Showing papers in "Helvetica Chimica Acta in 2002"

UV direct photolysis of N-nitrosodimethylamine (NDMA): Kinetic and product study

Abstract: The ultraviolet (UV) direct photolysis of N-nitrosodimethylamine (NDMA) in aqueous solutions at pH 3 and 7 leads to dimethylamine, and nitrite and nitrate ions as the major degradation products. In addition, small amounts of formaldehyde, formic acid, and methylamine are formed. When the initial concentration of NDMA was 1 mM, only a 13% decrease in the total organic carbon (TOC) was measured at pH 7, whereas no significant change in the TOC was observed at pH 3. In the concentration range 0.01–1 mM NDMA, zero-order kinetics is obeyed, whereas first-order kinetics is followed at concentrations below 0.01 mM. The photolysis occurs much faster at pH 3 than at pH 7, which is explained by the difference in the quantum yields of the process at these two pH values. UV Direct photolysis is an efficient process for the removal of NDMA from contaminated waters, and electrical energy per order (EEO) values as low as 0.3–0.5 kWh/order/m3 were calculated for treatment of low concentrations of NDMA (0.001 mM).

Computation of free energy

Abstract: Many quantities that are standardly used to characterize a chemical system are related to free-energy differences between particular states of the system. By statistical mechanics, free-energy differences may be expressed in terms of averages over ensembles of atomic configurations for the molecular system of interest. Here, we review the most useful formulae to calculate free-energy differences from ensembles generated by molecular simulation, illustrate a number of recent developments, and highlight practical aspects of such calculations with examples selected from the literature.

Catalytic Asymmetric Synthesis of O‐Acetylcyanohydrins from Potassium Cyanide, Acetic Anhydride, and Aldehydes, Promoted by Chiral Salen Complexes of Titanium(IV) and Vanadium(V)

Abstract: The utility of the chiral [Ti(μ-O)(salen)]2 complexes (R)- and (S)-1 (H2salen was prepared from (R,R)- or (S,S)-cyclohexane-1,2-diamine and 3,5-di(tert-butyl)-2-hydroxybenzaldehyde) as catalysts for the asymmetric addition of KCN and Ac2O to aldehydes to produce O-acetylcyanohydrins was investigated. It was shown that the complexes were active at a substrate/catalyst ratio of 100 : 1 and produced the O-protected cyanohydrins with ee in the range of 60–92% at −40°. Other complexes, [Ti2(AcO)2(μ-O)(salen)2] ((R)-4) and [Ti(CF3COO)2(salen)] ((R)-5), were prepared from (R)-1 by treatment with different amounts of Ac2O and (CF3CO)2O, and their catalytic activities were tested under the same conditions. The efficiency of (R)-4 was found to be even greater than that of (R)-1, whereas (R)-5 was inactive. The synthesis of the corresponding salen complexes of VIV and VV, [V(O)(salen)] ((R)-2) and [V(O)(salen)(H2O)] [S(O)3OEt] ((R)-3), was elaborated, and their X-ray crystal structures were determined. The efficiency of (R)-3 was sufficient to produce O-acetyl derivatives of aromatic cyanohydrins with ee in the range of 80–91% at −40°.

The α-L-Threofuranosyl-(3′→2′)-oligonucleotide System (‘TNA'): Synthesis and Pairing Properties

Abstract: Our studies of α-L-Threofuranosyl-(3′→2′)-oligonucleotides (‘TNA') are part of a systematic experimental inquiry into the base-pairing properties of potentially natural nucleic acid alternatives taken from RNA's close structural neighborhood. TNA is an efficient Watson-Crick base-pairing system and has the capability of informational cross-pairing with both RNA and DNA. This property, together with the system's constitutional and (presumed) generational simplicity, warrants special scrutiny of TNA in the context of the search for chemical clues to RNA's origin.

Toward an Understanding of the Chemical Etiology for DNA Minor-Groove Recognition by Polyamides

Abstract: Crescent-shaped polyamides composed of aromatic amino acids, i.e., 1-methyl-1H-imidazole Im, 1-methyl-1H-pyrrole Py, and 3-hydroxy-1H-pyrrole Hp, bind in the minor groove of DNA as 2 : 1 and 1 : 1 ligand/DNA complexes. DNA-Sequence specificity can be attributed to shape-selective recognition and the unique corners or pairs of corners presented by each heterocycle(s) to the edges of the base pairs on the floor of the minor groove. Here we examine the relationship between heterocycle structure and DNA-sequence specificity for a family of five-membered aromatic amino acids. By means of quantitative DNase-I footprinting, the recognition behavior of polyamides containing eight different aromatic amino acids, i.e., 1-methyl-1H-pyrazole Pz, 1H-pyrrole Nh, 5-methylthiazole Nt, 4-methylthiazole Th, 3-methylthiophene Tn, thiophene Tp, 3-hydroxythiophene Ht, and furan Fr, were compared with the polyamides containing the parent-ring amino acids Py, Im, and Hp for their ability to discriminate between the four Watson-Crick base pairs in the DNA minor groove. Analysis of the data and molecular modeling showed that the geometry inherent to each heterocycle plays a significant role in the ability of polyamides to differentiate between DNA sequences. Binding appears sensitive to changes in curvature complementarity between the polyamide and DNA. The Tn/Py pair affords a modest 3-fold discrimination of T⋅A vs. A⋅T and suggests that an S-atom in the thiophene ring prefers to lie opposite T not A.

Dramatically Enhanced Fluorescence of Heteroaromatic Chromophores upon Insertion as Spacers into Oligo(triacetylene)s

Abstract: In continuation of a previous study on the modulation of π-electron conjugation of oligo(triacetylene)s by insertion of central hetero-spacer fragments between two (E)-hex-3-ene-1,5-diyne ((E)-1,2-diethynylethene, DEE) moieties (Fig. 1), a new series of trimeric hybrid oligomers (14–18 and 22–24, Fig. 2) were prepared (Schemes 1–3). Spacers used were both electron-deficient (quinoxaline-based heterocycles, pyridazine) and electron-rich (2,2′-bithiophene, 9,9-dioctyl-9H-fluorene) chromophores. With 19–21 (Scheme 4), a series of transition metal complexes was synthesized as potential precursors for nanoscale scaffolding based on both covalent acetylenic coupling and supramolecular assembly. The UV/VIS spectra (Fig. 3) revealed that the majority of spacers provided hetero-trimers featuring extended π-electron delocalization. The new hybrid chromophores show a dramatically enhanced fluorescence compared with the DEE dimer 13 and homo-trimer 12 (Fig. 5). This increase in emission intensity appears as a general feature of these systems: even if the spacer molecule is non-fluorescent, the corresponding hetero-trimer may show a strong emission (Table 2). The redox properties of the new hybrid chromophores were determined by cyclic voltammetry (CV) and rotating-disk voltammetry (RDV) (Table 3 and Fig. 5). In each case, the first one-electron reduction step in the hetero-trimers appeared anodically shifted compared with DEE dimer 13 and homo-trimer 12. With larger spacer chromophore extending into two dimensions (as in 14–18, Fig. 2), the anodic shift (by 240–490 mV, Table 3) seems to originate from inductive effects of the two strongly electron-accepting DEE substituents rather than from extended π-electron conjugation along the oligomeric backbone, as had previously been observed for DEE-substituted porphyrins.

Mixed β2/β3-Hexapeptides and β2/β3-Nonapeptides Folding to (P)-Helices with Alternating Twelve- and Ten-Membered Hydrogen-Bonded Rings

Abstract: The structural properties of four mixed β-peptides with alternating β2/β3- or β3/β2-sequences have been analyzed by two-dimensional homonuclear 1H-NMR- and CD spectroscopic measurements. All four β-peptides fold into (P)-helices with twelve- and ten-membered H-bonded rings (Figs. 3–6). CD Spectra (Fig. 2) of the mixed β3/β2-hexapeptide 4a and β3/β2-nonapeptide 5a, indicating that peptides of this type also adopt the 12/10-helical conformation, were confirmed by NMR structural analysis. For the deprotected β3/β2-nonapeptide 5d, NOEs not consistent with the 10/12 helix have been observed, showing that the stability of the helix decreases upon N-terminal deprotection. From the NMR structures obtained, an idealized helical-wheel representation was generated (Fig. 7), which will be used for the design of further 12/10 or 10/12 helices.

Polymorphism vs. Desmotropy: The Cases of 3‐Phenyl‐ and 5‐Phenyl‐ 1H‐pyrazoles and 3‐Phenyl‐1H‐indazole

Abstract: Two desmotropes, 3-phenyl-1H-pyrazole (1a) and 5-phenyl-1H-pyrazole (1b) have been isolated and the conditions for their interconversion established. The X-ray structure of 1b has been determined (a=10.862(1), b=5.7620(5), c=12.927(2) A, β=111.435(2)°, space group P21/c), and both tautomers 1a and 1b were characterized by NMR in the solid state (13C- and 15N-CPMAS). In the case of 3-phenyl-1H-indazole (2a), two concomitant polymorphs have been analyzed by X-ray crystallography, and their NMR spectral properties were determined. The low-melting-point polymorph, at 106.7°, contains three molecules in the asymmetric unit (a=41.086(1), b=7.3860(2), c=23.391(1) A, β=117.697(1)°, space group C2/c) and the high-melting-point one, 115.3°, six molecules (a=13.7818(4), b=13.7976(5), c=18.9445(5) A, α=94.300(3), β=95.131(3), γ=119.428(3)°, space group P-1). Here, too, it has been experimentally determined how to transform one form into the other. Density-functional-theory calculations at the B3LYP/6-31G** level have been performed in both examples to rationalize the stability of the different tautomers.

Dendritic Iron(II) Porphyrins as Models for Hemoglobin and Myoglobin: Specific Stabilization of O2 Complexes in Dendrimers with H-Bond-Donor Centers

Abstract: Two types of dendritically functionalized iron(II) porphyrins were prepared (Scheme) and investigated in the presence of 1,2-dimethylimidazole (1,2-DiMeIm) as the axial ligand as model systems for T(tense)-state hemoglobin (Hb) and myoglobin (Mb). Equilibrium O2- and CO-binding studies were performed in toluene and aqueous phosphate buffer (pH 7). UV/VIS Titrations (Fig. 4) revealed that the two dendritic receptors 1⋅FeII-1,2-DiMeIm and 2⋅FeII-1,2-DiMeIm (Fig. 2) with secondary amide moieties in the dendritic branching undergo reversible complexation (Fig. 5) with O2 and CO in dry toluene. Whereas the CO affinity is similar to that measured for the natural receptors, the O2 affinity is greatly enhanced and exceeds that of T-state Hb by a factor of ca. 1500 (Table). The oxygenated complexes possess half-lives of several h (Fig. 6). This remarkable stability originates from both dendritic encapsulation of the iron(II) porphyrin and formation of a H-bond between bound O2 and a dendritic amide NH moiety (Fig. 11). Whereas reversible CO binding was also observed in aqueous solution (Fig. 10), the oxygenated iron(II) complexes are destabilized by the presence of H2O with respect to oxidative decay (Fig. 9), possibly as a result of the weakening of the O2⋅⋅⋅H−N H-bond by the competitive solvent. The comparison between the two dendrimers with amide branchings and ester derivative 3⋅FeII-1,2-DiMeIm (Fig. 2), which lacks H-bond donor centers in the periphery of the porphyrin, further supports the role of H-bonding in stabilizing the O2 complex against irreversible oxidation. All three derivatives bind CO reversibly and with similar affinity (Fig. 8) in dry toluene, but the oxygenated complex of 3⋅FeII-1,2-DiMeIm undergoes much more rapid oxidative decomposition (Fig. 7).

The Total Synthesis and Biological Assessment of trans‐Epothilone A

Abstract: The total synthesis of (12S,13S)-trans-epothilone A (1a) was achieved based on two different convergent strategies. In a first-generation approach, construction of the C(11)C(12) bond by Pd0-catalyzed Negishi-type coupling between the C(12)-to-C(15) trans-vinyl iodide 5 and the C(7)-to-C(11) alkyl iodide 4 preceded the (nonselective) formation of the C(6)C(7) bond by aldol reaction between the C(7)-to-C(15) aldehyde 25 and the dianion derived from the C(1)-to-C(6) acid 3. The lack of selectivity in the aldol step was addressed in a second-generation approach, which involved construction of the C(6)C(7) bond in a highly diastereoselective fashion through reaction between the acetonide-protected C(1)-to-C(6) diol 31 (‘Schinzer's ketone') and the C(7)-to-C(11) aldehyde 30. As part of this strategy, the C(11)C(12) bond was established subsequent to the critical aldol step and was based on B-alkyl Suzuki coupling between the C(1)-to-C(11) fragment 40 and C(12)-to-C(15) trans-vinyl iodide 5. Both approaches converged at the stage of the 3-O, 7-O-bis-TBS-protected seco acid 27, which was converted to trans-deoxyepothilone A (2) via Yamaguchi macrolactonization and subsequent deprotection. Stereoselective epoxidation of the trans C(12)C(13) bond could be achieved by epoxidation with Oxone ® in the presence of the catalyst 1,2 : 4,5-di-O-isopropylidene-L-erythro-2,3-hexodiuro-2,6-pyranose (42a), which provided a 8 : 1 mixture of 1a and its (12R,13R)-epoxide isomer 1b in 27% yield (54% based on recovered starting material). The absolute configuration of 1a was established by X-ray crystallography. Compound 1a is at least equipotent with natural epothilone A in its ability to induce tubulin polymerization and to inhibit the growth of human cancer cell lines in vitro. In contrast, the biological activity of 1b is at least two orders of magnitude lower than that of epothilone A or 1a.

Synthesis of Amphiphilic Fullerene Derivatives and Their Incorporation in Langmuir and Langmuir-Blodgett Films

Abstract: Various amphiphilic fullerene derivatives were prepared by functionalization of [5,6]fullerene-C60-Ih (C60) with malonate or bis-malonate derivatives obtained by esterification of the malonic acid mono-esters 5–7. Cyclopropafullerene 10 was obtained by protection of the carboxylic acid function of 6 as a tert-butyl ester, followed by Bingel addition to C60 and a deprotection step (Scheme 2). The preparation of 10 was also attempted directly from the malonic acid mono-ester 6 under Bingel conditions. Surprisingly, the corresponding 3′-iodo-3′H-cyclopropa[1,9][5,6]fullerene-C60-Ih-3′-carboxylate 11 was formed instead of 10 (Scheme 3). The general character of this new reaction was confirmed by the preparation of 15 and 16 from the malonic acid mono-esters 13 and 14, respectively (Scheme 4). All the other amphiphilic fullerene derivatives were prepared by taking advantage of the versatile regioselective reaction developed by Diederich and co-workers which led to macrocyclic bis-adducts of C60 by a cyclization reaction at the C-sphere with bis-malonate derivatives in a double Bingel cyclopropanation. The bis-adducts 37–39 with a carboxylic acid polar head group and four pendant long alkyl chains of different length were prepared from diol 22 and acids 5–7, respectively (Scheme 9). In addition, the amphiphilic fullerene derivatives 45, 46, 49, 54, and 55 bearing different polar head groups and compound 19 with no polar head group were synthesized (Schemes 11–13, 15, and 5, resp.). The ability of all these compounds to form Langmuir monolayers at the air-water interface was investigated in a systematic study. The films at the water surface were characterized by their surface pressure vs. molecular area isotherms, compression and expansion cycles, and Brewster-angle microscopy. The spreading behavior of compound 10 was not good, the two long alkyl chains in 10 being insufficient to prevent aggregation resulting from the strong fullerene-fullerene interactions. While no films could be obtained from compound 19 with no polar head group, all the corresponding amphiphilic fullerene bis-adducts showed good spreading characteristics and reversible behavior upon successive compression/expansion cycles. The encapsulation of the fullerene in a cyclic addend surrounded by four long alkyl chains is, therefore, an efficient strategy to prevent the irreversible aggregation resulting from strong fullerene-fullerene interactions usually observed for amphiphilic C60 derivatives at the air-water interface. The balance of hydrophobicity to hydrophilicity was modulated by changing the length of the surrounding alkyl chains or the nature of the polar head group. The best results in terms of film formation and stability were obtained with the compounds having the largest polar head group, i.e.45 and 46, and dodecyl chains. Finally, the Langmuir films obtained from the amphiphilic fullerene bis-adducts were transferred onto solid substrates, yielding high-quality Langmuir-Blodgett films.

Swimming against the Stream? A Discussion of the Bonding in d6 and d8 Fluoro Complexes and Its Consequences for Catalytic Applications

Abstract: Fluoride has recently found increasing application as coligand both in complexes of late transition metals and as a reagent in asymmetric catalysis. In recent papers, this topic was reviewed, with emphasis on the role played by so-called ‘push-pull interactions' between the fluoro ligand and a π acid in the stabilization of fluoro complexes with a d6 or d8 electron configuration. This picture has led to the concept that fluoride is the strongest π-donor in the halide series. Herein, the latter concept is discussed and criticized. In particular, the effect of the ionicity of the metal-fluoride bond is proposed as an alternative explanation to most of the observations that show a ‘reversed' halide order. The ionic character of the MF bond also accounts for its intrinsic reactivity and suggests some strategies for the stabilizatioin of fluoro complexes, including the use of coordinative unsaturation. The scope and limitations of the application of d6 and d8 fluoro complexes in catalysis are also discussed. The most promising application is the use of 16-electron fluoro complexes in the metal-promoted formation of the CF bond.

Evidence that the β‐Peptide 14‐Helix is Stabilized by β3‐Residues with Side‐Chain Branching Adjacent to the β‐Carbon Atom

Abstract: Oligomers of β-substituted β-amino acids (‘β3-peptides') are known to adopt a helical secondary structure defined by 14-membered ring hydrogen bonds ('14-helix'). Here, we describe a deca-β3-peptide, 1, that does not adopt the 14-helical conformation and that may prefer an alternative secondary structure. β3-Peptide 1 is composed exclusively of residues with side chains that are not branched adjacent to the β-C-atom (β3-hLeu, β3-hLys, and β3-hTyr). In contrast, an analogous β-peptide, 2, containing β3-hVal residues in place of the β3-hLeu residues of 1, adopts a 14-helical conformation in MeOH, according to CD data. These results illustrate the importance of side-chain branching in determining the conformational preferences of β3-peptides.

Facile Access to Versatile Polyaromatic Building Blocks: Selectively Protected Benzocyclobutenedione Derivatives via Regioselective [2+2] Cycloaddition of α-Alkoxybenzyne and Ketene Silyl Acetal

Abstract: A facile, divergent access to highly oxygenated benzocyclobutene derivatives was developed via the regioselective [2+2] cycloaddition of α-alkoxybenzynes and ketene silyl acetals. The cycloadducts could be converted to selectively protected alkoxybenzocyclobutenediones, an attractive class of compounds for the synthesis of polyaromatic compounds. As one possible application, divergent access to a regioisomer pair of sulfonylphthalides for the Hauser approach to polyaromatic compounds is described.

Enantioselective Heterogeneous Epoxidation and Hetero-Diels-Alder Reaction with Mn- and Cr-salen Complexes Immobilized on Silica Gel by Radical Grafting

Abstract: Vinyl-substituted chiral salens (salen=bis(salicylidene)ethylidenediamine) are used for attachment to Me3Si-hydrophobized silica gel (controlled-pore glass, CPG), carrying covalently bound mercaptopropyl ‘substituents', by AIBN-mediated radical addition of SH groups to styryl C=C bonds (Scheme 1, Table 1, and Figs. 1 and 2). The immobilized Mn- and Cr-salen complexes, thus accessible, have been employed in enantioselective epoxidations (Scheme 2, Tables 2 and 3, and Fig. 3) and hetero-Diels-Alder additions of aldehydes to Danishefsky's diene (Scheme 3, Tables 4 and 5, and Figs. 4 and 5), with an emphasis on multiple use of the immobilized catalysts. The enantioselectivities (es) of the two reactions were very similar to those reported for homogeneous conditions. After five to seven runs, all the CPG-bound Mn-salen complexes performed somewhat less well (70 instead of 75% es with styrene; Fig. 3). The Cr complex, which was shown to give rise to a linear relationship between the enantiomeric purities of ligand and product under homogeneous conditions (Fig. 4), exhibited the opposite behavior: after five runs, the enantioselecitivity of the hetero-Diels-Alder reaction had risen (from an average of 76 to ca. 83%) to remain constant for another five runs (Fig. 5). We have established for both catalysts that no reaction takes place in the supernatant solution (no leaching of catalytically active Mn or Cr species from the CPG into solution; heterogeneity test; Tables 3 and 5). The results described are yet another demonstration for the successful ‘conversion' of homogeneous to heterogeneous catalysts by immobilization on hydrophobic CPG, with multiple application of the same catalyst batch.

Lewis Base Catalyzed Aldol Reaction of Trimethylsilyl Enolates with Aldehydes

Abstract: A new Lewis base catalyzed aldol reaction of trimethylsilyl enolates with aldehydes is established in DMF or pyridine solvent by using a Lewis base such as lithium diphenylamide (Tables 4 and 5) or lithium 2-pyrrolidone (Tables 6–8). The effect of solvent suggests that this reaction proceeds via the pentacoordinated hypervalent silicate generated by the coordination of the above Lewis base to a trimethylsilyl enolate. Successive coordination of the solvent to the thus-formed pentacoordinated silicate leads to an active enolate intermediate having hexacoordinated silicate, which, in turn, attacks carbonyl compounds to form the desired aldols (Scheme 5).

Synthesis of α‐Nitro‐α‐diazocarbonyl Derivatives and Their Applications in the Cyclopropanation of Alkenes and in O ? H Insertion Reactions

Abstract: A facile and highly efficient method for the preparation of α-nitro-α-diazocarbonyl derivatives by a diazo-transfer reaction involving (trifluoromethyl)sulfonyl azide has been developed. These substrates undergo a rhodium-catalyzed cyclopropanation reaction with a variety of alkenes. A systematic study of the reaction indicated that the diastereoselectivity of the cyclopropanation could be effectively controlled through the modification of the steric bulk of the diazo reagent. A novel OH insertion reaction of the metalcarbene complex derived from the α-nitro-α-diazocarbonyl reagent afforded the corresponding novel α-nitro-α-alkoxy carbonyl derivatives.

Beta-Hairpins Generated from Hybrid Peptide Sequences Containing both Alpha- and Beta-Amino Acids

Abstract: The incorporation of the -amino acid residues into specific positions in the strands and -turn segments of peptide hairpins is being systematically explored. The presence of an additional torsion variable about the C()C() bond () enhances the conformational repertoire in -residues. The conformational analysis of three designed peptide hairpins composed of /-hybrid segments is described: Boc-Leu-Val-Val-DPro-Phe- Leu-Val-Val-OMe (1), Boc-Leu-Val-Val-DPro-Gly-Leu-Val-Val-OMe (2), and Boc-Leu-Val-Phe-Val-DPro- Gly-Leu-Phe-Val-Val-OMe (3). 500-MHz 1H-NMR Analysis supports a preponderance of -hairpin conformation in solution for all three peptides, with critical cross-strand NOEs providing evidence for the proposed structures. The crystal structure of peptide 2 reveals a -hairpin conformation with two -residues occupying facing, non-H-bonded positions in antiparallel -strands. Notably, Val(3 ) adopts a gauche conformation about the C()C() bond (65) without disturbing cross-strand H-bonding. The crystal structure of 2, together with previously published crystal structures of peptides 3 and Boc-Phe-Phe-DPro-Gly- Phe-Phe-OMe, provide an opportunity to visualize the packing of peptide sheets with local −polar segments× formed as a consequence of reversal peptide-bond orientation. The available structural evidence for hairpins suggests that -residues can be accommodated into nucleating turn segments and into both the H-bonding and non-H-bonding positions on the strands.

A Study of the Stereochemical Course of β-Oxygen Elimination with a Rhodium(I) Complex

Abstract: The stereochemical course of β-oxygen elimination of an organorhodium(I) complex was investigated through the Rh-catalyzed addition of phenylboronic acid to a chiral propargyl acetate to produce an allene. The degree of chirality transfer suggests that the β-oxygen elimination takes place in both syn and anti modes.

The Notion of a DNA Minimal Cell: A General Discourse and Some Guidelines for an Experimental Approach

Abstract: The staggering complexity of even the simplest living microorganisms on Earth elicits the question of whether such complexity is really necessary for life, or whether, instead, the basic functions of cellular life (homeostasis, reproduction, and evolution) can be, in principle, expressed by much simpler unicellular entities that contain only a few dozen genes. This suggests the notion of a minimal cell, i.e., the (potential) cell having the minimal sufficient molecular components to be defined as alive. The conceptual and practical implementation of such minimal cell(s) for our understanding of the notion of life, and also for possible biotechnological applications, is discussed here.

Analysis and Improvement of an Anion-Templated Rotaxane Synthesis

Abstract: A series of new rotaxanes with axles different in length was prepared. Following the synthetic protocol utilizing a known anion template effect (Scheme 1), surprisingly low yields in the order of 2–5% were obtained (Scheme 3), which furthermore significantly depended on the nature of the stopper (Fig. 1). Variations in the synthetic procedures and computational results from Monte Carlo simulations allowed us to analyze the origin of these findings: The rotaxane wheel 3 acts as a noncovalently bound ‘protecting group' for the stopper nucleophile. The protection of the nucleophilic phenolate O-atom depends much on the steric demands of the stoppers (see 2vs.10) which induce different conformations of the wheel. Based on this model, an improved synthetic scheme is suggested.

Preparation of Polystyrene Beads with Dendritically Embedded TADDOL and Use in Enantioselective Lewis Acid Catalysis

Abstract: A full account is given of the preparation and use of TADDOLates, which are dendritically incorporated in polystyrene beads (Scheme 1). A series of styryl-substituted TADDOLs with flexible, rigid, or dendritically branching spacers between the TADDOL core and the styryl groups (2–16 in number) has been prepared (5–7, 20, 21, 26 in Schemes 2–4 and Fig. 1–3). These were used as cross-linkers in styrene-suspension polymerization, leading to beads of ca. 400-μm diameter (Schemes 5 and 6, b). These, in turn, were loaded with titanate and used for the Lewis acid catalyzed addition of Et2Zn to PhCHO as a test reaction (Scheme 6). A comparison of the enantioselectivities and degrees of conversion (both up to 99%), obtained under standard conditions, shows that these polymer-incorporated Ti-TADDOLates are highly efficient catalysts for this process (Table 1). In view of the effort necessary to prepare the novel, immobilized catalysts, emphasis was laid upon their multiple use. The performance over 20 cycles of the test reaction was best with the polymer obtained from the TADDOL bearing four first-generation Frechet branches with eight peripheral styryl groups (6, p-6, p-6⋅Ti(OiPr)2): the enantioselectivity (Fig. 4), the rate of reaction (Fig. 5), and the swelling factor (Fig. 6) were essentially unchanged after numerous operations carried out with the corresponding beads of 400-μm diameter and a degree of loading of 0.1 mmol TADDOLate/g polymer, with or without stirring (Fig. 7). The rate with the dendritically polymer-embedded Ti-TADDOLate (p-6⋅Ti(OiPr)2) was greater than that measured with the corresponding monomer, i.e., 6⋅Ti(OiPr)2 (Fig. 8). Possible interpretations of this phenomenon are proposed. A polymer-bound TADDOL, generated on a solid support (by Grignard addition to an immobilized tartrate ester ketal) did not perform well (Scheme 4 and Table 2). Also, when we prepared polystyrene beads by copolymerization of styrene, a zero-, first-, or second-generation dendritic cross-linker, and a mono-styryl-substituted TADDOL derivative, the performance in the test reaction did not rival that of the dendritically incorporated Ti-TADDOLate ((p-6⋅Ti(OiPr)2) (Scheme 7 and Fig. 10). Finally, we have applied the dendritically immobilized Cl2 and (TsO)2Ti-TADDOLate as chiral Lewis acid to preferentially prepare one enantiomer of the exo and the endo (3+2) cycloadduct, respectively, of diphenyl nitrone to 3-crotonoyl-1,3-oxazolidinone; in one of these reaction modes, we have observed an interesting conditioning of the catalyst: with an increasing number of application cycles, the amount of polymer-incorporated Lewis acid required to induce the same degree of enantioselectivity, decreased; the degrees of diastereo- and enantioselectivity were, again, comparable to those reported for homogeneous conditions (Fig. 9).

Helix-Forming Oligoureas: Temperature-Dependent NMR, Structure Determination, and Circular Dichroism of a Nonamer with Functionalized Side Chains

Abstract: To further investigate the degree of structural homology between γ-peptides A and N,N′-linked oligoureas B, we prepared oligourea nonamer 2 containing Ala, Val, Leu, Phe, Tyr and Lys side chains. Oligomer 2 was synthesized on solid support from activated monomers, i.e., from enantiomerically pure succinimidyl {2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl}carbamates 3a–f that are further substituted at C(2) of the ethyl moiety. These precursors were conveniently prepared from N-Fmoc-protected β3-amino acids with corresponding side chains. Detailed NMR studies (DQF-COSY, TOCSY, and ROESY) in (D5)pyridine revealed that 2 adopts a regular (P)-2.5 helical secondary structure very similar to that previously determined for oligourea heptamer 1 and closely related to the (P)-2.614 helix of γ-peptides. Temperature-dependent NMR further demonstrated the conformational homogeneity and remarkable stability of the structure of 2 in pyridine. The CD spectrum of 2 (0.2 mM) was recorded in MeOH with the aim to gain more information about the conformation of oligoureas. In contrast to 2.6-helical γ-peptides, which display only a weak or no Cotton effect, oligourea 2 exhibits an intense positive Cotton effect at ca. 203 nm ([Θ]=+373000 deg cm2 dmol−1) that decreases only slowly upon increasing the temperature.

α-Helical Polypeptide Films Grown From Sulfide or Thiol Linkers on Gold Surfaces

Abstract: We prepared two new linkers, S-functionalized adamantane derivatives 2 and 3, which bind as monolayers on polycrystalline gold. From these surface anchors, both L- and D-isomers of alanine can be grown as thin films of α-helical polypeptides directed from the gold surface by using the appropriate N-carboxyalanine anhydride. FT-IR Studies show that these layers are roughly 1000-A thick and that, under the same growth conditions, the L-polypeptide layers grow at a rate ca. 30% greater than that of the non-natural D-amino acid. X-Ray photoelectron spectroscopy studies show that, upon equilibration, all three S-atoms of the sulfide moieties of 2 are bound to the gold surface, and that, on average, three of the four thiols of 3 are chemoadsorbed. The essential role of H2O on the surface of these films as a necessary component in these gas-phase polymerization reactions is demonstrated.

1,3-Diethynylallenes: Carbon-Rich Modules for Three-Dimensional Acetylenic Scaffolding

Abstract: 0-catalyzed cross-coupling of substrates, which bear bispropargylic leaving groups with silyl-protected alkynes, has provided access to a variety of 1,3-diethynylallenes, a new family of modules for three-dimensional acetylenic scaffolding In enantiomerically pure form, these C-rich building blocks could provide access ± by oxidative oligomerization ± to a fascinating new class of helical oligomers and polymers with all-carbon backbones (Fig 2) In the first of two routes, a bispropargylic epoxide underwent ring opening during S2-type cross-coupling, and the resulting alkoxide was silyl-protected, providing 1,3-diethynylallenes ()-8, ()-12 (Scheme 3), and ()-15 (Scheme 5) A more general approach involved bispropargylic carbonates or esters as substrates (Scheme 6 ± 8), and this route was applied to the preparation of a series of 1,3diethynylallenes to investigate how their overall stability against undesirable [2 2] cycloaddition is affected by the nature of the substituents at the allene moiety The investigation showed that the 1,3-diethynylallene chromophore is stable against [2 2] cycloaddition only when protected by steric bulk and when additional electron delocalization is avoided The regioselectivity of the cross-coupling to the bispropargylic substrates is entirely controlled by steric factors: attack occurs at the alkyne moiety bearing the smaller substituent (Schemes 9 and 10) Oxidative Hay coupling of the terminally mono-deprotected 1,3-diethynylallene ()-49 afforded the first dimer 50, probably as a mixture of two diastereoisomers (Scheme 12) Attempts to prepare a silyl-protected tetraethynylallene by the new methodology failed (Scheme 13) Control experiments (Schemes 14 ± 16) showed that the Pd 0 -catalyzed cross-coupling to butadiyne moieties in the synthesis of this still-elusive chromophore requires forcing conditions under which rapid [2 2] cycloaddition of the initial product cannot be avoided

New Steroidal Glycosides from Balanites aegyptiaca

Abstract: Five new steroidal glycosides were isolated from the roots of Balanites aegyptiaca, a widely used African medicinal plant. On the basis of spectroscopic and chemical evidence, their structures were determined as (3β,12α,14β,16β)-12-hydroxycholest-5-ene-3,16-diyl bis(β-D-glucopyranoside) (1), (3β,20S,22R,25R)- and (3β,20S,22R,25S)-26-(β-D-glucopyranosyloxy)-22-methoxyfurost-5-en-3-yl β-D-xylopyranosyl-(13)-β-D-glucopyranosyl-(14)[α-L-rhamnopyranosyl-(12)]-β-D-glucopyranoside (2 and 3, resp.), and (3β,20S,22R,25R)- and (3β,20S,22R,25S)-spirost-5-en-3-yl β-D-xylopyranosyl-(13)-β-D-glucopyranosyl-(14)[α-L-rhamnopyranosyl-(12)]-β-D-glucopyranoside (4 and 5, resp.)

The Enantioselectivity and the Stereochemical Course of Copper‐Catalyzed Intramolecular CH Insertions of Phenyliodonium Ylides

Abstract: The Cu-catalyzed intramolecular CH insertion of phenyliodonium ylide 1b was investigated at 0° in the presence of several chiral ligands. Enantioselectivities varied in the range 38–72%, and were higher than those resulting from reaction of the diazo compound 1c at 65°. The intramolecular insertion of the enantiomerically pure methyl diazoacetate (R)-20 and of the corresponding phenyliodonium ylide (R)-21 proceeded to (R)-23 with retention of configuration with [Cu(hfa)2] (hfa=hexafluoroacetylacetone=1,1,1,5,5,5-hexafluoropentane-2,4-dione) and [Rh2(OAc)4]. These results are consistent with a carbenoid mechanism for the Cu-catalyzed insertion with phenyliodonium ylides. However, the insertion of the perfluorosulfonated phenyliodonium ylide (R)-29 afforded with [Cu(hfa)2] as well as with [Rh2(OAc)4] the cyclopentanone derivative 30 as a cis/trans mixture with only 56–67% enantiomeric excess.

Structural properties governing retention mechanisms on immobilized artificial membrane (IAM) HPLC columns

Abstract: The aims of this study were to investigate whether three commercially available immobilized artificial membrane (IAM) HPLC columns yield collinear data for neutral compounds, and whether IAM scales are distinct from the log P-oct (partition coefficient in the octanol/H2O system) scale. With these objectives, the retention mechanisms on the IAM HPLC columns were analysed by linear solvation free-energy relationships (LSERs). A set of 68 neutral model compounds with known solvatochromic parameters and log P-oct values was investigated, allowing a regular and broad exploration of property space, The resulting solvatochromic equations clearly indicate that the three IAM stationary phases retain small neutral solutes by a balance of intermolecular forces closely resembling those underlying partitioning in octanol/H2O and retention on a reversed-phase LC-ABZ HPLC column. For all systems, the solute's size and hydrogen-bond-acceptor basicity are the two predominant factors, whereas dipolarity/polarisability and hydrogen-bond-donor acidity play only minor roles

Theoretical Prediction of Substituent Effects on the Intrinsic Folding Properties of β‐Peptides

Abstract: A systematic conformational analysis on blocked β-amino acids as constituents of β-peptides by ab initio MO theory reveals that the conformer pool of β-peptide monomers is essentially determined by the conformation of simple submonomer fragments. The influence of single and multiple substitutions at the C(α) and C(β) backbone atoms on the intrinsic folding properties of the monomers was estimated both in the single-molecule approximation and in a polar solvent continuum, applying a quantum-chemical SCRF model. Substitution at C(β) has a higher impact on the β-amino acid conformation than a substitution at C(α). It can be shown that the conformations of important periodic secondary structures in β-peptides belong to the conformer pool of the monomers, even for those secondary-structure elements where H-bond formation appears only in longer sequences. Rules for design of special secondary-structure types by selection of an actual substituent pattern in the β-amino acid constituents have been derived within the monomer approach.