ALBERT

Notizen: On the way to the fullerene-acetylene hybrid carbon allotropes 2 and 6, the oxidative homocoupling of the 2-functionalized 1-ethynylated C60 derivatives 11, 12, 14, and 15 was investigated. Under Glaser-Hay conditions, the two soluble dumbbell-shaped bisfullerenes 17 and 18, with two C60 moieties linked by a buta-1,3-diynediyl bridge, were formed in 52 and 82% yield, respectively (Scheme 2). Cyclic-voltammetric measurements revealed that there is no significant electronic communication between the two fullerene spheres via the buta-1,3-diynediyl linker. Removal of the 3,4,5,6-tetrahydro-2H-pyran-2-yl (Thp) protecting groups in 18 gave in 80% yield the highly insoluble dumbbell 19 with methanol groups in the 2,2′-positions of the buta-1,3-diynediyl-bridged carbon spheres. Attempted conversion of 19 to the all-carbon dianion 6 (C1242-) via base-induced elimination of formaldehyde was not successful presumably due to exo-dig cyclization of the formed alkoxides. The occurrence of this cyclization under furan formation was proven for 2-[4-(trimethylsilyl)buta-1,3-diyn-1-yl][60]fullerene-1-methanol (21), a soluble model compound for 19 (Scheme 3). To compare the properties of ethynylated fullerene mono-adducts to those of corresponding higher adducts, hexakis-adducts 26 and 28 with an octahedral functionalization pattern resulting from all-e (equatorial) additions were prepared by the reversible-template method of Hirsch (Scheme 4). Reaction of the ethynylated mono-adducts 25 or 13 with diethyl 2-bromomalonate/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in the presence of 1,9-dimethylanthracene (DMA) as reversible template led to 26 and 28 in 28 and 22% yield, respectively. Preliminary experiments indicated a significant change in reactivity and NMR spectral properties of the fullerene addends with increasing degree of functionalization.

Notizen: Supports consisting of a thin layer (2-10%) of polystyrene (PS) grafted onto a poly(tetrafluoroethylene) (PTFE) core are an interesting alternative to controlled pore glass (CPG) carriers in oligonucleotide synthesis. The beads are mechanically stable, do not show significant swelling, and allow effective removal of substrates by short washing steps with organic solvents. PTFE-PS as an organic polymer has generally more hydrophobic properties than inorganic polymer supports and, therefore, is well compatible with organic solvents such as anhydrous MeCN. We found PTFE with a content of 2-3% PS graft to be a very good support for the synthesis of oligonucleotides of extended length. In comparison, PTFE with 5-10% grafted PS is especially useful for large-scale syntheses. Functionalization procedures minimized in the extent of side reactions are described as well as examples for the use of the supports in syntheses of oligonucleotides both on large scale and of extended chain length.

Notizen: Reaction of ‘Push-Pull’ Enynes with Acids. First Observation of a Rearrangement of 5-Chloro-5-(dialkylamino)pentadienals‘Push-pull’-enynes 7 react easily with HCl as well as with AcOH to give 5-amino-5-chloropentadienals 8 and 5-(acetoxy)-5-aminopentadienals 13 as well as the corresponding ketones. In view of a postulated rearrangement of compounds 8 and 13 (Scheme 2), both types of compounds have been treated with traces of acid. While no definite reaction is observed in case of 13, HCl-addition products 8 easily and quantitatively rearrange to give 2H-pyran-2-iminium chlorides 10 which are the postulated intermediates of the rearrangement 8→12 (Scheme 2).

Notizen: The self-assembly of alkaline folates in isotropic water solutions, with or without added salts, has been investigated by small-angle neutron-scattering, circular-dichroism, and NMR techniques. The assembled species are chiral, cylindrical aggregates of finite length, composed of stacked tetramers; each tetramer is formed by Hoogsteen-bonded folate residues. The assembly process is more efficient in the presence of an excess of NaI ions, leading to longer aggregates with stronger tetramer-tetramer-tetramer interaction. In pure water, the rods are shorter and the tetramer-tetramer interaction weaker. Association between folates can be detected by circular-dichroism spectroscopy starting from a concentration of 6· 10-4 mol l-1, well below the critical concentration for the formation of the cholesteric mesophase (ca. 0.5 mol l-1).

Notizen: Bromination of the monosilylated dialkynylated monomer 1a (Scheme 1), dimer 3 and tetramer 5 by N-bromosuccinimide (NBS) in the presence of CF3COOAg gave 2, 4, and 6, respectively, in over 93%. Similar conditions led to bromodesilylation. Either silyl group of the diprotected monomer 1c was selectively removed by bromolysis. On the one hand, bromodesilylation of 1c gave 2 in yields varying between 80 and 99%. On the other hand, bromodesilylation of 7, obtained from 1c by hydrolytic removal of the tetrahydro-2H-pyran-2-yl (Thp) group, yielded 91% of 8. Mechanistic considerations suggested that the deprotective bromination should be improved by replacing the Me3Si by a Me3Ge group. Indeed, bromodegermylation of 1b was quantitative and ca. 60 times faster than bromodesilylation of 1c. The Me3Si and Me3Ge groups can be used for an orthogonal protection/activation of dialkynes. This was shown by desilylating 12 to 11 (Scheme 2), while bromination yielded 13. Both reactions proceeded in high yields; 9 was isolated as a minor by-product of 13. The reactivity towards bromolysis decreases in the series H-DOPS 〉 Me3Ge ≈ H 〉 Me3Si 〉 Thp-DOPS (DOPS = [dimethyl(oxy)-p ropyl]dimethylsilyl). Orthogonal bromolysis of DOPS- and Me3Ge-substituted dialkynes is slightly more selective than the one of Me3Si- and Me3Ge-substituted analogues. Coupling of 7 with the bromoalkyne 2 gave the dimer 15 (76%), 14 (2%), and 16 (4%) (Scheme 3). The binomial synthesis was optimized so that each cycle, doubling the size of the precursor, requires the minimal number of transformations (Scheme 4). The orthogonally protected monomer 1b, dimer 19, and tetramer 22 were, on the one hand, hydrolyzed to the alcohols 18 (95%), 21 (91%), and 24(91%), respectively, and, on the other hand, bromodegermylated to 2 (99%), 4 (97%), and 6(93%). Cross-coupling of 18 with 2, 21 with 4, and 24 with 6 gave the orthogonally protected dimer 19 (73%), tetramer 22 (87%), and octamer 25 (83%), respectively.

Notizen: The synthesis of novel thiazole-containing complexing agents and their luminescence properties with EuIII and TbIII ions are reported. One of these terpyridine analogues was also tested as an EuIII labelling reagent, and its luminescence properties as an antibody conjugate were studied.

Notizen: Chemical screening of the secondary metabolites from Halenia corniculata L. (CORNAZ), by LC/UV,LC/TSP-MS (thermospray), and LC/ES-MS (electrospray) was used for the targeted isolation of corniculoside (1), a new biosidic ester secoiridoid. The structure was established as 7-β-[(E)-4′-O-(β-D-glucopyranosyl)caffeoyloxy]-sweroside by 1D- and 2D-NMR, LC/UV, LC/MS, and FAB-MS data, in combination with chemical reactions.

Notizen: Addition reactions of organometallic reagents with 4,4-disubstituted 1,3-thiazole-5(4H)-thiones were studied. Whereas the reactions with alkyllithium and alkyl Grignard reagents occurred in the thiophilic manner, the carbophilic addition was observed with allyllithium and allyl Grignard reagents. A radical reaction mechanism is proposed for rationalizing these observations (Scheme 5). A radical cyclization of the prepared 5-allyl-4,5-dihydro-1,3-thiazole-5-thiol derivatives yielded 1,6-dithia-3-azaspiro[4.4]non-2-enes (Table 4).

Notizen: The syntheses of various fluorocarbon/fluorocarbon and fluorocarbon/hydrocarbon rac-1,2- and 1,3-di-O-alk(en)ylglycerophosphocholines and rac-1,2-di-O-alkylglycerophosphoethanolamines (see Fig.2), which may be used as components for drug-carrier and delivery systems, are described together with some results concerning their biological tolerance. They were obtained by phosphorylation of perfluoroalkylated rac-di-O-alk(en)ylgly-cerols using POCl3, then condensation with choline tosylate or N-Boc-ethanolamine (2-[(tert-butoxy)carbonyl-amino]ethanol) followed by Boc-deportection (Schemes 6-8). The fluorcarbon/fluorocarbon 1,2-di-O-alkylgly-cerols were prepared by O-alkylation of rac-1-O-benzylglycerol using perfluoroalkylated mesylates, then hydrogenolysis for benzyl deprotection (Scheme 1). The two different hydrophobic chains in the mixed fluorocarbon/fluorocarbon and fluorocarbon/hydrocarbon 1,2-di-O-alk(en)ylglycerols were introduced starting from 1,2-O-iso-propylidene- then O-trityl-protected glycerols or from 1,3-O-benzylidene-glycerol (Schemes 3 and 4). The perfluoroalkylated O-alkenylglycerols were obtained by O-alkylation of a glycerol derivative using an ω-unsaturated alkenyl reagent, the perfluoroalkyl segment being connected onto the double bond in a subsequent step (Schemes 1) and 3. The perfluoroalkylated symmetrical and mixed 1,3-di-O-alkylglycerols were synthesized by displacement of the Cl-atom in epichlorohydrin by perfluoroalkylated alcohols, then catalytic (SnCl4) opening of the oxirane ring of the resulting alkyl glycidyl ethers in neat alcohols (Scheme 5). When injected intravenously into mice, acute maximum tolerated doses higher than 1500 and 2000 mg/kg body weight were observed for the fluorinated glycerophosphocholines, indicating a very promising in vivo tolerance.

Notizen: Ten new α-diazo-β-oxoaldehydes were condensed with aniline, ammonia, hydroxylamine, and semicarbazide to yield new 4-acyl-(1-substituted)-1H-1,2,3-triazoles in moderate-to-good yields. The method is simple and regiospecific. The latter feature makes this method superior to the widely used acylacetylene + azide approach.

Notizen: The synthesis of oligonucleotides containing N7-(2-deoxy-β-D-erythro-pentofuranosyl)guanine (N7Gd; 1) is described. Compound 1 was prepared by nucleobase-anion glycosylation of 2-amino-6-methoxypurine (5) with 2-deoxy-3,5-di-O-(4-toluoyl)-α-D-erythro-pentofuranosyl chloride (6) followed by detoluoylation and displacement of the MeO group (8→10→1). Upon base protection with the (dimethylamino)methylidene residue (→11) the 4,4-dimethoxytrityl group was introduced at OH—C(5′) (→12). The phosphonate 3 and the phosphoramidite 4 were prepared and used in solid-phase oligonucleotide synthesis. The self-complementary dodecamer d(N7G—C)6 shows sigmoidal melting. The Tm of the duplex is 40°. This demonstrates that guanine residues linked via N(7) of purine to the phosphodiester backbone are able to undergo base pairing with cytosine.

Notizen: Starting from the esters (2E,4S)-6 and (2E,4R)-6, bromo aldehydes (S)-9 and (R)-9 as well as bromo alcohols (S)-10 and (R)-10, respectively, were prepared. Bromo alcohol (R)-8 was converted to the diol (2E,4R)-16. Ozonolysis of the latter led to aldehyde (R)-17, which was transformed, by a Wittig reaction, to (2R,4E,6R)-18, corresponding to the C(7)-to-C(14) segment of phomenoic acid (1). Attempts to improve the yields by applying a Julia coupling of (R)-23, which was prepared from (2E,4R)-7, with (R)-24 were unsuccessful. Finally, the coupling of the iodo derivative (2E,4S)-28 with the lithiated derivative of 1,3-dithiane 30 by the Corey-Seebach ‘Umpolung’ led to (3S,4E)-32 which is a derivative of the C(7)-to-C(14) segment of 1, suitable for further transformations.

Notizen: Monodisperse and polydisperse oligomers and polymers of 3-hydroxybutanoic acid (3-HB) containing 8, 16, ca. 28, 32, ca. 60, 64, 96, and ca. 3000 monomer units were incorporated into palmitoyl-oleoyl-phosphatidyl choline (POPC) planar bilayers. At concentrations of 0.1-5% of oligo(3-HB), the resulting phospholipid bilayers showed typical single-channel behavior for Rb+ and Ba2+ ions, using the patch clamp technique. Thus, channel-forming activity of a pure polyester has been demonstrated for the first time (Figs. 1, 3, and 6). Single-channel activity depends upon the following structural parameters of the 3-HB derivatives: unprotected OH and COOH groups on the chain ends; chain length ≥ 16 monomer units; no high-molecular-weight as in P(3-HB). The results are discussed in view of the Ca2+-specific channel formed with the P(3-HP)/Ca · PPi complex from genetically competent Escherichia coli and in view of the ubiquitous occurrence of low-molecular-weight P(3-HB) in prokaryotic and eukaryotic organisms. A simple model for the channel-causing structure is proposed, based on the proven tendency of oligo- and poly(3-HB) to form ca. 50-Å thick lamellar crystallites.

Notizen: The Synthesis of p-CumaroylspermidinesThe synthesis of three mono[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines, 10, 20, and 28, three bis[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines, 6, 16, and 25, and one tris[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]-spermidine is described.

Notizen: Four cyclotetrapeptides containing one (1, 2) or two (3, 4) chiral amino acids have been C-alkylated or C-hydroxyalkylated through Li+ or phosphazenium (P4 · H+) enolates. The reactions are completely diastereoselective (by NMR or HPLC analysis) with respect to the newly formed backbone stereogenic centres (Tables 2 and 3). The reactivity of the polylithiated species responsible for these alkylations is such that only highly reactive electrophiles (MeI, BnBr, primary allylic halides, aldehydes, CO2) can be employed. It is shown that the position, and thus the chirality sense, of the newly formed stereogenic centre in a given cyclotetrapeptide backbone is controlled by the positioning of N-methyl groups in the starting material (cf. cyclo(-MeLeu-Gly-D-Ala-Sar-) (3) and cyclo(-Leu-Sar-MeDAla-Gly-) (4) in Scheme 1). With Schwesinger's phosphazene P4-base, all NH groups are first benzylated and C-benzylation then takes place at a sarcosine, rather than an N-benzylglycine residue (Table 3). In contrast to open-chain N-benzyl peptides, the N-benzylated cyclotetrapeptides could not be debenzylated under dissolving-metal conditions (Na/NH3). Conformational analysis (NMR spectroscopy and X-ray diffraction) shows that the prevailing species have cis/trans/cis/trans(ctct) peptide bonds (zigzag conformation of Ci backbone symmetry, Figs. 2-4). However, a hitherto unknown conformation of cyclotetrapeptides has been found in CDCl3 solutions of the hydroxyalkylated products 18-21 (obtained with EtCHO and PhCHO as electrophiles; Fig.4). The new conformation has four trans peptide bonds and is believed to result mainly from intramolecular H-bond formation, involving the newly generated alkyl- or arylserine residue. This assumption has also been supported by modelling (TRIPOS force field, SYBYL, see Fig.5 and Table 6). The structure may be considered as a β-turn mimic.

Notizen: The synthesis of functionalized 1,1,2,2-tetraethynylethanes (= 3,4-diethynylhexa-1,5-diynes) as synthons for tetraethynylethenes (3,4-diethynylhex-3-ene-1,5-diynes) and as building blocks for three-dimensional acetylenic molecular scaffolding targeting the synthesis of the molecular carbon belts 3 and 4 is reported (Scheme 1). Reaction of diethyl oxalate and (trialkylsilyl)ethynyl Grignard reagents afforded the silyl-protected 3,4-diethynylhexa-1,5-diyne-3,4- diols 7 and 8 which were transformed in high yields into the cyclic carbonate 9 and the cyclic orthoesters 10-13, respectively (Scheme 2). The solid-state structures of 9 and 10 were elucidated by X-ray crystallography. The alkyne protecting groups in 9, 10, and 12 were smoothly removed to give the free tetraynes 14-16 as relatively stable oils in nearly quantitative yields (Scheme 3). Orthoesters 15 and 16 underwent Pd-catalyzed cross-coupling with iodobenzene to give the tetraphenyl derivatives 17 and 18 (Scheme 4). Thermal acid-catalyzed elimination of the orthoester moieties in 12 and 13 produced the silyl-protected tetraethynylethenes 19 and 20 and concluded a novel, simple three-step synthesis of these fully two-dimensionally conjugated π-chromophores (Scheme 5).

Notizen: A series of new carbocyclic C-nucleosides with a cis-4′-(hydroxymethyl)cyclopent-2′-enyl sugar moiety and unnatural pyrimidine bases (2-6) were synthesized in racemic form in two steps starting from the easily accessible cyclic carbonate 1.

Notizen: The synthesis and liquid-crystalline and thermal properties of a fullerene[60] functionalized by a framework containing two cholesterol derivatives through a methanofullerene structure are reported. The targeted fullerene derivative showed high thermal stability.

Notizen: The synthesis of the thymine- and adenine-containing 5′-epi-bicyclodeoxynucleosides 7 and 8 as well as of the corresponding building blocks 13 and 14 for oligonucleotide syntheis according to the phosphoramidite methodology is described. A conformational analysis of 7 and 8 by 1H-NMR spectroscopy, refined by molecular modeling, shows the preferred conformation of the furanose unit in these nucleosides to be of the 1′-exo/2′-endo type. The 5′-OH group on the carbocyclic ring prefers to be axially oriented, thus placing torsion angle γ in the unusual -syn-clinal (-sc) range. These epi-bicyclodeoxynucleosides were successfully incorporated into DNA decamers. From UV/melting curves of such decamers with DNA and RNA complements, a duplex destabilization of -2 to -9° per residue was observed. An oligonucleotide built completely from 5′-epi-bicyclothymidine shows no detectable affinity to its DNA or RNA complement anymore. CD Spectra of duplexes containing 5′-epi-bicyclodeoxynucleotide units are very similar to the natural reference systems, indicating no major structural changes. A molecular-dynamics simulation of a heptamer duplex containing one 5′-epibicyclothymidine residue in the center reveals a conformational change of its carbocyclic unit placing torsion angle γ in the (for the free mononucleoside unfavorable) -anti-clinal (-ac) conformation in the duplex. The role of torsion angle γ on DNA duplex stability is discussed.

Notizen: L-Aspartic acid by tosylation, anhydride formation, and reduction with NaBH4 was converted into (3S)-3-(tosylamino)butan-4-olide (8; Scheme 1). Tretment of 8 with ethanolic trimethylsilyl iodide gave the N-protected deoxy-iodo-β-homoserine ethyl ester 9. The latter, on successive nucleophilic displacement with lithium dialkyl-cuprates ( → 10a-e), alkaline hydrolysis ( → 11a-e), and reductive removal of the tosyl group, produced the corresponding 4-substituted (3R)-3-aminobutanoic acids 12a-e (ee 〉 99%). Electrophilic hydroxylation of 8 ( → 19; Scheme 3), subsequent iodo-esterification ( → 21; Scheme 4), and nucleophilic alkylation and phenylation afforded, after saponification and deprotection, a series of 4-substituted (2S, 3R)-3-amino-2-hydroxybutanoic acids 24 including the N-terminal acids 24e ( =3) and 24f ( =4) of bestatin and microginin (de 〉 95%), respectively.

Notizen: An asymmetric synthesis of the spermidine alkaloid (+)-cyclocelabenzine (1a) and its (-)-(13S)-epimer 1b is described using optically active (+)-(3S)-3-amino-3-phenylpropionic acid as the chiral building block. The isoquinolin-1-one fragment 15 was synthesized by a modified Bischler-Napieralski reaction. The relative configuration of the (-)-isomer was determined by an X-ray crystal-structure analysis, which enabled us to determine the absolute configuration of natural (+)-1a as (8S,13R).

Notizen: The methanolysis of the epimeric 7-chloro-7H-yohimbine derivatives 2 and 3 was reinvestigated. In case of the 7α-epimer 2, the reaction was uneventful and conformed with earlier observations, i.e., under sufficiently mild conditions, only the imino ether 4 (= imino ether A) was produced. Under the same conditions, the less reactive β-isomer 3 furnished a mixture of both imino ethers 4 and 5, accompanied by the elimination product 11, and by equal amounts of yohimbine (1) and 3,4,5,6-tetradehydroyohimbine (12), which are believed to arise through a disproportionation process of the putative intermediate 5,6-didehydroyhimbine (23). The nature of this divergent reactivity and of the ready equilibration of 4 and 5 was investigated by means of extensive force-field and semi-empirical calculations (AM1 and PM3) of various conformers of the compounds 2-5 and of some possible reaction intermediates.

Notizen: 2-Alkynylcyclohex-2-enones 1a-c and 2a-c react with H2O2/NaOH in MeOH to afford 1-alkynyl-7-oxabicyclo[4.1.0]heptan-2-ones 3a-c and 4a-c, respectively. The 3-unsubstituted bicyclic epoxy ketones 3a, 3b, and 4a, 4b react further with H2O2/NaOH, undergoing ring contraction and (formal) decarbonylation to give 2-alkynylcy-clopent-2-enols 5a, 5b, and 6a, 6b, respectively. Epoxy ketones 3 are also obtained under neutral conditions on irradiation (λ = 350 nm) of cyclohexenones 1 in air-saturated benzene solution. Similarly, under neutral conditions oxo-cycloalkenecarbonitriles 8 react (thermally) with H2O2 in MeCN to give the oxabicyclic carbonitriles 9.

Notizen: Oligonucleotides containing (2′-deoxy-β-D-xylofuranosyl)guanine have been prepared. For this purpose 2-aminoadenosine (5) was synthesized and converted to 2′-deoxy-β-D-xyloguanosine (1). The related 2′-deoxy-β-D-xyloisoguanosine (3) and 2′-deoxy-β-D-xyloxanthosine (4) were also synthesized. Compound 1 was converted to the phosphonate and phosphoramidite building blocks 10 and 11, respectively. The oligodeoxynucleotide (5′-3′)d(xG-xT-xA-xG-xA-xA-xT-xT-xC-xT-xA-xC-T) (18) formed a duplex with the same Tm as the parent (5′-3′)-(G-T-A-G-A-A-T-T-C-T-A-C) (19), but with an inverted CD spectrum.

Notizen: Early steps in the biosynthesis of dedecano-4-lactone in ripening nectarines (Prunus persica var. nucipersica) and strawberries (Fragaria ananassa) were studied using cis-9,10-([18O]epoxy)heptadecanoic acid (5), instead of the natural C18-precursor epoxystearic acid 1. In nectarines, an epoxide hydrolase catalyzed, in a highly regio- and enantioselective reaction, the attack of H2O at C(9) of epoxy acid 5 yielding preferentially (9R,10R)-dihydroxyheptadecanoic acid 6a as an early intermediate and, after further metabolization, undecano-4-lactone 7a. In strawberries, the same transformation exhibited only a moderate regio- and enantioselectivity. Besides the previously established function of phytogenic epoxide hydrolases involved in generating oxygenated fatty-acid derivatives, which are used in cutin monomer production and plant defence, a new rǒle for these enzymes now emerges in the enantioselective production of aroma components of ripening fruits. The cis-9,10-([18O]epoxy)heptadecanoic acid (≥ 98% 18O; 5) was obtained in good overall yield (68%) from isopropyl (9Z)-heptadec-9-enoate using 18O2 gas in a free-radical chain reaction in the presence of 2-methylbutanal.

Notizen: Synthesis of Trifluoromethyl-Substituted Sulfur Heterocycles Using 3,3,3-Trifluoropyruvic-Acid DerivativesThe reaction of methyl 3,3,3-trifluoropyruvate (1) with 2,5-dihydro-1,3,4-thiadiazoles 4a, b in benzene at 45° yielded the corresponding methyl 5-(trifluoromethyl)-1,3-oxathiolane-5-carboxylates 5a, b (Scheme 1) via a regioselective 1,3-dipolar cycloaddition of an intermediate ‘thiocarbonyl ylide’ of type 3. With methyl pyruvate, 4a reacted similarly to give 6 in good yield. Methyl 2-diazo-3,3,3-trifluoropropanoate (2) and thiobenzophenone (7a) in toluene underwent a reaction at 50°; the only product detected in the reaction mixture was thiirane 8a (Scheme 2). With the less reactive thiocarbonyl compounds 9H-xanthene-9-thione (7b) and 9H-thioxanthene-9-thione (7c) as well as with 1,3-thiazole-5(4H)-thione 12, diazo compound 2 reacted only in the presence of catalytic amounts of Rh2(OAc)4. In the cases of 7a and 7b, thiiranes 8b and 8c, respectively, were the sole products (Scheme 3). The crystal struture of 8c has been established by X-ray crystallography (Fig.). In the reaction with 12, desulfurization of the primarily formed thiirane 14 gave the methyl 3,3,3-trifluoro-2-(4,5-dihydro-1,3-thiazol-5-ylidene)propanoates (E)-and (Z)-15 (Scheme 4). A mechanism of the Rh-catalyzed reaction via a carbene addition to the thiocarbonyl S-atom is proposed in Scheme 5.

Notizen: The oligonucleotide building blocks, the phosphonates 1a, b and the phosphoramidites 2a, b derived from 7-iodo- and 7-bromo-7-deaza-2′-deoxyguanosines 3a, b were prepared. They were employed in solid-phase oligonucleotide synthesis of the alternating octamers d(Br7c7G-C)4 (8) and d(I7c7G-C)4 (9) as well as the homo-oligonucleotides d[(Br7c7G)5-G] (11) and d[(I7c7G)5-G] (12). The melting profiles and CD spectra of oligonucleotide duplexes were measured. The Tm values as well as the thermodynamic data were determined and correlated to the major-groove modification of this DNA. The self-complementary octamers 8 and 9 form more stable duplexes compared to the parent oligomer d(G-C)4. The heteroduplex of d[(I7c7G)5-G] (12) with d(C6) is slightly destabilized (ΔTm = -12°) over that of d[(c7G)5-G] with d(C6). However, the complex of 12 with poly(C) is more stable than that of d[(c7G5-G)] with poly(C).

Notizen: The molecular structure of the two complex ions [Co(tmen)3]3+ and [Co(tmen)3]2+ (tmen = 2,3-dimethylbutane-2,3-diamine) have been determined at 100 K. They show a strong trigonal distortion of the octahedral CoN6 core. The twist angle is 26.2(2.8)° for CoII and 43.9(9)° for CoIII. Average Co—N distances are 2.193(13) Å (CoII) and 1.997(2) Å (CoIII), 0.02 Å longer than for the main body of CoIII amines.

Notizen: Guanidinium compounds imitating the bis(arginine) structural motif of staphylococcal nuclease (e.g. 3) are known to be powerful catalysts for phosphoryl transfer reactions in dipolar aprotic solvents. Compound 3 also accelerates the hydrolysis of RNA (H2O, pH 7). However, due to diminished substrate affinity in H2O, the rate effects are less pronounced in aqueous than in aprotic solution. To test if a synthetic ribonuclease may be derived from the bis(guanidinium) moiety of 3 by the addition of RNA-binding substructures, the TAR sequence of HIV-1 was chosen as a target. The arginine residue of compound 4 serves as an extremely simplified mimic of tat, a protein responsible for boosting the viral transcription by complex formation with TAR. Here, we present the synthesis of 4 and its ability to bind and to cleave efficiently the truncated TAR sequence 1. In addition, the synthesis of an acridine arginine conjugate, 19, is reported in preliminary form. Compound 19 associates with 1 and completely blocks the cleavage induced by 4.

Notizen: Studies on post-angioplastic restenosis have shown the implication of angiotensin II (Ang) as a myoproliferative mediator. The antiproliferative efficacy of non-peptide Ang antagonists on the rat carotid model is of 50%, whereas a continuously infused peptide antagonist at low doses totally blocks neointimal growth. To explore the feasibility of depot forms of Ang that may be introduced during angioplasty and thus prevent restenois, lipid-masked Ang analogues of the following general structure were prepared: [Xxx°, Yyy1]Ang with Xxx = decanoyl or palmitoyl and Yyy = Ser, Cys, Asp, β-lactoyl, 3-mercaptopropanoyl or succinyl. All fatty acylated peptides [Xxx°, Yyy1]Ang were practically inactive, and O- or S-esterified Ser and Cys peptides underwent intramolecular transcylation giving inactive Nx-acylated peptides. O-Acylated [β-mercaptopropanoyl1]Ang were easily hydrolyzed into their biologically active[Yyy1]Ang forms, either by mild saponification or by lipase activity.

Notizen: Nortopsentin D (5), a bis(indole) alkaloid unique for bearing a 2-amino-methylimidazole appendage at the central 1H-imidazol-5(4H)-one nucleus, was isolated in abundance, besides the putative biogenetic precursor 6 of its appendage, from the deep-water axinellid sponge Dragmacidon sp. Structural elucidation of 5 by NMR and MS methods heavily relied on its N-methyl derivatives 8-11. Unusually for topsentin-type structures, natural 5 and semisynthetic methyl derivatives 8 and 10 proved inactive on KB tumoural cells, while introduction of the last three methyl groups, amazingly led to highly cytotoxic 11.

Notizen: The interaction between a vitamin B12 derivative containing a peripheral C18 alkyl chain (see 1a) and a (methyl)thiomalonate substrate bearing alkyl chains of various length at the thioester group (see 5) was investigated. A catalytic cycle was established for the methylmalonyl→succinyl rearrangement by using electrochemistry and photolysis (see Scheme 3). Increased yields of the succinate relative to the reduction product were obtained (2:3 ratio), when the reaction was run in MeOH/H2O, and when both the substrate and the catalyst had an octadecyl substituent capable of hydrophobic interactions.

Notizen: The electrospray tandem mass spectra (ESI-MS/MS) of the three N,N′-bis[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines 1-3 displayed the same fragment-ion signals. These isomers could not be differentiated by ESI-MS/MS, since their fragmentation patterns are similar. (E,E)-N-(3-[15N]Aminopropyl)-3,3′-bis(4- hydroxyphenyl)-N,N′-(butane-1,4-diyl)bis[prop-2-enamide] ([15N(1)])-(1) was synthesized in order to get further information about the fragmentation mechanisms. The comparison of the ESI-MS/MS of 1 and [15N(1)]-1 revealed a transamidation, the Zip reaction, under mass-spectral conditions of the [1 + H]+ ions. Because of this reaction, the three isomers 1-3 could not be distinguished.

Notizen: A total synthesis of cyclothialidine (1), a new DNA gyrase inhibitor isolated from Streptomyces filipinensis, is described. The synthetic concept was tested by preparing the lactone 13 (Scheme 2) which contains the characteristic bicyclic core entity of 1. Key features of the synthesis of 1 are: preparation of 3,5-dihydroxy-2,6-dimethylbenzoic acid (23) from 3,5-dihydroxybenzoic acid (19) by two consecutive Mannich aminomethylation/hydrogenation sequences; benzylic N-bromosuccinimide bromination of an ester derivative 25 thereof and its subsequent coupling with Boc-Ser-Cys-OMe (11); cyclization of the ω-hydroxy acid 29 29 to the 12-membered lactone 30 using preferably Mitsunobu conditions; completion of the peptidic side chains of 1 using Boc strategy (Scheme 4). Optically pure cis-N-(tert-butoxycarbonyl)-3-hydroxy-L-proline ((-)-14) was obtained by resolution of the racemate via an efficient reaction sequence containing a lipase-catalyzed enantiospecific acetate hydrolysis (Scheme 3). The structure of natural 1 was confirmed by comparison with the synthetic material. The synthetic route described provides also easy access to analogues of 1, e.g., via the intermediate 30.

Notizen: A comprehensive series of tetraethynylethenes (= 3,4-diethynylhex-3-ene-1,5-diynes, TEEs) bearing electrondonating (p-methoxyphenyl or p-aminophenyl) and/or electron-accepting (p-nitrophenyl) groups was prepared via [Pd]-catalyzed Sonogashira cross-coupling reactions. The electronic and photonic properties of these molecules were investigated with a special emphasis on the effects caused by degree and pattern of donor/acceptor substitution around the central TEE core. This analysis showed that intramolecular donor-acceptor interactions, as evidenced by a long-wavelength charge-transfer band, are considerably more effective in TEEs 44 and 46, with trans and cis, linearly-conjugated electronic pathways between donor and acceptor, than in 11, with a geminal, cross-conjugated electronic pathway. UV/VIS Spectroscopy revealed a steady bathochromic shift of the longest-wavelength absorption band (λmax) as the number of donor-acceptor conjugation paths increased upon changing from bis-arylated (11, 44, and 46) to tetrakis-arylated (14, 31, and 35) TEEs. The position of the longest-wavelength absorption was also found to be strongly dependent on the nature of the N-substituents in the R2NC6H4-donor groups. Electronic emission spectroscopic investigations demonstrated a considerable solvent dependency of the fluorescence of donor-acceptor-substituted TEEs such as 11 or 44, in agreement with the presence of highly polarized excited states in these molecules. Correspondingly, fluorescence spectra of TEEs bearing only donor or acceptor substituents showed little solvent dependency. The large majority of the donor/acceptor-substituted TEEs are thermally and environmentally stable molecules. They can be stored for months as solids in the air at room temperature, and many decompose only upon heating to temperatures above 200°. X-Ray analysis showed the conjugated C-atom scaffolds of 44, 46, and 67 to be essentially planar, whereas the aryl substituents in 28 and 30 are rotated out of the plane of the TEE core by varying degrees.

Notizen: 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.

Notizen: 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).

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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).

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: ‘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.

Notizen: 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).

Notizen: 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.

Notizen: 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).

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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).

Notizen: The β-hexapeptide (H-β-HVal-β-HAla-β-HLeu)2-OH (2) was prepared from the component L-β-amino acids by conventional peptide synthesis, including fragment coupling. A cyclo-β-tri- and a cyclo-β-hexapeptide were also prepared. The β-amino acids were obtained from α-amino acids by Arndt-Eistert homologation. All reactions leading to the β-peptides occur smoothly and in high yields. The β-peptides were characterized by their CD and NMR spectra (COSY, ROESY, TOCSY, and NOE-restricted modelling), and by an X-ray crystal-structure analysis. β-Sheet-type structures (in the solid state) and a compact, left-handed or (M) 31 helix of 5-Å pitch (in solution) were discovered. Comparison with the analogous secondary structures of α-peptides shows fundamental differences, the most surprising one at this point being the greater stability of β-peptide helices. There are structural relationships of β-peptides with oligomers of β-hydroxyalkanoic acids, and dissimilarities between the two classes of compounds are a demonstration of the power of H-bonding. The β-hexapeptide 2 is stable to cleavage by pepsin at pH 2 in H2O for at least 60 h at 37°, while the corresponding α-peptide H-(Val-Ala-Leu)2-OH is cleaved instantaneously under these conditions. The implication of the described results are discussed.

Notizen: Cholic-acid-type 3-keto steroids 1-8, all isolated from Deltocyathus magnificus (2-8 after CH2N2 treatment), are the first secondary metabolites obtained from a deep-water scleractinian. Steroids 1-3, 5, and 7 are new, their main structural oddities being loss of C(24) (see 5) or hydroxylation in the side chain (see 3 and 7). Steroids 4, 6, and 8, from the same coral, were previously known from other marine organisms.

Notizen: Rearrangement of 5α- and 5β-cholesta-6,8(14)-dienes (13a and 13b, resp.) in the presence of anhydrous toluene-4-sulfonic acid in acetic acid leads to 5α- and 5β-12(13 → 14)-abeo-cholesta-8,13(17)-dienes (15a and 15b, resp.) via 5α- and 5β-cholesta-8,14-dienes (14a and 14b, resp.), respectively. Epimerization at C(20) of the spirosteradienes 15a and 15b occurs with increasing reaction time. Molecular-mechanics calculation of the relative stabilities of these compounds and of congeners thereof is in agreement with the observed reaction pathway.

Notizen: The total syntheses of the spermidine alkaloids (-)-mayfoline (11) and (+)-N(1)-acetyl-N(1)-deoxymayfoline (12) are described. These macrocyclic lactams belong to the most interesting conjugates of the polyamine derivatives very commonly found in nature. The enantioselective syntheses were achieved through resolution of the methyl 3-amino-3-phenylpropanoate (2) by recrystallization of its (+)-L-tartrate salt. Construction of the 13-membered ring ensued through condensation, reductive ring expansion (internal bond cleavage), and finally a transamidation reaction involving a second ring expansion.

Notizen: A number of natural polyphenols (chlorogenic acid (9), cordigol (11), cordigone (12), danthrone (1), 1,5-dihydroxy-3-methoxyxanthone (2), eriosematin (7), flemichin D (8), frutinone A (6), mangiferin (4), quercetin (5), 1,3,6,7-tetrahydroxyxanthone (3) and verbascoside (10)) were investigated for their redox properties using cyclic voltammetry. The antioxidant properties of these compounds were also examined in two models, namely lipid peroxidation in rat synaptosomes and AAPH-mediated oxidation of serum albumin. Compounds with a catechol group (9, 4, 5, 3 and 10) were oxidized below 0.4 V and inhibited lipid peroxidation with IC50 values between 2 and 8 μM. Compounds having one or more isolated phenolic groups and showing an oxidation potential between 0.45 and 0.8 V (11, 12 and 8) inhibited lipid peroxidation with IC50 between 7 and 9 μM, except 2 (0.45 V), danthrone (0.96 V) and eriosematin which showed no or modest antioxidant activity. Some of the investigated compounds also protected albumin from oxidation, but no structure-activity relationship was apparent, suggesting that other factors beside redox potential influence this activity.

Notizen: To demonstrate the relevance of the kinetic acidity of individual OH groups for the regioselectivity of glycosylation by glycosylidene carbenes, we compared the glycosylation by 1 of the known triol 2 with the glycosylation of the diol D-3 and the fluorodiol L-4. Deoxygenation with Bu3SnH of the phenoxythiocarbonyl derivative of 5 (Scheme 1) or the carbonothioate 6 gave the racemic alcohol (±)-7. The enantiomers were separated via the allophanates 9a and 9b, and desilylated to the deoxydiols D- and L-3, respectively. The assignment of their absolute configuration is based upon the CD spectra of the bis(4-bromobenzoates) D- and L-10. The (+)-(R)-1-phenylethylcarbamates 13a and 13b (Scheme 2) were prepared from the fluoroinositol (±)-11 via (±)-4 and the silyl ether (±)-12 and separated by chromatography. The absolute configuration of 13a was established by X-ray analysis. Decarbamoylation of 13a ( → L-12) and desilylation afforded the fluorodiol L-4. The H-bonds of D-3 and L-4 in chlorinated solvents and in dioxane were studied by IR and 1H-NMR spectroscopy (Fig. 2). In both diols, HO—C(2) forms an intramolecular, bifurcated H-bond. There is an intramolecular H-bond between HO—C(6) and F in solutions of L-4 in CH2Cl2, but not in 1,4-dioxane; the solubility of L-4 in CH2Cl2 is too low to permit a meaningful glycosidation in this solvent. Glycosidation of D-3 in dioxane by the carbene derived from 1 (Scheme 3) followed by acetylation gave predominantly the pseudodisaccharides 18/19 (38%), derived from glycosidation of the axial OH group besides the pseudodisaccharides 16/17 (13%) and the epoxides 20/21 (7%), derived from protonation of the carbene by the equatorial OH group. Similarly, the reaction of L-4 with 1 (Scheme 4) led to the pseudodisaccharides 28/29 (46%) and 26/27 (14%), derived from deprotonation of the axial and equatorial OH groups, respectively. Formation of the epoxides involved deprotonation of the intramolecularly H-bonded tautomer, followed by intramolecular alkylation, elimination, and substitution (Scheme 4). The regio- and diastereoselectivities of the glycosidation correlate with the H-bonds in the starting diols.

Notizen: Using the chiral triazolium salt 1 as catalyst, a novel asymmetric variant of the benzoin reaction is reported. For the first time, the scope of the method is extended to a broader range of aromatic aldehydes 2, affording the acyloins 3a-h in yields of 22-72% and enantiomeric excesses up to 86%.

Notizen: Ninety years ago, chemical methods were used in solving biological problems. In our days, methods of evolutionary biology are going to be used in solving problems of synthetic chemistry.

Notizen: The cellobiose-derived dialkynes 14 and 15 were prepared by glycosidation of the acceptor 9 with the thioglycosides 12(82%) and 13(85%), respectively. The acceptor 9 was prepared from the known alcohol 2 via the lactone 7 in five steps (48% overall), and the donors 12 and 13 were prepared from the alkynylated anhydroglucose derivative 10 (60% overall). Acetolytic debenzylation of 14 and 15 (→16 and 17, resp.) followed by deacylation of 16 yielded 60% of the cellobiose-derived dialkyne 18. Deacylation of 14 (→19), methoxymethylation (→20) and trimethylgermylation led to the orthogonally protected dialkyne 21 (69% overall). Protodesilylation of 21 with K2CO3/MeOH gave 22 (90%), while the Me3Ge group was selectively removed with CuBr (19 mol-%) in THF/MeOH to give 20 (95%). Treatment of 21 with aqueous HCl solution led to 19 (80%). Bromodegermylation of 21 (NBS/AgOOCCF3) led to a mixture of 23 (85%) and 24 (11%). Similar conditions using CuBr instead of AgOOCCF3 gave exclusively the bromoalkyne 23 (93%). The temperature dependence of the δ values of the OH resonances of 18 in (D6)DMSO evidence a strong intramolecular H-bond between C(5′)—O…HO—C(5).

Notizen: The Cinchona alkaloid analogs (+)- and (-)-5 with a quinuclidine-2-methanol residue attached to C(2) of a 9,9′-spirobifluorene moiety were prepared as a racemic mixture by reacting lithiated 2-bromo-9,9′-spirobifluorene 7 with (2-ethoxycarbonyl)quinuclidine (±)-6 to give ketone (±)-8, followed by diastereoselective reduction with diisobutylaluminum hydride (DIBAL-H). The absolute configuration at C(9) and C(8), i.e., at the methanol bridge and the adjacent quinuclidine C-atom, in the two enantiomers of 5 is identical to the configuration at the corresponding centers in (-)-quinine (1) and (+)-quinidine (2), respectively. For the optical resolution of (±)-5, a chiral stationary phase for HPLC was prepared by covalently bonding quinine via a thiol spacer to a silica-gel surface. The enantiomer separation was accomplished at an α value of 1.61 with (±)-5 being eluted last, in agreement with 1H-NMR studies in CDCl3 which showed that (+)-5 underwent a more stable host-guest association with quinine than (-)-5. 1H{1H} Nuclear Overhauser effect (NOE) difference spectroscopical analysis of the host-guest associations with quinine in CDCl3, combined with computer-model examinations, allowed the assignment of the absolute configurations as (+)-(8R,9S)-5 and (-)-(8S,9R)-5. A detailed conformational analysis displayed excellent agreement between the results of computational methods (Monte Carlo multiple minimum simulations, analyses of the total energy as a function of the flexible dihedral angles in the molecule) and 1H{1H}-NOE difference spectroscopical data. It was found that (-)-5 and (+)-5 differ significantly in their conformational preference from their natural counterparts quinine (1) and quinidine (2). Whereas the natural alkaloids prefer the ‘open’ conformation, with the quinuclidine N-atom pointing away from the quinoline ring, analog (±)-5 adopts preferentially (by ca. 4 kcal mol-1) a ‘closed’ conformation, in which the quinuclidine N-atom points into the cleft of the 9,9′-spirobifluorene moiety. Since the basic quinuclidine N-atom in the ‘closed’ conformation is sterically shielded from forming strong H-bonds, the new Cinchona alkaloid analogs form less stable host-guest associations via H-bonding than quinine or quinidine.

Notizen: Acidic condensation of 2,4-dimethylfuran with acetaldehyde provided 2,2′-ethylidenebis[3,5-dimethylfuran] (7) which added 1 equiv. of methyl bromopropynoate to give a major adduct 8. Regio- and stereoselective hydroboration of the latter 7-oxanorbornadiene derivative followed by alcohol protection and methanolysis of its β-bromoacrylate moiety gave (1RS,2RS,4RS,5SR,6SR,1′RS)-methyl 4-[1′-(3″,5″-dimethylfuran-2″-yl)ethyl]-3,3-dimethoxy-6-exo-[(2-methoxy)ethoxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptane-2-endo-carboxylate (24) (Schemes 2 and 3). Reduction of 24 with LiAlH4, followed by H2O and MeOH elimination gave the 3-methyl-idene-7-oxanorbornan-2-one derivative 26 which underwent 7-oxa ring opening through a SN2′ type of reaction with Me2CuLi (Scheme 4). Stereoselective hydrogenation and ketone reduction provided (1RS, 2SR,3RS,4RS,5RS,6RS,1′SR)-1- [1″-(3 ″,5″-dimethylfuran-2″-yl)]-c-3-ethyl-c-5-[(2-methoxyethoxy)m e-c-ethyl-c-c-5-(2-methoxyethoxy)methoxy]-t-4,t-6-dimethyl-cyclohexane-r-1,c-2-diol (32), the oxidative cleavage of which with Pb(OAc)4 generated a 6-oxo-aldehyde 33 (Schemes 4 and 5). Chemoselective protection of 33 and chemo- and stereoselective reductions generated (2RS,3RS,4SR,5SR,6SR,7RS)-7-(3′,5″-dimethylfuran-2′-yl)-2-ethyl-6-hydroxy-4-[(2-methoxyethoxy)methoxy]-3,5-dimethyloct-1-yl pivaloate (36) and its 4-hydroxy 6-epimer 40 (12 and 13 steps, resp., from adduct 8; Scheme 5). Oxidation of the furan ring of 36 led to a (2RS,3SR,4RS,5SR,6RS,7RS)-7-ethyl-3,5,8-trihydroxy-2,4,6-trimethyl-octanoic acid derivative 44, a polypropionate fragment with six contiguous stereogenic centres (Scheme 6).

Notizen: Isomerization of (all-E)-Cycloviolaxanthin. Preparation and Characterization of (9Z)- and (13Z)-CycloviolaxanthinFrom (all-E)-cycloviolaxanthin (ex Capsicum annuum), (9Z)- and (13Z)-cycloviolaxanthin were prepared in a highly pure state. The configuration of both isomers was determined by means of UV/VIS, NMR, and CD spectroscopy.

Notizen: Cyclohexa-1,3-dienes 7-10 with a 1,5,6-substitution pattern were prepared in a one-pot reaction sequence by sequential addition of MeLi and propargyl bromides to the tricarbonylchromium complex 1a. These products were subjected to radical cyclization procedures. Vinyl radical generation by Bu3Sn addition to the propargyl group in 7-10 was followed by regio- and diastereoselective intramolecular ring closure. Two different 5-exo-trig cyclizations are possible via different vinyl radical intermediates and cyclization to one or the other of the termini of the cyclohexadiene moiety. Internal alkynes reacted to yield exclusively the cis-fused hexahydroindene products 12-14, whereas the terminal alkyne yielded bicyclo[3.2.1]octenes 11 as sole products.

Notizen: The first asymmetric intramolecular Stetter reaction is reported, using the chiral triazolium salt 1 as catalyst. Starting from the easily accessible 4-(2-formylphenoxy)but-2-enoates 2, this protocol opens up an enantioselective pathway to the benzo-annulated pyran-4-ones (chroman-4-ones) 3a-h with good yields and enantiomeric excesses of up to 74%.

Notizen: The 3-(2-propenylidene)-β-lactams 1a-c react as semicyclic dienes with the dihydrotriazole-diones 2 in a stereoselective fashion leading to the cycloadducts 3. The 3′,3′-disubstituted derivative 4 gives no [4 + 2]-cycloaddition products but forms the adducts 5 and 6. Sterochemistry and reaction pathways are discussed.

Notizen: Quantum-chemical calculations employing a density-functional theory/Hartree-Fock hybrid method (B3LYP) have been used to explore the mechanistic details of the C—C and C—H bond-activation processes in propane mediated by a bare Fe+ ion. While the theoretically predicted results are in complete accord with all available experimental data, they give rise to a different mechanistic picture than envisaged previously. In contrast to earlier speculation, the activation barriers for the initial insertion steps of Fe+ into a C—H or C—C bond are found to be significantly below the Fe+ + C3H8 channel. The rate-determining steps for both, the C—C and the C—H bond activation branches of the [FeC3H8]+ potential-energy surface rather occur late on the respective reaction coordinates and are connected with saddle points of concerted rearrangement processes. The C—C bond activation, which leads to the exothermic reductive elimination of methane, occurs via the C—C inserted species and not as a side channel originating from a C—H inserted ion, as assumed hitherto. For the C—H bond-activation processes, which finally results in the exothermic expulsion of molecular hydrogen, two energetically similar reaction channels for an [1,2]-elimination exist. The results clearly show, that an [1,3]-H2-elimination mechanism cannot compete with the [1,2]-elimination paths, in line with the experimental findings. Overall, a lower energy demand for the reductive elimination of methane compared to the loss of H2 is obtained, straightforwardly explaining the preference of the former process observed experimentally.

Notizen: At 0° in MeCN, 2,2-disubstituted 3-amino-2H-azirines 1 and 4,4-disubstituted 1,2-thiazetidin-3-one 1,1-dioxides 7 react smoothly to give 1,2,5-thiadiazepin-6-one 1,1-dioxides of type 8 (Scheme 2). The reaction mechanism of this regiospecific ring enlargement to seven-membered heterocycles follows previously described pathways. The structures of 7a and 8b were established by X-ray crystallography (see Figs. 1 and 2).

Notizen: (all-Z)-(9,10,12,13,15,16-2H6)Octadeca-9,12,15-trienoic acid ( = α-linolenic acid; D6-4) was synthesized to investigate the biochemical formation of linolenic-acid-derived aroma compounds in cultures of the yeast Sporobolomyces odorus, using an established gas chromatographic/mass spectrometric (GC/MS) method. Three compounds were identified as labeled: (Z)-dec-7-eno-5-lactone (δ-jasmin lactone), (Z,Z)-dodeca-6,9-dieno-4-lactone, and (2E,4Z)-hepta-2,4-dienoic acid. Both lactones were biosynthesized mostly under conservation of the initial configuration from their corresponding oxygenated linolenic-acid intermediates. The application of (13S,9Z,11E,15Z)-13-hydroxy(9,10,12,13,15, 16-2H6)octadeca-9,11,15-trienoic acid (D6-7) as a OH-functionalized precursor of δ-jasmin lactone allowed to gain insight into the stereochemical course of the biosynthesis to both enantiomers of this lactone. In this experiment, 88.3% of the metabolized labeled precursor was transformed under retention of the original configuration of the (R)-enantiomer. This investigation is also a contribution to a better understanding of the C=C bond isomerization steps which took place during the β-oxidative degradation of the substrate.

Notizen: 5,5′-Bi-5H-cyclopenta[2,1-b;3,4-b′]dipyridinylidene(1) was synthesized in three steps from 9,10-phenanthroline and characterized by UV/VIS and NMR spectroscopy, mass spectrometry, and cyclic voltammetry. Its ability to act as a bridging ligand is demonstrated by the synthesis of the complexes [Ru(bpy)2(1)](PF6)2 (6) and [{Ru(bpy)2}2(1)](PF6)4 (7) (bpy = 2,2′-bipyridine).

Notizen: The cyclododecadiynes 3b-d, 8b-d, and 10b-c with functionalities in two propargylic positions, as well as the monofunctionalized diyne 13b have been prepared from simple open-chain building blocks. In the DMPU ( = N,N'-dimethylpropyleneurea)-assisted ring-closing alkylation of 1,7-diynes, the twelve-membered ring compounds have been prepared in yields of 16-55%. The preparation of the diene-diyne 15 and the cyclododeca-5,11-diyne-1,4-dione 18 are described.