On the Synthesis of Pyrrolobenzo[<Emphasis Type="Italic">b</Emphasis>]thieno[1,4]diazepines

Summary. 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile was converted into the corresponding 2-(pyrrol-1-yl) derivative, followed by reduction of the latter compound into the corresponding amine. This amine and its acyl, aroyl, and arylidene derivatives were used as synthons in the synthesis of several title compounds.     

An Isomer of C60Cl10 Free of Skew‐Pentagonal‐Pyramidal C60Cl6 Substructure

Chlorination is an effective approach for understanding the feature of multiple additions on fullerene cages. The chlorofullerenes obtained are versatile synthons for further derivatization. However, chlorofullerenes used for chemical reaction studies are mainly based on the skew‐pentagonal‐pyramidal (SPP) C₆₀Cl₆. In this work, a new isomer of C₆₀Cl₁₀ that does not contain an SPP‐C₆₀Cl₆ substructure was identified. Its electrochemical properties give it unexpected cyclic voltammetric behavior at more negative potentials relative to other chlorofullerenes. Friedel–Crafts arylation shows good reactivity of this compound. These new findings challenge opinions of fullerene addition patterns and will break the monopoly of C₆₀Cl₆ as a precursor for fullerene modifications.     

Development of metallocomplex amino acids synthons for the asymmetric preparation of α-amino acids by stereoselective introduction of a side chain. Evaluation of the model asymmetric preparation of alanine and β-13C monolabelled α-aminoisobutyric acid

In this communication the evaluation of eleven new metallocomplex alanine synthons bearing C₂-symmetric benzyl groups with electron-donating and electron-withdrawing substituents is described. α-Methylated glycine synthons (alanine complexes) were evaluated alongside alanine synthons in order to obtain a deeper understanding of the relationship between their structures and stereochemistry of monoalkylated products and to choose several candidates for their further tests for stereospecific preparation of 6-[¹⁸F]FDOPA. Glycine-derived analogues of the complexes 3–5 are the best candidates for the development of a 6-[¹⁸F]FDOPA preparation procedure. In the model epimerisation reaction they demonstrated the best performance, much better compared to the previously described compound 2. Complexes 3, 5 and 8 are the best in asymmetric preparation of β-¹³C monolabelled α-aminoisobutyric acid. They have to be tested in the preparation of α-methyl amino acids like 6-[¹⁸F]-α-methylDOPA and 2-[¹⁸F]-α-methyltyrosine.     

An Easy Access to Organic Salt‐Based Stimuli‐Responsive and Multifunctional Supramolecular Hydrogels

By exploiting orthogonal hydrogen bonding involving supramolecular synthons and hydrophobic/hydrophilic interactions, a new series of simple organic salt based hydrogelators derived from pyrene butyric acid and its β‐alanine amide derivative, and various primary amines has been achieved. The hydrogels were characterised by microscopy, table‐top rheology and dynamic rheology. FTIR, variable‐temperature ¹H NMR and emission spectroscopy established the role of various supramolecular interactions such as hydrogen bonding and π–π stacking in hydrogelation. Single‐crystal X‐ray diffraction (SXRD) studies supported the conclusion that orthogonal hydrogen bonding involving amide–amide and primary ammonium monocarboxylate (PAM) synthons indeed played a crucial role in hydrogelation. The hydrogels were found to be stimuli‐responsive and were capable of sensing ammonia and adsorbing water‐soluble dye (methylene blue). All the hydrogelators were biocompatible (MTT assay in RAW 264.7 cells), indicating their suitability for use in drug delivery.     

Redox‐Assisted Self‐Assembly of a Water‐Soluble Cyanido‐Bridged Mixed Valence {CoIII/FeII}2 Square

The facile redox‐assisted assembly of a water‐soluble, extremely robust, cyanide‐bridged mixed‐valence [{Co^III{(Me)₂(μ‐ET)cyclen}}₂{(μ‐NC)₂Fe^II(CN)₄}₂]^2? square is reported. The preparation process involved the use of the enhanced lability of inert Co^III synthons triggered by outer‐sphere redox processes. Characterization of the final compounds has been carried out by NMR, UV/Vis, electrochemistry, and ICP analyses. DFT calculations have been conducted to optimize a structure that has the same hydrodynamic radius as that obtained from DOSY experiments. The new compound is extremely robust, surviving in aqueous solution within the 0–12 pH range for months. The species shows a high affinity for both protons and hydroxo ions in aqueous medium.     

Triterpene glycosides from <Emphasis Type="Italic">Astragalus</Emphasis> and their genins. LXXXVI. Chemical transformation of cycloartanes. VIII. Syntheses based on cycloorbicoside A

Nine new compounds 3–11 were synthesized from the principal glycoside of Astragalus orbiculatus Ledeb. (Leguminosae), cycloorbicoside A, and may be interesting on their own as potential biologically active compounds and synthons for other compounds.     

A novel framework of N—H...Br hydrogen bonds forming Br(4,4′‐bipyridinium)4 supramolecular synthons: bis(4,4′‐bipyridinium) tris[tetrabromidoferrate(III)] bromide

In the asymmetric unit of the title compound, (C₁₀H₁₀N₂)₂[FeBr₄]₃Br, the Fe atoms are in a distorted tetrahedral environment. The crystal structure contains a novel arrangement of Br(4,4′‐bipyridinium)₄ supramolecular synthons assembled via short N—H...Br hydrogen bonds (H...Br = 2.55, 2.40, 2.38 and 2.55 Å), where four cations surround one nonbonded bromide ion in a tetrahedral arrangement. These synthons are further connected by hydrogen bonds using the remaining terminal NH hydrogens in each cation and the Br⁻ ions to form an adamantoid‐like network and thus produce a three‐dimensional supramolecular architecture with the [FeBr₄]⁻ ions located in the cavities. The structure shows no significant intermolecular Br...Br, Br...aryl or aryl–aryl interactions.     

Racemic 1,2‐diphenylbut‐3‐yn‐2‐ol

Molecules of the title compound, C₁₆H₁₄O, are chiral and crystallize in space group P with Z′ = 2, and with one R and one S mol­ecule in the asymmetric unit. The conformations of the phenyl rings in the two independent mol­ecules differ slightly. Supramolecular organization in the crystal is via tetrameric O—H?H(O) hydrogen‐bonded synthons formed separately by each conformer. These tetrameric synthons stack along the c axis via C[triple‐bond]C—H?O(H) hydrogen bonds. The only link between the conformer stacks is provided by weaker C_methylene—H and C_phenyl—H interactions with π_arene density.     

Phosphine‐Catalyzed Annulations of 4,4‐Dicyano‐2‐Methylenebut‐3‐enoates with Maleimides and Maleic Anhydride

A novel phosphine‐catalyzed [4+1] annulation of maleimides with 4,4‐dicyano‐2‐methylenebut‐3‐enoates has been developed to afford spirocyclic products, and the maleimides serves as C₁ synthons. Moreover, a phosphine‐catalyzed formal [3+2] annulation between 4,4‐dicyano‐2‐methylenebut‐3‐enoates and maleic anhydride has been also achieved, and maleic anhydride behaved as a C₃ synthon in the reaction, thus efficiently affording the functionalized cyclopentenones. A stable phosphinium‐containing zwitterionic compound is the key reactive intermediate in both annulations and was successfully isolated. Plausible mechanisms have been proposed on the basis of control experiments and deuterium‐labeling experiments.     

A Switchable Domino Process for the Construction of Novel CO2‐Sourced Sulfur‐Containing Building Blocks and Polymers

α‐Alkylidene cyclic carbonates (αCCs) recently emerged as attractive CO₂‐sourced synthons for the construction of complex organic molecules. Herein, we report the transformation of αCCs into novel families of sulfur‐containing compounds by organocatalyzed chemoselective addition of thiols, following a domino process that is switched on/off depending on the desired product. The process is extremely fast and versatile in substrate scope, provides selectively linear thiocarbonates or elusive tetrasubstituted ethylene carbonates with high yields following a 100 % atom economy reaction, and valorizes CO₂ as a renewable feedstock. It is also exploited to produce a large diversity of unprecedented functional polymers. It constitutes a robust platform for the design of new sulfur‐containing organic synthons and important families of polymers.     

Characterization and identification of cleavage products of 3‐glycosyl‐5‐substituted‐2‐isoxazoline

We report herein the synthesis of new synthons obtained by reductive opening of 3‐glycosyl‐5‐substituted‐2‐isoxazolines. Different cleavage products have been obtained depending on the substituents (aliphatic or aromatic) in position five of the heterocycle ring. The new compounds are characterized physically and spectroscopically.     

Derivatives of <Emphasis Type="Italic">sym</Emphasis>-Triazine. 1. Synthesis and Conversions of Quaternary Methylammonium Salts of 2-Chloro-4,6-disubstituted 1,3,5-Triazines in Nucleophilic Substitution Reactions

New quaternary ammonium salts of monochloro-4,6-disubstituted 1,3,5-triazines have been obtained. These compounds are convenient synthons for the synthesis of new cyano, alkoxy, and other derivatives of sym-triazine. Some conversions of the synthesized salts have been studied. An elimination-isomerization reaction of the sym-triazine ring into a 2-oxo-1,2-dihydro-sym-triazine ring was discovered.     

Synthesis of Optically Active,Cyclic α‐Hydroxy Ketones and 1,2‐Diketones from Verbenone Epoxide

The reactivity of verbenone epoxide ( 5 ), a terpenoid from the pinane series, towards different aliphatic and aromatic aldehydes in the presence of natural montmorillonite (askanite–bentonite) clay has been studied. A series of mechanistically different transformations afforded a number of new, optically active, polyfunctional compounds ( 7, 8, 10 – 14, 16 ). These products are potentially interesting synthons in asymmetric synthesis.     

First asymmetric synthesis of the oxylipin, (6S,9R,10S)-6,9,10-trihydroxyoctadeca-7E-enoic acid

A brief and facile synthesis of the title compound has been developed using cyclohexylideneglyceraldehyde as a chiral template. The key steps in the synthesis were: (i) two highly diastereoselective organometallic addition reactions to the aldehyde to furnish the required synthons with the appropriate stereogenic centers, and (ii) their cross metathesis to give the E-olefin geometry of the target compound.     

4,4′‐(4,5‐Dimethyl‐1,2‐phenylene)bis(2‐methylbut‐3‐yn‐2‐ol): structural variation in vicinal dialkynols

The structure of the title compound, C₁₈H₂₂O₂, contains two non‐equivalent molecules which differ primarily in the location of the –OH groups on opposite sides or on the same side of the molecular plane. Inversion‐symmetric pairs of molecules form intermolecular O—H...O hydrogen‐bonded tetrameric synthons that link non‐equivalent molecules into an approximately square double layer parallel to (02). Recently reported fluorinated analogues [Kane, Meyers, Yu, Gerken & Etzkorn (2011). Eur. J. Org. Chem. pp. 2969–2980] have significantly different structures of varying complexity that incorporate intramolecular hydrogen bonding and suggest that further study of structure versus substituents in vicinal dialkynols could be fruitful.     

Library Design Guided by In-house Developed Computer Tools

In recent years, combinatorial library synthesis for drug discovery begins to migrate from library synthesis solely dictated by chemistry availability to design and synthesis of libraries with more drug-like properties. Lipinski's rule of five has been used to evaluate drug-like properties of individual compound; recently LibProTM, a new computation program has been developed at Pharmacopeia to evaluate durg-like properties of libraries. By using LibPrpTM, chemists at Pharmacopeia are able to obtain information of molecular weight and ClogP distribution of a library, and percentage of library members that violate Lipinski's rule after input structures of synthons for each combinatorial step. Currently, a "virtual library design” approach that is to calculate properties of a library at conceptual phase of the library design has been used to predetermine the value of the library. Also a new computer program used to predict "Absorption” of compounds will also be discussed.     

Stereoselective synthesis of 13Z retinoic acids via β-methylenealdehydes as synthons

A stereoselective synthesis of 13Z retinoic acids via β-methylenealdehydes is described. In methylene-de-oxo-bisubstitution reactions (Knoevenagel, Stobbe, etc.), these new synthons produce stereoselectively E olefins. Hence, a synthesis of 13Z retinoic acids is described, via a stereospecific monodecarboxylation of carboxy-14-retinoic acids.     

Catalytic asymmetric Henry reaction

The classical Henry reaction, the coupling of a nitroalkane with a carbonyl compound in the presence of a base, is an important C–C bond forming reaction in organic chemistry giving β-nitroalcohols, which are useful synthons in organic synthesis. However, an asymmetric version of the reaction, that has been developed recently, gives a new dimension to the classical Henry reaction whereby the control of stereochemistry of two newly generated carbon centres has become possible. In this review, the various catalytic methods for this purpose are discussed.     

Reactivity of Chiral Sesquiterpene Synthons Obtained by the Degradation of Maslinic Acid from Olive‐Pressing Residues

Maslinic acid, a naturally occurring compound isolated from the solid wastes of olive‐oil pressing, was fragmented through the C‐ring via oxidative procedures to obtain two structural fragments. The chemical behaviors of cis‐decalin, from the D and E rings, and of trans‐decalin fragments, from the A and B rings, were investigated in depth using several chemical and enzymatic reactions. These decalin chiral synthons are interesting intermediates to semisynthesize phenanthrene‐ and drimane‐type compounds and natural tricyclic triterpenes.     

Supramolecular synthons in fluorinated and nitrogen-rich <Emphasis Type="Italic">ortho</Emphasis>-diaminotriazoles

5-Substituted 3,4-diamino-1,2,4-triazoles can be obtained in moderate to good yields in a one-pot reaction starting from a carboxylic acid and dimethylaminoguanidine monohydrochloride in polyphosphoric acid (PPA) at 120 °C. Several triazoles and bistriazoles have been prepared in this way, with substituents ranging from alkyl to aryl, including perfluoroaryl or perfluoroalkyl substituents. The crystal structure analysis of three perfluorinated diaminotriazoles has evidenced a most stable R₂² (8) R_{2}^{2} (8) H bonding synthon, involving the amino CNH₂ donor and the adjacent nitrogen ring acceptor; additionally, two new synthons consisting of chains of rings have been identified. The relevance of the short F⋯F intermolecular contacts found in the structures is also discussed.