Electron transfer reactions. Reaction of dibenzobarrelenes with potassium

The results of our studies on potassium-induced transformations of several bridgehead-substituted dibenzobarrelenes are presented. The dibenzobarrelenes 1b,c,e,f having methyl, hydroxymethyl, methoxy and phenyl groups, respectively, at the bridgehead position and the bridgehead-dimethyl derivative 1g give, on treatment with potassium in THF, the corresponding anthracenes 8b,c,e-g, dihydrodibenzobarreneses 6b,c,e-g and benzoic acid (5). The dibenzobarrelenes 1b,g give, in addition to 8b,g, 6b,g and 5, the corresponding mono-debenzoylated products 7b,g, whereas the methoxy derivative 1e gives both anthraquinone (9) and an enol derivaiive 11, besides 8e, 6e and 5. In contrast, the reaction of the hydroxy derivative 1d with potassium in THF gives a mixture of 5, anthracene (8a), the anthrone 10 and the anthrol 12. To assess the role of oxygen in these reactions, if any, the reactions of some representative substrates such as 1b,d,e with potassium in THF, saturated with oxygen and with potassium superoxide have been studied. Cyclic voltammetric studies have been carried out to measuee the reduction potentials for both one electron and two electron processes, leading to the generation of the corresponding radical anions and dianion intermediates. The radical anions of 1b-g have also been generated pulse radiolytically in methanol and their spectra show absorption maxima in the regions 310-390 and 400-450 nm.     

Synthesis and conformational analysis of 9,10-bis-aminomethyl-11,12-dicarboxy-dibenzobarrelene derivatives

The synthesis of bis-γ-amino acid dibenzobarrelene derivatives (9,10-bis-aminomethyl-11,12-bis-carboxy-dibenzobarrelene) is presented. Bromomethylation of anthracene followed by azide substitution gave 9,10-bis-azidomethylanthracene. Azide reduction, N-Boc protection, and Diels-Alder cycloaddition in DMAD furnished the protected 9,10-bi-aminomethyl-11,12-dicarboxy-dibenzobarrelene derivative, which was further converted into the bis-γ-amino acid methyl ester, the N-Boc-protected bis-γ-amino methyl amide, and a bis-γ-lactam. Monte Carlo simulations and X-ray analysis of the 9,10-substituted dibenzobarrelenes revealed an exposed hydrophobic surface surrounded by amino and carboxy groups.     

Reagent Selector: using Synthon Analysis to visualize reagent properties and assist in combinatorial library design

Reagent Selector is an intranet-based tool that aids in the selection of reagents for use in combinatorial library construction. The user selects an appropriate reagent group as a query, for example, primary amines, and further refines it on the basis of various physicochemical properties, resulting in a list of potential reagents. The results of this selection process are, in turn, converted into synthons: the fragments or R-groups that are to be incorporated into the combinatorial library. The Synthon Analysis interface graphically depicts the chemical properties for each synthon as a function of the topological bond distance from the scaffold attachment point. Displayed in this fashion, the user is able to visualize the property space for the universe of synthons as well as that of the synthons selected. Ultimately, the reagent list that embodies the selected synthons is made available to the user for reagent procurement. Application of the approach to a sample reagent list for a G-protein coupled receptor targeted library is described.     

A new and convenient approach for the preparation of β-cyanoethyl protected trinucleotide phosphoramidites

Herein we report a convenient approach for the preparation of fully protected trinucleotide synthons to be used for the synthesis of gene libraries. The trinucleotide synthons bear β-cyanoethyl groups at the phosphate residues, and thus can be used in standard oligonucleotide synthesis without additional steps for deprotection and work-up.     

New aromatic annulation reaction via a C14 enaminone synthon: synthesis of ‘terpenoid-like chalcones’

Diverse functionalized synthons from a new enaminone are reported. These synthons were easily obtained in a one pot process starting from a compound derived from β-ionone. A new annulation reaction of this C-14 compound with several anions led to new ‘terpenoid-like’ chalcones.     

Versatile 2,7-substituted pyrene synthons for the synthesis of pyrene-fused azaacenes

A new synthetic route to prepare a series of versatile 2,7-substituted pyrene synthons for the synthesis of pyrene-fused azaacenes is described. By using such synthons, a library of eight pyrene-fused azacenes with different electronic structures and in most cases with enhanced solubility has been synthesized and characterized.     

Photochromic dibenzobarrlenes: long-lived triplet biradical intermediates

Upon exposure to UV light, the disubstituted dibenzobarrelene derivative 1a turns green in the solid phase and reverts back to its original pale-yellow color within several hours in the dark. The lifetime of the colored species in degassed benzene at room temperature is 37 +/- 2 s (Ea for decoloration is 14.5 +/- 0.7 kcal mol-1 and log A is 8.92 +/- 0.5 s-1) and highly sensitive to molecular oxygen; the Stern-Volmer quenching constant is 6.9 +/- 0.2 x 108 M-1 s-1. Similarly, the disubstituted dibenzobarrelenes 1b and 1c exhibited pink coloration when exposed to UV light in the solid phase. On the basis of combined experimental and theoretical evidence, it is proposed that upon photoexcitation the excited singlet state of 1a undergoes rapid intersystem crossing to its triplet state, followed by intramolecular delta-H abstraction, to yield the triplet biradical intermediate (3)2. Upon prolonged irradiation, 2 undergoes cyclization to the alcohol 3, which affords the enone 4 as the final photoproduct. The delta-H abstraction on the triplet-state potential energy surface, calculated at the B3LYP/6-31G* level of density functional theory (DFT), has an activation energy of 18.5 kcal/mol. Further, the absorption spectrum of the triplet biradical (3)2, obtained from time-dependent DFT calculations, displays an intense absorption maximum at 670 nm, which is in good agreement with the observed absorption peak at 700 nm. The molecular-orbital analysis of the triplet diradical (3)2 suggests that its long-wavelength absorption involves the transition of the unpaired electron from the comparatively localized benzyl-type HOMO to the extensively conjugated benzoyl-type LUMO. The present experimental and theoretical results strongly support the intervention of a long-lived triplet biradical (3)2 in the photochromism of appropriately substituted dibenzobarrelenes.     

A facile two synthon approach to the camptothecin skeleton

A synthesis of deethyldesoxycamptothecin via the reaction of two readily accessible synthons is described. One of the synthons constitutes the ABC ring system of camptothecin, while the second provides all the C atoms of the rings D and E. The synthetic approach is suited for the total synthesis of camptothecin analogues.     

Extending the supramolecular synthon based fragment approach (SBFA) for transferability of multipole charge density parameters to monofluorobenzoic acids and their cocrystals with isonicotinamide: importance of C-H···O, C-H···F, and F···F intermolecular regions

An extension of the supramolecular synthon-based fragment approach (SBFA) method for transferability of multipole charge density parameters to include weak supramolecular synthons is proposed. In particular, the SBFA method is applied to C-H···O, C-H···F, and F···F containing synthons. A high resolution charge density study has been performed on 4-fluorobenzoic acid to build a synthon library for C-H···F infinite chain interactions. Libraries for C-H···O and F···F synthons were taken from earlier work. The SBFA methodology was applied successfully to 2- and 3-fluorobenzoic acids, data sets for which were collected in a routine manner at 100 K, and the modularity of the synthons was demonstrated. Cocrystals of isonicotinamide with all three fluorobenzoic acids were also studied with the SBFA method. The topological analysis of inter- and intramolecular interaction regions was performed using Bader's AIM approach. This study shows that the SBFA method is generally applicable to generate charge density maps using information from multiple intermolecular regions.     

Graph theory of synthons

A graph-theory model of synthons is suggested. A synthon is a special kind of the molecular graph in which some vertices are distinguished from other ones, and they are called the virtual vertices. The most important property of the synthons is that the constraint of strict stoichiometry is removed and the virtual vertices formally correspond to functional groups that are not closely specified.     

Multicomponent Crystal of Metformin and Barbital: Design,Crystal Structure Analysis and Characterization

The formation of most multicomponent crystals relies on the interaction of hydrogen bonds between the components, so rational crystal design based on the expected hydrogen-bonded supramolecular synthons was employed to establish supramolecular compounds with desirable properties. This theory was put into practice for metformin to participate in more therapeutic fields to search for a fast and simple approach for the screening of candidate crystal co-formers. The prediction of intermolecular synthons facilitated the successful synthesis of a new multicomponent crystal of metformin (Met) and barbital (Bar) through an anion exchange reaction and cooling crystallization method. The single crystal X-ray diffraction analysis demonstrated the hydrogen bond-based ureide/ureide and guanidine/ureide synthons were responsible for the self-assembly of the primary structural motif and extended into infinite supramolecular heterocatemeric structures.     

Electron impact mass spectrometry of some benzodioxole derivatives of pharmacological interest,their synthons and synthetic intermediates

The mass spectrometric behaviour of two newly synthesized β-blocking benzodioxole derivatives, their synthons and synthetic intermediates has been studied in detail with the aid of exact mass measurements, linked scans, collisionally activated decomposition mass analysed ion kinetic energy spectra and deuterium labelling experiments. A retrosynthetic process, leading to the original synthons, is described.     

The nature of halogen...halide synthons: theoretical and crystallographic studies

Two types of halogen...halide synthons are investigated on the basis of theoretical and crystallographic studies; the simple halogen...halide synthons and the charge assisted halogen...halide synthons. The former interactions were investigated theoretically (ab initio) by studying the energy of interaction of a halide anion with a halocarbon species as a function of Y...X- separation distance and the C-Y...X- angle in a series of complexes (R-Y...X-, R=methyl, phenyl, acetyl or pyridyl; Y=F, Cl, Br, or I; X-=F-, Cl-, Br-, or I-). The theoretical study of the latter interaction type was investigated in only one system, the [(4BP)Cl]2 dimer, (4BP=4-bromopyrdinium cation). Crystal structure determinations, to complement the latter theoretical calculations, were performed on 13 n-chloropyridinium and n-bromopyridinium halide salts (n=2-4). The theoretical and crystallographic studies indicate that these interactions are controlled by electrostatics and are characterized by linear C-Y...X- angles and separation distances less than the sum of van der Waals radius (rvdW) of the halogen atom and the ionic radii of the halide anion. The strength of these contacts from calculations varies from weak or absent, e.g., H3C-Cl...I-, to very strong, e.g., HCC-I...F- (energy of interaction ca. -153 kJ/mol). The strengths of these contacts are influenced by four factors: (a) the type of the halide anion; (b) the type of the halogen atom; (c) the hybridization of the ipso carbon; (d) the nature of the functional groups. The calculations also show that charge assisted halogen...halide synthons have a comparable strength to simple halogen...halide synthons. The nature of these contacts is explained on the basis of an electrostatic model.     

A survey of tellurium-centered secondary-bonding supramolecular synthons

The crystal structures of tellurium compounds frequently display intermolecular contacts between the chalcogen and atoms possessing lone pairs of electrons. Analysis of the data deposited in the Cambridge crystallographic database shows that the shortest secondary bonding interactions (SBIs) are formed when oxygen, nitrogen or chlorine are the donor atoms for SBIs. In addition, these SBIs are shortest when they occur opposite to a bond between tellurium and oxygen, nitrogen, fluorine, chlorine or the nitrile functional group. The structural motifs assembled in these systems fall within eight general categories, from single to multiple bonded supramolecular synthons. The use of multiple points of attachment between molecules leads, in principle, to stronger and more directional supramolecular synthons. The overall structures assembled by the most important tellurium-based supramolecular synthons and prospects for their application in crystal engineering are discussed.     

Total Synthesis of d,l-Isospongiadiol: An Intramolecular Radical Cascade Approach to Furanoditerpenes

A stereoselective oxidative free-radical cyclization of beta-keto ester polyenes 7 and 19 has been accomplished as a one-step entry to the tricarbocyclic synthons 8and 21 which contain five and six stereogenic centers, respectively. These key synthons possessing an axial carboethoxy group at C-4 were ultimately converted to the spongian skeleton (8--> 14 and 21 --> 25 -->14). The synthesis of d,l-isospongiadiol (3) from the common intermediate 14 was realized after introduction of the 2alpha-hydroxy group in the spongian A-ring via epoxidation of silyl enol ether 28 and subsequent desilylation.     

2,4,6-Tris(4-nitrophenoxy)-1,3,5-triazine: a hexagonal host framework stabilised by the NO2-trimer supramolecular synthon

The title molecule forms a honeycomb network of molecular and nitro-trimer synthons with guest species included in the hexagonal voids.     

Efficient Synthesis of 2—Ethyl—A—ring Analogues of 19—Nor—1α,25—dihydroxy Vitamin D3

The novel 19-nor-1α,25-dihydroxy vitamin D3 analogues possessing an ethyl at the 2-position(4 and 5).were synthesized by coupling 25-hydroxy Windaus-Grundmann ketone derivative 20 with A-ring synthons(15 and 19)respectively.The enantioselective synthesis of substituted bicyclic[3,1,0]hexanes structure A-ring synthons,started from all-cis-3,5-dihydroxy-4-ethyl-1-(methoxycarbonyl)cyclohexane via lipase-catalyzd asymmetrization,was demonstratcd.     

Construction of C2-Spirocyclopropyl-Indolin-3-Ones through Base-Promoted [2+1] Annulation Reaction of Indolin-3-ones with Bromosulfonium Salts

A simple base-promoted [2+1] annulation of indolin-3-ones and bromosulfonium salts has been developed in this article. This strategy uses simple and easily prepared indolin-3-ones 1 as C1 synthons and bromosulfonium salts 2 as C2 synthons under mild reaction conditions, and 33 examples of C2-spirocyclopropyl-indolin-3-ones were obtained with up to 99 % yield and >20 : 1 dr.     

Generation of carbamoyl- and thiocarbamoyllithium synthons having a hydrogen(s) or an aryl group on the nitrogen and their trapping with carbonyl electrophiles

Dimetalated amides 1 (Y = O) were generated as the synthons of carbamoyllithiums 2 (Y = O) by the reaction of isocyanates with iBu2AlTenBu and a subsequent tellurium-lithium exchange reaction. A series of amide derivatives 3 (Y = O) were obtained by the trapping of dianion 1 with electrophiles. This transformation can be successfully applied to the generation and trapping of thiocarbamoyllithium synthons 1 (Y = S) as well as to the nucleophilic introduction of the parent carbamoyl moiety H2NC(O).     

Crystal structure prediction of aminols: advantages of a supramolecular synthon approach with experimental structures

The supramolecular synthon approach to crystal structure prediction (CSP) takes into account the complexities inherent in crystallization. The synthon is a kinetically favored unit, and through analysis of commonly occurring synthons in a group of related compounds, kinetic factors are implicitly invoked. The working assumption is that while the experimental structure need not be at the global minimum, it will appear somewhere in a list of computationally generated structures so that it can be suitably identified and ranked upward using synthon information. These ideas are illustrated with a set of aminophenols, or aminols. In the first stage, a training database is created of the 10 isomeric methylaminophenols. The crystal structures of these compounds were determined. The prototypes 2-, 3-, and 4-aminophenols were also included in the training database. Small and large synthons in these 13 crystal structures were then identified. Small synthons are of high topological but low geometrical value and are used in negative screens to eliminate computationally derived structures that are chemically unreasonable. Large synthons are more restrictive geometrically and are used in positive screens ranking upward predicted structures that contain these more well-defined patterns. In the second stage, these screens are applied to CSP of nine new aminols carried out in 14 space groups. In each space group, up to 10 lowest energy structures were analyzed with respect to their synthon content. The results are encouraging, and the predictions were classified as good, unclear, or bad. Two predictions were verified with actual crystal structure determinations.