Electrooxidative dearomatization of biaryls: synthesis of tri- and difluoromethylated spiro[5.5]trienones

Radical spirocyclization via dearomatization has emerged as an attractive strategy for the rapid synthesis of structurally diverse spiro molecules. We report the use of electrochemistry to perform an oxidative dearomatization of biaryls leading to tri- and difluoromethylated spiro[5.5]trienones in a user friendly undivided cell set-up and a constant current mode. The catalyst- and chemical oxidant-free dearomatization procedure features ample scope, and employs electricity as the green and sole oxidant.

Radical spirocyclization via dearomatization has emerged as an attractive strategy for the rapid synthesis of structurally diverse spiro molecules.     

Application of the Pictet-Spengler reaction to aryl amine-based substrates having pyrimidine as a π-nucleophile: synthesis of pyrimidoquinolines with structural analogy to benzonaphthyridines present in alkaloids

Synthesis of pyrimidine annulated quinolines, structurally analogous to biologically active benzonaphthyridines present in alkaloids, has been described. Our synthetic strategy is based on the modified Pictet-Spengler reaction involving substrates comprising deactivated pyrimidine ring as the nucleophilic partner whereas aryl amine originating from the C-4 of the pyrimidine ring served as the source for electrophilic partner. The resulting substrates 5-7 with diversity at 2- and 6-position after condensation with a variety of aldehydes underwent 6-endo cyclization to furnish pyrimido[5,4-c]quinolines 14 in good yields. However, attempts to further extend this strategy on new structurally analogous substrate involving the pyridine ring as nucleophilic partner failed, thus limiting the scope of the reaction.     

Rational design of molecular sheets composed of interconnecting eight- and twenty-four-membered rings: use of lithiated aggregates to control network assembly

The lithiated (organo)sulfonylacetonitrile complex [MeSO(2)CHCNLi.THF] (3) has been prepared and structurally characterized in order to demonstrate that well-known molecular aggregates of s-block metals may be used as building blocks in the controlled assembly of complex supramolecular architectures. The solid state structure of 3 can be described as a novel basket-weaved, 2-D network, composed of (SO(2)Li)(2) "dimeric" rings joined via "interdimer" donation of nitrile units.     

Affinity screening by packed capillary high-performance liquid chromatography using molecular imprinted sorbents. I. Demonstration of feasibility

Molecular imprint polymers (MIPs) are synthetic polymers capable of selectively binding a template molecule. In this work, the potential utility of MIP-based chromatographic sorbents for affinity screening of structurally similar compounds was investigated as alternatives to in vitro bioassays and biological targets bound to chromatographic supports. A group of structurally similar tricyclic antidepressant drugs and related compounds were used to simulate a combinatorial library. One of the antidepressants, nortriptyline (NOR), was selected as the template species. Using capillary HPLC columns packed with NOR-imprinted MIP particles, the simulated library was screened and the degree of selective interaction of each compound was determined. This correlated with each compound's affinity for the NOR binding site in the polymer. The results of the study revealed that library species which possess the major structural features of the template, specifically the ring structure and pendant secondary amine, were best "recognized" by the MIP, while the most structurally dissimilar compounds exhibited the least selective interaction. An investigation of the retention mechanism on these MIPs provided evidence that hydrogen bonding between the pendant amine group on the antidepressants and a methacrylic acid moiety on the polymer surface was critical in the molecular recognition process.     

"Molecular chameleons". Design and synthesis of C-4-substituted imidazole fleximers

The synthesis of two flexible nucleosides is presented. The "fleximers" feature the purine ring system split into its imidazole and pyrimidine components. This modification serves to introduce flexibility to the nucleoside while still retaining the elements essential for molecular recognition. As a result, these structurally innovative nucleosides can more readily adapt to capricious binding sites and, as such, should find use for investigating enzyme-coenzyme as well as nucleic acid-protein interactions.     

Synthesis of metallacarborane ruthenium(<Emphasis Type="SmallCaps">ii</Emphasis>) and ruthenium(<Emphasis Type="SmallCaps">iii</Emphasis>) complexes with chelate 1,3-bis(diphenylphosphino)propane ligand and their mutual transformation in one-electron redox reactions

The first example of 12-vertex metallapolyhedra, namely, tris-phosphorus-containing closo-metallacarborane ruthenium(II) cluster Open image in new window , was synthesized and structurally studied. A principal possibility of the use of aliphatic amines as one-electron reducing agents converting carborane ruthenium(III) complexes to structurally close ruthenium(II) compounds was experimentally demonstrated.     

"Molecular chameleons". Design and synthesis of a second series of flexible nucleosides

The second series of flexible shape-modified nucleosides is introduced. The "fleximers" feature the purine ring systems split into their individual imidazole and pyrimidine components. This structural modification serves to introduce flexibility to the nucleoside while still retaining the elements essential for recognition. As a consequence, these structurally innovative nucleosides can more readily adapt to their environment and should find use as bioprobes for investigating enzyme-coenzyme binding sites as well as nucleic acid and protein interactions. Their design and synthesis is described.     

Synthesis of large quantities of single-walled aluminogermanate nanotube

A simple aqueous synthesis yielded about 100 times more structurally well-organized single-walled aluminogermanate nanotubes than previously reported "standard" procedures. The structure analyses using XRD, IRTF, TEM, and XAS were greatly facilitated by the high concentrations available, and they ascertained the imogolite-like structure of the nanotubes. Simplicity and yield of the synthesis protocol are likely to favor commercial applications of theses materials as well as simplified syntheses of other nanophases.     

Neighborhood behavior of in silico structural spaces with respect to in vitro activity spaces-a novel understanding of the molecular similarity principle in the context of multiple receptor binding profiles

As a consequence of recent advances in the field of High Throughput Screening, the systematic testing ("in vitro profiling") of compounds against a panel of targets covering different therapeutic areas is nowadays used to generate relevant information with respect to the in vivo behavior of drug candidates. However, the development of chemoinformatics tools required for the exploitation of such data is yet in an incipient phase. In this paper, a formalism for the analysis of activity profile vectors (describing the experimental responses of compounds in each of the considered activity tests) is introduced and applied at the study of Neighborhood Behavior (NB; the hypothesis that structurally similar compounds display similar biological properties) of molecular similarity metrics. The experimental activity profiles define an Activity Space in which more than 500 drugs and reference compounds are positioned, their coordinates being inhibitory propensities in the included tests and unambiguously characterizing a molecule in terms of its receptor binding properties. While previous studies of Neighborhood Behavior had to rely on a loose classification of compounds in terms of the therapeutic areas they were designed for, here the NB of a calculated "in silico" similarity metric has been redefined as a relationships between intermolecular dissimilarity scores in the "structural" and "activity" spaces, respectively, and expressed in terms of two quantitative criteria: "consistency" (the propensity of the metric to selectively rank activity-related compound pairs among the structurally most similar pairs) and "completeness" (monitoring the retrieval rate of activity-related compound pairs among the best ranked pairs of structural neighbors). These criteria were used to calibrate and validate a similarity metric based on Fuzzy Bipolar Pharmacophore Fingerprints.     

Structural covariance of graphs

Algebraic structures including multiple rank tensors, linear and non-linear operators are related to and represented with various types of graphs. Special emphasis is placed on linear operators e.g. on the Hibert space. A different graph represents the same operator depending on the basis frame used, in general non-orthonormal. All such graphs are shown to belong in one equivalence class and are termed structurally covariant. Crucial indices related to eigenvalues but invariant under any basis frame changes including non-orthonormal ones provide one way to characterize each class. A set of rules are given that allow one to find the graphs structurally covarinat with a given one and/or to deduce the class indices directly by simple pictorial manipulations on a graph. Applications in various fields including the quantum theory of molecules and reactions are indicated.     

Comparative study of large molecules. Highly accurate calculation of a limit for infinite systems from data on finite systems

Summary We have initiated a comparative study of several families of structurally closely related large benzenoid hydrocarbons of increasing number of fused benzene rings. Local and global properties of such molecules have been studied with a particular interest in investigating the closeness of finite-size molecules for modelling infinite polymeric structures having the same structural patterns. We focus in this report on two questions: (1) how large is a finite molecule which well approximates an infinite system? and (2) how do terminal groups influence local properties in the central part of the molecule as we approach the infinite system. Emphasis in this report is on extraction of high-accuracy limiting values for selected molecular properties from limited data on a few smaller members of structurally related molecules.On leave from Department of Mathematics and Computer Science, Drake University, Des Moines, IA 50311, USAOn leave from The Rugjer Bokovi Institute, P.O. Box 1016, HR-41001 Zagreb, Croatia     

Interaction of the diethylacetal of epoxybutyraldehyde with primary and secondary amines

Conclusions The reaction of the diethylacetal of trans-2-3-epoxybutyraldehyde with primary amines proceeds structurally and sterically selectively and leads to-hydroxy--amino compounds of the erythro series. Under the action of secondary amines, the reaction also proceeds structurally selectively; however, in the case of diethylarnine, a small amount of the corresponding threo-isomer could be isolated.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 9, pp. 1669–1671, September, 1966.     

Ortho-silylated derivatives of tetrakis(2-hydroxyphenyl)ethene: a sterically isolated structural model for oxo-surface binding domains

The introduction of sterically isolating ortho-trialkylsilyl, -aryldialkylsilyl, and -diarylalkylsilyl substituents onto the structurally preorganized tetrakis(2-hydroxyphenyl)ethene ligand framework has been accomplished by a 4-fold retro-Brook rearrangement. Installation of the most sterically demanding silyl substituents required the development of an iterative procedure, involving successive double silylation/metalation/migration sequences without the isolation of intermediates. This system was designed to function as a soluble structural model for the planar binding domains of heterogeneous "oxo-surfaces" of silica and alumina supports.     

Deformational covariance of graphs

Graphs on n vertices are classified into equivalence classes under the linear group L(n). All graphs representing the same operator on a vector space V _n belong to the same class. Graphs of different operators may or may not belong to the same class as ascertained by rules that were given by the author. Graphs in the same class are structurally covariant. If, in addition, two graphs can be continuously deformed into each other in the sense of varying line strengths while remaining structurally covariant throughout, then the two graphs are termed deformationally covariant along such paths. Applications in the quantum theory of chemistry and to the dynamic stability theory of coupled reaction systems which occur in various fields are indicated.     

Antarafacial mediation of oxygen delivery by a phenylsulfinyl group in the epoxidation of proximal double bonds: intramolecular trapping of an early Pummerer intermediate with stereoelectronic control

Stereospecific intramolecular antarafacial epoxidation of a double bond via an early Pummerer reaction intermediate has been demonstrated. The intermediate is presumably generated via trifluoroacetylation of a sulfoxide precursor. Ionization of trifluoroacetate would formally generate a dipositive "sulfenium" equivalent. This species attacks an otherwise unactivated, proximal olefinic linkage in an antiperiplanar fashion, with trifluoroacetate serving as the nucleophile. Proposed mechanistic intermediates were characterized structurally (in several cases by crystallographic means) and shown to serve as precursors en route to the final antarafacial epoxides. The sense of the cyclization seems to be driven by principles inherent in Markovnikov's rule.     

Facile "one pot" route to the novel benzazulene-type dye class: asymmetric, derivatizable, 5-7-6 fused ring puckered half BODIPY design

A novel fluorescent difluoroboroazaoxobenzazulene dye has been synthesized from commercially available substrates in "one pot"; it was characterized structurally and spectroscopically, derivatized and finally compared to a related BODIPY system that demonstrates "turn-on" H(+) (42-fold) and F(-) (~5-fold) responses.     

Organostannoxane-supported Pd(0) nanoparticles as efficient catalysts for Heck-coupling reactions

A new functional organostannoxane cage, SnP, that contains phosphine ligands in its periphery has been structurally utilized as support palladium(0) nanoparticles SnPPd. The latter was shown to catalyze the Heck coupling reactions of wide variety of functionalities efficiently.     

Modeling of protease I collagenolytic enzyme from the fiddler crab Uca pugilator

Summary Collagenolytic protease I from the fiddler crab Uca pugilator belongs to the serine proteases of the trypsin family. A graphic molecular model was built using information from sequences and X-ray structures of four homologous proteins which were superimposed to define structurally conserved regions. Protease I sequence was aligned, with sequences of the model proteins, without permitting any deletion or insertion in these regions. Elastase -carbon chain was selected as a template molecule. For the structurally variable regions, fragments of the four homologous proteins which were closest in sequence were selected. Intramolecular steric hindrance, that resulted from the substitution of the residues of the templates by protease I residues, was corrected by adjustment of the side-chain conformational angles. The model was then optimized by energy minimization. The primary specificity pocket in the model of collagenolytic protease I predicts a substrate preference for both P1 hydrophobic and positively charged residues which is in agreement with the biochemical observations. As soybean trypsin inhibitor (STI) is known to inhibit collagenolytic protease I, a tentative model of the complex was constructed and possibilities of interaction examined.     

Extrapolative prediction using physically-based QSAR

Surflex-QMOD integrates chemical structure and activity data to produce physically-realistic models for binding affinity prediction. Here, we apply QMOD to a 3D-QSAR benchmark dataset and show broad applicability to a diverse set of targets. Testing new ligands within the QMOD model employs automated flexible molecular alignment, with the model itself defining the optimal pose for each ligand. QMOD performance was compared to that of four approaches that depended on manual alignments (CoMFA, two variations of CoMSIA, and CMF). QMOD showed comparable performance to the other methods on a challenging, but structurally limited, test set. The QMOD models were also applied to test a large and structurally diverse dataset of ligands from ChEMBL, nearly all of which were synthesized years after those used for model construction. Extrapolation across diverse chemical structures was possible because the method addresses the ligand pose problem and provides structural and geometric means to quantitatively identify ligands within a model’s applicability domain. Predictions for such ligands for the four tested targets were highly statistically significant based on rank correlation. Those molecules predicted to be highly active (\(\hbox {pK}_i \ge 7.5\)) had a mean experimental \(\hbox {pK}_i\) of 7.5, with potent and structurally novel ligands being identified by QMOD for each target.     

Polygermoxanes suitable for biochemical purposes: II Linear trigermoxanes (high-viscosity oils)

Linear trigermoxanes, R¹ RGeOGe(R³)₂OGeRR¹, a new series of organogermanium compounds, were synthesized by reaction of a lithium organogermanolate with a suitable organogermanium dihalide. With alkyl or phenyl substituents, these trigermoxanes are structurally unstable viscous oils, due to redistribution reactions. When R³ substituents are bulky groups, such as mesityl, trigermoxanes are thermally and structurally stable oils; depending on the R¹ and R² substituents their viscosities lie in the range 240 to more than 1500 cPo (mPa s) at 20°C. When both terminal germanium atoms are substituted with two mesityl groups, trigermoxanes are stable glassy solids.