ALBERT

Notes: The calculated molecular surfaces for some Sandalwood-odor molecules and structurally similar inactive compounds were compared with the calculated mean surface obtained from five Sandalwood odorants included in the set, and their individual agreement and deviations were estimated. Especially the investigation of selected parts of the surfaces seems very promising in finding structure subunits which might be important for an association to a possible receptor site.

Notes: Catalytic hydrogenation of the Δ3-unsaturated (9R,10 R)- and (9S,10 S)-epoxyenol lactones 3a, b., and 4a, b., respectively, affords, in addition to the expected saturated epoxylactones 5a, b and 7a, b, also open-chain products, i.e. the diastereoisomeric (9R,10R)- and (9S,10S)-9,10-expoxy-8-oxo-4,5-secosteroklastan-5-oic acids 6a, b. and 8a, b. Alkaline hydrolysis of the lactone ring of compounds 5 and 7 and subsequent acetylation of the corresponding hydroxy derivatives give as the major products the open-chain, diasteroisomeric (9R,10R)- and (9S,10S)-4-acetoxy-9,10-epoxy-methyl esters 9a, b and 11a, b, respectively, and, but only in the androstane series, the tetrahydropyran derivatives 10a and 12a, as the minor components.

Notes: The kinetics of pyridine exchange on trans-[MO2(py)4]+ have been followed by 1H-NMR in CD3NO2 for M = Re, Tc: k298S-1 = (5.5 ± 0.1) × 10-6, 0.04 ± 0.02; ΔH≠/kJmol-1 = 111 ± 3, 101 ± 9; ΔS≠/JK-1mol-1 = +28 ± 10, +68 ± 35. For the Rev complex, pyridine and oxygen exchanges have been measured simultaneously by 1H- and 17O-NMR in deuterated water: k298/s-1 = (8.6 ± 0.2) × 10-6 (py), (14.5 ± 0.3) × 10-6 (oxygen); ΔH≠/kJmol-1 = 111 ± 1, 91 ± 1; ΔS /JK-1mol-1 = +32 ± 3, -32 ± 4. For both complexes, the rate law for pyridine exchange is first-order in complex and zero-order in pyridine; together with the activation parameter values, and the fact that the rate does not depend significantly on the nature of the solvent, this strongly implies the operation of a dissociative mechanism. The ratio of pyridine exchange rates for the Tc and Re complexes at room temperature is ca. 8000. The consequences of these observations for radiopharmaceutical synthesis are discussed.

Notes: Why Pentose and Not Hexose Nucleic Acids? Part I . Introduction to the Problem, Conformational Analysis of Oligonucleotide Single Strands Containing 2′,3′-Dideoxyglucopyranosyl Building Blocks (‘Homo-DNA’), and Reflections on the Conformation of A- and B-DNA Summary in collaboration with Prof. Dr. C.E. Wintner, Haverford College, Haverford, PA 19041-1392; academic guest, ETH, March and June/July, 1991.Chemical rationalization of the structure of a biomolecule can be sought through consideration of two criteria: first, the relationship between the structure and its biological function; and second, the structure's potential for constitutional self assembly. The latter criterion convers the judgment, by chemical reasoning, of the chance of its preformation, that is, a synthetic event which must have been undergone by any molecular structure in order to have been selected (or to have selected itself) to become a biomolecule. One way to further the task of rationalizing a biomolecule's structure by experimental means is the design, synthesis, and study of structural alternatives which might have become biomolecules on the basis of either criterion, but which do not, in fact, appear in Nature today.In the formation of sugar phosphates from glycolaldehyde phosphate under basic conditions, straightforward and selective formation of rac-hexose 2,4,6-triphosphates is observed in the absence of formaldehyde, while rac-pentose 2,4-diphosphates are dominant, when (0.5 equiv.) formaldehyde is present [1]. This and other observations indicate that hexose sugars should be regarded to have had a chance of preformation comparable with that of pentose sugars. Why, then, did Nature choose pentoses and not hexoses as the sugar building blocks of nucleic acids? The reason must be functional; it must be the case that pentose nucleic acids are biologically superior to potential hexose alternatives. To the extent that biological function is a consequence of molecular structure and reactivity, the origin of this superiority should be decipherable through chemical experiment, that is, through synthesis of hexose nucleic acids, systematic study of their chemical properties, and comparison of these properties with those of their natural counterparts. This has been the object of the present investigation, initiated in 1986. The paper introduces a series of papers which will describe the results of a model study, namely, the synthesis, pairing properties and structure of homo-DNA oligonucleotides.

Notes: From a MeOH extra of Psiadia trinervia, seven phenolic compounds were isolated by gel filtration and reversed-phase chromatography. Six of them are known compounds, namely 3,4-di-O-caffeoylquinic acid (2), 3,5-di-O-caffeoylquinic acid (3), caffeic acid, and three 3-methoxyflavonoids. Compound 1 is a 3,4-di-O-caffeoyl derviative of (1S,3R,4R,5R)-1,3,4, 5-tetrahydroxycyclohexanecarboxylic acid, a novel steroisomer of (-)-quinic acid. Following hydrolytic treatment of the MeOH extract, ethyl 3-O-caffeoylquinate (4), ethyl 3,4-di-O-caffeoylquinate (5), and ethyl 3,5-O-caffeoylquinate (6) were isolated. The latter three compounds are artifacts. The configuration of 1-3 was established by NMR and CD (exciton chirality method).

Notes: The carbohydrate-derived lactone phenylsemicarbazones 3 and 4 were prepared from 5 and 8 (Scheme). Treatment with 4-phenylsemicarbazide gave 6 and 7 (77:23) and 9 and 19 (76:24), respectively. Oxidation of 6 and 9 by CrO3-pyridine to 11 and 13, followed by deprotection, yeilded 3 and 4. The structure of 3 was established by X-ray analysis. Enzyme-inhibition studies using revealed that 3 is a competitive inhibitor with Ki = 23 μm. The activity of 4 was examined using N-acetylglucosaminidase from bovine kidney, Aspergillus niger, and Artemia salina. compound 4 was found to be a competitive inhibitor of all three enzymes with Ki values of 0.13, 6.0, and 0.71 μm and KM/Ki values of 6910, 45, and 465, respectively.

Notes: Radical anions of ten monocyclic and bicyclic azoalkanes containing the azo group in (Z)-conformation, have been fully characterized by their hyperfine data with the use of ESR, ENDOR, and general-TRIPLE-resonance spectroscopy. These azoalkanes are represented by 3,3,5,5-tetramethyl-1-pyrazline (1), 2,3-diazabicyclo[2.2.1]hept-2-ene (4), and 2,3-diazabicyclo[2.2.2]oct-2-ene (9), as well as by their derivatives 2, 3, 5-8, and 10. For all radical anions \documentclass{article}\pagestyle{empty}\begin{document}$1^{- \atop \dot{}}-10^{- \atop \dot{}}$\end{document}, the 14N-coupling constant, aN, is in the range of +0.83 to +0.97 mT; this finding indicates that the spin population is essentially restricted to the π system of the azo group. The 14N-hyperfine anisotropy largely affects the width of ESR lines, particularly at low temperatures. Substantial coupling constants of 7Li-, 23K-, and 133Cs-nuclei point to a close association of the radical anions with their alkakimetal counterions. With the exception of 39K, these nuclei give rise to readily observable ENDOR signals which appear along with those stemming from protons. The prominent hyperfine features of \documentclass{article}\pagestyle{empty}\begin{document}$1^{- \atop \dot{}}-10^{- \atop \dot{}}$\end{document} are discussed.

Notes: The radical mono-ions of three azoalkanes in which the azo group is connected to the polycyclic alkane moieties at the bridgehead C-atoms, i.e. 1,1′-azonorbornane (1), 1,1′-azotwistane (2), and 1,1′-azobicyclo[3.2.1]octane (3), were studied in fluid solution by ESR spectroscopy. According to the ESR parameters and MO models, the radical cations of 1-3 should be considered as σ radicals, whereas the corresponding radical anions are π radicals. INDO calculations point to a a remarkable dependence of the 14N-coupling constants on the geometry at the N-atoms in the radical cations of aliphatic azo compounds.

Notes: The use of α,α,α′,α′ -tetraaryl-1,3-dioxolane-4,5-dimethanols ( = TADDOLs;1) as chiral NMR shift reagents (1H, 13C, 19F) is described. In many cases, the ratio of enantiomeric alcohols and amines can be determined under standard conditions of measurement (CDCl3 as solvent, room temperature). The preparation and use of a new type of TADDOL, the tetrakis(dimethylamino) derivative 1d, is described. Menthol, octan-2-ol, and oct-1-yn-3-ol are partially resolved by crystallization of clathrates with 1c and 1d.

Notes: Reactions of monosubstituted alkenes RCH = CH2 and [Re(η5-C5H5)(CH2Cl2) (NO)(PPh3)]+BF4- give complexes ([Re(η5-C5H5))(CH2=CHR)(NO) (PPh3)]+BF4- (1a-g) in 63-99% yields as mixtures of (RS,SR)- and (RR,SS)-diastereoisomers (1a (R = Me), 66:34; 1b (R = Pr), 63:37; 1c (R = PhCH2), 70:30; 1d (R = Ph), 75:25; 1e (R = i-Pr), 64:36; 1f (R = t-Bu), 84:16; 1g (R = Me3Si), 69:31; Scheme 2). These differ in the C=C enantioface bound to the chiral Re fragment. In most cases, the analogous reactions of RCH=CH2 and [Re(η5-C5H5) (C6H5Cl)(NO)(PPh3)]+ BF4+ give comparable results. When 1a-e, g are heated in PhCl at 95-100°, equilibration to 96:4, 97:3, 97:3, 90:10, 〉 99:〈 1, and 〉 99:〈 1 (RS,SR)/(RR,SS) mixtures occurs (79-99% recoveries; Tables 1 and 2). Thus, thermodynamic enantioface-binding selectivities are much higher than kinetic binding selectivities. This phenomenon is analyzed in detail. A crystal structure of (RS,SR)-1e (monoclinic, P21/c, a = 10.256(1) Å. b = 17.191(1) Å, c = 16.191(1) Å, β = 101.04(1)°, Z = 4) shows that the Re-C(1)-C(2) plane (see Fig.2) is nearly coincident with the Re-P bond (angle 15°), and that the i-Pr group is ‘syn’ to the nitrosyl ligand.

Notes: A synthetically useful C—C bond formation involving the photochemical addition of quinoxaline-2(1H)-thiones to alkenes is described. Irradiation of the quinoxaline-2(1H)-thiones 1-4 in the presence of the alkenes 7 gave the 2-(2′-mercaptoalkyl)quinoxalines 8-11 in moderate-to-good yields via ring cleavage of an intermediate aminothietane with aromatization of the quinoxaline ring. The latter was formed by [2+2] photocycloaddition of the C=S bond of the quinoxaline-2(1H)-thione and the C=C bond of the alkene.

Notes: Perylene quinone compounds of natural and syntheitc origin have been investigated for their quantum efficiency of singlet-oxygen production (ΦΔ). The results may be interpreted by a qualitative relation between ΦΔ and the planarity of the sensitizer molecules, highest values (0.8-0.9) being observed where planarity is favoring tautomeric structures. On the other hand, derivatives exhibiting non-planar quinoid structures show lower ΦΔ, and methylated derivatives react photochemically.

Notes: Multi-O4-phospho-L-tyrosine-containing peptides can be synthesized by the global as well as the buildingblock approach. Thus, we prepared by both strategies the triphosphorylated and the three regioisomeric diphosphorylated insulin-receptor-(1142-1153)-dodecapeptide derivatives 7 and 4-6, respectively, of the parent Thr-Arg-Asp-Ile-Tyr-Glu-Thr-Asp-Tyr-Tyr-Arg-Lys (3). These phosphorylated peptides are valuable tools to study the regioselectivity of dephosphorylation by phosphatases.

Notes: Michael addition of N-nitroacetyl derivatives 1 of proline esters using KF under phase-transfer catalysis resulted in the formation of adducts 3-9 with chemical yields ranging from 40-90% (Scheme). Stereoselectivity of up to 51% was obtained on addition of benzyl N-(nitroacetyl)-L-prolinate (1a). The absolute configuration at the newly created chiral centre was established in the case of 9 by carrying out a reductive acylation and comparing the product 10 with an authentic sample of ethyl N-(O5-ethyl N2-acetyl-L-glutam-1-yl)-L-prolinate (L, L-10).

Notes: By unambiguous methods, (Z)- and (E)-2, 3-dimethyl(1, 1, 1, 4, 4, 4-2H6)but-2-enes (3) were synthesized and transformed to the epoxides 4 with 3-chloroperbenzoic acids. Both the isotopomeric olefins and the epoxides are detected separately by 1H-NMR at 400 MHz. Epoxidation of (Z)-3 with [RhICl(PPh3)3]/cumene hydroperoxide resulted in a 1: 1 mixture of (Z)- and (E)-4, while reaction of (Z)-3 with [FeIII(tpp)]Cl/PhIO gave only (Z)-4 (tpp = tetraphenylporphyrin).

Notes: A regio- and stereoselective didehydrodimerization procedure, whose key step involves the anodic oxidation, allows the conversion of β-anilinoacrylic alkaloids belonging to the Aspidosperma class, typified by tabersonine (1) and its 3-oxo derivative 2, into the hitherto unknown 16,10′-didehydro dimers 3 and 7, respectively.

Notes: Synthesis of (6R, all-E)-Neoxanthin and Related Allenic CarotenoidsWe present the first synthesis of enantiomerically pure neoxanthin (1) by a Wittig-Horner condensation between the ylide from the novel diethyl 12′-apo-15, 15′-didehydroviolaxanthin-12′-phosphonate (35) and the allenic C15-aldehyde 31 (Scheme 4) via the crystalline 15, 15′-didehydroneoxanthin (36; 70% yield). After partial hydrogenation of the triple bond of 36 and isomerisation of the (15Z)-intermediate 37, neoxanthin (1) was obtained in good yield. Similar syntheses gave (15Z, 9′Z)-neoxanthin (45; Scheme 5) and (9Z)-15, 15′-didehydroneoxanthin (47; Scheme 6). Comparison of the physical data of synthetic 1 with those of a freshly isolated sample of neoxanthin from the flowers of Trollius europaeus confirmed their identity. The unusually low melting point of 1 is caused by a very easy thermal isomerisation into a mixture of the neochromes 4 and 5 (Scheme 1). Such a thermal rearrangement is not observed with 15, 15′-didehydroneoxanthin (36). To explain this, we assume a zwitterionic excited state of the allenic group that induces the rearrangement of the violaxanthin end group into the furanoid epoxide (Scheme 7).

Notes: Three new saponins, alatoside A-C (4a, 5, and 6a, resp.), with a 18,19-secours-12-ene skeleton were isolated from the aerial parts of Sesamum alatum THONN. (Pedaliaceae) by preparative liquid chromatography. Their structures were elucidated by spectroscopic methods, including X-ray diffraction analysis, and by chemical degradation (acidic and enzymatic hydrolyses). In addition, verbascoside (1) and two cyclohexylethanol derivatives, rengyol (2a) and isorengyol (3a), were isolated and identified.

Notes: The 1D- and 2D-6Li, 6Li-INADEQUATE experiments are described as new tools for the detection of scalar coupled nonequivalent 6Li nuclei in organolithium clusters. Practical applications of these sequences are demonstrated for the 6Li-NMR spectra of (E)-1-lithio-2-(2-lithiophenyl)-1-phenylhex-1-ene (1) and (E)-2-lithio-1-(2-lithiophenyl)-1-phenylpent-1-ene (2), where signals due to dimers and monomers can be distinguished. The performance of the 2D-6Li, 6Li-INADEQUATE and the 6Li, 6Li-COSY-45-LR experiment are compared. The 6Li chemical shifts of 1 and 2 are discussed.

Notes: [2.2] Paracyclophan-1-ene (1) and [2.2] paracyclophane-1,9-diene (6) apparently act as dienophiles with inverse electron demand and smoothly react with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (2a) at room temperature forming dihydropyridazine adducts, which are dehydrogenated to the pyridazino-anellated [2.2] paracyclophanes 5a and 8a, respectively. The molecular structure of 5a is determined by X-ray crystal-structure analysis. Under more rigorous conditions, phenyl-substituted derivatives 5b and 8b are obtained from 1 and 6, respectively, with 3,6-diphenyl-1,2,4,5-tetrazine. Compounds 1 and 6 are less reactive dienophiles than other strained cyclic olefins as shown by kinetic measurements.

Notes: Tris(trimethylsilyl)silane (2) is an efficient hydrosilylating agent of 1,6-dienes 1 operating via a free-radical chain mechanism. The intermediate alkyl radical 3 attacks the second olefinic bond of the diene 1 and forms cyclopentylalkyl radical 4. Using a low concentration of the hydrogen donor 2, a radical substitution reaction at the Si-center of cis-4 occurs and yields the bicyclic silane 6. The rate of this homolytic substitution at the Si-atom is 2.4 · 105 s-1 (80°).

Notes: (R)- and (S)-α-ionone ((R)- and (S)-1, resp.) were prepared from (R)- and (S)-α-damascone ((R)- and (S)-3, resp.) without racemization in 48% yield employing a new enone transposition. The described transposition is complementary to existing methods whose application is often prohibited by the structural requirements of the substrate. The now easily accessible α-ionones of desired absolute configuration are useful as chiral building blocks for terpenoid synthesis.

Notes: Catalytic double osmylation is described for a series of cyclohexadienes in acetone/H2O in the presence of the co-oxidant N-methylmorpholine N-oxide (NMO). The formation of polyols occurred stereospecifically with cyclohexadienes 3,7, and 11a, leading thereby to tetrols 5a, and 9a and to allo-inositol (14a), respectively. To the contrary, trans-cyclohexadiene-diol 15a gave a mixture of the stereoisomeric inositols 18a (epi), 19a (neo), and 20a (chiro). High-field NMR let to clearcut conformational analyses of the polyhydroxylated derivatives.

Notes: Esculetin (1) and the novel compounds 5-chloroesculetin (5) and 5-bromoesculetin (6) were obtained from a light-induced cyclization of trans-caffeic acid (3) catalyzed by [FeNa(edta)] and/or H2SO4, HCI, or HBr (Scheme 1). The experimental conditions for trans-cis-isomerization of the cinnamic-acid derivative 3 and subsequent non-enzymatic cyclization were described. The photoperiod and the presence of air and iron-chelate catalyst are shown to be important parameters that markedly affect yields. The reactions probably occur by a free-radical mechanism involving a photo-initiated one-electron redox process (Scheme 2).

Notes: The protected disaccharide 44, a precursor for the synthesis of allosamidin, was prepared from the glycosyl acceptor 8 and the donors 26-28, best yields being obtained with the trichloroacetimidate 28 (Scheme 6). Glycosidation of 8 or of 32 by the triacetylated, less reactive donors 38-40 gave the disaccharides 46 and 45, respectively, in lower yields (Scheme 7). Regioselective glycosidation of the diol 35 by the donors 38-40 gave 42, the axial, intramolecularly H-bonded OH—C(3) group reacting exclusively (Scheme 5). The glycosyl acceptor 8 was prepared from 9 by reductive opening of the dioxolane ring (Scheme 3). The donors 26-28 were prepared from the same precursor 9 via the hemiacetal 25. To obtain 9, the known 10 was de-N-acetylated (→ 18), treated with phthalic anhydride (→ 19), and benzylated, leading to 9 and 23 (Schemes 2 and 3). Saponification of 23, followed by acetylation also gave 9. Depending upon the conditions, acetylation of 19 yielded a mixture of 20 and 21 or exclusively 20. Deacetylation of 20 led to the hydroxyphthalamide 22. De-N-acetylation of the 3-O-benzylated β-D-glycosides 11 and 15, which were both obtained from 10, was very sluggish and accompanied by partial reduction of the O-allyl to an O-propyl group (Scheme 2). The β-D-glycoside 30 behaved very similarly to 11 and 15. Reductive ring opening of 31, derived from 29, yielded the 3-O-acetylated acceptor 32, while the analogous reaction of the β-D-anomer 20 was accompanied by a rapid 3-O→4-O acyl migration (→34; Scheme 4). Reductive ring opening of 21 gave the diol 35. The triacetylated donors 38-40 were obtained from 20 by debenzylidenation, acetylation (→36), and deallylation (→37), followed by either acetylation (→38), treatment with Me3SiSEt (→39), or Cl3CCN (→ 40).

Notes: Bare FeO+ reacts in the gas phase with benzene at collision rate (k = 1.3 × 10-9 cm3 molecule-1 s-1), giving rise to the formation of Fe(C6H4)+/H2O(5%), Fe(C5H6)+/CO(37%), Fe(C5H5)+/CO/H. (2%), and Fe+/C6H5OH (56%). Neither the reaction rate nor the product distribution are subject to a significant kinetic isotope effect, thus, ruling out several mechanistic variants described in the literature to the operative for ‘analogous’ arene oxidation processes in solution. A mechanism is suggested which is in keeping with the experimental findings, and which also accounts for some remarkable results obtained, when two [Fe, C6,H6H6O]+ isomers are generated and subjected to a neutralization-re-ionization experiment in the gas phase.

Notes: Quinic acid (1a), shikimic acid (2), and their derivatives were acylated in organic solvents by several lipases and by the protease subtilisin Carlsberg. The most satisfactory results were obtained with methyl (or benzyl) quinate (7a (or 8a)) and lipase from Chromobacterium viscosum adsorbed on Celite, which showed an overshelming preference towards the acylation of OH-C(4). Under optimized conditions, the syntehtically useful 4-O -acetylquinate 8d was isolated in ca. 90% yield. On the other hand, acylation of methyl shikimate (10a) showed no regioselectivity with any of the enzymes tested. A possible rationale for the different behavior of Chromobacterium viscosum lipase towards 7a and 10a is given, comparing the conformations of these two molecules, as deducted from 1H-NMR and molecular-mechanics calculation.

Notes: A general synthetic strategy for the preparation of polyazamacrocycles containing long aliphatic chains is reported. These compounds are 22- or 24-membered hexaazamacrocycles incorporating two diethylenetriamine subunits (H2NCH2CH2NHCH2CH2NH2) linked together either by two CH2CH2OCH2CH2 (see 4-6), two tetramethylene (see 7), or two pentamethylene (see 8) fragments. Whereas for compound 4, one of the centrally located amine functionalities of the triamine subunit bears a hexadecyl chain, for compound 5, two of such chains are centrally attached to both subunits. In macrocycles 6-8, all six amino functionalities bear hexadecyl chains. Compounds 4-8 are potential candidates for the construction of selective chemical sensors such as specific electrodes for adenosine mono-, di-, and tri-phosphate. They may also be used for nucleoside polyphosphates extraction and/or transport.

Notes: The absolute configuration of the gamete-releasing and -attracting pheromone 2-vinyl-3-(5′-vinylcyclopent-2′-enyl)oxirane ( =(+)-caudoxirene; (+)-1) of the marine brown alga Perithalia caudata is established as (2R,3R,1′S,5′S). Highly diastereoselective syntheses and the biological activities of three diastereoisomers of 1 are described. Compound (+)-(2R,3R,1′S,5′S)-1 is the first fully characterized epoxypheromone from marine brown algae (Phaeophyceae).

Notes: A new series of channel-type molecules presenting the features of potential transmembrane structures is described. They result from the grafting of amphiphilic side chains on a β-cyclodextrin derivative 3 that constitutes the organizing core. They belong to the ‘bouquet’ family (B). Compounds bearing poly(oxyethylene) side chains, BCDo16 and 17, and their polymethylene analogues BCDC18 and 19, were synthesized. The properties investigated emphasize the suitability of such molecules to be incorporated into lipid bilayer membranes.

Notes: Reactions of 4-Bromo-1,6-methano[10]annulene-3-carbaldehyde: Syntheses of 3,4-Heteroanellated 1,6-Methano[10]annulenesSimilarly to β-chlorovinyl ketones, the title compound 1 reacts with dinucleophiles to give the 3,4-heteroanellated 1,6-methano[10]annulenes 2-4, 6, and 12-16, containing thiophene, pyrazole, pyrimidine, and thiazepine rings (Schemes 2 and 3). On reaction of 1 with tert-butylhydrazin, an unusual Michael-addition-dehydrogenation sequence, resulting in 2,3-anellation of a pyrazole ring (→5), is observed. Synthetic as well as some mechanistic aspects are briefly discussed.

Notes: The exchange of butane with deuterium on a nickel/alumina catalyst is studied over a wide range of temperatures (50-230°) and for three hydrocarbon/deuterium ratios. The initial distribution is used to propose a reaction scheme by considering different adsorbed species such as: alkyl-(α), alkene-(α, β) and allyl-(α,β,γ) species, where α, β, and γ are different C-atoms. It is assumed that each adsorbed species can either desorb directly while exchanging one, two, and three H-atoms or undergo multiple exchange before desorption. It is shown that by reducing the activity of the catalyst a back-exchange of the fully deuterated species sets in a lower temperature; a systematic deviation of all model calculations for the estimation of the concentrations of the C4HD9 and C4D10 is, thus, explained. The exchange of CH3CD2CD2CH3 and CD3CH2CH2CD3 with H2 and D2 is also studied, and similar results are obtained as with exchanges of CH3CD2CH3 and CD3CH2CD3. With the help of very-high-resolution mass spectra, it is shown that the initial degree of deuteration, i. e. the degree of deuteration after one adsorption step, is 84% for the methylene and 57% for the methyl group respectively. The hydrogenolysis reactions of butane is studied in the same system between 180° and 230°. A wide range of conversion is covered, and the product distributions are fitted to kinetic equations in order to obtain the initial rate constants. On the nickel/alumina catalyst one or several C-C bonds are broken before the desorption of the species. Under the conditions used in these experiments, the surface cracking is the rate-limiting step. An isotope effect is observed for the decomposition in D2, the production of propane being favored.

Notes: The title compund, 1a, has been synthesised in racemic form from ethyl (E)-4-chloro-3-ethoxybut-2-enoate in 43% overall yield in five steps. Several routes to the final product are described, but the most efficient involves hydrogenation of a C(5)-unsubstituted tetramic acid 5b. The instability of this class of compounds required the use of a catalyst which could operate under very acidic aqueous conditions, a role that was successfully filled by a 5% Ru/C catalyst.

Notes: Synthesis of 2-Substituted and 2,3-Disubstituted Alkyl- und Aryl-thiophenes and Related 2,3-Anellated Thiophene Derivatives, Using Ketones and Carbonodithioic Acid O-Ethyl S-(2-Oxoethyl) Ester as the Building BlocksA simple method to synthesize 2-substituted and 2,3-disubstituted alkyl- and aryl-thiophenes as well as related 2,3-anellated thiophenes 6, starting from ketones 1 as C2-fragment and the S-protected carbonodithionic-acid derivative 3 as a C2S-fragment is described. The aldols 4 are intermediates of the two step process.

Notes: A set of derivatives of cyclopentaneacetic acid cis-substituted at position 3 by nucleoside bases (both purines and pyrimidines) were prepared and characterized (see 11, 14, and 23a, b; Schemes 2-4). These molecules are carbocyclic analogs of 2′,3′-dideoxy-5′-homonucleosides. In this synthesis, the skeleton was constructed from norbornanone and a novel method based on Mitsunobu chemistry used for the introduction of nucleoside-base substituents. The scope of this method was further explored via the preparation of a cyclobutyl analog of dideoxyguanosine (see 17, Scheme 3).

Notes: α-Chamigren-3-one (+)-8 bearing an axial CI-atom at C(8) exists as a largely dominant conformer with Me - C(5) at the envelope-shaped enone ring pointing away from CIax-C(8) at the cyclohexane ring (= B) in the ‘normal’ chair conformation, as shown by 1H-NMR. In contrast, the α-chamigren-3-ols (+)-9 and (+)-10, obtained from hydride reduction of (+)-8, show a temperature-dependent equilibrium of conformers where the major conformers have ring B in the inverted-chair (and twist-boat for (+)-9) conformation to avoid repulsions between Me-C(5) and CIax-C(8) (Scheme 1). This is in agreement with the conformation of the epoxidation product (+)-12 of (+)-9 where Me-C(5) is pushed away from CIax-C(8) in a ring-B chair similar to that of (+)-8 (Scheme 2). Introduction of a pseudoequatorial Br-atom at C(2) of (+)-8, as in enone (+)-15 (Scheme 3), does not affect the conformation; but a pseudoaxial Br—C(2) experiences repulsive interactions with Heq-C(7), as shown by the 1H-NMR data of the isomeric enone (+)-16 where the ‘normal’-chair conformer Cβ-16 is in an equilibrium with the inverted chair conformer ICβ-16 (Scheme 3). These results and the accompanying paper allow a unifying view on the conformational behavior of marine polyhalogenated α-chamigrenes. This view is supported by the acid-induced isomerization of α-chamigrene (+)-9 (inverted chair) to β-chamigrene (+)-17 (‘normal’ chair; Scheme 4), the driving force being the lesser space requirement of CH2=C(5) than of Me-C(5). This explains why β-chamigrenes are so common in nature.

Notes: The tris-carotenoid macrobicycles 1 and 2 were obtained in good yields in a one-step macrobicyclisation condensation between the tripode N(CH2CH2NH2)3 and the polyolefinic dialdehydes 5 and 6. They form dinuclear cryptates by complexation of two CuI ions. The crystal structure of the tris-carotenoid compound 2 confirms that it contains three parallel polyolefinic strands. These substances may formally be considered as prototypes of molecular ‘cables’ formed by three electron-conducting molecular wires.

Notes: Coprine (1), a toxine of the mushroom Coprinus atramentarius, was synthesized starting from the 2-amino and 1-carboxy-protected L-glutamic acids 4 and 12. Compound 4 was first decarboxylated by a radical chain reaction to bromide 5 which underwent ring closure to cyclopropanecarboxylate 6 on treatment with NaH (Scheme 1). Subsequent oxidative electrolysis of 7 to form tert-butyl N-(1-ethoxycyclopropyl)carbamate (8) and acidic hydrolysis yielded the 1-aminocyclopropanol hydrochloride (9). Selective cleavage of the amino-protecting group of 8 (→ 10 or 11), coupling of the corresponding amine 13 with L-glutamic acid 12, and acidic hydrolysis of the resulting L-glutamine derivative 17 yielded O-ethylcoprine (3) and coprine (1).

Notes: The 1,7-dideaza-2′-deoxyadenosine (c1c7Ad; 1) was converted into building blocks 3a,b for solid-phase oligodeoxyribonucleotide synthesis. Testing various N-protecting groups - benzoyl, phenoxyacetyl, [(fluoren-9-yl)methoxy]carbonyl, and (dimethylamino)methylidene - only the latter two were found to be suitable (1 → 4b, d). Ensuing 4,4′-dimethoxytritylation of 4d and phosphitylation afforded the 3′-phosphonate 3a or the 3′-[(2-cyanoethyl)diisopropylphosphoramidite] 3b. Self-complementary oligonucleotides with alternating dA or c1c7Ad and dT residues (7 and 8) as well as palindromic oligomers such as d(C-G-C-G-c1c7 A-c1c7 A-T-T-C-G-C-G) (10) and d(G-T-A-G-c1c7 A-c1c7 A-T-T-C-T-A-C) (12) were synthesized. Duplex stability was decreased because 1 cannot form Watson-Crick or Hoogsteen base pairs if incorporated into oligonucleotides. On the other hand, the structural modifications in 10 and 12 forced these palindromic oligomers to form hairpin structures.

Notes: Synthesis and Photochrmic Characteristics of 1,3-Dihydrospiro[2H-indole-2,3′-[3H-]pyrimido[5,4-f][1,4]benzoxazines] and 1,3-Dihydrospiro[2H-indole-2,7′[7H]thiazolo[5,4-f][1,4]benzoxazines]Two new series of 1,3-dihydrospiro[2H-indole-ozazine] derivatives were synthesized, the 1,3-dihydrospiro[2H-indole-2,3′-[3H]pyrimido[5,4]pyrimido[5,4-f][1,4]benzoxaines] 4-10 and the 1,3-dihydrospiro[2H-indole2,7′-[7H]thiazolo-[5,4-f][1,4]benzoxaines] 11-17. These series extend the available range of photochromic properties (rate constant of thermal bleaching, UV/VIS spectrum of the opened coloured form, and photocoloration yield), an interesting feature of variable-transmission materials. The synthesis of these compounds (Scheme 1) required the preliminary synthesis of intermediate β-hydroxy-α-nitrosotherocycles 18 and 19 (Scheme 2). Important amounts of a coloured, non-photochromic, stable secondary product (See 20) were found in the condensation in the spiro[indole-thiazolobenzoxazine] series. The photochromic characteristics of the new derivatives were determined using a flash-photolysis apparatus coupled to a fast-scanning spectrometer. The role of the heteroatoms in the oxazine moiety and the role of substitutents in the indole moiety were investigated quantitatively through the study of the photochromic properties and the solvent effects. The presence of an S-atom gives rise to interesting properties which open up new prospects for synthesis and application.

Notes: The titanates derived from α,α,α′,α′-tetraaryl-1,3-dioxolane-4,5-dimethanols (TADDOLs, prepared from tartrate) act as catalysts for enantioselective additions of dialkylzinc compounds to aldehydes. For the standard reaction chosen for this investigation of the mechanism, the addition of diethylzinc to benzaldehyde, there is very little change of selectivity with different aryl substituents on the TADDOLate ligands (Tables 2-4, examples). With 0.02 to 0.2 equiv. of the chiral titanates, selectivities above 90% are observed only in the presence of excess tetraisopropyl titanate! According to NMR measurements (Fig. 2), the chiral bicyclic titanate and the achiral titanate do not react to give new species under these conditions. From experiments with different stoichiometries of the components, and with different achiral or chiral OR groups on the Ti-atom of the seven-membered ring titanate, it is concluded (i) that a single chiral titanate is involved in the product-forming step, (ii) that the bulky TADDOLate ligand renders the Ti-center catalytically more active than that of (i-PrO)4Ti, due to fast dynamics of ligand exchange on the sterically hindered Ti-center (Table 5, Fig. 3), and (iii) that the role of excess (i-PrO)4Ti is to remove - by ligand exchange - the product alkoxides (R*O) from the catalytically active Ti-center (Scheme 4, Table 6). Three new crystal structures of TADDOL derivatives (two clathrates with secondary amines, and a dimethyl ether) have been determined by X-ray diffraction (Figs. 5-7), and are compared with those previously reported. The distances between the C(aryl)2O oxygen atoms in the C2- and C1-symmetrical structures vary from 2.58 to 2.94 Å, depending upon the conformation of their dioxolane rings and the presence or absence of an intramolecular H-bond (Fig. 8). A single-crystal X-ray structure of a spiro-titanate, with two TADDOLate ligands on the Ti-atom, is described (Fig. 9); it contains six different seven-membered titanate-ring conformations in the asymmetric unit (Fig. 10), which suggests a highly flexible solution structure. The structures of Ti TADDOLate complexes are compared with those of C2-symmetrical Ru, Rh, and Pd disphosphine chelates (Table 7). A common topological model is presented for all nucleophilic additions to aldehydes involving Ti TADDOLates (Si attack with (R,R)-derivatives, relative topicity unlike; Fig. 11). Possible structures of complexes containing bidentate substrates for Ti TADDOLate-mediated ene reactions and cycloadditions are proposed (Fig. 12). A simple six-membered ring chair-type arrangement of the atoms involved can be used to describe the result of TADDOLate-mediated nucleophilic additions to aldehydes and ketones, with Ti, Zr, Mg, or Al bearing the chiral ligand (Scheme 6). A proposal is also made for the geometry of the intermediate responsible for enantioselective hydrogenation of N-(acetylamino)cinnamate catalyzed by Rh complexes containing C2-symmetrical diphosphines (Fig. 13).

Notes: A new base pair (called κ-π) of Watson-Crick type, with an H-bond pattern different from that in A-T and G-C base pairs, has been recently synthesized by Benner and coworkers and shown to be stable and incorporable into duplex DNA and RNA by polymerases. This new base pair, which contains three H-bonds, is compared with G-C, in the framework of modern dynamical theory of quantum nonlocality and quantum correlations (also called Einstein-Podolsky-Rosen correlations). Connection with the traditional treatment of proton transfer in DNA base pairs, which uses the adiabatic approximation (thus considering the protons as classical particles), is explicitly made. As a result, the dynamics of the H-bond pattern of G-C is shown to exhibit a specific quantum-mechanical phase stability (or: rigidity, stiffness), which is clearly missing in the case of κ-π. This finding is discussed and illustrated, also in connection with recent quantum chemical calculations of proton transfers in DNA base pairs. Additionally, certain speculations concerning a probable ‘evolutionary advantage’ of G-C with respect to κ-π are shortly considered.

Notes: The leaves of a New Caledonian celastraceae, Pleurostylia opposita (WALL.) MERRILL-METCALF, have yielded three new spermidine alkaloids, 7-hydroxypleurostyline (1), 7-hydroxycelacinnine (2), and 7′-hydroxy-7′,8′-dihydropleurostyline (3), as minor basic constituents, together with three related alkaloids pleurostyline (4), celacinnine (5), and celallocinine (6).

Notes: 6-Thioxanthopterin (13) was synthesized in four steps starting from 2-amino-4-(penthyloxy)pteridine (3) via the 8-oxide 4, its subsequent interconversion to the 6-chloro (7) and 6-thio derivative (12) and final hydrolysis of the pentyloxy group. 7-Thioisoxanthopterin (15) was derived analogously from 2-amino-4-(pentyloxy)pteridine-7(8H)-thione (14) by alkaline hydrolysis. The various 6- and 7-thiopteridines were methylated to give the corresponding 6- (10, 11) and 7-(methylthio) derivatives (16, 17). The newly synthesized compounds have been characterized by elemental analyses, their UV spectra, and the determination of the acidic and basic pKa values. The spectral relationships are discussed in detail.

Notes: The syntheses and characterization of four new linear pentadentate ligands and their CoIII complexes are described: N,N′-[(pyridine-2,6-diy)bis(methylene)]bis[sarcosine] (sarmp), N,N′-[(pyridine-2,6-diyl)bis(methylene)]bis[(R)- or (S)-proline] ((R,R)- or (S,S)-promp), N,N′-[(pyridine-2,6-diyl)bis(methylene)]bis[N-(methyl)-(R)- or (S)-alanine] ((R,R)- or (S,S)-malmp); 2,2′-[pyridine-2,6-diyl]bis[(S)- or rac-N-(acetic acid)pyrrolidine] ((S,S)- or rac-bapap). The complexes were characterized and, with but one exception, complex formation is stereospecific: Δ-exo-(R,R) (or Λ-exo-(S,S)) for promp and Λ-(R,R) (or Δ-(S,S)) for bapap. The exception is [Co((R,R)- or (S,S)-malmp)H2O]ClO4 for which two forms are obtained, to which Λ-endo-(R,R) (or Δ-endo-(S,S)) and, tentatively, Δ-unsymmetric-(R,R)- (or Λ-unsymmetric-(S,S)-) configurations are assigned. X-Ray crystal structures are presented for the complexes [Co(sarmp)H2O]ClO4, [Co((S,S)-promp)H2O]ClO4, [Co(rac-bapap)H2O]ClO4 and endo-[Co(rac-malmp)H2O]ClO4. Ligand acid dissociation and CoII and FeII complex-formation constants are reported.

Notes: The molecular structures of the title compounds 3 and 5 were investigated by NMR and X-ray structural methods. The NMR results suggest two equivalent halves for both molecules. The X-ray study shows an approximate mirror plane for 3 and an approximate twofold axis for a significant portion of the macrocycle of 5.

Notes: In two steps, 5,5-dimethyl-1H-pyrrol-2(5H)-one (3a) was prepared from 5,5-dimethylpyrrolidine-2,4-dione ( = dimethyltetramic acid; 4) in 71% overall yield (Scheme 1) and further converted to N-substituted derivatives 3b-f via acylation, alkylation, or methoxycarbonylation of its anion (Scheme 2). The substituents on the N-atom exert a strong influence on the photochemical reactivity ([2 + 2] photocycloaddition to 2,3-dimethylbut-2-ene, photocyclodimerisation, photoreduction) of these aza-enones 3 (Scheme 3). In general, N-alkyl compounds react much slower and with less efficiency than either the (N-unsubstituted) title compound 3a or its N-acetyl and N-(methoxycarbonyl) derivatives 3e and 3f, respectively. These compounds behave similarly to the corresponding lactone, 5,5-dimethyl-2(5H)-furanone, studied previously.

Notes: Mechanistic questions regarding the reductive cleavage of sulfonium ions by the NiI form of coenzyme F430 pentamethyl ester (F430M) were addressed in a series of kinetic studies and isotope labeling experiments. In neat DMF, methane formation from dialkyl(methyl)sulfonium ions consistently showed a delay time of ca. 1 h. In the presence of excess propanethiol, no delay was observed and methane formation followed pseudo-first-order kinetics with a logarithmic dependence of the initial rate on the concentration of propanethiol. From the temperature dependence of the reaction rate, an estimate for the activation parameters of ΔH# = 49 kJ mol-1 and (apparent) ΔS# = -114 J K-1 mol-1 was derived. The observation of deuterium incorporation into methane from (CH3)2CHOD, but not from (CH3)2CDOH, indicates that the fourth H-entity is introduced into CH4 as a proton, and that free CH3 radicals are not involved. In contrast to the reaction with the homogeneous one-electron reductant sodium naphthalide, the F430M-catalyzed reduction of mixed dialkyl(methyl)sulfonium ions showed a pronounced selectivity for the cleavage of Me—S over that of alkyl-S (alkyl ≠ Me) bonds. Mechanisms that are consistent with these results, as well as possible explanations for the time delay and the apparent highly negative entropy of activation, are discussed.

Notes: Why Pentose and Not Hexose Nucleic Acids? Part II . Preparation of Oligonucleotides Containing 2′,3′-Dideoxy-β-D-glucopyranosyl Building Blocks(7)This paper describes the preparation of the 2′,3′-dideoxy-β-D-glucopyranosyl-( = 2′,3′-dideoxy-β-D-erythro-hexopyranosyl)-derived nucleosides of the five bases adenine, cytosine, guanine, thymine, and uracil ( = ‘homo-de-oxyribonucleosides’) as well as the synthesis of oligonucleotides derived from them. The methods used for both nucleoside and oligonucleotide synthesis closely follow the known methods of synthesis in the corresponding series of natural 2′-deoxyribonucleosides and oligonucleotides. The efficient methods of automated DNA synthesis proved to be fully applicable to the synthesis of homo-DNA oligonucleotides, the only change necessary for achieving satisfactory coupling yields being a slight lengthening of the coupling time. Homo-DNA oligonucleotides with chain lengths of up to twelve nucleoside units were assembled on solid support either manually or on a commercial DNA synthesizer in scales of 0.4 μmol to as much as 200 μmol and were purified by either reversed-phase or ion-exchange HPLC to single-peak purity according to both chromatographic systems (estimated purity 〉 95%). The choice of the specific base sequences to be synthesized was determined primarily by the constitutional problems of base pairing that emerged from experimental observations made in the course of systematic studies of the pairing properties of homo-DNA oligonucleotides. About 100 homo-DNA sequences were prepared for this purpose. Their pairing properties will be described in Part III of this series; the present paper is restricted to the characterization of the purity and constitutional integrity of a few selected (single-stranded) oligonucleotides by 1H-, 31P-, and 13C-NMR spectroscopy as well as by FAB and time-of-flight mass spectroscopy.The English Footnotes to Schemes 1-9, Fig. 1-12, and Table 1 provide an extension of this summary.

Notes: The copper-catalyzed oxidation of ascorbic acid (AscH2) has been studied with a Clark electrode in aqueous MeCN. CuI or CuII may be equally used as the source of metal ion, without influence on the rate law. At sufficiently high [MeCN], the rate of the overall reaction is essentially given by the rate of CuI autoxidation: the reaction is of first order with respect to [CutotI,II] and [O2] and shows an inverse-square dependence on [MeCN] as observed for the autoxidation of Cuaq+. The pH dependence is complicated by the combination of the intrinsic pH effect on autoxidation with an additional term in the rate law which is directly proportional to [AscH-]. The latter term is explained by direct oxidation of the organic substrate by the primary dioxygen adduct of CuI, CuO2+. For [MeCN] 〈 0.7M, a gradual and pH-dependent transformation of this rate law and deviation from the first-order dependence on [O2] is indicated.

Notes: The fate of tetrahydrolipstatin (1) incubated with human carboxyl-ester lipase (HCEL) was investigated. The primary metabolite was identified as δ-(N-formyl-L-leucyloxy)-β-hydroxy acid 2a with conserved configuration. It is formed by attack of the active-site serine of HCEL at the carbonyl C-atom of the β-lactone ring of 1 followed by hydrolysis of the intermediate serine ester. Further products isolated were identified and a complete degradation scheme is proposed.

Notes: ESR and cyclic voltammetry investigations show that isomerization of the radical cation of cis-1,1′-azonorbornane (cis-1) to the trans-radical ion proceeds too fast in solution for direct investigation of the cis-radical ion even at -78°. The facile isomerization of the radical cation is in agreement with PM3 calculations proposing an activation barrier of only 17 kJ/mol. As a consequence, quantitative cis → trans isomerization of 1,1′-azonorbornane can effectively be accomplished by addition of catalytic amounts of one-electron oxidants. This is the first evidence for a radical-cation-catalyzed cis → trans isomerization of azo compounds.

Notes: Irradiation (λ = 350 nm) of newly synthesized 2-acetyl- or 2-methyl-2-(alk-2-enyl)furan-3(2H)-ones 1 and 2-acetyl- or 2-methyl-2-(prop-2-enyl)thiophen-3(2H)-ones 2 affords the corresponding 1-acetyl- or 1-methyl-substituted 7-oxa- and 7-thiatricyclo[3.2.1.03,6]octan-2-ones 10 and 11, respectively, via regioselective intramolecular [2 + 2] photocycloaddition in 65-95% yield (Scheme 2). The 1-acetyl-substituted O-derivatives 10b and 10c undergo ring opening on treatment with MeONa in MeOH at-78° to afford stereoselectively methyl 3-exo-acetyl-2-oxabicyclo[3.2.0]heptane-7-endo-carboxylates 12b and 12c, respectively, while a 2:1 diastereoisomeric mixture of methyl 3-acetyl-2-thiabicyclo[3.2.0]heptane-7-endo-carboxylates 13 and 14 is obtained from the corresponding S-derivative 11b. The outcome of the Huang-Minlon reduction of the 1-methyl-substituted ketones 10a and 11a is again influenced by the heteroatom in the tricycle. While 1-methyl-7-oxatricyclo[3.2.1.03,6]-octane (15) is the only product from the corresponding oxatricyclooctanone 10a, a 1:2 mixture of 1-methyl-7-thiatricyclo[3.2.1.03,6]-octane (16) and 3-methylbicyclo[3.1.1]hept-2-ene-6-endo-thiol (17) is obtained from the analogous S-compound 11a, both products stemming from a common carbanion precursor.

Notes: The reaction of highly alkylated azulenes with dimethyl acetylenedicarboxylate (ADM) in decalin or tetralin at 180-200° yields, beside the expected heptalene- and azulene-1,2-dicarboxylates, tetracyclic compounds of type ‘anti’-V and tricyclic compounds of type E (cf. Schemes 2-4 and 8-11). The compounds of type ‘anti’-V represent Diels-Alder adducts of the primary tricyclic intermediates A with ADM. In some cases, the tricyclic compounds of type E also underwent a consecutive Diels-Alder reaction with ADM to yield the tetracyclic compounds of type ‘anti’- or ‘syn’-VI (cf. Schemes 2 and 8-11). The tricyclic compounds of type E, namely 4 and 8, reversibly rearrange via [1,5]-C shifts to isomeric tricyclic structures (cf. 18 and 19, respectively, in Scheme 6) already at temperatures 〉 50°. Photochemically 4 rearranges to a corresponding tetracyclic compound 20 via a di-π-methane reaction. The observed heptalene- and azulene-1,2-dicarboxylates as well as the tetracyclic compounds of type ‘anti’'-V are formed from the primary tricyclic intermediates A via rearrangement (→heptalenedicarboxylates), retro-Diels-Alder reaction (→ azulenedicarboxylates), and Diels-Alder reaction with ADM. The different reaction channels of A are dependent on the substituents. However, the main reaction channel of A is its retro-Diels-Alder reaction to the starting materials (azulene and ADM). The highly reversible Diels-Alder reaction of ADM to the five-membered ring of the azulenes is HOMO(azulene)/LUMO(ADM)-controlled, in contrast to the at 200° irreversible ADM addition to the seven-membered ring of the azulenes to yield the Diels-Alder products of type E. This competing reaction must occur on grounds of orbital-symmetry conservation under SHOMO(azulene)/LUMO(ADM) control (cf. Schemes 20-22). Several X-ray diffraction analyses of the products were performed (cf. Chapt. 4.1).

Notes: The synthesis of glycerolipids linked to hydroxamate derivatives designed for two-dimensional crystallization of aminopeptidase M is reported. The lipid moieties are readily obtained using a convergent pathway. Their structure allows the introduction of a wide variety of ligands of biological interest.

Notes: Two new enantioselective syntheses of the naphthopyranquinone antibiotic frenolicin B (1), of its enantiomer 2, and of its diastereoisomers 3 and 4 were accomplished using two different routes from optically active β-Hydroxy esters (R)- and (S)-11 and 18. β-Hydroxy esters (R)- and (S)-11 were prepared stereoselectively from optically active sulfenylacetates (S)- and (R)-10, respectively (Scheme 2, Method A). Alternatively, compound 18 was obtained in excellent yield by enantioselective hydrogenation of the corresponding β-keto ester 17, using a chiral ruthenium-complex catalyst (Scheme 3, Method B). Subsequently, compounds (S)-11 and 18 were transformed into frenolicin B (1). In analogy, Stereoisomers 2-4 were prepared from (S)- and (R)-11 in good yields.

Notes: The 2′-deoxyisoguanosine phosphonates 3a and 4a and the phosphoramidites 3b and 4b were prepared as building blocks for solid-phase oligonucleotide synthesis. The diphenylcarbamoyl (dpc) residue was introduced as 2-oxo protecting group which stabilizes the N-glycosylic bond against hydrolysis and prevents the molecule from side reactions. The dpc-protected building blocks 4a, b were employed in solid-phase synthesis and were found to be much more efficient than the unprotected compounds 3a, b. Oligonucleotides with alternating (11) or consecutive isoguanine residues (13-15) were synthesized. They form duplexes with parallel chain orientation. The aggregate d(T4-iG4-T4) (15) containing four consecutive 2′-deoxyisoguanosine is shown to be a tetramer similar to that of d(T4-G4-T4).

Notes: Khusimone (1), one of the main odor-donating compounds of vetiver oil is subject of the following study on structure/odor relationship. The omittance of the ethano bridge of the tricyclic khusimone leads to a bicyclic system. The stereoselective approach to this degraded structure is described, and the olfactory properties are studied. The key step of the synthesis of the hydrindane nucleus is based on a highly diastereoselective conjugate addition to a chiral oxo-cyclopentene-2-carboxylate.

Notes: The (2-dansylethoxy)carbonyl (= {2-{[5-(dimethylamino)naphthalen-l-yl]sulfonyl}ethoxy}carbonyl; dnseoc) group was employed for protection of the amino functions of the aglycone residues. The lactam function of 2′-deoxyguanosine was on the one hand unprotected and on the other hand alkylated at O6 of the aglycone with the 2-(4-nitrophenyl)ethyl (npe) and 2-(phenylsulfonyl)ethyl (pse) group, respectively. The syntheses of monomeric building blocks, both phosphoramidites and nucleoside- functionalized supports, are described for the three common 2′-deoxynucleosides (2′-deoxycytidine, 2′-deoxyadenosine, 2′-deoxyguanosine). As kinetic studies with the tritylated nucleosides showed, the dnseoc group is more labile towards DBU cleavage than the corresponding 2-(4-nitrophenyl)ethyl-(npe) and [2-(4-nitrophenyl)ethoxy]carbonyl(npeoc)-protected analogues (see Table 2). These results were confirmed by the very fast deprotection rate of the dnseoc groups at some oligonucleotides.

Notes: The absolute configuration of 3-methylpyrrolidine alkaloids isolated from the poison gland of ants Leptothoracini was determined as (3R). The enantiomeric separation by chiral gas chromatography and unambiguous structural assignment of the target compounds are described.

Notes: The synthesis of π-substituted heptalenecarboxylates or -dicarboxylates, starting with the easily available dimethyl 9-isopropyl-1, 6-dimethylheptalene-4, 5-dicarboxylate (2b), are described. Treatment of 2b with t-BuOK and C2Cl6 at -78° leads to the chemoselective introduction of a Cl substituent in Me-C(1) (see 5b in Scheme 1). Formation of the corresponding triphenylphosphonium salt 7b via the iodide 6b (Scheme 2) allowed a Wittig reaction with cinnamaldehyde in the two-phase system CH2Cl2/2N NaOH. Transformation of the 4, 5-dicar-boxylate of 2b into the corresponding pseudo-ester 10b allowed the selective reduction of the carbonyl function at C(4) with DIBAH to yield the corresponding 4-carbaldehyde 11b (Scheme 3). Wittig reaction of 11b with (benzyl) triphenylphosphonium bromide led to the introduction of the 4-phenylbuta-1, 3-dienyl substituent at C(4). The combination of both Wittig reactions led to the synthesis of the 1, 4-bis(4-phenylbuta-1, 3-dienyl)-substituted heptalene-5-carboxylate (all-E)-17b (Scheme 5). In a similar manner, by applying a Horner-Wadsworth-Emmons reaction, followed by the Wittig reaction, the donor-acceptor substituted heptalene-5-carboxylate (E;E)-22b was synthesized (Scheme7). Most of these new heptalenes are in solution, at room temperature, in thermal equilibrium with their double-bond shifted (DBS) isomers. In the case of (all-E)-17b and (E;E)-22b, irradiation of the thermal equilibrium mixture with light of λ -(439 ± 10) nm led to a strong preponderance ( 〉 90%) of the DBS isomers 17a and (E;E)-22a, respectively (Schemes 6 and 7). Heating of the photo-mixtures at 40° re-established quickly the thermal equilibrium mixtures. Heptalenes-carboxylates (all-E)-17a and (E;E)-22a which represent the off-state of a 1,4-conjugative switch (CS) system show typical heptalene UV/VIS spectra with a bathochromically shifted heptalene band III and comparably weak heptalene bands II and I which appear only as shoulders (Figs. 4 and 5). In contrast, the DBS isomers (all-E)-17b and (all-E)-22b, equivalent to the on-state of a 1,4-CS system, exhibit extremely intense heptalene bands I and, possibly, II which appear as a broad absorption band at 440 and 445 nm, respectively, thus indicating that the CSs (all-E)-17a⇌(all-E)-17b and (E;E)-22a⇌(E;E)-22b are perfectly working.

Notes: Configurational and Conformational Isomeric Antiaromatic [28]Tetraoxaporphyrinoids(4.2.4.2) and Aromatic [26]Tetraoxaporphyrin(4.2.4.2) Dications. A New Type of Molecular Dynamics in Macrocyclic SystemsThe [28]tetraoxaporphyrinoids(4.2.4.2) 6 are synthesized by cyclizing Wittig reaction of (E, E)-5, 5′-(buta-1, 3-diene-1, 4-diyl)bis[furan-2-carbaldehyde] (8) with (E, E)-{(buta-1, 3-diene-diyl)bis[(furan-5, 2-diyl)methylene]}bis-[triphenylphosphonium] dibromide (9) and 3, 3′-{[(E)-ethene-1, 2-diyl]bis(furan-5, 2-diyl)}bis[(E)-prop-2-enal] (22) with (E)-{(ethene-1, 2-diyl)bis[(furan-5.2- diy)methylene]}bis[triphenylphosphonium] dibromide (23). An alternative path to get 6 is the McMurry condensation of 8. Four different configurational isomers of 6 could be isolated and characterized by 1H-NMR spectroscopy. The (Z, EE, Z, EE)-isomer 6a is the first macrocyclic system where the inner and outer protons of the (E, E)-dienediyl bridges exchange by rotation around the adjacent single bonds. In the (Z, EE, E, EE)-isomer 6b, the (E)-ethenediyl bridge is rotationally active, while in the (E, ZE, E, EZ)-isomer 6c and in the (E, EZ, E, EZ)-isomer 6e, the rotation of both (E)-ethenediyl bridges is observed. When in the dynamic systems the rotation of the active (E)-double bonds at temperatures T 〈 -90° is frozen, all configurational isomers of 6 appear to be antiaromatic and paratropic. The oxidation of the [28]tetraoxaporphyrinoids 6c and 6e with DDQ yields the aromatic, diatropic [26]tetraoxaporphyrin(4.2.4.2) dications 21e/21e′ both with (E, EZ, E, EZ)-configuration but different fixed conformations. (Z, EE, Z, EE)-Isomer 6a is oxidized to give the (Z, EE, Z, EE)-dication 21a, while the oxidation of 6b yields a mixture of 21a and 21e/21e′. The standard formation enthalpies of the obtained and expected [28]tetraoxaporphyrinoids 6 and [26]tetraoxaporphyrin dications 21 have been calculated with the AM1 method, showing good accordance with the experimental results.

Notes: The synthesis of substituted cyclododeca-1,6-diallenes.( = cyclododeca-1,2,6,7-tetraenes) from cyclododeca-5,11-diyne-1,4-diols is described (Schemes 1 and 3). The ca. 1:1 mixtures of the stereoisomers of the cyclododeca-1,6-diallenes were formed in high yields from the ca. 1:1 diastereoisomer mixtures of the 1,4-disubstituted cyclododeca-5,11-diynes by reactions with Me2CuLi or t-BuMgCl/CuII. In mechanistically relevant experiments with the pure diastereoisomers of 1,4-dimethylcyclododeca-5,11-diyne-1,4-diol, it is demonstrated that the configuration is conserved in these reactions. The first synthesis of a 1-substituted cyclododeca-2,8-diyne bearing only one propargylic leaving group gives access to a mixed 12-membered allen-yne (Scheme 5).

Notes: This study was designed to unravel lipophilicity changes associated with the oxidation state of the S-atom in model compounds, drugs, and metabolites, special attention being given both to intermolecular and intramolecular effects. The methods used were experimental (potentiometry, CPC, and shake-flask techniques to measure lipophilicity, 13C-NMR spectroscopy to investigate tautomeric equilibria) and computational (quenched molecular dynamics and molecular lipophilicity potential). Simple, monofunctional model compounds were used to assess intermolecular forces, as revealed by the Δlog Poct-alk and Δlog Poct-chf parameters. Drugs and their metabolites proved to be good probes to study intramolecular effects in both neutral and anionic forms, as revealed by the difference between calculated and experimental log Poct values (the diff(log Pexp-calc) parameter). Sulindac and its metabolites showed a normal partitioning behavior, whereas the lipophilicity of sulfmpyrazone and its metabolites' was markedly affected by tautomeric and conformational equilibria.

Notes: The synthesis of (E)-hex-3-ene-l, 5-diynes and 3-methylidenepenta-1, 4-diynes with pendant methano[60]-fullerene moieties as precursors to C60-substituted poly(triacetylenes) (PTAs, Fig. 1) and expanded radialenes (Fig. 2) is described. The Bingel reaction of diethyl (E)-2, 3-dialkynylbut-2-ene-1, 4-diyl bis(2-bromopropane-dioates) 5 and 6 with two C60 molecules (Scheme 2) afforded the monomeric, silyl-protected PTA precursors 9 and 10 which, however, could not be effectively desilylated (Scheme 4). Also formed during the synthesis of 9 and 10, as well as during the reaction of C60 with thedesilylated analogue 16 (Scheme 5), were the macrocyclic products 11, 12, and 17, respectively, resulting from double Bingel addition to one C-sphere. Rigorous analysis revealed that this novel macrocyclization reaction proceeds with complete regio- and diastereoselectivity. The second approach to a suitable PTA monomer attempted N, N′-dicyclohexylcarbodiimide(DCC)-mediated esterification of (E)-2, 3-diethynylbut-2-ene-l, 4-diol (18, Scheme 6) with mono-esterified methanofullerene-dicarboxylic acid 23; however, this synthesis yielded only the corresponding decarboxylated methanofullerene-carboxylic ester 27 (Scheme 7). To prevent decarboxylation, a spacer was inserted between the reacting carboxylic-acid moiety and the methane C-atom in carboxymethyl ethyl 1, 2-methano[60]fullerene-61, 61-dicarboxylate (28, Scheme 8), and DCC-mediated esterification with diol 18 afforded PTA monomer 32 in good yield. The formation of a suitable monomeric precursor 38 to C60-substituted expanded radialenes was achieved in 5 steps starting from dihydroxyacetone (Schemes 9 and 10), with the final step consisting of the DCC-mediated esterification of 28 with 2-[1-ethynyl(prop-2-ynylidene)]propane-1, 3-diol (33). The first mixed C60-C70 fullerene derivative 49, consisting of two methano[60]fullerenes attached to a methano[70]fullerene, was also prepared and fully characterized (Scheme 13). The Cs-symmetrical hybrid compound was obtained by DCC-mediated esterification of bis[2-(2-hydroxy-ethoxy)ethyl] 1, 2-methano[70]fullerene-71, 71-dicarboxylate (46) with an excess of the C60-carboxylic acid 28. The presence of two different fullerenes in the same molecule was reflected by its UV/VIS spectrum, which displayed the characteristic absorption bands of both the C70 and C60 mono-adducts, but at the same time indicated no electronic interaction between the different fullerene moieties. Cyclic voltammetry showed two reversible reduction steps for 49, and comparison with the corresponding C70 and C60 mono-adducts 46 and 30 indicated that the three fullerenes in the composite fullerene compound behave as independent redox centers.

Notes: By the tether-directed remote functionalization method, a series of bis- to hexakis-adducts of C60, i.e., 1-7 (Fig. 1), had previously been prepared with high regioselectivity. An efficient method for the removal of the tether-reactive-group conjugate was now developed and its utility demonstrated in the regioselective synthesis of bis- to tetrakis(methano)fullerenes ( = di- to tetracyclopropafullerenes-C60-Ih) 9-11 starting from 4, 5, and 7, respectively (Schemes 2, 4, and 5). This versatile protocol consists of a 1O2 ene reaction with the two cyclohexene rings in the starting materials, reduction of the formed mixture of isomeric allylic hydroperoxides to the corresponding alcohols, acid-promoted elimination of H2O to cyclohexa-1,3-dienes, Diels-Alder addition of dimethyl acetylenedicarboxylate, retro-Diels-Alder addition, and, ultimately, transesterification. In the series 9-11, all methano moieties are attached along an equatorial belt of the fullerene. Starting from C2v-symmetrical tetrakis-adduct 15, transesterification with dodecan-1-ol or octan-1-ol yielded the octaesters 16 and 17, respectively, as noncrystalline fullerene derivatives (Scheme 3). The X-ray crystal structure of a CHCl3 solvate of 11 (Fig. 3) showed that the residual conjugated π-chromophore of the C-sphere is reduced to two tetrabenzopyracylene substructures connected by four biphenyl-type bonds (Fig. 5). In the eight six-membered rings surrounding the two pyracylene (= cyclopent[fg]acenaphthylene) moieties, 6-6 and 6-5 bond-length alteration (0.05 Å) was reduced by ca. 0.01 Å as compared to the free C60 skeleton (0.06 Å) (Fig. 4). The crystal packing (Fig. 6) revealed short contacts between Cl-atoms of the solvent molecule and sp2- and sp3-C-atoms of the C-sphere, as well as short contacts between Cl-atoms and O-atoms of the EtOOC groups attached to the methano moieties of 11. The physical properties and chemical reactivity of compounds 1-11 were comprehensively investigated as a function of degree and pattern of addition and the nature of the addends. Methods applied to this study were UV/VIS (Figs. 7-11), IR, and NMR spectroscopy (Table 2), cyclic (CV) and steady-state (SSV) voltammetry (Table 1), calculations of the energies of the lowest uunoccupied mmolecular orbitals (LUMOs) and electron affinities (Figs. 12 and 13), and evaluation of chemical reactivity in competition experiments. It was found that the properties of the fullerene derivatives were not only affected by the degree and pattern of addition but also, in a remarkable way, by the nature of the addends (methano vs. but-2-ene-1, 4-diyl) anellated to the C-sphere. Attachment of multiple thano moieties along an equatorial belt as in the series 8-11 induces only a small perturbation of the original fullerene π-chromophore. In general, with increasing attenuation of the conjugated fullerene π-chromophore, the optical (HOMO-LUMO) gap in the UV/VIS spectrum is shifted to higher energy, the number of reversible one-electron reductions decreases, and the first reduction potential becomes increasingly negative, the computed LUMO energy increases and the electron affinity decreases, and the reactivity of the fullerene towards nucleophiles and carbenes and as dienophile in cycloadditions decreases.

Notes: Crystal and solution structures of the enantiomerically pure and the racemic pairs of (η3-allyl) {2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-phenyloxazole}palladium(II) hexafluorophosphates (1, and rac-1, resp.) and tetraphenylborates (2, and rac-2, resp.) as well as (η3-allyl){2-[2′-(diphenylphosphino)phenyl]-4,5-dihydro-4-isopropyloxazole}palladium(II) tetraphenylborate (3) were characterized by X-ray crystallography and 1H-NMR spectroscopy. In the solid state, rac-1 and rac-2 proved to be disordered with both diastereoisomeric complexes in the crystal. The complexes 2 and 3 exist only in the ‘exo’ form. The X-ray structures show that the [PdII(η3-allyl)] moiety may adopt different configurations between a nearly symmetrical three-electron PdII(π3-allyl) system and an asymmetrical allyl group with a η1- and a η2-bonding to the metal center. The [PdII(η3-allyl)] system of rac-1 and of ‘endo’ rac-2 is closer to the former, and that of 2, ‘exo’-rac-2, and 3 closer to the later geometry. The 1H-NMR spectra of the hexafluorophosphates 1 and rac-1 show two sets of signals of the allylic protons in an ‘exo’/‘endo’ ratio of 2:3. The tetraphenylborates 2, rac-2, and 3 give only one set of broad signals of the allylic protons.

Notes: ‘Acetyleno-oligosaccharides’ in which two terminal ethynyl substituents enclose an angle (significantly) below 180° are building blocks for the preparation of cyclodextrin analogues. This is illustrated by the preparation of a cyclotrimer and a cyclotetramer; the C3-symmetrical cyclotrimer 18 (Scheme 1) was synthesized in 13 steps (7.7%) and the C4-symmetrical cyclotetramer 51 (Scheme 3) in 14 steps (4.3%) from the known dialkyne 21. The solubilities of 18 and 51 in H2O were determined by gravimetry; a saturated solution is 130 mM in the trimer 18 and 12.8 mM in the tetramer 51. The dependence of the optical rotation of 18 and 51 in H2O on the concentration, and the concentration dependence of the 1H-NMR chemical shift of the signals of the 1CH groups of 51 (D2O) suggest that there is no significant self-association of 18 and 51.

Notes: The chiral biyclic bis-lactams of structures 3 and 4 were synthesized from the key intermediate 2′b, the N,N′-bis(4-methoxybenzyl) derivative of 2 (X = MeO) (Scheme 6). The synthesis of this intermediate involved two key steps: (1) a double condensation of glyoxylic acid/anisamide (= oxoacetic acid/4-methoxybenzamide) adduct 11c with veratrole (1,2-dimethoxybenzene; 10) allowed the introduction of two glycine units at the 4,5-positions of the veratrole ring to give 18c (Schemes 3 and 4); (2) in order to circumvent the hydrolysis of 4-methoxybenzoyl protective groups which proved to be unfeasible, these groups were transformed into 4-methoxybenzyl groups through a sequence involving thiocarbonylation followed by reduction (Scheme 5). Thereafter, the double intramolecular cyclization of the resulting diamino diester 22c proceeded easily to afford 2′b. This intermediate may be transformed via the tetrol 2′g or the diol 2′h into the N-protected derivatives of 2 (X = OR) and of 3 (X = OCOR). Cleavage of the 4-alkuxybenzyl groups was achieved by ceric ammonium nitrate. However, when the aromatic ring bore ether functions (N-protected 2), this normal reaction was accompanied by the oxidative ring cleavage to give the diene-diester structure 4 (Schemes 5 and 6).

Notes: The kinetics of the Cu2+ complexation by macrocycles 1 (4-[(l,4,8,11-tetraazacyclotetradec-1-yl)methyl]-benzoic acid) and 2 (N-propyl-4-[(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]-benzamide) as well as by macrocycle 1 conjugated to bovine serum albumin (bsa) and to ribonuclease A (rnase) were studied by stopped flow techniques. For 1 and 2, the kinetics were followed in the mM range monitoring the d-d* absorption band of the Cu2+ complex. From the pH dependence of kobs, the rate law is v = [Cu2+] (kLH[LH] + kLH2[LH2]), where kLH and kLK2 are the bimolecular rate constants for Cu2+ with the diprotonated (LH2) and monoprotonated (LH1) form of the ligand, respectively. The values are kLH2 = 1.7(1) M-1s-1 and kLH = 2.3(1) 105 M-1s-1 for 1, and kLH2, = 0.28(9) M-1s-1 and kLH = 2.0(1) 105 M-1s-1 for 2. The kinetics of the Cu2+ incorporation into 1,2 and 1 conjugated to bsa and rnase, i.e., 3 and 4, respectively, were also followed using nitroso-R salt as a metal indicator in the μM range, i.e., under conditions typical for the ‘post-labeling’ technique to give radiolabeled monoclonal antibodies. In these cases, the reaction takes place between the 1:1 complex of Cu2+ with nitroso-R-salt and the macrocycle. At pH 6.5, the rates are very similar to each other indicating that the complexation properties of the macrocycle attached to a protein are not very different from those of the free ligand under comparable conditions.

Notes: The synthesis of a variety of hydroxylactams from ω-phthalimidoalkanoates using a triplet-sensitized photodecarboxylation reaction initiated by intramolecular photo electron transfer is described. Ring sizes available by this method span from 4 (benzazepine-1,5-dione 7) to 26 (cyclodipeptide 26e). Ground-state template formation is proposed as the explanation for the high efficiency of this reaction and for the decrease in reactivity in the presence of organic bases instead of metal carbonates. The crucial step in this macrocyclization reaction seems to be the protonation of the intermediary ketyl radials (Scheme 4). Spacer groups investigated were alkyl chains (C3-C11: 5c-h, 11a, 12), ether (16, 18), ester (20, 22), and amide (26a-f) linkages. Within the detection limits, no dimeric (= decarboxylative coupling) products were observed, indicating the high preference for intra-vs. intermolecular photoelectron transfer. The C,C radical combination step proceeds with low stereoselectivity (cf, products 11 and 12) in contrast to comparable singlet reactions. Except for the lactones 22, all products were stable under the photolysis conditions. Prolonged irradiation of 22 led to the formation of the spiro compounds 23, probably via an intermediary acyliminium betaine (Scheme 8). One serious limitation of the decarboxylative macrocyclization is its incompatibility with the glycine spacer (as in 27a and 27b), probably the consequence of a strong intramolecular H-bond (Scheme 10).

Notes: A novel tricyclic dipeptide template, formally derived by coupling (2S,4S)-4-aminoproline (Pro(NH2)) and (S)-2-(carboxymethyl)proline (Pro(CH2COOH)) as a diketopiperazine, has been synthesized in a form suitable for solid-phase peptide synthesis using Fmoc chemistry. This template was incorporated into the cyclic molecule cyclo(-Ala1-Asn2-Pro3-Asn4-Ala5-Ala6-Temp-) (Temp = template), whose conformation in H2O was studied by NMR methods. Average solution structures derived by restrained simulated annealing point to a highly populated βI-turn within the Asn-Pro-Asn-Ala motif and also indicate which conformations are likely to be preferred by the template.

Notes: The syntheses of both diastereoisomers of 5′-ethyl-substituted thymidine dimers, the (5′R)- and (5′S)-configurated 33a and 33b respectively, in which the natural phosphodiester linkage is replaced by an amide group (C(3′)-CH2CONH-CH(5′)(Et)), arc described. Their fully protected derivatives 35a and 35b, respectively, are suitable for incorporation into antisense oligonucleotides. Unexpectedly, an attempted PdII-catalysed aza-Claisen rearrangement of trichloroacetimidate 7 provided the diastereoisomerically pure cyclopropane derivative 17, whose structure was confirmed by X-ray analysis.

Notes: New Pathways to Precursors of PentalenePentalene dimers 2 and 3 are easily available in moderate yields by CuCl2-induced oxidative coupling of dilithium-pentalenediide (5) (Scheme 1). On the other hand, NBS bromination of 1,5-dihydropentalene (4) or of 1,2-dihydropentalene (8) gives unstable 1-bromo-1,2-dihydropentalene (9), while subsequent in-situ elimination with Et3N exclusively gives syn-cis-pentalene dimer 2 in moderate yields (Scheme 3). NMR-Spectroscopic evidence for compounds 2, 3, and 9 is presented, and mechanistic alternatives for the formation of pentalene dimers 2 and 3 are discussed.

Notes: Four new iridoid glucosides 1-4, named blumeosides A-D, were isolated from the methanolic stem-bark extract of Fagraea blumei G. DON. (Loganiaceae). They were accompanied by the benzyl-alcohol derivative di-O-methylcrenatin (5) and the flavone C-glucoside swertisin (6). The structures of 1-4 were established by spectroscopic methods, including FAB-MS, and 1H- and 13C-NMR, and by alkaline hydrolysis. Blumeosides A (1) and C (3) are 10-O-(2,5-dihydroxytercphthalo) adoxosidic acid and 10-O-(2-hydroxyterephthalo)adoxosidic acid, respectively. In blumeosides B (4) and D (2), both carboxylic groups of the terephthalic-acid moiety are esterified by adoxosidic-acid units, Blumeosides A-D (1-4) inhibited bleaching of crocin induced by alkoxyl radicals. Blumeosides A (1) and D (2) also demonstrated scavenging properties towards the 2,2-diphenyl-1-picryl-hvdrazvl (CDPPH) radical in TLC autographic and spectrophotometric assays.

Notes: The kinetic model of column chromatography is revisited to explicitly show that this approach yields, when neglecting axial dispersion, a rather simple analytical expression depending only on two dimensionless parameters, namely a dimensionless kinetic retention parameter and a dimensionless time parameter. An expression for the time corresponding to the maximum of the peak is also proposed.

Notes: The αv/β3 integrin is implicated in human tumor metastasis and angiogenesis. It has been shown that structures of the sequence cyclo(-Arg1-Gly2-Asp3-D-Phe4-Xaa5-) (I) and cyclo(-Arg1-Gly2-Asp3-Phe4-D-Xaa5-) (II) bind with high affinity and the latter with high selectivity to this receptor. The residues Xaa and D-Xaa accept a broad variety of amino acids. Here, we report on the synthesis, activities, and conformational analysis of cyclic Arg-Gly-Asp (RGD) peptides containing liophilic amino acids Xaa or D-Xaa in position 5. For I, these were (2S)-2-aminohexadecanoic acid (Ahd) and N′-hexadecylglycine (Hd-Gly) and in II, D-Ahd and Hd-Gly, and, for control purposes, Ahd were incorporated (Fig. 1). The enantiomerically pure a-amino acids were obtained by non-enantioselective synthesis and subsequent enzymatic separation of isomers using acylase I (Scheme). Hd-Gly was prepared in a modified procedure according to Stewart from ethyl bromoacetate and hexadecylamine (Scheme). The synthesis and physicochemical properties of the corresponding (9H-fluoren-9-ylmethoxy)carbonyl (Fmoc) derivatives, compatible with solid-phase peptide synthesis, are described. Structure elucidation by NMR reveals that the lipid modification has no significant impact on the template structures when incorporated into them. For peptides I with Xaa = Ahd or Hd-Gly (1 or 2), a βII′/γ-turn-like arrangement with D-Phe in i+1 position of the β-turn is found. Peptides II with D-Xaa = D-Ahd or Hd-Gly (3 or 4) exhibit a βII′/γ-turn conformation with Gly in i+1 position of the β-turn, whereas II with Ahd instead of D-Xaa, i.e., lacking a D-amino acid in position 4 or 5 (5). adopts no defined conformation. However, in assays of receptor specificity employing human αvv/β3 integrin, the compounds exhibit IC50 values ranging from nanomolar to less than millimolar. These results indicate that although the arrangement of the pharmacophoric groups is preserved in the target compounds, the biological activity is highly dependent on spatial requirements of the lipid anchor in the receptor binding pocket. Obviously, only certain positions do not affect the binding.

Notes: The conformational analysis of naturally occurring cytostatic cyclic heptapeptides axinastatin 2, 3, and 4 was carried out by two-dimensional NMR spectroscopy in combination with distance-geometry (DG) and molecular-dynamics (MD) calculations in explicit solvents. The synthesized secondary metabolites were examined in (D6)DMSO. Axinastatin 2 was also investigated in CD3OH. In all structures, Pro2 is in the i + 1 position of a βI turn and Pro6 occupies the i + 2 position of a βVIa turn about the cis amide bond between residue 5 and Pro6. In all peptides, a bifurcated H-bond occurs between residue 4 CO and the amide protons of residue 1 and 7. For axinastatin 2 and 3, an Asn Ig turn was found about Asn1 and Pro2. We compared these structures with conformations of cyclic heptapeptides obtained by X-ray and NMR studies. A β-bulge motif with two β turns and one bifurcated H-bond is found as the dominating backbone conformation of cyclic all-L-heptapeptides. Axinastatin 2, 3, and 4 can be characterized by six trans and one cis amide bond resulting in a β/βVI(a)-turn motif, a conformation found for many cyclic heptapeptides. Detailed biological tests of the synthetic compounds in different human cancer cell lines indicates these axinastatins to be inactive or of low activity.

Notes: In the presence of activating agents, the N-acylglycine 8 reacts with electrophilic alkynes via the münchnone9 to the pyrrolopyridines (= indolizines) 10, 18, and 19 (Scheme 1 ), Depending on the nature of the activating agent and the reaction temperature, the formation of the pyrroles was accompanied by partial epimerization to the manna-configurated epimers 16 and 17. The gluco-configurated pyrrolopyridine 10 was deprotected to 12. Silylation of 12, followed by reduction and desilylation, gave the hexol 15. Cycloaddition of 9 to 4-toluenesulfonyl cyanide yielded 53% of the imidazole 23, while cycloaddition to phenyl cyanate gave the phenoxyimidazole 28 in low yields only (Scheme 2). As expected, the deprotected pyrroles 12, 15, 20, and 21 are weak inhibitors of retaining β-glucosidases, while the deprotected imidazole 24 derived from 23 proved a good inhibitor of sweet-almond β-glucosidases and a powerful inhibitor of Caldocellum saccharolyticum β-glucosidase.

Notes: Tetrahydrobenzo[a]pyrrolizidines (= octahydro-1H-pyrrolo[2,1-a]isoindoles) and tetrahydrobenzo[a]indo-lizidines, (= decahydropyrido[2,1-a]isoindoles) were prepared stereoselectively in four steps through an amineinduced ring-opening of 3-bromo-2,5-dimethylthiophene 1,1-dioxide (1) with L-prolinol (9), piperidine-2-methanol (10), and piperidine-2-ethanol (11), yielding the dienes (2S)-1-[(2E,4Z)-4-bromohexa-2,4-dienyl]pyrrolidine-2-methanol (12), 1-[(2E,4Z)-4-bromohexa-2,4-dienyl]piperidine-2-methanol (13), and 1-[(2E,4Z)-4-bromo-hexa-2,4-dienyl]piperidine-2-ethanol (14; Scheme2), which, after conversion into their α,β-unsaturated esters, cyclized in a TiCl4-catalyzed intramolecular Diets-Alder reaction (Scheme3). A discussion on the mechanism of the ring opening reaction including semiempirical and ab initio calculations is also presented.

Notes: The X-ray crystal-structure analyses of two N-enoyl-toluenesultam derivatives 1 are reported. The structural differences with their bornanesultam analogues 2 as well as stereochemical aspects with respect to their [4 + 2] and [3 + 2] cycloadditions are discussed.

Notes: Boophiline (1), a new sterol amide was isolated from the cattle tick Boophilus microplus (Ixodidae). The structure was assigned as N-[3-(sulfooxy)-25ξcholest-5-en-26-oyl]-L-isoleucine by detailed 2D NMR investigations in conjunction with FAB mass spectrometry and acidic hydrolyses. Complete assignment of the diastereotopic methylene protons of the ring system could be deduced from the NMR data. In agar dilution assays, 1 exhibited antifungal properties against Cladosporium cucumerinum and antibacterial activity against Bacillus subtilis and Escherichia coli.

Notes: The classical rules for Cope rearrangements predict a transition state with chair form to be favored over the boat form. On the other hand, bridged homotropylidenes, which allow only a boat-form transition state by steric reasons, have extremely low barriers. A controversy about the correct pathway and the different possible intermediates and transition states of the reaction has gone on for years. In this work, the hypersurfaces of barbaralane, in comparison with the boat- and chair-form of hexa-1,5-diene, are computed by the ab inito CASSCF (6,6)/6-31G** method starting with UMP2/6-31G** natural orbitals (NO's). All three hypersurfaces show characteristic features, and, moreover differ from each other. A hitherto undiscussed intermediate, bicyclo[2.2.0]hexane, was localized on the boat-hexa-1,5-diene pathway. So it is noteworthy that our transition state for the boat-hexa-1,5-diene does not correspond to the transition states found by other authors for this conformation. The computed enthalpies of activation of boat- and chair-hexa-1,5-diene, and barbaralane are in good agreement with the experimental data.

Notes: As one of the regulatory gene products in the HIV-1 genome, Rev protein must be translocated from the nucleus to the cytoplasm to exert its function. Therefore, inhibition of Rev protein translocation could be a useful target for HIV therapy. An extract from the Streptomyces strain A92-308902 with very potent inhibitory activity was found in the course of a high throughput screening with a Rev translocation assay (RTA). Bioassay-guided fractionation with gel filtration, normal-phase and reversed-phase chromatography yielded six RTA-active metabolites belonging to the leptomycin family, the known leptomycin A (1), leptomycin B (2), kazusamycin B (3), and kazusamycin A (4). and the hitherto unknown dilactonmycin (5) and delactonmycin (6), together with an inactive cyclic hexadepsipeptide L-156,620 (7). The structures were established mainly by spectroscopic methods (UV, FT-IR, FAB-MS, 1H-NMR, 13C-NMR(JMOD), DQ-COSY, ROESY, HSQC, and HMBC). The configuration of all C=C bonds of 1-6 was unambiguously established by analysis of coupling constants and ROESY spectra. All isolated leptomycins 1-6 inhibit Rev translocation at nanomolar concentrations. Six derivatives (2a-c and 4a-c) of leptomycin B (2) and kazusamycin A (4) were also prepared and tested in the RTA for preliminary investigations on structure-activity relationships.

Notes: The olefins mentioned in the title were copolymerized with CO in the presence of palladium catalysts modified with dicyclohexyl{(R)-1-[(S)-2-(diphenylphosphino)ferrocenyl]ethyl}phosphine. Productivities up to 95 g/(gPd · h) were achieved. The obtained copolymers were recovered in the pure, regio- und stereoregular polyketone structures3. The isotactic poly[2-benzyl-1-oxopropane-1,3-diyl] (3a) and its analogues 3b, c were found to isomerize to the corresponding spirocyclic poly[3-(arylmethyl)tetrahydrofuran-2,2-5,5-tetrayl-2-oxy-2-methylene]s 4 in a suspension in CHC13, thus indicating that the spiroketal structure is thermodynamically the most stable for these copolymers. However, the atactic material did not undergo any structural transformation. These results show that regularity at the centers of chirality in the main chain is a prerequisite for the conversion of the polyketone to the spiroketal structure.

Notes: Methyl 2-acetyl-3-{[2-(dimethylamino)-1-(methoxycarbonyl)ethenyl]amino}prop-2-enoate (4) and phenyl-methyl 2-acetyl-3-{[2-(dimethylamino)-1(methoxycarbonyl)ethenyl]amino}prop-2-enoate (5) were prepared in three steps from the corresponding acetoacetic esters, and used as reagents for the preparation of N3-protected 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 10-12, 5H-thiazolo[3,2-a]pyrimidin-5-one 13, 4H-pyrido[1,2-a]-pyridin-4-one 19 and 2H-1-benzopyran-2-ones 20-23. Free 3-amino-4H-pyrido[1,2-a]pyrimidin-4-ones 24-26 were prepared from 10-12 by removal of the 2-(methoxycarbonyl)-3-oxobut-1-enyl or 3-oxo-2-[(phenyl-methoxy)carbonyl]but-1-envl as N-protecting group by various methods.

Notes: Cyclophanes 3 and 4 were prepared as initiator cores for the construction of dendrophanes (dendritic cydophanes) 1 and 2, respectively, which mimic recognition sites buried in globular proteins. The tetra-oxy[6.1.6.1]paracyclophane 3 was prepared by a short three-step route (Scheme 1) and possesses a cavity binding site shaped by two diphenylmethane units suitable for the inclusion of flat aromatic substrates such as benzene and naphthalene derivatives as was shown by 1H-NMR binding titrations in basic D2O phosphate buffer (Table 1). The larger cyclophane 4, shaped by two wider naphthyl(phenyl)methane spacers, was prepared in a longer, ten-step synthesis (Scheme 2) which included as a key intermediate the tetrabromocyclophane 5. 1H-NMR Binding studies in basic borate buffer in D2O/CD3OD demonstrated that 4 is an efficient steroid receptor. In a series of steroids (Table 1), complexation strength decreased with increasing substrate polarity and increasing number of polar substituents; in addition, electrostatic repulsion between carboxylate residues of host and guest also affected the binding affinity strongly. The conformationally flexible tetrabromocyclophane 5 displayed a pronounced tendency to form solid-state inclusion compounds of defined stoichiometry, which were analyzed by X-ray crystallography (Fig. 2). 1,2-Dichloroethane formed a cavity inclusion complex 5a with 1:1 stoichiometry, while in the 1:3 inclusion compound 5b with benzene, one guest is fully buried in the macrocyclic cavity and two others are positioned in channels between the Cyclophanes in the crystal lattice. In the 1:2 inclusion compound 5c, two toluene molecules penetrate with their aromatic rings the macrocyclic cavity from opposite sides in an antiparallel fashion. On the other hand, p-xylene (= 1,4-dimethylbenzene) in the 1:1 compound 5d is sandwiched between the cyclophane molecules with its two Me groups penetrating the cavities of the two macrocycles. In the 1:2 inclusion compound 5e with tetralin (= 1,2,3,4-tetrahydronaphthalene), both host and guest are statically disordered. The shape of the macrocycle in 5a-e depends strongly on the nature of the guest (Fig. 4). Characteristic for these compounds is the pronounced tendency of 5 to undergo regular stacking and to form channels for guest inclusion; these channels can infinitely extend across the macrocyclic cavities (Fig. 6) or in the crystal lattice between neighboring cyclophane stacks (Fig. 5). Also, the crystal lattice of 5c displays a remarkable zig-zag pattern of short Br…O contacts between neighboring macrocycles (Fig. 7).

Notes: Photolysis and Ag-benzoate-catalyzed decomposition of the diazo ketones 2 and 4 derived from Z-Ala-OH and Z-Ala-Ala-OH in the presence of oligonucleotide derivatives bearing at the 5′-terminus an NH2 instead of the OH group, or an aminohexyl phosphate group lead to Z-protected 3-aminobutanoyl and to Z-Ala-β-HAla derivatives, respectively (conjugates 12, 13, and 17-23, Schemes 3-5), In solution, this amide-forming acylation reaction could be realized only with oligomers containing up to 8 unprotected nucleotide building blocks (Schemes 3 and 4). With the analogous polymer-bound and protected oligonucleotide derivatives as amino nucleophiles, excellent yields were obtained with all chain lengths tested (up to 15mer Scheme 5), The products were purified by reversed-phase HPLC and characterized by MALDI-TOF mass spectrometry (Figs. 2-4, Table 2) and by capillary gel electrophoresis (Fig.2).

Notes: We describe a versatile novel approach for the synthesis of 2, 4, 6-trisubstituted pyrimidines on solid support. Thus, polymer-boun J thiouronium salt 2 reacted in high yield in a cyclocondensation reaction with the acetylenic ketones 3 to form, after tert-butyl-ester cleavage, the polymer-bound carboxylic acids 4, which were cleaved by oxidation with 3-chloroperbenzoic acid and pyrrolidine to form the 2-pyrrolidinylpyrimidine-4-carboxylic acids 6a-c in high yields and purities without further purification (Scheme 1). Alternatively, acid 4a was subjected to an Ugi four-component condensation which gave the polymer-bound Ugi products 9a-e in good yields (Scheme 2). Multidirectional cleavage reaction of sulfone 8a with different nucleophiles resulted in the clean formation of pyrimidine-4-carboxamides 10-13 (Scheme 3). This strategy combines efficiently solid-phase chemistry with a multicomponent reaction and a multidirectional cleavage step to form highly diverse pyrimidines in a parallel array.

Notes: The title compounds 4 are obtained by photolysis of simple N-alkylpyridinium salts in H2O or alcohol. On reaction with [Fe2(CO)9] in THF, 4 gives bicyclic tricarbonyliron complexes 13a-d, which on oxidative decomplexation with ceric ammonium nitrate afford cis-fused cyclopenteno-β-lactams 15a-d.