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PubMed2004

Structural characterization of modular supramolecular architectures in solution.

Structures of modular supramolecular architectures consisting of a hexameric, diphenylethyne-linked porphyrin macrocyclic array and the corresponding host-guest complex formed by inclusion of a tripyridyl guest molecule were characterized in solution using high-angle X-ray scattering. Scattering measurements made to 6 A resolution coupled with pair distance function (PDF) analyses demonstrated that (1) the porphyrin architectures are not rigid but are distributed across a conformational ensemble with a mean diameter that is 1.5 A shorter than the diameter of a symmetric, energy-minimized model structure, (2) the conformational envelope has limits of 3 A positional dispersion and full rotational freedom for all six porphyrin groups, and (3) insertion of the tripyridyl guest molecule expands the diameter of the host conformer by 0.6 A and decreases the configurational dispersion by approximately 2-fold. These results validate the molecular design, provide a new measure of conformational ensembles in solution that cannot be obtained by other techniques, and establish a structural basis for understanding the photophysical and guest-hosting functions of the hexameric porphyrin architectures in liquids.

Journal Article↗
PubMed2005

Modular monodentate phosphoramidite ligands for rhodium-catalyzed enantioselective hydrogenation.

A new class of monodentate phosphoramidite ligands (DpenPhos) has been developed on the basis of the modular concept for Rh(I)-catalyzed asymmetric hydrogenations of a variety of olefin derivatives, affording the corresponding optically active compounds in excellent yields and enantioselectivities. The ligands have the advantages of facile preparation, tunable structure, and broad scope of substrates in their Rh(I) complex-catalyzed asymmetric hydrogenations.

Journal Article↗
PubMed2005

A modular nanoparticle-based system for reagentless small molecule biosensing.

Metalloprotein tethered CdSe nanoparticles have been generated to provide selective and reagentless maltose biosensing. As opposed to cell or protein detection by semiconducting nanoparticle bioconjugates, a modular method for small-molecule detection using semiconducting nanoparticle bioconjugates has been difficult. Here we report a method for reagentless protein-based semiconducting nanoparticle biosensors. This method uses Ru(II) complex-CdSe nanoparticle interactions and the maltose-induced conformation changes of maltose binding protein to alter the CdSe nanoparticle fluorescence emission intensity. In this proof-of-principle system, the maltose-induced protein conformation changes alter the Ru(II) complex-CdSe nanoparticle interaction, which increases the CdSe emission intensity. Altered CdSe emission intensity effects are best described as electron transfer from the Ru(II) complex to the CdSe excited state forming the nonfluorescent CdSe anion. Four surface-cysteine, Ru(II) complex-attached maltose-binding proteins have been studied for maltose dependent alteration of CdSe emission intensities. With 3.0-3.5 nm diameter CdSe nanoparticles, all ruthenated maltose-binding proteins display similar maltose-dependent increases (1.4-fold) in CdSe emission intensity and maltose binding affinities (KA = 3 x 106 M-1). For these four systems, the only difference was the sample-to-sample variation in maltose-dependent responses. Thus, very few surface cysteine mutations need to be examined to find a successful biosensor, as opposed to analogous systems using organic fluorophores. This strategy generates a unimolecular, or reagentless, semiconducting nanoparticle biosensor for maltose, which could be applied to other proteins with ligand-dependent conformation changes.

Biosensing Techniques↗
PubMed2005

A modular and efficient synthesis of functional titanocenes.

A modular synthesis of functional titanocenes featuring building blocks is described. The approach allows straightforward access to large numbers of structurally diverse titanocenes that are pertinent for catalysis, structural studies, and bioinorganic chemistry. Among the functional groups introduced are amino acids, sugars, and fluorescence labels that are attached to the cyclopentadienyl ligand as esters and amides.

Crystallography, X-Ray↗
PubMed2006

A very simple, highly stereoselective and modular synthesis of ferrocene-based P-chiral phosphine ligands.

A very simple, highly stereoselective and modular synthesis of ferrocene-based P-chiral phosphine ligands has been developed. On the basis of this new methodology, several new families of ferrocene-based phosphine ligands have been prepared coupling chirality at phosphorus with other, more standard stereogenic features. The introduction of P-chirality into ferrocene-based phosphine ligands enhances the enantioselective discrimination produced by the corresponding Rh catalyst when a matching among the planar chirality, carbon chirality, and the chirality of phosphorus is achieved.

Journal Article↗
PubMed2006

A modular approach to ferroelectric polymers with chemically tunable curie temperatures and dielectric constants.

We present a modular approach toward poly(vinylidene fluoride)-based ferroelectric fluoropolymers with high dielectric constants. This strategy is based on a two-step reaction, including the copolymerization of vinylidene fluoride and chlorotrifluoroethylene and a subsequent hydrogenation reaction. The chemical structures and compositions of the resulting polymers can be precisely controlled, leading to tunable Curie temperatures and dielectric constants and a systematical study of structure-property correlations.

Journal Article↗
PubMed2006

A modular strategy for tailoring fluorescent biosensors from ribonucleopeptide complexes.

Fluorescent biosensors that facilitate reagentless sensitive detection of small molecules are crucial tools in the areas of therapeutics and diagnostics. However, construction of fluorescent biosensors with desired characteristics, that is, detection wavelengths and concentration ranges for ligand detection, from macromolecular receptors is not a straightforward task. An ATP-binding ribonucleopeptide (RNP) receptor was converted to a fluorescent ATP sensor without chemically modifying the nucleotide in the ATP-binding RNA. The RNA subunit of the ATP-binding RNP and a peptide modified with a pyrenyl group formed a stable fluorescent RNP complex that showed an increase in the fluorescence intensity upon binding to ATP. The strategy to convert the ATP-binding RNP receptor to a fluorescent ATP sensor was applied to generate fluorescent ATP-binding RNP libraries by using a pool of RNA subunits obtained from the in vitro selection of ATP-binding RNPs and a series of fluorophore-modified peptide subunits. Simple screening of the fluorescent RNP library based on the fluorescence emission intensity changes in the absence and presence of the ligand afforded fluorescent ATP or GTP sensors with emission wavelengths varying from 390 to 670 nm. Screening of the fluorescence emission intensity changes in the presence of increasing concentrations of ATP allowed titration analysis of the fluorescent RNP library, which provided ATP sensors responding at wide concentration ranges of ATP. The combinatorial strategy using the modular RNP receptor reported here enables tailoring of a fluorescent sensor for a specific ligand without knowledge of detailed structural information for the macromolecular receptor.

Adenosine Triphosphate↗
PubMed2006

Modular alpha-helical mimetics with antiviral activity against respiratory syncitial virus.

A 13-residue peptide sequence from a respiratory syncitial virus fusion protein was constrained in an alpha-helical conformation by fusing two back-to-back cyclic alpha-turn mimetics. The resulting peptide, Ac-(3-->7; 8-->12)-bicyclo-FP[KDEFD][KSIRD]V-NH(2), was highly alpha-helical in water by CD and NMR spectroscopy, correctly positioning crucial binding residues (F488, I491, V493) on one face of the helix and side chain-side chain linkers on a noninteracting face of the helix. This compound displayed potent activity in both a recombinant fusion assay and an RSV antiviral assay (IC(50) = 36 nM) and demonstrates for the first time that back-to-back modular alpha-helix mimetics can produce functional antagonists of important protein-protein interactions.

Amino Acid Sequence↗
PubMed2006

Asymmetric modular synthesis of highly functionalized medium-sized carbocycles and lactones via ring-closing metathesis of sulfoximine-substituted trienes.

A modular asymmetric synthesis of medium-sized carbocycles and lactones has been developed that affords highly substituted 7-, 9-, and 11-membered rings. The key steps are (1) the highly diastereoselective synthesis of sulfoximine-substituted homoallylic alcohols from allylic sulfoximines and unsaturated as well as saturated aldehydes, (2) an E-stereoselective alkylation and hydroxyalkylation of sulfoximine-substituted alkenyllithium derivatives, (3) the esterification of sulfoximine-substituted homoallylic alcohols, and (4) the ring-closing metathesis reaction of sulfoximine-substituted trienes with the ruthenium catalyst 8. Two examples for the further synthetic elaboration of the sulfoximine-substituted carbocycles are provided. The selective cleavage of the tert-butyldimethylsilyl group of 12 in the presence of the triethylsilyl group afforded the allylic alcohol 18 which was oxidized to enone 19. A cross-coupling reaction of the sulfoximine-substituted carbocycle 9 with LiCuMe2 furnished the methyl-substituted derivative 20.

Journal Article↗
PubMed2001

A modular approach for the synthesis of oligosaccharide mimetics.

To allow modular syntheses of oligosaccharide mimetics, the potentially trifunctional glycoside 7 was synthesized and used as a scaffold for the successive attachment of further monosaccharide derivatives to lead to the di-, tri-, and tetrasaccharide mimetics 11, 13, and 16. This synthetic strategy can also be used to prepare oligovalent neoglycoconjugates, e.g., 18, which contains nine mannosyl units. The applied concept implies numerous options for the synthesis of a wide array of structural variations, biolabeling, or solid-phase synthesis as well as combinatorial approaches.

Combinatorial Chemistry Techniques↗
PubMed2001

Modular furanoside phosphite ligands for asymmetric Pd-catalyzed allylic substitution.

A series of diphosphite, phosphine-phosphite, and thioether-phosphite ligands 1-5 with a furanoside backbone have been used in the enantioselective palladium-catalyzed allylic substitution of rac-1,3-diphenyl-2-propenyl acetate giving low to high enantioselectivies (from close to 0% to 97% ee). The modular nature of these ligands enables systematic investigations of the effect of the ligand structure on the enantioselectivity. The enantioselectivity is mainly determined by the configuration of the stereogenic center C-3 of the furanose backbone. From this we conclude that the attack of the nucleophile takes place trans toward the donating group at the stereogenic C-5 atom. Systematic variation of the donor group attached to the carbon atom C-5 indicated that the presence of a bulky phosphite functionality has a positive effect on enantioselectivity. Thus, the highest ee's are obtained using the bulky diphosphite ligand 1b containing a xylofuranoside backbone.

Journal Article↗
PubMed2002

Chiral diphosphites derived from D-glucose: new highly modular ligands for the asymmetric catalytic hydrogenation.

A series of novel diphosphite ligands derived from readily available D-(+)-glucose have been synthesized. These ligands were screened in the Rh-catalyzed hydrogenation of a series of alpha,beta-unsaturated carboxylic acid derivatives. Both excellent enantioselectivities (ee up to >99%) and activities were achieved. The advantage of these ligands is that their modular nature allows an easy systematic variation in the configuration of the stereocenters (C-3, C-5) at the ligand backbone and in the biaryl substituents, so the optimum configuration for maximum enantioselectivity in asymmetric hydrogenation can be determined. Results show that enantiomeric excesses depend strongly on the absolute configuration of C-3 and slightly on the stereocenter carbon C-5, while the sense of the enantiodiscrimination is predominantly controlled by the configuration of the biaryls at the phosphite moieties. Moreover, the presence of bulky substituents at the ortho-positions of the biaryl diphosphite moieties has a positive effect on enantioselectivity.

Catalysis↗
PubMed2003

Modular approach to novel chiral aryl-ferrocenyl phosphines by Suzuki cross-coupling.

Two novel planar chiral and atropisomeric P,N and P,O aryl-ferrocenyl ligand systems have been developed. The strategy is short and involves a new synthetic approach to aryl-ferrocenyl compounds via a Suzuki cross-coupling procedure. The modular design can easily give access to variety of chiral mono- and bidentate ligands. Two simple derivatives of a novel chiral bidenate P,N ligand belonging to the MOPF family have been synthesized and tested in the enantioselective copper-catalyzed addition of diethyl zinc to an enone and a "difficult" diester. Moderate to excellent yields and enantioselectivities up to 58% were obtained using 1 mol % Cu(OTf)(2) and 1.5 mol % chiral ligand.

Journal Article↗
PubMed2003

A modular synthesis of annonaceous acetogenins.

A synthesis of four Annonaceous acetogenins, asiminocin, asimicin, asimin, and bullanin, by a modular approach from seven fundamental subunits, A-G, is described. The approach employs a central core aldehyde segment, C, to which are appended an aliphatic terminus, A or B, a spacer subunit, D or E, and a butenolide terminus, F or G. Coupling of the A, B, D, and E segments to the core aldehyde unit is effected by highly diastereoselective additions of enantiopure allylic indium or tin reagents. The butenolide termini are attached to the ACD, BCE, or BCD intermediates by means of a Sonogashira coupling. The design of the core, spacer, and termini subunits is such that any of the C30, C10, or C4 natural acetogenins or stereoisomers thereof could be prepared. IC50 values for the four aforementioned acetogenins against H-116 human colon cancer cells were found to be in the 10(-3) to 10(-4) microM range. The IC90 activities were ca. 10(-3) microM for asimicin and asimin but only 0.1-1 microM for bullanin and asiminocin.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Modular amino alcohol ligands containing bulky alkyl groups as chiral controllers for Et2Zn addition to aldehydes: illustration of a design principle.

A new family of enantiomerically pure (1S,2R)-1-alkyl-2-(dialkylamino)-3-(R-oxy)-1-propanols containing a very bulky alkyl substituent (tert-butyl or 1-adamantyl) on their hydrocarbon chains has been synthesized from the corresponding enantiopure epoxy alcohols, arising from the catalytic Sharpless epoxidation, by protection of the primary hydroxy group and subsequent regioselective ring opening of the epoxide by a secondary cyclic amine (C-2 attack). The performance of these amino alcohols as ligands for the catalytic enantioselective addition of diethylzinc to benzaldehyde has been studied, with enantioselectivities of 92-96% being recorded. The best performing ligands, those with a bulky R-oxy group, also depict a convenient activity and selectivity profile in the addition of Et(2)Zn to a representative family of aldehydes. An anomalous structure/enantioselectivity relationship of some ligands in the tert-butyl series has been studied using PM3 calculations, and conclusions have been drawn on the possible effects of including in modular designs structural fragments giving rise to a variety of rotameric transition states.

Journal Article↗
PubMed2003

Synthesis of iduronic acid building blocks for the modular assembly of glycosaminoglycans.

The modular synthesis of glycosaminoglycans requires straightforward methods for the production of large quantities of protected uronic acid building blocks. In particular, the preparation of fully differentiated iduronic acids has proven particularly challenging. An efficient route to methyl 3-O-benzyl-1,2-O-isopropylidene-alpha-l-idopyranosiduronate 6 from diacetone glucose in nine steps and 36% overall yield is described. Idopyranosiduronate 6 is useful as a glycosyl acceptor and as an intermediate that may be further elaborated into iduronic acid trichloroacetimidate glycosyl donors for the assembly of glycosaminoglycan structures as illustrated here.

Combinatorial Chemistry Techniques↗
PubMed2003

Chiral N-acylethylenediamines as new modular ligands for the catalytic asymmetric addition of alkylzinc reagents to aldehydes.

Chiral N-acylethylenediamines represent a new class of modular ligands for the catalytic asymmetric addition of alkylzinc reagents to aldehydes. The N-acylethylenediamine moiety serves as a metal binding site, while attached amino acids provide the source of chirality. Three sites of diversity on the ligands were optimized to enhance the enantioselectivity of the catalysts using an iterative optimization procedure. The most effective ligand, 4k, was synthesized in a single reaction step from inexpensive and commercially available starting materials. This ligand (10 mol %) catalyzed the addition of Me2Zn to 2-naphthaldehyde, benzaldehyde, and 4-chlorobenzaldehyde to give the corresponding alcohol products in 86%, 84% and 81% ee, respectively.

Journal Article↗
PubMed2003

Modular ligands derived from amino acids for the enantioselective addition of organozinc reagents to aldehydes.

A new series of modular chiral ligands that are derived from amino acids were prepared and tested for their ability to catalyze the asymmetric addition of alkylzinc reagents to aromatic and aliphatic aldehydes. The ligands contain a tertiary amine, an amino acid side chain, and a carbamate or amide functional group. One ligand, which was synthesized from Ile, catalyzes the addition of diethylzinc to cyclohexanecarboxaldehyde in 99% ee.

Aldehydes↗