Barry R. Steele

An iminophosphine dendrimeric ligand and its evaluation in the Heck reaction

Abstract DAB- dendr -(NH 2 ) 32 has been modified to produce two novel dendrimeric P , N -ligands, DAB- dendr -[1,2-(NCHC 6 H 4 PPh 2 )] 32 and DAB- dendr -[1,2-(NHCH 2 C 6 H 4 PPh 2 )] 32 . These were both found to activate electron rich aryl bromides in the Heck reaction. The reactions seem to proceed better in a novel solvent system consisting of an equimolar mixture of a tertiary amine with acetic acid. A marked dependence of the conversion on the [equivalents of dendrimeric ligand]/[Pd] ratio has been observed with conversion decreasing as the ratio of dendrimer equivalents to Pd increases. This phenomenon is attributed to interactions of the arms bearing the metal with neighboring ones within the dendrimer.

Activated alkyl- and allyl-alkali metal reagents: Contrasting behaviour towards ethylene

Abstract Ethylene, hex-1-ene and (+)-α-pinene were readily metallated in methylcyclohexane with the system n BuLi/LiK(OCH 2 CH 2 NMe 2 ) 2 . The regioselectivity of the reaction of metallated hex-1-ene and (+)-α-pinene with CO 2 could be substantially modified by the addition of Mg(OCH 2 CH 2 OEt) 2 . Addition of the latter also solubilizes the organometallic reagents. The allylmetallic products from the metallation of hex-1-ene and α-pinene added to ethylene under mild conditions. Whereas up to four molecules of ethylene added to metallated hex-1-ene, only one or two, depending on the reactant ratios, added to metallated α-pinene. Similar reactions involving use of a variety of other strong bases such as n BuLi/ t C 5 H 11 OK and n BuM (M  Li, Na, K), with and without added TMEDA, indicated that the presence of a tertiary amine, apart from assisting the metallation reaction, is essential for the occurrence of the addition.

Dendrimers and the development of new complex nanomaterials for biomedical applications.

New nano-scale drug carriers offer the possibility of increasing the therapeutic index of drug molecules by increasing their effectiveness, diminishing their toxicity against physiological tissues and achieving controlled therapeutic levels for a prolonged time. This review gives an overview of approaches to the development of these novel complex nanocarriers with emphasis on those involving dendrimers and related systems. The combination of two of more nano-sized units for producing an overall system with unique properties could be advantageous compared to more simple nanotechnology-based carriers. Recent advances in medicinal chemistry offer the possibility of exact tailoring of the properties of such complex systems which, in conjunction with full physicochemical characterization, may lead to novel and highly effective drug products. An assessment is given of the potential of systems such as chimeric advanced Drug Delivery nano Systems (chi-aDDnSs) for the delivery of drugs compared with conventional carriers. Rational synthesis of molecules that can act as modulators of the properties of chi-aDDnSs and may be the future in the design and development of nanocarriers, not only for the delivery of drug molecules but also for genetic material and imaging agents is sought.

Comparison of thermal effects of stilbenoid analogs in lipid bilayers using differential scanning calorimetry and molecular dynamics: correlation of thermal effects and topographical position with antioxidant activity

In previous studies it was shown that cannabinoids (CBs) bearing a phenolic hydroxyl group modify the thermal properties of lipid bilayers more significantly than methylated congeners. These distinct differential properties were attributed to the fact that phenolic hydroxyl groups constitute an anchoring group in the vicinity of the head-group, while the methylated analogs are embedded deeper towards the hydrophobic region of the lipid bilayers. In this work the thermal effects of synthetic polyphenolic stilbenoid analogs and their methylated congeners have been studied using differential scanning calorimetry (DSC). Molecular dynamics (MD) simulations have been performed to explain the DSC results. Thus, two of their phenolic hydroxyl groups orient in the lipid bilayers in such a way that they anchor in the region of the head-group. In contrast, their methoxy congeners cannot anchor effectively and are embedded deeper in the hydrophobic segment of the lipid bilayers. The MD results explain the fact that hydroxystilbenoid analogs exert more significant effects on the pretransition than their methoxy congeners, especially at low concentrations. To maximize the polar interactions, the two phenolic hydroxyl groups are localized in the vicinity of the head-group region, directing the remaining hydroxy group in the hydrophobic region. This topographical position of stilbenoid analogs forms a mismatch that explains the significant broadening of the width of the phase transition and lowering of the main phase-transition temperature in the lipid bilayers. At high concentrations, hydroxy and nonhydroxy analogs appear to form different domains. The correlation of thermal effects with antioxidant activity is discussed.

Aryllithiums with Increasing Steric Crowding and Lipophilicity Prepared from Chlorides in Diethyl Ether. The First Directly Prepared Room-Temperature-Stable Dilithioarenes

A convenient procedure has been developed for the preparation of synthetically useful, room-temperature-stable aryllithiums starting from aryl chlorides and lithium metal. The method provides a route to aryllithiums which have previously not been accessible cleanly or could only be prepared by using more expensive starting materials.

Reductive lithiation of alkyl phenyl sulfides in diethyl ether. A ready access to α,α-dialkylbenzyllithiums

Diethyl ether is a convenient solvent for the conversion of benzylic phenyl sulfides to the corresponding organolithiums by an uncatalyzed reductive metalation, while catalysis by naphthalene is required to achieve the same reaction for alkyl phenyl sulfides. The addition of magnesium 2-ethoxyethoxide to solutions of unstable alkyllithiums prepared in this way provides storable reagents.

Synthesis of lithium ω-(m- and p-lithiophenoxy)alkoxides modified with magnesium 2-ethoxyethoxide. Crystal structures of bis[4-(2-hydroxyethoxy)phenyl]mercury and bis[4-(3-hydroxypropoxy)phenyl]mercury

m - and p -Chlorinated ω-phenoxyalcohols 1 , were transformed into the corresponding lithium ω-( m - and p -lithiophenoxy)alkoxides 4 , respectively, by successive deprotonation with n -butyllithium and subsequent chlorine–lithium exchange by lithium naphthalene radical anion in THF–methylcyclohexane. Lithium 2-(4-lithiophenoxy)ethoxide ( 4a′ ) was also prepared by bromine–lithium exchange of 2-(4-bromophenoxy)ethanol ( 2a′ ) with two equivalents of n -butyllithium. The organolithiums were modified with magnesium 2-ethoxyethoxide in order to avoid ortho -metallation of the above-mentioned substituted arenes. Subsequent reaction of these intermediates with the electrophiles carbon dioxide, benzophenone, benzonitrile and 0.5 equivalents of mercuric chloride yielded the expected m - and p -substituted (ω-hydroxyalkoxy)benzenes in yields ranging from 50 to 75%. The crystal structures of the organomercurials 8a′ and 8b′ have been determined and revealed the Hg atom to occupy a crystallographic center of symmetry in a linear CHgC arrangement.

Biological and computational evaluation of resveratrol inhibitors against Alzheimer's disease.

Abstract It has been reported that beta amyloid induces production of radical oxygen species and oxidative stress in neuronal cells, which in turn upregulates β-secretase (BACE-1) expression and beta amyloid levels, thereby propagating oxidative stress and increasing neuronal injury. A series of resveratrol derivatives, known to be inhibitors of oxidative stress-induced neuronal cell death (oxytosis) were biologically evaluated against BACE-1 using homogeneous time-resolved fluorescence (TRF) assay. Correlation between oxytosis inhibitory and BACE-1 inhibitory activity of resveratrol derivatives was statistically significant, supporting the notion that BACE-1 may act as pivotal mediator of neuronal cell oxytosis. Four of the biologically evaluated resveratrol analogs demonstrated considerably higher activity than resveratrol in either assay. The discovery of some “hits” led us to initiate detailed docking studies associated with Molecular Dynamics in order to provide a plausible explanation for the experimental results and understand their molecular basis of action.

PHOSPHORUS-31 CONTACT SHIFTS AS A MEASURE OF WEAK LIGAND AFFINITIES. INTERACTION BETWEEN ALKALI METAL FLUORENONE RADICAL ANIONS AND CERTAIN PHOSPHORUS (III OR V) LIGANDS

The nuclear magnetic resonance shifts, δobs, induced to 31P in Ph3P, (MeO)3P and (MeO)3PO by alkali metal fluorenone radical anions in tetrahydrofuran solutions were measured. These parameters, which depend significantly on the cation for a given ligand, and also on the ligand for a given cation, were used to extract the corresponding 31P contact shifts, δc(M). The latter parameters are proposed as a measure of the ligand affinity of a given phosphorus compound for a particular alkali metal. Trimethyl phosphate exhibits the greatest affinity for the lithium cation. The magnitudes of δc(M) imply some covalency between the cation and the radical anion and the ‘paradox’ of a heavier alkali metal such as potassium being covalently bonded to fluorenone radical anion has been explained. The transferability of the reported ligand affinities of Li+, Na+ and K+ is discussed.

Formation of ketones in the reaction of aldehydes with unsolvated dibutylmagnesium in hydrocarbon solvents under homogeneous conditions, and its implications

Abstract Unsolvated dibutylmagnesium reacts with aldehydes in the presence of lithium alkoxide in methylcyclohexane to give not only the expected secondary alcohol but also the ketone formed by oxidation of the alcohol. The amount of ketone produced depends on the reactant ratios, which can be chosen so that the ketone is the major product. The relevance of these observations to the reactions of aldehydes with organomagnesium and organolithium reagents in general is discussed.