Showing papers in "Helvetica Chimica Acta in 1999"

β-Peptides as Inhibitors of Small-Intestinal Cholesterol and Fat Absorption

Abstract: Selective lipid transport through the brush-border membrane in the small intestine of mammals is mediated by membrane-bound proteins, the so-called scavenger receptors of class B, type I or II (SR-BI or -BII). These, in turn, are inhibited by certain proteins and synthetic α-peptides that have an amphipathic helix as the binding motif (Fig. 1). In whole cells (test with human colonic carcinoma cells, CaCo-2), on the other hand, the inhibitors are subject to proteolysis. We have now tested six β-peptides (hexa-, hepta-, and nonamers 1 – 6), each carrying one to seven water-solubilizing side chains of either Ser or Lys, with a brush-border-membrane (BBM) vesicle model system (rate and IC50 values in Figs. 2 and 3) and with a tightly packed monolayer of CaCo-2 cells (rate in Fig. 4), to find that the rate of transport of cholesterol can be reduced to what may be considered the passive diffusion (`background') level. There is a correlation between the ability of the β-peptides to form an amphipathic-type 314-helical secondary structure in MeOH and their inhibitory effect (Table 1 and Fig. 5). Although the inhibitory activity of the β-peptides is in only the mM range (Table 2), it is to be compared with no activity at all of previously tested α-peptides and proteins (built of L-amino acids) in CaCo-2 cells. Furthermore, these active β-peptides (1, 5, and 6) contain only seven or nine residues and must be considered simple, first-generation models capable of mimicking the biological activity of amphipathic α-peptide helices in living whole cells.

C−H Insertion Reactions of Nucleophilic Carbenes

Abstract: Syntheses and characterizations are described for C−H insertion products derived from 1,3-dimesityldihydroimidazol-2-ylidene (1) with acetylene, acetonitrile, methyl phenyl sulfone, and chloroform. In the reaction with acetylene, both acetylenic H-atoms are reactive so that 1 : 1 and 2 : 1 adducts can be obtained. The acetylene and methyl-phenyl-sulfone adducts are structurally characterized by means of single-crystal X-ray structure determinations. The reactions of 1,3,4,5-tetramethylimidazolidin-2-ylidene (8) with chloroform or chlorodifluoromethane are shown to yield 2-(dihaloalkyl)imidazolium salts that arise from a failure of the intermediate 2-protioimidazolium salt to capture the initially formed halocarbanion.

Synthesis, Crystal Structures, and Modelling ofβ-Oligopeptides Consisting of 1-(Aminomethyl)cyclopropanecarboxylic Acid: Ribbon-Type Arrangement of Eight-Membered H-Bonded Rings

Abstract: Partially and fully protected, and unprotected β-oligopeptides (3 – 9) were prepared from 1-(aminomethyl)cyclopropanecarboxylic acid, which, in turn, is readily available from cyanoacetate and dibromoethane. N-Boc and C-OMe protection were applied for the fragment-coupling (1-hydroxy-1H-benzotriazole (HOBt)/1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC)) solution synthesis. X-Ray crystal structures of the dimer (3), trimer (5), and tetramer (6) are described, and compared with those of the Boc-protected building blocks (2) and of the corresponding trimer (10) consisting of 1-(aminomethyl)cyclohexanecarbonyl residues (cf. Figs. 1 and 2). While the cyclohexane derivative forms ten-membered hydrogen-bonded rings, the characteristic secondary-structural motif in the cyclopropane derivatives is an eight-membered ring with H-bonding between next neighbors (Fig. 1). All cyclopropanecarbonyl moieties in the reported structures have the – generally more stable – s-cis (`bisected') conformation of the C=O groups on the three-membered rings (not preferred with the cyclohexane analog, the exocyclic CO group of which may be in an s-trans, a perpendicular, an axial, or an equatorial position). The bisecting effect and the large exocyclic bond angle (120°) in the cyclopropane units are proposed to provide the `ordering' elements – on top of the staggering effect of the C(2)−C(3) ethane bond in all β-peptides – which lead to the observed substituent-induced turn formation. A high degree of intramolecular H-bonding is evident also from IR spectroscopy (Fig. 3), and concentration- and temperature-dependent NMR measurements (Fig. 4) of CHCl3 and CD2Cl2 solutions, indicating that the boat-type arrangement of the eight-membered rings with their unusual H-bonding geometry (Fig. 1, f ) is also present in solution. A possible structure of a poly[1-(aminomethyl)cyclopropane-carboxylic acid] consisting of a flight of stairs formed by folded H-bonded eight-membered rings is modelled, using the oligomer X-ray data (Fig. 5). The type of secondary structure found in the solid state of the β2,2-peptides reported here is unprecedented in the realm of α-peptides and proteins.

Structure-Lipophilicity Relationships of Neutral and Protonated β-Blockers, Part I, Intra- and Intermolecular Effects in Isotropic Solvent Systems

Abstract: The objectives of this study were to validate new experimental techniques used to measure the log P of protonated drugs, and to investigate the inter- and intramolecular forces influencing the partitioning behavior of β-blockers in isotropic biphasic solvent systems. The lipophilicity parameters of a number of β-blockers were measured by two-phase titration, centrifugal partition chromatography (CPC), and cyclic voltammetry (CV) in one or more of the following solvent systems: octanol/water, 1,2-dichloroethane/water, and dibutyl ether/water. CV proved to be a promising technique for measuring the lipophilicity of protonated β-blockers. Derived parameters such as Δlog P (difference between log P in two different solvent systems, a parameter valid for a given solute in a given electrical form) and diff (difference between log P of two different electrical forms of a given solute, in the same system) yielded insights into inter- and intramolecular interactions characteristic of β-blockers. The relevance of these parameters in structure-permeation relationships is explored.

Enantioselective Fluorogenic Assay of Acetate Hydrolysis for Detecting Lipase Catalytic Antibodies

Abstract: An enantioselective fluorogenic assay for the kinetic resolution of chiral alkyl acetates is demonstrated with 7-(3-acetoxybutoxy)-2H-1-benzopyran-2-ones (R)- and (S)-4 or 7-(3-acetoxy-2-methylpropoxy)-2H-1benzopyran-2-ones (R)-4 and (S)-6. The alcohols released by hydrolysis of these acetates are oxidized by horseliver alcohol dehydrogenase to unstable b-(aryloxy)carbonyl compounds, which undergo b-elimination of the strongly fluorescent product umbelliferone (a 7-hydroxy-2H-1-benzopyran-2-one; 3 )( l ema 460 20 nm, lexa 360 20 nm). Enantioselectivities are calculated from the reaction rates for each enantiomeric acetate. For a series of representative lipases, the reactivities and enantioselectivities under preparative conditions are predicted accurately. This highly sensitive enantioselective assay detects as little as 10 mg/ml of hydrolytic enzyme, can be carried out in 96-well microtiter plates, and is compatible with cell-culture media. It is, therefore, suited for screening libraries of antibodies for enantioselective lipase catalytic antibodies.

Novel Nucleoside Analogues with Fluorophores Replacing the DNA Base.

Abstract: We describe the preparation and fluorescence properties of a set of new nucleosides in which a known hydrocarbon or oligothiophene fluorophore replaces the DNA base at C(1) of the deoxyribose moiety (see 3a – f). These compounds are potentially useful as probes in the study of the structure and dynamics of nucleic acids and their complexes with proteins. In addition, they may find use as fluorescent labels for nucleic-acid-based biomedical diagnostics methods. The fluorophores conjugated to deoxyribose at C(1) in the α-d-form include terphenyl, stilbene, terthiophene, benzoterthiophene, and pyrene. Also included is a non-fluorescent spacer in which cyclohexene replaces the DNA base. The nucleosides are derived from brominated fluorophore precursors and Hoffer’s 2-deoxy-3,5-di-O-(p-toluoyl)-d-ribofuranosyl chloride. The emission maxima of the free nucleosides range from 345 to 536 nm. Also described are the 5′-(dimethoxytrityl) 3′-O-phosphoramidite derivatives 5a – f, suitable for incorporation into oligonucleotides by automated synthesizers.

Synthesis of Conformationally Restricted Carbocyclic Nucleosides: The Role of the O(4′)-Atom in the Key Hydration Step of Adenosine Deaminase

Abstract: Conformationally restricted carbocyclic nucleosides with either a northern(N)-type conformation, ie, N-type 2′-deoxy-methanocarba-adenosine 8 ((N)MCdAdo), or a southern(S)-type conformation, ieS-type 2′-deoxy-methanocarba-adenosine 9, ((S)MCdAdo), were used as substrates for adenosine deaminase (ADA) to assess the enzyme's preference for a fixed conformation relative to the flexible conformation represented by the carbocyclic nucleoside aristeromycin (10) Further comparison between the rates of deamination of these compounds with those of the two natural substrates adenosine (Ado; 1) and 2′-deoxyadenosine (dAdo; 2), as well as with that of the conformationally locked nucleoside LNA-Ado (11), which, like the natural substrates, has a furanose O(4′) atom, helped differentiate between the roles of the O(4′) anomeric effect and sugar conformation in controlling the rates of deamination by ADA Differences in rates of deamination as large as 10000 can be attributed to the combined effect of the O(4′) atom and the enzyme's preference for an N-type conformation The hypothesis proposed is that ADA's preference for N-type substrates is not arbitrary; it is rather the direct consequence of the conformationally dependent O(4′) anomeric effect, which is more efficient in N-type conformers in promoting the formation of a covalent hydrate at the active site of the enzyme The formation of a covalent hydrate at the active site of ADA precedes deamination A new and efficient synthesis of the important carbobicyclic template 14a, a useful intermediate for the synthesis of (N)MCdAdo (8) and other conformationally restricted nucleosides, is also reported

Catalytic Dendrophanes as Enzyme Mimics: Synthesis, Binding Properties, Micropolarity Effect, and Catalytic Activity of Dendritic Thiazolio‐cyclophanes

Abstract: Catalytic dendrophanes9 and 10 were prepared as functional mimics of the thiamine-diphosphate-dependent enzyme pyruvate oxidase, and studied as catalysts in the oxidation of naphthalene-2-carbaldehyde (4) to methyl naphthalene-2-carboxylate (8) (Scheme 1). They are composed of a thiazolio-cyclophane initiator core with four generation 2 (G-2) poly(etheramide) dendrons attached. The two dendrophanes were synthesized by a convergent growth strategy by coupling dendrons 11 and 12, respectively (Scheme 2) with (chloromethyl)-cyclophane 42 (Scheme 5) and subsequent conversion with 4-methylthiazole (Scheme 7). The X-ray crystal structures of cyclophane precursors 30 (Scheme 3), 37, and 38 (Scheme 5) on the way to dendrophanes were determined (Fig. 1). The crystal-structure analysis of the benzene clathrate of 37 revealed the formation of channel-like stacks by the cyclophane which incorporate its morpholinomethyl side chain and the enclathrated benzene molecule (Fig. 2). The interactions of the enclathrated benzene molecule with the phenyl rings of the two adjacent cyclophane molecules in the stack closely resemble those between neighboring benzene molecules in crystalline benzene (Fig. 3). The characterization by MALDI-TOF-MS (Fig. 4), and 1H- and 13C-NMR spectroscopy (Fig. 5) proved the monodispersity of the G-2 dendrophanes 9 and 10 with molecular weights up to 11500 Da (for 10). 1H-NMR and fluorescence binding titrations in H2O and aqueous MeOH showed that 9 and 10 form stable 1 : 1 complexes with naphthalene-2-carbaldehyde (4) and 6-(p-toluidino)naphthalene-2-sulfonate (48, TNS) (Tables 1 and 2). The evaluation of the fluorescence emission maxima of bound TNS revealed that the dendritic branching creates a microenvironment of distinctly reduced polarity at the cyclophane core by limiting its exposure to bulk solvent. Initial rate studies for the oxidation of naphthalene-2-carbaldehyde to methyl naphthalene-2-carboxylate in basic aqueous MeOH in the presence of flavin derivative 6 revealed only a weak catalytic activity of dendrophanes 9 and 10 (Table 3), despite the favorable micropolarity at the cyclophane active site. The low catalytic activity in the interior of the macromolecules was explained by steric hindrance of reaction transition states by the dendritic branches.

Self-Assembly of Synthetic Zinc Chlorins in Aqueous Microheterogeneous Media to an Artificial Supramolecular Light-Harvesting Device

Abstract: Self-assembled aggregates of a synthetic zinc chlorin in an aqueous suspension with either α-lecithin or Triton X-100 exhibit unique structural and functional properties. Absorption, circular dichroism, fluorescence, and resonance Raman spectra indicate that the supramolecular structure in an aqueous microheterogeneous medium is very similar to that of the bacteriochlorophyll c aggregates in non-polar organic solvents and in chlorosomes, the main light-harvesting antennae of green photosynthetic bacteria. The nature of the aggregates is controlled by structure and/or concentration of the added surfactants. When a small amount of metal-free bacteriochlorin is present it acts as an efficient energy acceptor from the aggregated zinc chlorins. Thus, self-assembly of synthetic zinc chlorins, doped with appropriate energy acceptors and surrounded with surfactants, affords an artificial supramolecular light-harvesting device in aqueous environment.

Oligomers ofβ2- and ofβ3-Homoproline: What are the Secondary Structures ofβ-Peptides Lacking H-Bonds?

Abstract: To study the role of H-bonds in stabilizing β-peptidic secondary structures, we have synthesized β-oligopeptides (up to the octadecamer 12) consisting of β2- and β3-homoproline, i.e., β-peptides lacking amide protons. The enantiomer purity of the building block β2-homoproline (nipecotic acid, 4) was determined by HPLC analysis of the N-(2,4-dinitrophenyl) derivative 5 on a Chiralcel-OD column (cf. Fig. 2). The CD spectra of the all-(S)-β2- and all-(S)-β3-HPro-containing β-peptides display novel and intensive CD patterns which may be indicative of a secondary structure (cf. Fig. 3). It is noteworthy that a distinct CD pattern was observed with the β3-HPro derivatives containing as few as three residues (7a). The crystal structure of a N-deprotected β3-HPro-tripeptide 7c is presented (cf. Figs. 4 and 5), and a model for the structure of β-peptides consisting of β3-HPro is discussed (cf. Figs. 6 and 7).

Direct Observation of Intermediates in the Reaction of Peroxynitrite with Carbon Dioxide

Abstract: Peroxynitrite (ONOO−, oxoperoxonitrate(1−)) reacts with carbon dioxide to form an adduct that absorbs with a maximum at 640 nm and an extinction coefficient of ca. 2 × 102 M−1 cm−1. Within 0.1 s at 4°, this absorption decreases while the maximum is shifted to lower wavelengths, which indicates that trioxocarbonate(1−) radicals (CO3.−) are formed. This interpretation is supported by the observation of a weak ESR signal at g=2.013.

Synthesis of anL-Fucose-Derived Cyclic Nitrone and its Conversion toα-L-Fucosidase Inhibitors

Abstract: The L-fuco-nitrone 1 has been synthesized from allyl 4,6-O-benzylidene-α-D-glucopyranoside (4) in 11 steps and an overall yield of 18%. The key step is the intramolecular alkylation of an intermediary 1,1-bis(hydroxylamine) derived from the tosyloxy oximes (E/Z)-2. The nitrone 1 has been transformed into the diamine 30, the indolizidines 39 and 40, the indolizidinones 34 and 35, and the imidazole 44, all inhibiting bovine epididymis α-L-fucosidase with IC50 values between 105 nM and 240 μM.

β‐Thiopeptides: Synthesis, NMR Solution Structure, CD Spectra, and Photochemistry

Abstract: To test the effect of NH-C(=S) groups on the stability of beta-peptide secondary structures, the authors have synthesized three beta-thiohexapeptide analogs I (X = S, Y = Z = O; X = Z = S, Y = O; X = Y = Z = S) of H-(beta-HVal-beta-HAla-beta-HLeu)2-OH I (X = Y = Z = O). The first C=S group was introduced selectively by treatment with Lawesson reagent of Boc-beta-dipeptide esters II and III. A series of fragment-coupling steps (with reagents for the corresponding sulfur-free building blocks) and another thionation reaction led to the beta-thiohexapeptides. The sulfur derivs., esp. those with three C=S groups, were much more sol. in org. media than the sulfur-free analogs ( > 1000-fold in CHCl3). The UV and CD spectra (in CHCl3, MeOH, and H2O) of the three new beta-thiopeptides were recorded and compared with those of the parent beta-hexapeptide I (X = Y = Z = O); they indicate the presence of more than one secondary structure under the various conditions. Most striking is a pronounced exciton splitting (Deltalambda ca. 20 nm, amplitude up to +121000) of the pipi*C=S band near 270 nm with the beta-trithiohexapeptide (with and without terminal protecting groups), and strong, so-called "primary solvent effects", in the CD spectra. The CD spectrum of the beta-dithiohexapeptide I (X = Z = S, Y = O) undergoes drastic changes upon irradn. with 266-nm laser light of a MeOH soln. The NMR structure in CD3OH of the unprotected beta-trithiohexapeptide I (X = Y = Z = S) was detd. to be an (M)-314-helix, very similar to that of the non-thionated analog. NMR and mass spectra of the beta-hexapeptides with C=S and with C=O groups are compared.

Catalytic Enantioselective Hydrosilylation of Ketones with Rhodium‐Phosphite Complexes Containing a TADDOLate and a Dihydrooxazole Unit

Abstract: New types of chiral phosphorus/nitrogen ligands, capable of forming six-membered-ring metal chelates have been prepared from α,α,α′,α′-tetraaryl-1,2-dioxolane-4,5-dimethanols (TADDOLs), PCl3, and dihydrooxazole alcohols (from amino acids) (7 in Scheme 1). The X-ray crystal structure of a Rh complex of one of these ligands, 8b, has been determined (Scheme 2 and Fig.). Enantioselective hydrosilylations of dialkyl and aryl alkyl ketones with Ph2SiH2/0.01 equiv. RhI⋅7 have been studied and found to provide secondary alcohols in enantiomer ratios of up to 97 : 3 (Scheme 3 and Table). The ligand prepared from (R,R)-TADDOL and the (R)-valine-derived (R)-α,α-dimethyl-4-isopropyl-4,5-dihydrooxazole-2-methanol gives better results than the (R,R,S)-isomer (7dvs.7c in Scheme 3), and an i-Pr group on the 4,5-dihydrooxazole ring gives rise to a slightly better selectivity than a Ph group. With the (R,R,R)-ligands the hydrogen transfer occurs from the Re face of the oxo groups (Scheme 4).

Enantioselective Preparation ofγ-Amino Acids andγ-Lactams from Nitro Olefins and Carboxylic Acids, with the Valine-Derived 4-Isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one as an Auxiliary

Abstract: Titanium enolates of acyl-oxazolidinones 1, derived from acetic, propanoic, 3-methylbutanoic, and 4-methylpentanoic acids and 4-isopropyl-5,5-diphenyl-1,3-oxazolidin-2-one, are added to aliphatic and aromatic nitro olefins in the presence of TiCl4 (Schemes 2 – 4). The products, 4-nitro carboxylic-acid derivatives 2, are formed in high diastereoselectivities (ds 80 to >99%) and in good yields (50 – 75% of purified samples of ds >98%). Hydrogenation over Raney-Ni of the NO2 group in the adducts leads directly to the corresponding γ-lactams (3 and 8; 80 – 92%), with recovery of the insoluble auxiliary (ca. 95%). Ring opening is achieved through the N-Boc-lactams (4), which are converted to N-Boc-protected γ-amino acids 5 or to their benzyl and methyl esters (6 and 7; Scheme 5). The configuration of the products (containing up to three new stereogenic centers; Scheme 1) is assigned by comparison with literature data, by X-ray crystal-structure analysis (for 2c, g, f, 8, Fig.), and by analogy. Thus, the (S)-auxiliary gives rise to combination of the trigonal centers of enolate and nitro olefin with Si/Si topicity (relative topicity all-lk; cf. A).

Fast and Reliable Automated Synthesis of RNA and Partially 2′-O- Protected Precursors (`Caged RNA') Based on Two Novel, Orthogonal 2′-O-Protecting Groups, Preliminary Communication

Abstract: Two sets of RNA phosphoramidites, carrying the (fluoride-labile) 2'-O-[(triisopropylsilyl)oxy]methyl (tom) group and the (photolabile) [(R)-1-(2-nitrophenyl)ethoxy]methyl ((R)-npeom) group, were prepd. The two protecting groups were completely orthogonal to each other. Three ribozyme-substrate constructs, protected each by a (R)-npeom group, were synthesized; on photolysis, efficient cleavage of this remaining protecting group occurred. It could be demonstrated that the presence of one (R)-npeom group within a RNA strand has only a minor influence on the pairing properties of corresponding duplexes. [on SciFinder (R)]

Dichloro[TADDOLato(2−)-O,O′]titanium/Dichlorobis[1-methylethoxy]titanium-Mediated, Highly Diastereo- and Enantioselective Additions of Silyl Enol Ethers to Nitro Olefins and [3+2] Cycloadditions of Primary Adducts to Acetylenes

Abstract: The diastereoselective, Ti-Lewis-acid-mediated, low-temperature addition of silyl enol ethers to 1-aryl-2-nitroethenes (Scheme 1) occurs enantioselectively with dichloro[TADDOLato(2−)-O,O′]titanium 3 (TADDOL=α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanol) (Scheme 2). At least 3 equiv. of Lewis acid are required for high conversions (yields). However, the chiral Lewis acid 3 can be `diluted' with the achiral Cl2Ti(OCHMe2)2 analog (ratio 1 : 2.5), with hardly any loss of enantioselectivity! Both, the primary (4+2) cycloadducts (B, 9) and the γ-nitro ketones (A, 1a – h, 5, 7), formed by hydrolysis, can be isolated in good yields and with high configurational purities (Schemes 3 and 4, and Table 1). The relative and absolute configurations (2S,1′R) of the products 1 from cyclohexanone silyl enol ether and 1-aryl(including 1-heteroaryl)-2-nitroethenes (obtained with (R,R)-TADDOLate) are assigned by NMR spectroscopy, and optical comparison and correlation with literature data, as well as by anomalous-dispersion X-ray crystal-structure determination (nitro ketone 1c; Fig.). The nitro ketone 7 from cyclohex-2-enone and 4-methoxy-β-nitrostyrene was cyclized (via a silyl nitronate C; Scheme 5) to the nitroso acetal 8, and one of the bicyclic nitronate primary adducts 9 underwent a [3+2] cycloaddition to phenylacetylene and to ethyl 2-butynoate to give, after a ring-contracting rearrangement, tricyclic aziridine derivatives with five consecutive stereocenters (10, 11; Scheme 5 and Table 2), in enantiomerically pure form. With an aliphatic nitro olefin, the Ti-TADDOLate-mediated reaction with (silyloxy)cyclohexene led to a moderate yield, but the product 4 was isolated in a high configurational purity.

Preparation and Olfactory Characterization of the Enantiomerically Pure Isomers of the Perfumery Synthetic Galaxolide

Abstract: The commercially important isochromane musk odorant Galaxolide® (=1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta[g]-2-benzopyran; HHCB; 3) was separated into its diastereoisomers via the tricarbonyl(η6-cyclopenta[g]-2-benzopyran)chromium complexes 10. Since GC/olfactometry indicated that only one enantiomer of each diastereoisomer (4RS,7RS)-3 and (4RS,7SR)-3 determines the odor characteristics of the commercial product, all four stereoisomers (4S,7R)-, (4S,7S)-, (4R,7S)-, and (4R,7R)-3 were synthesized by Friedel-Crafts alkylation of 1,1,2,3,3-pentamethylindane (11) with (S)- and (R)-methyloxirane ((S)- and (R)-12, resp.), acid-catalyzed reaction of the resulting products with paraformaldehyde, and separation of the formed diastereoisomer pairs via the tricarbonyl(η6-cyclopenta[g]-2-benzopyran)chromium complexes 10. The powerful musk odor of Galaxolide ® (3) was thus attributed to its (−)-(4S)-isomers (4S,7R)- and (4S,7S)-3, while the (+)-(4R)-isomers (4R,7S)- and (4R,7R)-3 were weak to almost odorless.

Synthesis of Zn-, Mn-, and Fe-Containing Mono- and Heterometallated Ethanediyl-Bridged Porphyrin Dimers

Abstract: New ethanediyl-bridged unsymmetrical mono- and heterometallated dimers of 2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphyrin (H2oep) containing transition-metal ions (Mn and Fe) were synthesized by a facile stepwise metallation/demetallation process under mild conditions. The novel metallation strategy initially involved the predominant insertion of Zn into one of the two porphyrin rings of the free-base dimer, followed by the incorporation of Mn or Fe into the other porphyrin ring under exceptionally mild conditions, giving corresponding heterometallic dimers; the subsequent removal of Zn yielded mono-transition-metal dimers. The emission spectrum of the monozinc dimer predominantly exhibited fluorescence bands of the free-base porphyrin component, indicating a very efficient energy-transfer process. Conversely, emission of the free-base or Zn porphyrin component of transition metal containing dimers was strongly quenched due to photoinduced electron transfer.

Single- and Two-State Reactivity in the Gas-Phase C−H Bond Activation of Norbornane by `Bare' FeO+

Abstract: The potential-energy surface for C−H bond activation of norbornane by `bare' FeO+ is examined at the B3LYP/6-31G** level of theory. The free reactants combine to form norbornane/FeO+ ion-dipole clusters in which the FeO+ unit can bind at either the exo or endo face of norbornane. The transition structures for insertion of FeO+ into the exo and endo C−H bonds are located at least 9 kcal⋅mol−1 below the entrance channel, thus accounting for the observed unit efficiency of the C−H bond activation reported in previous gas-phase ion-cyclotron resonance experiments (Helv. Chim. Acta1995, 78, 1013). Interesting features of the reaction profiles are crossovers of the high-spin sextet (S=5/2) and low-spin quartet (S=3/2) states en route to the transition structures (TS); this type of behavior has been termed two-state reactivity (Helv. Chim. Acta1995, 78, 1393). The branchings between the endo and exo pathways are simulated by Rice-Ramsperger-Kassel-Marcus (RRKM) theory with the calculated harmonic frequencies. Additionally, hydrogen/deuterium kinetic isotope effects are computed using RRKM theory and compared with the experimental data. The simulated KIEs differ for high-spin and low-spin TSs, suggesting that isotope effects can be used as sensitive probes for diagnosing spin-crossover mechanisms.

Mono(di)nuclear Europium(III) Complexes of Macrobi(tri)cyclic Cryptands Derived from Diazatetralactams as Luminophores in Aqueous Solution

Abstract: To increase the excellent light-emitting properties of the Eu3+ ion, macrobicyclic and macrotricyclic ligands 7 – 10, incorporating a 18-membered tetralactam ring (acting as a lanthanide binding site) and a sensitizer group (2,2′-bipyridine or 2,2′-bipyridine 1,1′-dioxide moiety), were synthesized. The mononuclear and dinuclear europium cryptates derived from these ligands were isolated and characterized. Their luminescent properties and those of the corresponding cryptates containing a phenanthroline group (see 11 and 12) were examined in H2O and D2O solutions at 77 and 300 K. It results that the tetralactam moiety plays a major role in the efficient shielding of the complexed Eu3+ ion from the water environment. The cryptands incorporating the bipyridine unit are the most promising labels according to their photophysical properties (excitation maxima, emission decay lifetime, relative luminescent yield). In contrast with literature data, introduction of N-oxide groups in the bipyridine chromophore weakens the luminescence properties of the cryptate.

Transition-Metal-Catalyzed Carbenoid Reactions of Sulfonium Ylides

Abstract: Olefins undergo cyclopropanation with diphenylsulfonium (ethoxycarbonyl)methylide (=diphenylsulfonium 2‐ethoxy‐2‐oxoethylide; 3a) in the presence of chiral CuI or RhII catalysts. trans/cis Ratios and ee's of the cyclopropanes 6 obtained with this ylide in the presence of a chiral CuI catalyst 7 are identical with those obtained with ethyl diazoacetate (4). In the case of catalysis with RhII, the trans/cis ratios of the cyclopropanes as well as the enantioselectivity change slightly upon going from the ylide 3a to diazoacetate 4.

Size complementarity of macrocyclic cavities and stoppers in amide-rotaxanes

Abstract: New [2]rotaxanes were prepared by the threading and the slipping procedure, the latter having the advantage of not needing templating interactions As a consequence, the first [2]rotaxane consisting of a tetraamide macrocycle and a pure hydrocarbon thread was synthesized (see 12a in Scheme 2) Sterically matching wheels and axles being the basic requirement of a successful slipping approach to rotaxanes, mono- and bishomologous wheels 5b,c with larger diameters than the parent 5a were synthesized and mechanically connected to amide axles 10a – c which were stoppered with blocking groups of different spatial demand (Scheme 1) The deslipping kinetics of the resulting rotaxanes 8a – c and 9a,b were measured and compared; it emerges that even slight increases in the wheel size require larger stoppers to stabilize the mechanical bond Moreover, when the deslipping rate of 8a (amide wheel and amide axle) was determined in either DMF or THF, a strong dependence on the solvent polarity, which is caused by a differing extent of intramolecular H-bonds between the wheel and the axle, was observed As expected, no such dependence was detected for rotaxane 12a (amide wheel and hydrocarbon axle) whose components cannot interact via H-bonds The comparison of the sterically matching pairs of macrocycles and blocking groups, found by a systematic fitting based on the results of slipping and deslipping experiments, with other rotaxane types bearing similar stoppers allows conclusions concerning the relative cavity size of wheels of various structure

Carbon−Fluorine Bond Formationvia a Five-Coordinate Fluoro Complex of Ruthenium(II), Preliminary Communication

Abstract: The 16-electron, five-coordinate fluoro complex [RuF(dppp)2]PF6 (1a; dppp=propane-1,3-diylbis[diphenylphosphine] smoothly reacts with 1,3-diphenylallyl bromide (=1,1′-(3-bromoprop-1-ene-1,3-diyl)bis[benzene]) in dry CDCl3 to give 1,3-diphenylallyl fluoride and [RuBr(dppp)2]+ in nearly quantitative yield. Under similar conditions, bromide (or chloride)/fluoride exchange also occurs with chlorotriphenylmethane, bromodiphenylmethane, and tert-butyl bromide. The crystal structure of 1a is reported.

Carbasaccharides via Ring‐Closing Alkene Metathesis. A Synthesis of (+)‐Valienamine from D‐Glucose

Abstract: (+)-Valienamine (16) was prepared in seven steps and in an overall yield of 17% from commercially available 2,3,4,6-tetra-O-benzyl-D-glucopyranose. Stereoselective addition of vinylmagnesium bromide to the 1,3,4,5-tetra-O-benzyl-6,7-dideoxy-L-xylo-hept-6-en-2-ulose (2) gave diene 3 (86%). Ring-closing alkene metathesis of 3 in the presence of 0.15 equiv. of Grubb's catalyst 1 gave the cyclohexene 4 (58%), that was converted into (+)-valienamine (16) in three steps and in 47% yield. Similarly, ring-closing alkene metathesis of the D-mannose-derived diene 20 gave the cyclohexene 21 (89%).

Cyclophane-type fullerene-dibenzo[18]crown-6 conjugates with trans-1, trans-2, and trans-3 addition patterns: Regioselective templated synthesis, x-ray crystal structure, ionophoric properties, and cation-complexation- dependent redox behavior

Abstract: The fullerene-crown ether conjugates (±)-1 to (±)-3 with trans-1 ((±)-1), trans-2 ((±)-2), and trans-3 ((±)-3) addition patterns on the C-sphere were prepared by Bingel macrocyclization. The trans-1 derivative (±)-1 was obtained in 30% yield, together with a small amount of (±)-2 by cyclization of the dibenzo[18]crown-6(DB18C6)-tethered bis-malonate 4 with C60 (Scheme 1). When the crown-ether tether was further rigidified by K+-ion complexation, the yield and selectivity were greatly enhanced, and (±)-1 was obtained as the only regioisomer in 50% yield. The macrocyclization, starting from a mixture of tethered bis-malonates with anti (4) and syn (10) bisfunctionalized DB18C6 moieties, afforded the trans-1 ((±)-1, 15%), trans-2 ((±)-2, 1.5%), and trans-3 ((±)-3, 20%) isomers (Scheme 2). Variable-temperature 1H-NMR (VT-NMR) studies showed that the DB18C6 moiety in C2-symmetrical (±)-1 cannot rotate around the two arms fixing it to the C-sphere, even at 393 K. The planar chirality of (±)-1 was confirmed in 1H-NMR experiments using the potassium salts of (S)-1,1′-binaphthalene-2,2′-diyl phosphate ((+)-(S)-19) or (+)-(1S)-camphor-10-sulfonic acid ((+)-20) as chiral shift reagents (Fig. 1). The DB18C6 tether in (±)-1 is a true covalent template: it is readily removed by hydrolysis or transesterification, which opens up new perspectives for molecular scaffolding using trans-1 fullerene derivatives. Characterization of the products 11 (Scheme 3) and 18 (Scheme 4) obtained by tether removal unambiguously confirmed the trans-1 addition pattern and the out-out geometry of (±)-1. VT-NMR Studies established that (±)-2 is a C2-symmetrical out-out trans-2 and (±)-3 a C1-symmetrical in-out trans-3 isomer. Upon changing from (±)-1 to (±)-3, the distance between the DB18C6 moiety and the fullerene surface increases and, correspondingly, rotation of the ionophore becomes increasingly facile. The ionophoric properties of (±)-1 were investigated with an ion-selective electrode membrane (Fig. 2 and Table 2), and K+ was found to form the most stable complex among the alkali-metal ions. The complex between (±)-1 and KPF6 was characterized by X-ray crystal-structure analysis (Figs. 3 and 4), which confirmed the close tangential orientation of the ionophore atop the fullerene surface. Addition of KPF6 to a solution of (±)-1 resulted in a large anodic shift (90 mV) of the first fullerene-centered reduction process, which is attributed to the electrostatic effect of the K+ ion bound in close proximity to the C-sphere (Fig. 5). Smaller anodic shifts were measured for the KPF6 complexes of (±)-2 (50 mV) and (±)-3 (40 mV), in which the distance between ionophore and fullerene surface is increased (Table 3). The effects of different alkali- and alkaline-earth-metal ion salts on the redox properties of (±)-1 were investigated (Table 4). These are the first-ever observed effects of cation complexation on the redox properties of the C-sphere in fullerene-crown ether conjugates.

Oligonucleotides containing 7-deazaadenines : the influence of the 7-substituent chain length and charge on the duplex stability

Abstract: Oligonucleotides carrying alkynyl and aminoalkynyl chains at the position 7 of 7-deazaadenine are synthesized, and the chain lengths as well as the bulkiness of the substituents are varied. The corresponding nucleosides 1a – f are prepared from 7-deaza-2′-deoxy-7-iodoadenosine and the particular alkynes by the Pd0-catalyzed cross-coupling reaction. The nucleosides are converted to the phosphoramidites 2a – f, which are used in solid-phase oligonucleotide synthesis. The stability of the duplexes is determined by the Tm values and the thermodynamic data. Compared to adenine or the unsubstituted 7-deazaadenine, the incorporation of a 7-ethynyl chain in a 7-deazaadenine moiety increases the duplex stability significantly, while a dodecynyl residue or a bulky steroid moiety leads to a duplex destabilization. A 3-aminoprop-1-ynyl residue (see 1g) or a 5-aminopent-1-ynyl residue (see 1h), which are charged under neutral conditions, lead to zwitterionic DNA. A high density of charged residues as found in homomers impairs duplex formation, most probably by counter-ion condensation.

Temperature-Dependent NMR and CD Spectra ofβ-Peptides: On the Thermal Stability ofβ-Peptide Helices - Is the Folding Process ofβ-Peptides Non-cooperative?

Abstract: Temp.-dependent NMR and CD spectra of MeOH solns. of a beta-hexapeptide and of a beta-heptapeptide between 298 and 393 K are reported. They establish the fact that the 314-helical secondary structures of the 2 beta-peptides do not "melt" in the temp. range investigated. This is in sharp contrast to the behavior of the helixes of alpha-peptides and proteins which undergo cooperative unfolding (denaturing) upon heating. A non-cooperative mechanism is proposed, with a stepwise, rather than an unzipping opening of H-bonded rings. The exptl. results are regarded as evidence that, of the 3 effects which were identified as contributing to the stability of beta-peptide helixes, i.e., H-bonding, hydrophobic interactions, and ethane staggering, the latter one is predominant.