative synthetic methodologies have been developed for the preparation of bis(cyclobutane) beta-dipeptides in high yields. Among them, enantio and diastereomers have been synthesized. beta,beta- and beta,delta-Dimers resulting from the coupling of a cyclobutane residue and a linear amino acid have also been prepared. The ability of the cyclobutane ring as a structure-promoting unit both in the monomers and in the dimers has been manifested. The NMR structural study and DFT theoretical calculations evidence the formation of strong intramolecular hydrogen bonds giving rise to cis-fused [4.2.0]octane structural units that confer high rigidity on these molecules both in solution and in the gas phase. The contribution of a cis-trans conformational equilibrium derived from the rotation around the carbamate N-C(O) bond has also been observed, the trans form being the major conformer. In the solid state, this equilibrium does not exist, and moreover, intermolecular hydrogen bonds are present.
Asunto(s)
Aminoácidos/química , Ciclobutanos/química , Péptidos/síntesis química , Ácidos Carboxílicos/química , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Péptidos/química , EstereoisomerismoRESUMEN
A general strategy for the construction of the 1-azabicyclo[5.3.0]decane core of Stemona alkaloids is developed. Our diversity-oriented approach exploits 1,3-dipolar cycloaddition of five-membered cyclic nitrones to C(6) olefins, followed by N-O reductive cleavage and azepine closure. The use of various enantiopure pyrroline N-oxides allows for a practical, stereoselective preparation of several putative precursors of different Stemona alkaloids.