Showing papers in "Helvetica Chimica Acta in 2003"

Chiral and Achiral Crystal Structures

Abstract: An extensive study and analysis of the concepts, classification, presentation, and nomenclature of chirality and lack of chirality in crystal structures and their constituents is presented. Oriented crystal structures are classified. The chirality rules for existence of molecular crystal structures are examined and the relation to segmentation and latent symmetry highlighted. The nomenclature of chirality and related terms, and the relationship of chirality to optical activity is covered. The uses and limitations of the Euclidean normalizer are treated. An improved glossary of terms is included. 1. Introduction. ± In dealing with chirality in relation to crystal structures it is essential to distinguish between three different objects that may be either chiral or achiral. These three are 1) the molecular components of the crystal, 2) the crystal structure itself and 3) the symmetry group of the crystal structure, viz., its space group. The interrelationship between these chiral or achiral objects is the main theme of this paper. Some consideration will also be given to physical properties and nomenclature in their relationship to chirality. An improved glossary of appropriate terms is presented in Appendix A. Whether an object is chiral or achiral depends on its symmetry group. Restricting all considerations in this paper to three-dimensional physical space (but see Sect. 4.1), the symmetry group of a chiral object contains symmetry operations of only the first kind (viz., rotations and translations) and none of the second kind (viz., roto-inversions), whereas that of an achiral object contains symmetry operations of both kinds in equal numbers. These statements are formalized and proven below. The symmetry group of a molecule is its point group, that of a crystal structure is its space group, and that of a space group is its Euclidean normalizer [1]. The origin of the distinction of enantiomorphs is physical. Rigid-body motions of an object are isometries of the first kind. The interconversion of an object between enantiomorphs requires an isometry of the second kind, but there is no corresponding physical action for a rigid body. Although the energies of the enantiomorphs are identical, the energy barrier to interconversion is excessive for a rigid body. In the presence of parity violation mitigated through the weak neutral current, an energy difference between the two enantiomorphs appears but this is many orders of magnitude (10 17 ) smaller than kT at room temperature. Differences in the activation energies for forward and backward enantiomerisation reactions are possible, even when the energies of the end states are identical [2 ± 4].

Ultrafast electron diffraction (UED) a new development for the 4D determination of transient molecular structures

Abstract: With properly timed sequences of ultrafast electron pulses, it is now possible to image complex molecular structures in the four dimensions of space and time with resolutions of 0.01 A and 1 ps, respectively. The new limits of ultrafast electron diffraction (UED) provide the means for the determination of transient molecular structures, including reactive intermediates and non-equilibrium structures of complex energy landscapes. By freezing structures on the ultrafast timescale, we are able to develop concepts that correlate structure with dynamics. Examples include structure-driven radiationless processes, dynamics-driven reaction stereochemistry, pseudorotary transition-state structures, and non-equilibrium structures exhibiting negative temperature, bifurcation, or selective energy localization in bonds. These successes in the studies of complex molecular systems, even without heavy atoms, and the recent development of a new machine devoted to structures in the condensed phase, establish UED as a powerful method for mapping out temporally changing molecular structures in chemistry, and potentially, in biology. This review highlights the advances made at Caltech, with emphasis on the principles of UED, its evolution through four generations of instrumentation (UED-1 to UED-4) and its diverse applications.

The Cofactor of Tetrachloroethene Reductive Dehalogenase of Dehalospirillum multivorans Is Norpseudo‐B12, a New Type of a Natural Corrinoid

Abstract: The corrinoid cofactor of the tetrachloroethene reductive dehalogenase of Dehalospirillum multivorans was isolated in its Coβ-cyano form. This cofactor represents the main corrinoid found in D. multivorans cells. Analysis of the isolated cyano-corrinoid by a combination of HPLC and UV/VIS-absorbance spectroscopy revealed it to be nonidentical to a variety of known natural B12 derivatives. From high-resolution mass-spectrometric analysis, the molecular formula of the corrinoid isolated from D. multivorans could be deduced as C58H81CoN17O14P. The sample of the novel corrinoid from D. multivorans was further analyzed by UV/VIS, CD, and one- and two-dimensional 1H-, 13C-, and 15N-NMR spectroscopy, which indicated its structure to be closely related to that of pseudovitamin B12 (Coβ-cyano-7″-adeninylcobamide). By the same means, the corrinoid could be shown to differ from pseudovitamin B12 only by the lack of the methyl group attached to carbon 176, and, therefore, it was named norpseudovitamin B12 (or, more precisely, 176-norpseudovitamin B12). Norpseudovitamin B12 represents the first example of a ‘complete’ B12-cofactor that lacks one of the methyl groups of the cobamide moiety, indicating that the B12-biosynthetic pathway in D. multivorans differs from that of other organisms. X-Ray crystal-structures were determined for norpseudovitamin B12 from D. multivorans and the analogues pseudovitamin B12 and factor A (Coβ-cyano-7″-[2-methyl]adeninylcobamide). These first accurate crystal structures of complete corrinoids with an adeninyl pseudonucleotide confirmed the expected coordination properties around Co and corroborated the close conformational similarity of the nucleotide moieties of norpseudovitamin B12 and its two homologues.

Probes for Narcotic Receptor Mediated Phenomena

Abstract: The synthesis of a series of epoxy 5-phenylmorphans is being explored in order to determine the conformational requirements of the phenolic ring in a phenylmorphan molecule that may be needed both for binding to a specific opioid receptor and for exhibiting opioid agonist or antagonist activity. Of the twelve possible ortho- and para-bridged isomers (a–f) (Fig. 1), we now report the synthesis of the para-d isomer, rac-(3R,6aS,11aR)-2-methyl-1,3,4,5,6,11a-hexahydro-2H-3,6a-methanobenzofuro[2,3-c]azocin-8-ol (3). Compound 3 was synthesized via construction of the 5-phenylazabicyclo[3.3.1]non-3-ene skeleton (Scheme 1) and subsequent closure of the epoxy bridge (Scheme 2). As determined by an X-ray diffraction study, the epoxy bridge, restricting the phenyl-ring rotation, fixed the dihedral angle between the least-squares planes through the phenyl ring and atoms N(2), C(3), C(11a), and C(6a) of the piperidine ring (Fig. 2) at 43.0°, and the torsion angle C(12)C(6a)C(6b)C(10a) at −95.0°.

Helicity-Encoded Molecular Strands: Efficient Access by the Hydrazone Route and Structural Features

Abstract: Control over the folding of molecular strands may be achieved by appropriate choice of the constituting subunits, in particular for chains of specific heterocycles such as sequences of directly connected pyridine (py) and pyrimidine (pym) rings, which are known to fold into extended helical structures. Since the hydrazone (hyz) group represents an isomorphic analogue of a py site, the condensation of hydrazine and carboxaldehyde derivatives of pym offers a very efficient approach to strands incorporating hyz instead of py units and constituted by sequences of alternating hyz and pym groups. A series of such strands of different lengths, up to ten hyz units, i.e., 1–7, were synthesized. Their spectral properties indicate that they fold indeed into helical shapes. Extensive characterization was performed in solution by 1HNMR spectroscopy and in the solid state by determination of the crystal structures of eight such strands. They all display the expected helical geometry with up to 3 1/3 turns and direct stacking contacts. The efficiency and flexibility of the synthetic approach as well as its wide potential for generation of diversity through lateral decoration make the (hyzpym) subunit a particularly attractive helicity codon.

Helix formation and folding in γ-peptides and their vinylogues

Abstract: A complete overview of all possible periodic structures with characteristic H-bonding patterns is provided for oligomers composed of -amino acids (-peptides) and their vinylogues by a systematic conformational search on hexamer model compounds employing ab initio MO theory at various levels of approximation (HF/631G*, DFT/B3LYP/6-31G*, SCRF/HF/6-31G*, PCM//HF/6-31G*). A wide variety of structures with definite backbone conformations and H-bonds formed in forward and backward directions along the sequence was found in this class of foldamers. All formally conceivable H-bonded pseudocycles between 7- and 24-membered rings are predicted in the periodic hexamer structures, which are mostly helices. The backbone elongation in comparison to - and -peptides allows several possibilities to realize identical H-bonding patterns. In good agreement with experimental data, helical structures with 14- and 9-membered pseudocycles are most stable. It is shown that the introduction of an (E)-double bond into the backbone of the -amino acid constituents, which leads to vinylogous -amino acids, supports the folding into helices with larger H-bonded pseudocycles in the resulting vinylogous -peptides. Due to the considerable potential for secondary-structure formation, -peptides and their vinylogues might be useful tools in peptide and protein design and even in material sciences. 1. Introduction. ± The imitation and the improvement of structural features of peptides and proteins are great challenges for chemists and biochemists. The application of native peptides for pharmacological and pharmaceutical purposes often suffers from their insufficient resistance to proteases and their unfavorable transport properties. Besides, better selectivity for different receptor subtypes is desired [1] [2]. It is an old idea to solve these problems by substitution of non-proteinogenic amino acids for one or several natural amino acids in the sequence. In the last years, the consistent extension of this idea led to the search for oligomers that are composed only of nonproteinogenic amino acids [3 ± 11]. Since protein and peptide structures are essentially determined by characteristic secondary-structure elements such as helices, sheets, and turns, the modified compounds still have to reflect the steric and electronic properties of their native counterparts to keep or even to improve the biological activity. Consequently, such oligomers should be able to form definite backbone conformations. All these efforts to develop efficient peptidomimetics could be considered part of a general search for oligomers built from −any× chemical monomer unit that folds into definite conformational states. The term foldamer was suggested for such structures [4]. It is obvious that this concept goes far beyond the structural imitation of peptides or the other two major backbones of biopolymers, ribonucleic acids, and polysaccharides, even if peptidomimetics remain a topic of outstanding interest [4 ± 11]. Due to the wide

Two New and a Known Compound from Lawsonia inermis

Abstract: A new obtusafuran derivative, lawsonicin (1), and a new naphthaquinone, lawsonadeem (2), along with a known constituent, vomifoliol (3), were isolated from the aerial parts of Lawsonia alba and characterized by chemical transformation and spectroscopic experiments, including 2D-NMR techniques.

Designing Novel Contrast Agents for Magnetic Resonance Imaging. Synthesis and Relaxometric Characterization of three Gadolinium(III) Complexes Based on Functionalized Pyridine-Containing Macrocyclic Ligands

Abstract: The three novel pyridine-containing 12-membered macrocyclic ligands 1–3 were synthesized. The coordinating arms are represented by three acetate moieties in 1 and 3 and by one acetate and two phosphonate moieties in 2. In all three ligands, the acetate arm in the distal position is substituted, with a benzyl group in 1 and 2 and with an arylmethyl moiety in 3. The relaxivities r1p (20 MHz, 25°) of GdIII complexes are: GD⋅1, r1p=8.3 mM−1 s−1; GD⋅2, r1p8.1 mM−1 s−1; Gd⋅3, r1p10.5 mM−1 s−1. 1H-NMRD and 17O-NMR T2 data show that Gd⋅1 and Gd⋅3 contain two H2O molecules in the inner sphere, whereas the presence of two phosphonate arms allows the coordination of only one H2O molecule in Gd⋅2. Interestingly, the exchange lifetime of coordinated H2O in the three complexes is similar in spite of the difference in the coordination number of the GdIII ion (i.e., 9 in Gd⋅1 and Gd⋅3, and 8 in Gd⋅2). 1H-Relaxometric measurements at different pH and in the presence of lactate and oxalate were carried out to get some insight into the formation of ternary complexes from Gd⋅1 and Gd⋅3. Finally, it was found that binding to human-serum albumin (HSA) of Gd⋅1 and Gd⋅2, though weak, yields limited relaxivity enhancements, likely as a consequence of effects on the hydration sphere caused by donor atoms on the surface of the protein.

Molecular Shape and Intermolecular Liaison: Hydrocarbons and Fluorocarbons

Abstract: Whereas aliphatic hydrocarbon/fluorocarbon mixtures show mutual ‘phobicity’ (e.g., positive deviations from Raoult's Law), their aromatic counterparts show the opposite behavior. Hexafluorobenzene forms co-crystals with many aromatic hydrocarbons, but co-crystals are unknown in the aliphatic series. This remarkable contrast between the behaviors of aliphatic and aromatic hydrocarbon/fluorocarbon mixtures calls for explanation, and we attempt to provide one in terms of the difference in overall molecular shape – disk vs. cylinder – using the new PIXEL method for calculating intermolecular energies.

Synthesis and glycosidase inhibitory activity of 7-deoxycasuarine

Abstract: Reaction of 1,4-anhydro-2,3,5-tri-O-benzyl-1-deoxy-1-imino-D-arabinitol N-oxide (8) with allyl alcohol produced a 3.6:1 mixture of the two pyrrolo[1,2-b]isoxazole derivatives 13 and 14. The major adduct 13 was converted to 7-deoxycasuarine (7), a potent, specific, and competitive inhibitor of amyloglucosidase from Rhizopus mold (see Table).

Synthesis, CD Spectra, and Enzymatic Stability of β2‐Oligoazapeptides Prepared from (S)‐2‐Hydrazino Carboxylic Acids Carrying the Side Chains of Val, Ala, and Leu

Abstract: β-Peptides offer the unique possibility to incorporate additional heteroatoms into the peptidic backbone (Figs. 1 and 2). We report here the synthesis and spectroscopic investigations of β2-peptide analogs consisting of (S)-3-aza-β-amino acids carrying the side chains of Val, Ala, and Leu. The hydrazino carboxylic acids were prepared by a known method: Boc amidation of the corresponding N-benzyl-L-α-amino acids with an oxaziridine (Scheme 1). Couplings and fragment coupling of the 3-benzylaza-β2-amino acids and a corresponding tripeptide (N-Boc/C-OMe strategy) with common peptide-coupling reagents in solution led to β2-di, β2-tri-, and β2-hexaazapeptide derivatives, which could be N-debenzylated (4–9; Schemes 2–4). The new compounds were identified by optical rotation, and IR, 1H- and 13C-NMR, and CD spectroscopy (Figs. 4 and 5) and high-resolution mass spectrometry, and, in one case, by X-ray crystallography (Fig. 3). In spite of extensive measurements under various conditions (temperatures, solvents), it was not possible to determine the secondary structure of the β2-azapeptides by NMR spectroscopy (overlapping and broad signals, fast exchange between the two types of NH protons!). The CD spectra of the N-Boc and C-OMe terminally protected hexapeptide analog 9 in MeOH and in H2O (at different pH) might arise from a (P)-314-helical structure. The N-Boc-β2-tri and N-Boc-β2-hexaazapeptide esters, 7 and 9, were shown to be stable for 48 h against the following peptidases: pronase, proteinase K, chymotrypsin, trypsin, carboxypeptidase A, and 20S proteasome.

Crystals and Life

Abstract: The record of life×s emergence on Earth has been thoroughly obliterated by the remelting and turnover of the crust, soggy and pliable from the water, retained by the planet×s gravitational field. Provided that life existed on a smaller body such as Mars with an arrested crustal evolution, a protected sedimentary record there may give clues to the decisive events in the first 500 million years in the history of our solar system. Until such records become available, we have in our guesswork to rely on laboratory constructions that need to satisfy the demands both of chemical feasibility and environmental boundary conditions. The combination leaves few survivors among competing hypotheses. As life entails a decrease in entropy and creation of order, the origin and propagation of crystalline order has become a guiding theoretical concept. Recognizing Jack Dunitz×s fundamental contribution to this field of knowledge, I wish to dedicate my modest discourse to this great scientist upon his scoring of the fourth significant time mark on the staff of life.

Cobalamin-Dependent and Cobalamin-Independent Methionine Synthases: Are There Two Solutions to the Same Chemical Problem?

Abstract: ),John C.Evans, and Martha LudwigDepartment of Biological Chemistry, the Biophysics Research Division, and the Life Sciences Institute,University of Michigan, Ann Arbor,MI48109-1055, USADedicated to Professor DuilioArigonion the occasion of his 75th birthday.−Ifindthereactioncatalyzedbycobalamin-dependentmethioninesynthaseimprobableandthatcatalyzedbycobalamin-independentmethioninesynthaseimpossible.×DuilioArigonito RowenaMatthews, Z¸rich, 1989Two enzymes in Escherichiacoli, cobalamin-independent methionine synthase (MetE) and cobalamin-dependent methionine synthase (MetH), catalyze the conversion of homocysteine (Hcy) to methionine usingN(5)-methyltetrahydrofolate (CH

Cocrystallization with acetylene. The 1:1 Complex with benzene: Crystal growth, X-ray diffraction and molecular simulations.

Abstract: The crystal structure of an unusual 1 : 1 molecular complex between benzene and acetylene, two very small and apolar molecules, has been determined by X-ray-analysis of crystals grown by first mixing the two liquids under conditions of low temperature and high pressure in a capillary, followed by repeated zone melting to form crystals directly on the goniometer head of a diffractometer. Each acetylene molecule is clamped between two parallel benzene rings, with its molecular axis apparently perpendicular to the benzene planes. Closer inspection of thermal-motion data from the diffraction experiment suggests that the acetylene molecule undergoes a wobbling, or precession, motion between the two rings so that it is perpendicular to them only in a time-averaged sense. The results of quantum-chemical calculations on isolated molecular dimers and trimers support this conclusion. In addition, the calculation of separate coulombic, dispersion, polarization and repulsion contributions to intermolecular bonding reveals that the CH⋅⋅⋅π-bond interaction between acetylene and benzene in a T-shaped dimer consists of a mixture of coulombic and polarization interactions. In the benzeneacetylene cocrystal, its magnitude is quantitatively comparable with that of other dispersive interactions. 5.4 ns Molecular-dynamics simulations of the liquid mixture reveal that the two components are persistently miscible, a possible key to the formation of the cocrystal. No structure is, however, observed in the solution during the relatively short simulation time.

Pre-irradiation grafting of styrene/divinylbenzene onto poly(tetrafluoroethylene-co-hexafluoropropylene) from non-solvents

Abstract: Pre-irradiation grafting of styrene/divinylbenzene (DVB) onto poly(tetrafluoroethylene-co-hexafluoropropylene) (FEP) films was studied with respect to the influence of solvent. Particularly favorable grafting conditions with long radical lifetimes and reasonably high polymerization rates were achieved with solvents that are precipitants for the newly formed polystyrene, e.g., low-molecular-mass alcohols like iPrOH, AcOH, their mixtures with H2O, and H2O/surfactant systems. Using one of these solvents significantly extended the range of accessible graft levels, and a specific degree of grafting was obtained at a much lower monomer concentration and irradiation dose than with grafting in a good solvent such as toluene. As practical consequences, the monomer was used more efficiently, and the radiation damage of the perfluorinated base material was reduced with the result of improved mechanical properties of the grafted films.

Intercalating nucleic acids with pyrene nucleotide analogues as next-nearest neighbors for excimer fluorescence detection of single-point mutations under nonstringent hybridization conditions

Abstract: Fluorescence and hybridization specificity is reported for intercalating nucleic acids (INAs), which are here oligodeoxynucleotides (ODNs) synthesized with insertions using (S)-1-[bis(4-methoxyphenyl)(phenyl)methoxy]-3-[(pyren-1-yl)methoxy]propan-2-ol phosphoramidites. It is shown that an INA with two insertions placed as next-nearest neighbors can be used for discrimination between nucleic acids and their single-point mutants. Quenching of an excimer band at 480 nm is observed upon hybridizing to a complementary sequence, whereas the excimer band is present when the nucleobase pair between the two pyrene moieties is mismatched. It is the first example of a solution based on fluorescence detection of single-point mutants that uses excimer formation and does not rely on stringent hybridization conditions. Furthermore, it is shown that INAs with pyrene insertions retain their sequence specificity in thermal melting.

Synthesis and Biological Evaluation of 14‐Alkoxymorphinans. Part 19

Abstract: The 14-O-benzylnaltrexones 3–6 were prepared from naltrexone (2) in several steps. The novel compounds were biologically evaluated in radioligand binding and in [35S]GTPγS functional assays in comparison to the reference compound naltrexone. In the binding assay, compounds 3–6 exhibited preference for κ opioid receptors, while the parent compound naltrexone shows preference for μ receptors. In the functional assay, μ antagonist potency of compounds 3–6 was in the range of naltrexone, while κ antagonist potency was considerably higher for most novel compounds in comparison to naltrexone.

Three Tyrosinase Inhibitors and Antioxidant Compounds from Salsola foetida

Abstract: Phytochemical investigation on the whole plant of Salsola foetida resulted in the isolation of three new phenolic compounds 1, 2, and 3, which exhibit tyrosinase inhibition with moderate antioxidant activity. Compounds 1–3 inhibited tyrosinase with IC50 2.61, 1.85, and 0.40 μM, while exhibiting DPPH radical scavenging activity with IC50 383, 427 and 378 μM, respectively. The structures of 1, 2, and 3 were determined by modern spectroscopic techniques.

Comparing intrinsic reactivities of the first- and second-generation ruthenium metathesis catalysts in the gas phase

Abstract: An experimental comparison of the gas-phase reactivity of the 14-electron reactive intermediates produced by phosphine dissociation from the first- and second-generation ruthenium metathesis catalysts, (L)Cl2RuCHR (L=PCy3 or NHC), supports Grubbs's contention that the second-generation catalysts show hundred-fold higher phenomenological activity despite a slower phosphine dissociation because of a much more-favorable partitioning of the 14-electron active species towards product-forming steps. The gas-phase study finds, in ring-opening metathesis of norbornene as well as acyclic metathesis of ethyl vinyl ether, that the first-generation systems display evidence for a higher barrier above that for phosphine dissociation; the second-generation systems, on the other hand, behave as if there is no significantly higher barrier.

The Composition of Keto Aldoses in Aqueous Solution as Determined by NMR Spectroscopy

Abstract: Keto aldoses usually form complex mixtures of equilibrating isomers in solution. This is due to the two different positions that may be used for ring closure in dicarbonyl sugars. The composition of various 2-keto aldoses 1–5 and 8, the 3-keto aldose 2-deoxy-D-erythro-hexos-3-ulose (9), and the ketose 1-deoxy-D-ribulose (10) in aqueous solution has been determined by NMR spectroscopy. The investigated keto aldoses form equilibria containing three to fifteen isomers. Among various furanose and pyranose ring structures stemming from 1,4-, 1,5-, 2,5-, and 2,6-cyclization, bicyclic forms were also found in several cases. The 2-keto aldoses mainly exist as hydrated isomers in H2O. Therefore, these forms and their proportions were compared to forms found in two homomorphous aldoses and one homomorphous ketose as model compounds. Besides the NMR data, also the composition of the 2-keto aldoses agreed with the average of forms found in the model compounds, a finding that might eventually be useful for deducing the composition of other keto aldoses.

Potentiometric, NMR, and Fluorescence-Emission Studies on the Binding of Adenosine 5-Triphosphate (ATP)by Open-Chain Polyamine Receptors Containing Naphthylmethyl and/or Anthrylmethyl Groups

Abstract: The interaction in aqueous solution of adenosine 5′-triphosphate (ATP) with a series of open-chain polyamines linked at one or both ends to anthrylmethyl or naphthylmethyl fragments was followed by potentiometric titration, 1H-, 13C-, and 31P-NMR spectroscopy, and by steady-state fluorescence measurements. The results revealed greater stabilities for the compounds containing one anthracene moiety than for those with one naphthalene moiety, the stabilities of the compounds with both ends N-substituted with naphthylmethyl groups being close to those containing just one anthrylmethyl unit. The 1H-NMR spectra showed that in all systems, there is involvement of π-π stacking interactions in the stabilization of the adduct species. The competitive effect of the anions afforded by the supporting electrolyte was checked in some of the studied systems working at two different ionic strenghts (0.15M and 1.0M NaCl). The joint analysis of the spectrofluorimetric titrations and pH-metric species-distribution curves showed that for all the ATPreceptor systems, a quenching of the fluorescence occurred upon protonation of the adenine N(1)atom. Steady-state fluorescence and time-correlated single-photon-counting analysis of a system made up of ATP and a bis-chromophoric polyamine receptor containing anthracene and naphthalene fluorophores established that the energy-transfer process between the naphthalene and anthracene moieties is still operative despite the presence of ATP.

On the enantioselectivity of transition metal-catalyzed 1,3-cycloadditions of 2-diazocyclohexane-1,3-diones

Abstract: The formal 1,3-cycloaddition of 2-diazocyclohexane-1,3-diones 1a–1d to acyclic and cyclic enol ethers in the presence of RhII-catalysts to afford dihydrofurans has been investigated. Reaction with a cis/trans mixture of 1-ethoxyprop-1-ene (13a) yielded the dihydrofuran 14a with a cis/trans ratio of 85 : 15, while that with (Z)-1-ethoxy-3,3,3-trifluoroprop-1-ene (13b) gave the cis-product 14b exclusively. The stereochemical outcome of the reaction is consistent with a concerted rather than stepwise mechanism for cycloaddition. The asymmetric cycloaddition of 2-diazocyclohexane-1,3-dione (1a) or 2-diazodimedone (=2-diazo-5,5-dimethylcyclohexane-1,3-dione; 1b) to furan and dihydrofuran was investigated with a representative selection of chiral, nonracemic RhII catalysts, but no significant enantioselectivity was observed, and the reported enantioselective cycloadditions of these diazo compounds could not be reproduced. The absence of enantioselectivity in the cycloadditions of 2-diazocyclohexane-1,3-diones is tentatively explained in terms of the Hammond postulate. The transition state for the cycloaddition occurs early on the reaction coordinate owing to the high reactivity of the intermediate metallocarbene. An early transition state is associated with low selectivity. In contrast, the transition state for transfer of stabilized metallocarbenes occurs later, and the reactions exhibit higher selectivity.

N‐(4‐Biphenylmethyl)imidazoles as Potential Therapeutics for the Treatment of Prostate Cancer: Metabolic Robustness Due to Fluorine Substitution?

Abstract: 3,3′,5,5′- And 2,2′,6,6′-tetrafluoro-substituted 1-[(1,1′-biphenyl]-4-yl)methyl]-1H-imidazoles were synthesized as inhibitors of 17α-hydroxylase-C17,20-lyase (P450 17, CYP 17). P450 17 is the key enzyme of androgen biosynthesis. Its inhibition is a novel therapeutic approach for treatment of prostate cancer. To increase the so-far insufficient in vivo lifetime of such compounds, the metabolically sensitive positions were blocked by F-substitution. The meta- and ortho-F-substituted compounds were prepared by selective metallation or halogen/metal permutation reactions performed on symmetrically substituted 1,1′-biphenyls. Compared with the halogen-free compounds, the ortho-F-substituted derivatives did not match the activity, whereas the meta-F-substituted isomers equaled or surpassed the latter.

Structural Basis for Recognition of Guanosine by a Synthetic Tricyclic Cytosine Analogue: Guanidinium G-Clamp

Abstract: An oligonucleotide analogue containing a novel heterocyclic analogue, the guanidinium G-clamp, was designed to allow formation of five H-bonds to guanosine. The guanidinium group was introduced postsynthetically by treatment of the deprotected oligonucleotide containing a free amino group with a solution of 1H-pyrazole-1-carboxamidine and purified by a combination of size-exclusion chromatography and reversed-phase HPLC. A single incorporation of this modification into an oligodeoxynucleotide sequence was found to increase duplex stability by 13{sup o} and 16{sup o} per modification to RNA and DNA, respectively. Crystals of a self-complementary decamer sequence containing this modification were grown and diffracted to 1-{angstrom} resolution. The structure was solved by molecular replacement and revealed that the modification forms additional H-bonds to O(6) and N(7) of guanosine through the amino and imino N-atoms, respectively. The origins of enhanced duplex stability are also attributed to increased stacking interactions mediated by the phenoxazine moiety of the G-clamp and formation of H-bond networks between the positively charged guanidinium group, H{sub 2}O molecules, and negatively charged O-atoms from phosphates on the adjacent strand.

Synthesis and Conformational Switching of Partially and Differentially Bridged Resorcin[4]arenes Bearing Fluorescent Dye Labels. Preliminary Communication

Abstract: We report the synthesis of modified Cram-type cavitands bearing one or two fluorescent labels for single-molecule spectroscopic studies of vasekite conformational switching (Scheme 3). Syntheses were performed by stepwise bridging of the four couples of neighboring H-bonded OH groups of resorcin[4]arene bowls (Schemes 2 and 3). The new substitution patterns enable the construction of a large variety of future functional architectures. 1H-NMR Investigations showed that the new partially and differentially bridged cavitands feature temperature- and pH-triggered vasekite conformational isomerism similar to symmetrical cavitands with four identical quinoxaline bridges (Table). It was discovered that vasekite switching of cavitands is strongly solvent-dependent.

A new family of C3-Symmetrical carbohydrate receptors

Abstract: The formation of the new optically active C3-symmetrical receptors (S,S,S)-2–4 (Fig. 1), incorporating 1,3,5-triphenylbenzene and 1,3,5-tris(phenylethynyl)benzene platforms as ‘floors' and ‘ceilings', is described. The tris(phenylethynyl)benzene derivatives 9 and (S,S,S)-10 (Scheme 1) for the three-fold peptide coupling to yield the macrocyclic skeletons (Scheme 2) were prepared starting from 1,3,5-triethynylbenzene by the Sonogashira cross-coupling reaction. The optical rotations of the three macrocycles (S,S,S)-2–4, two of which ((S,S,S)-2 and (S,S,S)-3) are constitutional isomers, differ significantly, which is explained by differential twists induced into the macrocyclic skeletons by the leucine spacer in these bridges. 1 : 1 Host–guest complexes of (S,S,S)-2–4 with octyl glucosides (Fig. 3) in CDCl3 are of modest stability (Ka≤270 M−1 at 300 K). In these complexes, the monosaccharides are most probably nesting on one of the H-bonding faces of the receptor rather than being accommodated in the cavity.

The RE M E Phases

Abstract: In the second contribution on the RE M E phases, we enumerate the distinct networks resulting from the stacking in an eclipsed fashion of graphitic and puckered layers. Specifically, we derive all the distinct hypothetical lattices for up to N=7 layers per unit cell for planar (graphitic) sheets, and up to N=10 for slightly puckered layers. For the networks with slightly puckered layers, there can be only an even number of layers/unit cell, N. Additionally, we formulate an empirical rule for network stability: the structure should have either a mirror plane or a twin operation (mirror plane, followed by a color change) bisecting it half-way up the stacking axis. Using these simple principles, from the original multitude of 2N−1 structures for a given N, we are able to significantly narrow down the number of potential combinations. Thus, for N=2, we find two nets, for N=4, one, for N=6, two, for N=8, there are no such viable arrangements, and for N=10, we exclude all but two distinct lattices. We sketch further guidelines to continue the enumeration for higher Ns. We also propose an ‘overlapping' Aufbau, by which more-complex structures are derived from the smaller, basic ones. In the last part, we analyze the eclipsed stacking of diamond-type layers; the resulting networks are analogous (in sequencing) to those determined for slightly puckered sheets. The networks formed from staggered diamond-type layers are briefly discussed in the context of the related SiC polytypes.

Cytotoxic Pentacyclic Triterpenoids from the Rhizome of Astilbe chinensis

Abstract: Guided by in vitro antineoplastic tests, four cytotoxic pentacyclic triterpenoids, 3beta-hydroxyolean-12-en-27-oic acid (1), 3beta-hydroxyurs-12-en-27-oic acid (2), 3beta,6beta-dihydroxyolean-12-en-27-oic acid (3), and 3beta-acetoxyolean-12-en-27-oic acid (4) were isolated from the rhizome of Astilbe chinensis. Their structures were determined on the basis of chemical evidence and extensive spectroscopic methods including one-dimensional and two-dimensional NMR. These compounds showed cytotoxic activities against HO-8910, Hela and HL60 cell lines. In addition, beta-sitosterol palmitate, daucosterol, and beta-sitosterol have also been isolated.

The RE M E Phases I. An Overview of Their Structural Variety

Abstract: nanionic sublattices. We start with a detailed description of the EuAuSn lattice, by emphasizing its essential building blocks and the symmetry operations connecting them, in order to set up a way of describing systematically the geometric features of other RE M E frameworks. Nearly all these phases have eclipsed hexagonal layered arrangements (with only ME bonds within these slabs) in the ME sublattice. In most cases, stacking the puckered layers in the third dimension gives rise to ME, MM, or EE bonds, alternating in certain patterns. We point to several interesting sets of RE M E compounds, of like structure, but whose electron counts vary significantly. The structures of nonlayered networks and their mostcommon electron counts are also introduced.

Syntheses and CD-Spectroscopic Investigations of Longer-Chain β-Peptides: Preparation by Solid-Phase Couplings of Single Amino Acids, Dipeptides, and Tripeptides

Abstract: The synthesis and CD-spectroscopic analysis of eleven water-soluble β-peptides composed of all-β3 or alternating β2- and β3-amino acids is described. Different approaches for the efficient syntheses of longer-chain β-peptides (>9 residues) were investigated. They were synthesized on solid phase with Fmoc-protected amino acids or Fmoc-protected di- or tripeptide fragments (assembled using solution-phase synthesis). The use of preformed fragments significantly increased the purity of the crude peptides and facilitated purification. Especially, the use of Fmoc-protected β2/β3-dipeptides for the synthesis of a ‘mixed' β2/β3-nonapeptide proved to be remarkably effective, yielding the crude peptide in 95% purity and without detectable epimerization of the β2-amino acid residues. This is a significant improvement over previously reported procedures for the solid-phase synthesis of β-peptides, and foreshadows that the field of β-peptide research will now switch from synthesis to the design and study of complex functional ‘β-proteins'.