Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures

The chemistry of lithium enolates is used to demonstrate that complex structures held together by noncovalent bonds (“supramolecules”) may dramatically influence the result of seemingly simple standard reactions of organic synthesis. Detailed structural data have been obtained by crystallographic investigations of numerous Li enolates and analogous derivatives. The most remarkable features of these structures are aggregation to give dimers, tetramers, and higher oligomers, complexation of the metal centers by solvent molecules and chelating ligands, and hydrogen-bond formation of weak acids such as secondary amines with the anionoid part of the enolates. The presence in nonpolar solvents of the same supramolecules has been established by NMR-spectroscopic, by osmometric, and by calorimetric measurements. The structures and the order of magnitude of the interactions have also been reproduced by ab-initio calculations. Most importantly, supramolecules may be product-forming species in synthetic reactions of Li enolates. A knowledge of the complex structures of Li enolates also improves our understanding of their reactivity. Thus, simple procedures have been developed to avoid complications caused by secondary amines, formed concomitantly with Li enolates by the common methods. Mixtures of achiral Li enolates and chiral Li amides can give rise to enantioselective reactions. Solubilization by LiX is observed, especially of multiply lithiated compounds. This effect is exploited for alkylations of N-methylglycine (sarcosine) CH₂ groups in open-chain oligopeptides. Thus, the cyclic undecapeptide cyclosporine, a potent immunosuppressant, is converted into a THF-soluble hexalithio derivative (without epimerization of stereogenic centers) and alkylated by a variety of electrophiles in the presence of either excess lithiumdiisopropyl amide or of up to 30 equivalents of lithium chloride. Depending on the nature of the LiX additive, a new stereogenic center of (R) or (S) configuration is created in the peptide chain by this process. A structure-activity correlation in the series of cyclosporine derivatives thus available is discussed.     

Selective alkylation and Suzuki coupling as an efficient strategy for introducing functional anchors to the ethylene-bis(indenyl) ligand

Chiral ansa-ethylene-bis(indenyl)-metal complexes, EBI-MX₂, are useful pre-catalysts for a wide variety of reactions, including hydrogenations, hydrosilylations, and polymerization reactions. In order to immobilize these complexes onto heterogeneous supports, a new methodology was developed to introduce functional anchors to the ethylene-bis(indenyl) ligand, EBI. This was accomplished by selective alkylation of indene to form toluene-4-sulfonic acid 2-(3H-inden-1-yl)-ethyl ester, which was then used to alkylate 6-bromoindene. The selective introduction of an aryl bromide then undergoes coupling reactions with aryl borates via the Suzuki coupling to efficiently introduce an alkenyl or alcohol, functional anchor in a simple four step synthesis.     

Formal synthesis of tubelactomicins via a transannular Diels-Alder approach

A formal synthesis of the antimicrobial tricyclic macrolides, tubelactomicins A and E, featured by a transannular Diels-Alder (TADA) approach, has been explored. The key issue for the transannular cyclization was the synthesis of a 24-membered macrolactone equipped with all the requisite functionalities, which has been achieved using an intramolecular Hiyama cross-coupling strategy. The Hiyama coupling reaction spontaneously triggered off the TADA reaction. From the endo-TADA adduct, formal syntheses of tubelactomicins A and E were achieved. The 24-membered macrolactone formation was also achieved via an intramolecular ring-closing metathesis approach.     

The effect of grass fiber filler on curing characteristics and mechanical properties of natural rubber

Natural rubber is reinforced with a novel type of grass fiber (Cyperus Tegetum Rox b). The effects of fiber loading of different mesh sizes on curing characteristics and mechanical properties of grass fiber filled natural rubber composite are studied. Since 400 mesh grass fiber loaded natural rubber composite shows superior mechanical properties, therefore the effect of silane coupling agent was studied for this particular composite. Here composites were prepared by using water leached grass fiber. Optimum cure time increases with the increase in fiber loading but the change in scorch time is less. The same trend of increase in optimum cure time is observed in the presence of Si69. But the value is higher compared to that of rubber composite without Si69. With increase in the fiber loading, modulus and hardness of the composite increases but tensile strength decreases. The mechanical properties of the composite, namely moduli at 200 and 300% elongation and hardness increase in the presence of Si69 but tensile strength is less compared to that of the composite without Si69. Elongation at break is not much affected due to the presence of Si69. Copyright © 2004 John Wiley & Sons, Ltd.     

A study of the formation of silica-supported mixed magnesium-manganese spinel oxides from multicomponent gels

The effects of thermal treatment on composite materials prepared by the gelation of sols comprising large concentrations of metal oxide precursor salts have been investigated, in order to determine the compositional and thermal requirements for forming spinel magnesium manganates in such systems. The preparative technique has been found to give rise to derived gel materials in which the metal oxide phase, in the form of regular spherical particles, is dispersed throughout a continuous silica matrix. Silica-supported mixed magnesium and manganese spinel oxide phases were obtained for systems comprising at least 30 wt% metal nitrate after heating to temperatures between 700 and 850°C, but not without concomitant formation of Mn₂O₃ and modification of the silica network by magnesium.     

Synthesis and in Vitro Evaluation of N-[[4-[2-(Carboxyl)-1-Cycloalken-1-yl]Phenyl]Methyl]Imidazoles as Nonpeptide Angiotensin II Receptor Antagonists

A series of nonpeptide angiotensin II receptor antagonists was synthesized via palladium-assisted cross coupling of aryl stannane and cycloalkenyl triflates and subsequent alkylation of silyl-protected imidazole. Our compounds, which have a terminal five- to seven-membered cycloalkenyl ring, are compared to DuPont EXP7711, an N-[(2′-carboxybiphenylyl)methyl]imidazole, which has a terminal phenyl moiety. Physicochemical properties of the compounds, such as lipophilicity, steric bulk, conformation, and the relative spatial proximity of the 2-carboxyl and the middle phenyl, are quantitated by computational chemistry. Potency in terms of binding affinity to AT₁ receptors in rat adrenal glomerulosa and rabbit aorta is maximized when the terminal ring is aromatic.     

Cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic and benzylic Grignard reagents and their application to tandem radical cyclization/cross-coupling reactions

Details of cobalt-catalyzed cross-coupling reactions of alkyl halides with allylic Grignard reagents are disclosed. A combination of cobalt(II) chloride and 1,2-bis(diphenylphosphino)ethane (DPPE) or 1,3-bis(diphenylphosphino)propane (DPPP) is suitable as a precatalyst and allows secondary and tertiary alkyl halides--as well as primary ones--to be employed as coupling partners for allyl Grignard reagents. The reaction offers a facile synthesis of quaternary carbon centers, which has practically never been possible with palladium, nickel, and copper catalysts. Benzyl, methallyl, and crotyl Grignard reagents can all couple with alkyl halides. The benzylation definitely requires DPPE or DPPP as a ligand. The reaction mechanism should include the generation of an alkyl radical from the parent alkyl halide. The mechanism can be interpreted in terms of a tandem radical cyclization/cross-coupling reaction. In addition, serendipitous tandem radical cyclization/cyclopropanation/carbonyl allylation of 5-alkoxy-6-halo-4-oxa-1-hexene derivatives is also described. The intermediacy of a carbon-centered radical results in the loss of the original stereochemistry of the parent alkyl halides, creating the potential for asymmetric cross-coupling of racemic alkyl halides.     

Compatibility Studies of Multicomponent Tablet Formulations. DSC and experimental mixture design

An experimental mixture design was applied to a differential scanning calorimetry (DSC) study performed to evaluate naproxen compatibility in tablet formulations consisting of four classic excipients (sorbitol, sodium carboxymethylcellulose, poly(ethylene glycol) 20000 and Veegum) each in adequate concentration ranges accounting for the relevant values actually used in pharmaceutical formulations. Twenty-seven different tablets were obtained from as many mixtures prepared according to the experimental design plan and analyzed in a random order by DSC. Statistical evaluation of experimental data enabled correlation of both enthalpy and onset temperature variations of drug melting endotherm (selected as responses indicative of the presence of drug-excipient interactions) with the mixture composition. Variance analysis (Anova) confirmed the reliability of the postulated polynomial model in providing adequate prediction of true system behaviour. This revised version was published online in August 2006 with corrections to the Cover Date.     

稀土金属作用下芳香醛、酮的还原偶联反应

由Ln/ROH/TMSCl组成的体系能选择性地使芳香族醛、酮还原偶联形成频哪醇, 产率优良, 而对脂肪族醛酮呈惰性。     

Cyclizations via Palladium-Catalyzed Allylic Alkylations [New Synthetic Methods (79)]

The history of ring systems in organic chemistry parallels their synthetic accessibility. Transition-metal-catalyzed cyclizations offer a new opportunity to create carbo- and heterocyclic compounds with great facility. Among these methods, allylic alkylations catalyzed by palladium have proven unusually productive because of the extraordinary chemo-, regio-, and diastereoselectivity and the continuing possibility for the development of enantioselectivity. The rules for ring closure differ from those for non-transition-metal-catalyzed reactions. A major benefit is the ability to generate medium (eight-, nine-, ten-, and eleven-membered) and large rings in preference to normal (five-, six- and seven-membered) rings. With the appropriate substrate, efficient macrocyclizations are possible under conditions of normal concentrations. A second major benefit derives from the complementary stereochemistry of the metalcatalyzed substitution (net retention of configuration) compared to non-metal-catalyzed reactions (inversion of configuration). Further, the requirement for the substrate to conform to the transition-metal template may impose a stereochemical preference in the intermediate that ultimately translates into the thermodynamically less stable organic product regardless of the stereochemistry of the starting material. While more work has focused on carbocyclic synthesis, the possibilities for heterocyclic synthesis are just beginning to be tapped. In addition to forming heterocycles by C? C bond formation, use of a heteroatom as a nucleophile has already proven effective for oxygen and nitrogen, with other nucleophiles awaiting investigation. New dimensions for cyclization via allylic alkylation arise by generating the requisite π-allylpalladium intermediates by methods other than palladium(0)-initiated allylic ionizations. In addition, metals other than palladium will clearly expand the possibilities, but as yet remain untapped.