Synthesis in the plakortone series: Plakortone E

A Pd(II)-mediated hydroxycyclisation-carbonylation-lactonisation sequence has operated efficiently with racemic enediol (8) to furnish (four) separable diastereomers of the bicyclic lactone system assigned to the sponge-derived, bioactive plakortone E. All four are cis ring-fused, and one is identical, on the basis of H-1 and C-13 NMR spectroscopic comparisons, with plakortone E, thus confirming its constitution and relative stereochemistry about the bicyclic lactone core. This synthetic approach, when applied to stereoisomer (13), will establish the absolute stereochemistry of plakortone E, likely to be that shown for (14).

Investigating direct routes to an advanced intermediate for the synthesis of C-20 diterpene alkaloids

Rapid access to the ABCE ring system of the C-20 diterpene alkaloids was achieved by silver (I) promoted intramolecular Friedel-Crafts arylation of a functional group specific 5-bromo-3-azabicyclo[3.3.1]nonane derivative. (c) 2005 Elsevier Ltd. All rights reserved.

Synthesis, biological activity, and preliminary pharmacokinetic evaluation of analogues of a phosphosulfomannan angiogenesis inhibitor (PI-88)

The phosphosulfomannan 1 (PI-88) is a mixture of highly sulfated oligosaccharides that is currently undergoing clinical evaluation in cancer patients. As well as it's anticancer properties, 1 displays a number of other interesting biological activities. A series of analogues of 1 were synthesized with a single carbon (pentasaccharide) backbone to facilitate structural characterization and interpretation of biological results. In a fashion similar to 1, all compounds were able to inhibit heparanase and to bind tightly to the proangiogenic growth factors FGF-1, FGF-2, and VEGF. The compounds also inhibited the infection of cells and cell-to-cell spread of herpes simplex virus (HSV-1). Preliminary pharmacokinetic data indicated that the compounds displayed different pharmacokinetic behavior compared with 1. Of particular note was the n-octyl derivative, which was cleared 3 times less rapidly than 1 and may provide increased systemic exposure.

A straightforward wet-chemical route to the nanocomposites of general layered clays and metal sulfides

The nanocomposites of general layered clays and metal sulfides could be produced from reactions of the layered clay aqueous suspensions and water-soluble metal-thiourea complexes. The clay could be saponite, montmorillonite, hectorite and laponite, while the metal sulfide could be cobalt sulfide, nickel sulfide, zinc sulfide, cadmium sulfide, and lead sulfide. In the nanocomposites, the clay could be incorporated with the metal sulfide pillars and metal sulfide nanoparticles. (c) 2006 Elsevier B.V. All rights reserved.

Azedaralide: total synthesis, relative and absolute stereochemical assignment

Azedaralide, a potentially advanced intermediate for the total synthesis of various tetranortriterpenes, was constructed utilising the Fernandez-Mateos protocol and assigned both relative and absolute stereochemistries. Both asymmetric aldol and classical chiral resolution attempts failed to deliver pure enantiomers whereas preparative chiral chromatography resolved racemic azedaralide with ease. (c) 2006 Elsevier Ltd. All rights reserved.

Towards the total synthesis of vibsanin E, 15-O-methylcyclovibsanin B, 3-hydroxyvibsanin E, furanovibsanin A, and 3-O-methylfuranovibsanin A

Studies detailing synthetic approaches to a variety of biosynthetically related vibsanin-type diterpenes (i.e. vibsanin E, 15-O-methylcyclovibsanin B, 3-hydroxy-vibsanin E, furano-vibsanin A, and 3-O-methylfuranovibsanin A) are discussed. Biogenetically modelled approaches are coupled with an in-vestigation of classical and modern six- to seven-membered ring-expansion protocols, which gain access to the central core of these natural products. (c) Wiley-VCH Verlag GmbH & Co.

Dde as a protecting group for carbohydrate synthesis

Oligosaccharide synthesis using aminosugars requires the presence of a suitable amino protecting group. A number of protecting groups are currently used, and while many display favorable properties, most agents available still suffer from certain disadvantages. This report details the use of a hydrazine labile aminosugar protecting group, N -[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl] (Dde), which can be introduced and removed in a facile and cost-effective manner.

Base modified peptidic nucleic acids: synthesis and crystallographic analysis of intermediates

Peptidic Nucleic Acids (PNAs) are achiral, uncharged nucleic add mimetics, with a novel backbone composed of N-(2-aminoethyl)glycine units attached to the DNA bases through carboxymethylene linkers. With the aim of extending and improving upon the molecular recognition properties of PNAs, the aim of this work was to synthesjse PNA building block intermediates containing a series of substituted purine bases for subsequent use in automated PNA synthesis. Four purine bases: 2,6~diaminopurine (D), isoGuanine (isoG), xanthine (X) and hypoxanthine (H) were identified for incorporation into PNAs targeted to DNA, with the promise of increased hybrid stability over extended pH ranges together with improvements over the use of adenine (A) in duplex formation, and cytosine (C) in triplex formation. A reliable, high-yielding synthesis of the PNA backbone component N -('2- butyloxycarbonyl-aminoethyl)glycinate ethyl ester was establishecl. The precursor N~(2-butyloxycarbonyl)amino acetonitrile was crystallised and analysed by X-ray crystallography for the first time. An excellent refinement (R = 0.0276) was attained for this structure, allowing comparisons with known analogues. Although chemical synthesis of pure, fully-characterised PNA monomers was not achieved, chemical synthesis of PNA building blocks composed of diaminopurine, xanthine and hypoxanthine was completely successful. In parallel, a second objective of this work was to characterise and evaluate novel crystalline intermediates, which formed a new series of substituted purine bases, generated by attaching alkyl substituents at the N9 or N7 sites of purine bases. Crystallographic analysis was undertaken to probe the regiochemistry of isomers, and to reveal interesting structural features of the new series of similarly-substituted purine bases. The attainment of the versatile synthetic intermediate 2,6-dichloro~9- (carboxymethyl)purine ethyl ester, and its homologous regioisomers 6-chloro~9- (carboxymethyl)purine ethyl ester and 6-chloro-7-(carboxymethyl)purine ethyl ester, necessitated the use of X-ray crystallographic analysis for unambiguous structural assignment. Successful refinement of the disordered 2,6-diamino-9-(carboxymethyl) purine ethyl ester allowed comparison with the reported structure of the adenine analogue, ethyl adenin-9-yl acetate. Replacement of the chloro moieties with amino, azido and methoxy groups expanded the internal angles at their point of attachment to the purine ring. Crystallographic analysis played a pivotal role towards confirming the identity of the peralkylated hypoxanthine derivative diethyl 6-oxo-6,7-dihydro-3H-purlne~3,7~djacetate, where two ethyl side chains were found to attach at N3 and N7,

Solvothermal Synthesis, Structure and Optical Property of Nanosized CoSb3 Skutterudite

Binary skutterudite CoSb3 nanoparticles were synthesized by solvothermal method. The nanostructuring of CoSb3 material was achieved by the inclusion of various kinds of additives. X-ray diffraction examination indicated the formation of the cubic phase of CoSb3. Structural analysis by transmission electron microscopy analysis further confirmed the formation of crystalline CoSb3 nanoparticles with high purity. With the assistance of additives, CoSb3nanoparticles with size as small as 10 nm were obtained. The effect of the nanostructure of CoSb3on the UV–visible absorption and luminescence was studied. The nanosized CoSb3 skutterudite may find application in developing thermoelectric devices with better efficiency. K

Exploring coordination-driven self-assembly with autonomous chemical robots

The work presented herein focused on the automation of coordination-driven self assembly, exploring methods that allow syntheses to be followed more closely while forming new ligands, as part of the fundamental study of the digitization of chemical synthesis and discovery. Whilst the control and understanding of the principle of pre-organization and self-sorting under non-equilibrium conditions remains a key goal, a clear gap has been identified in the absence of approaches that can permit fast screening and real-time observation of the reaction process under different conditions. A firm emphasis was thus placed on the realization of an autonomous chemical robot, which can not only monitor and manipulate coordination chemistry in real-time, but can also allow the exploration of a large chemical parameter space defined by the ligand building blocks and the metal to coordinate. The self-assembly of imine ligands with copper and nickel cations has been studied in a multi-step approach using a self-built flow system capable of automatically controlling the liquid-handling and collecting data in real-time using a benchtop MS and NMR spectrometer. This study led to the identification of a transient Cu(I) species in situ which allows for the formation of dimeric and trimeric carbonato bridged Cu(II) assemblies. Furthermore, new Ni(II) complexes and more remarkably also a new binuclear Cu(I) complex, which usually requires long and laborious inert conditions, could be isolated. The study was then expanded to the autonomous optimization of the ligand synthesis by enabling feedback control on the chemical system via benchtop NMR. The synthesis of new polydentate ligands has emerged as a result of the study aiming to enhance the complexity of the chemical system to accelerate the discovery of new complexes. This type of ligand consists of 1-pyridinyl-4-imino-1,2,3-triazole units, which can coordinate with different metal salts. The studies to test for the CuAAC synthesis via microwave lead to the discovery of four new Cu complexes, one of them being a coordination polymer obtained from a solvent dependent crystallization technique. With the goal of easier integration into an automated system, copper tubing has been exploited as the chemical reactor for the synthesis of this ligand, as it efficiently enhances the rate of the triazole formation and consequently promotes the formation of the full ligand in high yields within two hours. Lastly, the digitization of coordination-driven self-assembly has been realized for the first time using an in-house autonomous chemical robot, herein named the ‘Finder’. The chemical parameter space to explore was defined by the selection of six variables, which consist of the ligand precursors necessary to form complex ligands (aldehydes, alkineamines and azides), of the metal salt solutions and of other reaction parameters – duration, temperature and reagent volumes. The platform was assembled using rounded bottom flasks, flow syringe pumps, copper tubing, as an active reactor, and in-line analytics – a pH meter probe, a UV-vis flow cell and a benchtop MS. The control over the system was then obtained with an algorithm capable of autonomously focusing the experiments on the most reactive region (by avoiding areas of low interest) of the chemical parameter space to explore. This study led to interesting observations, such as metal exchange phenomena, and also to the autonomous discovery of self assembled structures in solution and solid state – such as 1-pyridinyl-4-imino-1,2,3-triazole based Fe complexes and two helicates based on the same ligand coordination motif.

Aryne Reactions in the Synthesis of Heterocyclic Molecules

Reactive intermediates play an important the within the realm of chemical synthesis. Their high energy and transient nature make them difficult to observe and characterize, but it is these same properties that empower them to form bonds traditionally seen as difficult to prepare and unusual architectures quickly and efficiently. Herein, two reactive intermediates, arynes and transitient (2azaaryl)-cuprates, are exploited for their abilities to prepare important chemical motifs. Both serve as an avenue into the functionalization of arenes to provide products which hold value in a variety of fields including natural product total syntethis, pharmaseuticals and ligand design.

4-Hydroxy-4,4-diphenylbutan-2-one

The mol­ecules of the title compound, C16H16O2, display an intra­molecular O—HO hydrogen bond between the hydroxyl donor and the ketone acceptor. Inter­molecular C—Hπ inter­actions connect adjacent mol­ecules into chains that propagate parallel to the ac diagonal. The chains are arranged in sheets, and mol­ecules in adjacent sheets inter­act via inter­molecular O—HO hydrogen bonds.

Azoporphyrin : the porphyrin analogue of azobenzene

Azobenzenes (1,2-diaryldiazenes) are very important organic pigments, and they have a unique place in the field of photoresponsive conjugated molecules due to their (usually) reversible E/Z photoisomerisation. The current intense interest in molecular analogues of mechanical components and information storage and processing elements has stimulated research into conjugated molecules whose shape and/or optical properties can be switched electro- or photochemically. Among the classes of conjugated pigments being explored in these contexts are the porphyrinoids, which offer advantages of intense light absorption, a variety of accessible oxidation states, and synthetic control of properties through peripheral or central substitution. Extension of porphyrinoid conjugation can be achieved by linking the peripheral carbons either by three direct bonds (as in the “porphyrin tapes” of Osuka et al.) or through potentially conjugating bridges such as alkenes or, even better, alkynes.