Library

Notes: The chemical synthesis of 2′-amino-2′-deoxyribonucleosides of uracil, cytosine, adenine, and guanine, and their conversion into suitably protected 3′-phosphoramidite building blocks 35-40 for oligonucleotide synthesis are described. The aglycone and the 2′-amino functions were protected using the 2-(4-nitrophenyl)ethoxycarbonyl (npeoc) group. The synthesis of the 3′-O-succinyl (3′-O-(3-carboxypropanoyl))-substituted starting nucleoside 41 is described and its behavior examined in solution and on solid phase with regard to an anticipated migration during 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) deprotection. Oligonucleotides were prepared using the new building blocks, and their hybridization properties were studied by UV-melting techniques.

Notes: Chiral supermolecules may be obtained from suitable achiral molecular constituents associated through a dissymmetrizing interaction mode. This is the case for the supermolecules I-IV formed by hydrogen-bonding association between the achiral complementary components 1a,b and 2a,b,c. The crystal structures of the supermolecular pairs I-III and of the homochiral aggregate of two ternary supermolecules IV have been determined. The structural data are discussed.

Notes: Various bifunctional amino-protecting groups such as the phthaloyl, succinyl, and glutaryl group were investigated as potential linker molecules for attachment to solid-support materials. Pentane-1,3,5-tricarboxylic acid 1,3-anhydride (16) offered the best properties and reacted with the amino groups of differently sugar-protected adenosine (see 20 and 22), cytidine (see 29), and guanosine derivatives (see 32) to the corresponding 2-(2-carboxyethyl)glutaryl derivatives 23, 24, 30, and 33. The usefulness of the new linker-type molecules was demonstrated by the solid-support synthesis of the potentially antivirally active 3′-deoxyadenylyl-(2′-5′)-2′-adenylic acid 2′-{2-[(adenin-9-yl)methoxy]ethyl} ester (38) starting from the 2′-end with N6,N6-[2-(2-carboxyethyl)glutaryl]-9-{{2-[(4,4′-dimethoxytrityl)ethoxy]methyl}adenine (12).

Notes: An efficient stereocontrolled synthesis of (S)-N-Cbz-serine (Cbz = benzyloxycarbonyl; 12) and of its (R)-enantiomer is reported. Kinetic resolution of the easily available racemic 3-(hydroxymethyl)-1,4-benzodiazepin-2-ones is performed in the key step via acetylation by the immobilized Mucor miehei lipase (Lipozyme IM) at 60°. This method is characterized by high enantiomer purity (ee's ges; 99%) of the intermediary alcohols (+)-8 and (+)-9 and acetates (-)-10 and (-)-11, as well as of the final products (S)- and (R)-N-Cbz-serine, simple recycling of the biocatalyst, complete recovery of 2-aminobenzophenones (3 and 4) and their recycling into production of 1,4-benzodiazepines, and possibility to selectively racemize ‘wrong’ enantiomers of the alcohols 8 and 9 in the presence of Amberlite CG 400.

Notes: The fate of an insect juvenile hormone analog applied to the insect body of the flesh fly (Sarcophaga bullata) or the tsetse fly (Glossina palpalis), respectively, was studied using three different radiolabeled positions in the parent biologically active compound 1. Several metabolites were found and analyzed. A mechanism of degradation of the applied molecule was designed using a combination of several radioanalytical methods. A unique monitoring of the applied compound and its metabolites was provided, based on the different radiolabeling of the structure (cf. 1a-1c), and established their fate in an insect body during a 10-day experiment. A 14C and 3H radiolabeling, respectively, was employed to synthesize three different radiolabeled forms 1a-1c derived from the parent non-labeled 1. A combination of three different ways of radiolabeling resulted in an advantage in tracing the metabolic pathway of degradation of the employed compound 1 in its radiolabeled forms 1a-1c.

Notes: Previous work has indicated orbital-symmetry effects upon forward electron transfer in bimolecular systems, with magnitude similar to that encountered in rigid monomolecular systems. The present work, which employs back electron transfer, supports and extends these earlier findings.

Notes: According to ab-initio calculations, the CF…HO H-bond in 1,3-diaxial 3-fluorocyclohexanol is characterized by d(F…H) = 2.08 Å, and ∠ (F…H—O) = 138°, and by ΔE between 1.2 and 4.1 kcal/mol, depending upon the reference system. Relative to the OH stretching frequency of axial cyclohexanol, the OH stretching frequency of 1,3-diaxial 3-fluorocyclohexanol is shifted by Δω = 7 cm-1. The rigid fluoro diols D-4 and L-4 were prepared from tetrahydroxy-p-benzoquinone in 11 steps and 1% overall yield. The IR spectrum of 4 in CCl4 soln. is characterized by Δν = 7 cm-1 for the axial and Δν = 44 cm-1 for the equatorial OH group. A relatively strong intramolecular CF…HO bond of 4 in CCl4 is evidenced by the large through-space coupling 5J(F,HO) of 9.3 Hz. Nevertheless, this FHO bond is disrupted in ethereal solvents, while the bifurcated O…HO bond subsists. In CCl4, the carbene generated from the glucosylidene-derived diazirine 5 reacted more rapidly with the axial OH group of D-4 and L-4 than with the equatorial one. This regioselectivity is in keeping with the weaker H-bond of the axial OH group. The regioselectivity is lower in ethers, but its solvent dependence does not parallel solvent basicity. This is not satisfactorily explained by the differential interaction of the ether solvents with the axial and equatorial OH groups, as evidenced by the solvent dependence of their chemical shift, but must also reflect the different interaction of the solvents with the carbene derived from 5, leading to ylides. The lower solvent dependence of the anomeric selectivity for the glycosidation of the equatorial OH group is a consequence of the coordination of the intermediate oxycarbenium ion with O—C(1) and O—C(3) rather than with the solvent. Under conditions of competitive glycosylation in CCl4, the fluoro alcohol D-22 reacted more slowly than the alcohol L-24, evidencing the intramolecular F…HO H-bond.

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 methano bridge of the tricyclic khusimone should lead to the bicyclic partial structure (-)-2. Unexpectedly, (-)-2 could not be obtained since epimerization favored (-)-16. The stereochemical key step of the synthesis of the hydrazulene nucleus is based on a highly diastereoselective conjugate addition to a chiral oxocyclopent-1-ene-1-carboxylate.

Notes: A convenient preparation of (1R,2S,3R,4S)-3-(neopentyloxy)isoborneol (= (1R,2S,3R,4S)-3-(2,2-dimethyl-propoxy)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 1a), a valuable chiral auxiliary, is described. The synthesis involves six steps starting from the readily available camphorquinone (5) and gives 1a in 48% overall yield. The key step is the chemoselective hydrolysis of the less hindered 1,3-dioxolane moiety in the camphorquinone di-acetal 4.

Notes: A novel general synthesis of 2,4,5-tri- and 2,4,5,6-tetrasubstituted pyrimidines 5a-d and 7a, e, f, g by condensation of thiouronium salts of type 3 with (ethoxymethylidene)malononitrile (4) and [bis(methylthio)methylidene]malononitrile (6), respectively, was first established in solution (Scheme 1) and successfully transferred onto solid support by using the polymer-bound thiouronium salt 11 (Scheme 3). Further investigations were directed toward a multidirectional cleavage procedure of the 2-(alkylsulfinyl) intermediates, obtained from the 2-(alkylthio)pyrimidines 7a (Scheme 2) or 12 and 14 (Schemes 3 and 4), with different nucleophiles to form highly substituted pyrimidines. In addition, fused-heterocycle derivatives 22a--h, 24a-c, and 26a-e were generated in good-to-excellent yields by condensation of 7a, e, h with versatile isocyanates and isothiocyanates, with subsequent alkylation (Scheme 5).

Notes: Introduction of the non-complexing chiral (S)-2-methylbutoxy substituent close to the complexing site of a bis[(bipyridinyl)methoxy]calixarene podand resulted in the induction of an enantiomeric excess of ca. 30 % in the corresponding chiral CuI complex. Structural investigations by high-resolution NMR studies led us to propose the left-handed prohelical [CuI(bpy)2] substructure for the major enantiomer.

Notes: The insecticidal polyether antibiotic X-206 (1) complexes potassium ions using nearly all of its O-atoms either for binding to the metal ion or for participation in a H-bonding network which helps to hold X-206 in the ionophoric tertiary structure. The group OH—C(22) is not involved in these processes. It was supposed that derivatization of this group would not affect the ionophoric properties and would produce insecticidally active compounds. The chemistry leading to selective modification of OH—C(22) via the intermediate 6 was developed. The potassium-binding properties and insecticidal activities of the MeCOO—C(22) and MeO—C(22) compounds 3 and 11, respectively, confirmed that derivatization of the peripheral OH—C(22) was a valid strategy for the synthesis of biologically active compounds.

Notes: The lactam 21 was obtained in an overall yield of 72% from the hydroxy amide 16 by oxidation with the Dess-Martin periodinane, acid-catalysed isomerization of the oxidation products in toluene, whereupon 18/19 precipitated, and reductive dehydroxylation of 18/19 (Et3SiH/BF3 · OEt2; Scheme 1). The amide 16 was obtained by ammonolysis of the N-acetylglucosamine-derived lactone 15. Depending on the oxidation method, 16 yielded the keto amide 17, the hydroxy lactams 18/19, and the pyrrolidinecarboxamide 20 in widely different proportions. The pyrrolidinecarboxamide 20 was not reduced under the conditions of the reductive dehydroxylation. Hydrogenolysis of the benzyl-protected lactam 21 gave the trihydroxy lactam 22, while reduction with NaBH4/BF3 · OEt2 led to the 2-acetamidopiperidine derivative 24 (Scheme 2). Selective (tert-butoxy)carbonylation of the lactam 21 (→ 25) followed by NaBH4 reduction and acid-catalysed solvolysis in EtOH led to the α-ethoxycarbamates 28/29. Similarly, (tert-butoxy) carbonylation of 1 (→ 31) followed by reduction to 32/33 and glycosidation yielded the ethoxycarbamate 34. Treatment of the GlcNAc-derived ethyl glycosides 28/29 with Me3SiCN/BF3 · OEt2 gave the equatorial amino nitrile 30. Under similar conditions, the Glc-derived glycoside 34 led to the iminooxazolidinone 35. In the presence of a larger proportion of Me3SiCN at 5°, 34 was transformed into the axial, selectively monodebenzylated amino nitrile 36.

Notes: The reaction of 2-(trimethylsilyl)thiazole (2-TST) with several ketones was tested in the presence or absence of aldehydes. The keto aldehyde 5 (Scheme 2) was prepared from 1 via the hydroxy aldehyde 4 in 3 steps. It reacted with 2-TST to give, after desilylation and acetylation, the bis-thiazole 6. The ketone 11, obtained from 4 in 3 steps, reacted with 2-TST to give, after desilylation, 12. The ketofuranose 17 (Scheme 3) reacted with 2-TST to yield exclusively the more stable D-gluco epimer 18. The reaction of the ketone 11 (Scheme 2) with 2-TST was faster in the presence of 1 equiv. of the keto aldehyde 5, suggesting that an aldehyde promotes the indirect and intermolecular addition of 2-TST to a ketone. We have studied the effect of several aldehydes on the rate of the reaction of the ketones 11 and 17 with 2-TST at different temperatures and at different concentrations of the ketones and of the aldehydes. Electrophilic aldehydes, and particularly 2-fluorobenzaldehyde (0.1 equiv.), promote the addition of 2-TST to electrophilic ketones.

Notes: The synthesis of the Fmoc-protected amino acid 2 is presented. First attempts of amide-bond formation to the homodimer 4 in solution showed only poor coupling yields indicative for the low reactivity of the amino and carboxy groups in the building blocks 1 and 2, respectively (Scheme 1). Best coupling yields were found using dicyclohexylcarbodiimide (DCC) without any additive. The oligomerization of building block 2 adopting the Fmoc ((9H-fluoren-9-ylmethoxy)carbonyl) solid-phase synthesis yielded a mixture of N-terminal-modified distamycin-NA derivatives. By combined HPLC and MALDI-TOF-MS analysis, the N-terminal functional groups could be identified as acetamide and N,N-dimethylformamidine functions, arising from coupling of the N-terminus of the growing chain with residual AcOH or DCC-activated solvent DMF. An improved preparation of building block 2 and coupling protocol led to the prevention of the N-terminal acetylation. However, ‘amidination’ could not be circumvented. A thus isolated tetramer of 2, containing a lysine unit at the C-terminus and a N,N-dimethylformamidine-modified N-terminus, not unexpectedly, showed no complementary base pairing to DNA and RNA, as determined by standard UV-melting-curve analysis.

Notes: (S)-4,4,4-Trifluoro-3-hydroxybutanoic acid was used as a starting material for the synthesis of dendritic branches (16-21, 30-32) which were attached to a chiral triol (6 or ent-6), derived from (R)-3-hydroxybutanoic acid, to give CF3-substituted dendrimers (33-36, 38-40) and dendritic compounds (37) of 1st and 2nd generation. The key steps in these syntheses are diastereoselective aldol additions of dioxanone enolates (building blocks and intermediates 6-15, 22, 23, and 25-28) and Williamson etherifications of benzylic-branch bromides with triols (intermediates and products 16-21, 28, and 30-40). The surfaces of the dendrimers are covered with MeO (33-35, 38-40) or allyloxy groups (36 and 37). The new dendrimers are characterized by NMR and mass spectroscopy. 19F-NMR Signals of the CF3 groups reveal constitutional heterotopicities caused by substituents which are separated from the F-nuclei by up to 15 bonds (through a 1,1′-biphenyl-4,4′-diyl spacer!) (Fig. 6).

Notes: An explanation for the very high diastereoselectivity observed for the reactions of carbonyl-substituted (arylsulfinyl)methyl radicals is presented, based on experimental results and semiempirical calculations. The influence of dipole-dipole interactions, allylic 1,3-strain (A1,3 strain), allylic 1,2-strain (A1,2 strain), and coulombic interactions is discussed based on stereoselectivities observed with (alkoxycarbonyl)-, cyano-, and aryl-substituted (arylsulfinyl)methyl radicals. In the second part, the effect of solvents and Lewis acids on the stereoselectivity of reactions of (arylsulfinyl)- and (alkylsulfinyl)benzyl radicals has been examined.

Notes: Compounds 6-13 were prepared starting from 1-(triphenlymethyl)-protected 1H-imidazoles 14 and 15 in several steps. Lithiation with BuLi in THF followed by reaction with (triphenylmethoxy)acetaldehyde (16) afforded 17 and 18, respectively. O-Methylation of 17 and 18 gave diethers 19 and 20, respectively. The N- and O-trityl protecting groups of 17-20 were cleaved by acid treatment to give deprotected compounds 21-24. Acylation with equimolar amounts (for mono- or di-O-acylation) of the corresponding acyl chlorides yielded 1H-imidazoles 6-13. Compounds 7, 8, 10, and 11 exhibited moderate protein kinase C inhibition.

Notes: The indolomorphinans 4-7 were prepared from their corresponding morphinan-6-one derivatives 8-11 via Fischer indole synthesis. Compounds 4 and 5 exhibited higher antagonist potency at δ opioid receptors in the mouse vas deferens preparation than the reference drug HS 378 (2), while compounds 6 and 7 were less potent.

Notes: 8-Fluoro-6-(methoxymethoxy)quinoline (1) was synthesized, and the reactivity of 1 against organolithium compounds was studied under different reaction conditions. With BuLi, directed ortho-metalation (DoM) was accompanied by 1,2-addition to the C=N bond. 1,2-Addition was exclusively observed with t-BuLi. Selective ortho-metalation was achieved with MeLi (Table). Based on these findings, a short and high-yielding synthesis of the highly functionalized quinolines 12a-c was developed.

Notes: The new derivatives 7a-c, of vitamin B12, with a peripheral tris(oxyethylene) chain linked to the corrin ring by an amide or ester group, are prepared, and their ligand-exchange reactions are investigated. Upon reduction of the aqua-cyano complexes 8a-c with NaBH4, cleavage of the ‘outer’ ester and amide group is observed.

Notes: Investigation of the inhibition of δ-chymotrypsin with the four novel, optically active, axially and equatorially substituted cis-3-(2,4-dinitrophenoxy)-2,4-dioxa-3λ5-phosphabicyclo[4.4.0]decan-3-ones (= 3-(2,4-dinitrophenoxy)hexahydro-4H-1,3,2-benzodioxaphosphorin 2-oxides) showed only the equatorially substituted enantiomer (-)-4b to be an irreversible inhibitor of the enzyme, and (-)-4b at pH 7.8 revealed a quickly rising resonance at -2.49 ppm assigned to the hydrolysis product 8 and later, while inhibition proceeded, a second one at -4.08 ppm. attributed to the δ-chymotrypsin adduct 7 (Scheme 3). Comparision of the latter signal with the 31P-NMR chemical shifts of the covalent phosphoserine model compounds (-)-6a (-5.67 ppm, axial substitution) and (+)-6b (-4.02 ppm, equatorial substitution) suggests that the inhibition proceeded via neat retention of the configuration at the P-atom of (-)-4b yielding the equatorially substituted covalent Ser195 adduct 7.

Notes: The synthesis of 8-azaadenosine (1a; z8A) has been performed by SnCl4-catalyzed glycosylation of 8-azaadenine (4) with 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (5), followed by the separation of the regioisomers 6 and 7 and subsequent deacetylation. The ribonucleoside 1a as well as its 2′-deoxy derivative 1b (z8Ad) were converted into oligonucleotide building blocks-the phosphonate 2 as well as the phosphoramidites 3 and 19. They were used to prepare the oligoribonucleotide (z8A-U)6 and oligodeoxyribonucleotides. The Tm values and the thermodynamic data of duplex formation of the modified duplexes showed no significant changes compared to those containing Ad or A residues. This indicates that the stereoelectronic effect of the 8-azaadenine base which was found for the monomeric nucleoside has only a minor influence on the duplex stability.

Notes: Short, dye-labeled oligonucleotides have been used as primers in template-controlled polymerization reactions of RNA. The synthesis of appropriate acridine derivatives and their attachments to nucleic acids is described. In the nonenzymatic oligomerization of 2-methyl-1H-imidazole-activated guanosine 5′-monophosphate, two observations deserve special notice: (1) reaction rates are almost unchanged by variations of the Na+ concentration; (2) the conformational type of the primer-template duplex (A vs. B) has considerable influence on the rates and yields of RNA oligomerization. When the incorporation of cytidine was studied in the presence of 1M Na+ or K+, the process was almost inhibited by quadruplex formation of the oligo-dG template. However, if these cations were omitted, an efficient primer extension could be observed using template concentrations as high as 100 μM. The chances for nonenzymatic self-replication of RNA thus might be distinctly better than previously assumed.

Notes: The reaction of ω-keto amides with Lawesson's reagent (LR: 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide) is described. Treatment of 3-keto amides (2-acylacetamides) 1 with LR gave the corresponding 3-keto thioamides 2, along with 1,2-dithiole-3-thiones 3. Treatment of 4-keto amides, 3-acyl propionamides 5, with LR yielded five-membered heterocycles, pyrroles 6 and/or 2-aminothiophenes 7. 5-Keto amides, 3-benzoyl butyramides 8, reacted with LR to give dihydrothiopyran-2-thione 9 as the sole product, but in low yield. 2-Acylbenzamides 10 also reacted with LR to afford 3-mercaptoisoindolin-2-ones 11 or dihydroisobenzothiophene-1-thiones 12.

Notes: A novel and more efficient synthesis of 14-alkoxy-substituted indolo- and benzofuro-morphinans in three steps starting from either naltrindole (1) or naltriben (2), using methoxymethyl or silyl protecting groups, is reported. The 14-O-alkyl group is introduced at the penultimate step of the procedure. This is an additional advantage of the described procedure since the late introduction of the 14-O-alkyl group makes it much easier to produce a greater diversity of 14-alkoxy derivatives in this series of δ opioid receptor antagonists. Thus, compounds 14-19, 20-25, and 27-29 were synthesized.

Notes: Variously β-substituted (2R)-N-[(E)-α,β-enoyl]bornane-10,2-sultams were oxidized with OsO4/4-methylmorpholine 4-oxide in a highly stereoselective manner. In all cases, the attack occurred on the C(α)-re face. The absolute configurations of all products were determined by chemical correlation. Mechanistic considerations about the reactive conformation as well as fully refined X-ray crystal structures of the dihydroxylated products are discussed. New neutral conditions for sultam acylation, applicable to the preparation of the taxol and Taxotere® C(13) side chain as well as of Cardizem® and chloramphenicol precursors, are also presented.

Notes: α-Bromination of 9-acetoxy rubanone 2 and subsequent reaction with secondary amines gave bicyclic α-amino ketones as a kinetic product and a 4-oxa-1-azatwistan-2-one 6 under thermodynamic conditions. This two-step procedure represents a concise 1,2-carbonyl transposition and provides a short route to lactam alkaloids.

Notes: Macrocyclic [4n + 2]-Hückel Aromatic Systems up to n = 9 and [4n] Antiaromatic Systems up to n = 10: Homologous Sequences from Tetraepoxy[24]annulene(2.0.2.0) to Tetraepoxy[40]annulene(12.0.12.0) and from the ‘Tetraoxa[22]porphyrin(2.0.2.0)-’ to the ‘Tetraoxa[38]porphyrin(12.0.12.0’-Dication1)2)Tetraepoxy[32]annulene(8.0.8.0) 3, tetraepoxy[36]annulene(10.0.10.0) 4, and tetraepoxy[40]annulene(12.0.12.0) 5 are synthesized and oxidized to give the ‘tetraoxa[30]-’, ‘tetraoxa[34]-’, and ‘tetraoxa[38]porphyrin’ dications 8-10. The annulenes as well as the ‘porphyrins’ are mixtures of at least two different configurational isomers, which can be analyzed by 1H-NMR techniques. Together with systems described already earlier, a complete homologous sequence from tetraepoxy[24]annulene(2.0.2.0) to tetraepoxy[40]annulene(12.1.12.0) and from ‘tetraoxa[22]porphyrin(2.0.2.0)’ to ‘tetraoxa[38]porphyrin(12.0.12.0)’ dications are available for the first time. The UV/VIS-absorptionmaxima in the annulene series are shifted to longer wavelengths with an increment of 12 nm per additional C=C bonds, and the Δδ values of the 1H-NMR spectra demonstrate a decreasing paratropic character (Δδ = 5.97 (1), 2.80 (3), and 4.23 ppm (4). The averaged λmax values of the Soret bands of the ‘tetraoxaporphyrin’ dications show a linear bathochromic shift with an increment Δδ of 58 nm per two additional double bonds, the absorptions of the most intensive Q-bands also increase linearly with an increment of ca. 160 nm. The Δδ values of the 1H-NMR spectra of the ‘tetraoxaporphyrin’ dications are increasing with the ring size (Δδ = 24.04 (7a) to 25.17 (9a) ppm), respectively, decreasing (Δδ = 21.55 (6) to 21.50 (9b) ppm) with a small maximum of 22.60 ppm for 7b, depending on the configuration of the isomers. The results confirm the antiaromatic character of the annulenes with up to 40π electrons and the aromatic character of the ‘tetraoxaporphyrin’ dications with up to 38π electrons.

Notes: A broad variety of new acyclic vinyl ethers (see 6-41) have been synthesized via the vinyl-interchange reaction of ethyl vinyl ether at room temperature using mercury(II) trifluoroacetate as a highly efficient catalyst. The appropriate vinyl ethers were reacted under acidic conditions with 3′,5′-O-silyl-protected uridine 42 to the corresponding 2′-O-(1-alkoxyethyl) derivatives 43-83 which gave, on desilylation of F- ions, in high yields the uridine-2′-O-acetal derivatives 84-124. The relative stabilities of the newly synthesized compounds under acidic and basic conditions were determined using TLC and HPLC techniques. Protected protecting groups offer the best properties for oligoribonucleotide syntheses. Interestingly, the very acid-stable acetals of the β-substituted ethyl-type 118-121 and 123 can be cleaved by a β-elimination process providing a series of base-labile acetals of potential synthetic value.

Notes: Enantioselectivity of acetylation by vinyl acetate/AcOEt catalyzed by immobilized Candida antarctica lipase (Novozym 435) is studied for rac-3-(hydroxymethyl)-1,4-benzodiazepin-2-ones 7, 9, 14 (n = 1; number of CH2 groups in the chain at C(3)), 20 (n = 2), and for prochiral 3,3-bis(hydroxymethyl) derivative 16. Enantiomeric excess (ee [%]) is correlated with conformational properties of substrates (relative conformation, energy difference between two boat-like ground-state conformations, ring-inversion barrier) as determined by DNMR and MM2 calculations. (3S)-Enantiomers of acetates (+)-8, (+)-10, (+)-15, and (+)-21 were preferentially formed. In the case of the acetate (-)-17 (ee 90.2%), formation of the (3R)-enantiomer was favored. C(3)—OH Group with hemiaminal-like character in rac-3 (n = 0) cannot be acetylated by any of 23 tested lipases and four esterases. For racemic alcohols 7, 9, 14, and 20, preferred acetylationof the (3S)-enantiomers, present in solution in absolute (M)-conformation, was established; only in prochiral diol 16 (n = 1) the CH2OH group in the (pro-R)-position is prevalently acetylated, presumably due to the binding to the enzyme, in absolute (P)-conformation. Temperature dependence of enantioselectivity revealed inverse correlation of the E value of rac-9, and ee values for prochiral 16, with T[K], indicating prevalent contribution of the enthalpy term to enantioselection. Absolute conformation (M/P) and absolute configuration at C(3) of all products was determined by combining CD and 1H-NMR data.

Notes: In spite of the higher reactivity of styrene with respect to ethene for the alternating copolymerization with carbon monoxide, catalyzed by chiral (dihydrooxazole)(phosphino)palladium complexes, ethene is preferentially (and randomly) enchained in terpolymerization experiments; enantioface selection for styrene is comparably high in both copolymerization and terpolymerization processes.

Notes: The successful application of the Arndt-Eistert protocol starting from commercially available N-{[(9H-fluoren-9-yl)methoxy]carbonyl}-protected (Fmoc) α-amino acids leading to enantiomerically pure N-Fmoc-protected β-amino acids in only two steps and with high yield is reported.

Notes: 8,19-Dimethyl-tetraepoxy[22]annulen(2.1.2.1): The First Tetraepoxy-Bridged Aromatic[22]AnnuleneBy McMurry reaction of 5,5′-ethylidenebis[furan-2-carbaldehyde] (15), a syn/anti mixture 16 of (E,E)- and (Z,Z)-8,19-dihydro-8,19-dimethyl-tetraepoxy[22]annulene is obtained. The (E/E)-isomers 16 are the first rotation- ally active noncyclic conjugated macrocycles, where the (E)-ethenediyl moieties rotate around the connecting single bonds. The dihydro-tetraepoxy[22]annulenes 16 are dehydrogenated by (Ph3C)BF4 as well as by O2 to give the tetraepoxy[22]annulene 11. The spectroscopic data support the character of 11 as an aromatic, diatropic ring system, which is rather sensitive towards O2. In the oxidation mixture obtained from 11, beside polymeric products, two compounds 19 and 20 can be isolated, carrying one and two CHO groups, respectively, resulting by oxidation of one or both Me-groups but having retained the aromatic 22π system of 11.

Notes: Three double-decker cyclophane receptors, (±)-2, (±)-3, and (±)-4 with 11-13-Å deep hydrophobic cavities were prepared and their steroid-binding properties investigated in aqueous and methanolic solutions. Pd°-Catalyzed cross-coupling reactions were key steps in the construction of these novel macrotricyclic structures. In the synthesis of D2-symmetrical (±)-2, the double-decker precursor (±)-7 was obtained in 14% yield by fourfold Stille coupling of equimolar amounts of bis(tributylstannyl)acetylene with dibromocyclophane 5 (Scheme 1). For the preparation of the macrotricyclic precursor (±)-15 of D2-symmetrical (±)-3, diiodocylophane 12 was dialkynylated with Me3SiC≡CH to give 13 using the Sonogashira cross-coupling reaction; subsequent alkyne deprotection yielded the diethynylated cyclophane 14, which was transformed in 42% yield into (±)-15 by Glaser-Hay macrocyclization (Scheme 2). The synthesis of the C2-symmetrical conical receptor (±)-4 was achieved via the macrotricyclic precursor (±)-25, which was prepared in 20% yield by the Hiyama cross-coupling reaction between the diiodo[6.1.6.1]paracyclophane 19 and the larger, dialkynylated cyclophane 17 (Scheme 4). Solid cholesterol was efficiently dissolved in water through complexation by (±)-2 and (±)-3, and the association constants of the formed 1:1 inclusion complexes were determined by solid-liquid extraction as Ka = 1.1 × 106 and 1.5 × 105 l mol-1, respectively (295 K) (Table 1). The steroid-binding properties of the three receptors were analyzed in detail by 1H-NMR binding titrations in CD3OD. Observed steroid-binding selectivities between the two structurally closely related cylindrical receptors (±)-2 and (±)-3 (Table 2) were explained by differences in cavity width and depth, which were revealed by computer modeling (Fig. 4). Receptor (±)-2, with two ethynediyl tethers linking the two cyclophanes, possesses a shallower cavity and, therefore, is specific for flatter steroids with a C(5)=C(6) bond, such as cholesterol. In contrast, receptor (±)-3, constructed with longer buta-1,3-diynediyl linkers, has a deeper and wider hydrophobic cavity and prefers fully saturated steroids with an aliphatic side chain, such as 5α-cholestane (Fig. 7). In the 1:1 inclusion complexes formed by the conical receptor (±)-4 (Table 3), testosterone or progesterone penetrate the binding site from the wider cavity side, and their flat A ring becomes incorporated into the narrower [6.1.6.1]paracyclophane moiety. In contrast, cholesterol penetrates (±)-4 with its hydrophobic side chain from the wider rim of the binding side. This way, the side chain is included into the narrower cavity section shaped by the smaller [6.1.6.1]paracyclophane, While the A ring protrudes with the OH group at C(3) into the solvent on the wider cavity side (Fig. 8). The molecular-recognition studies with the synthetic receptors (±)-2, (±)-3, and (±)-4 complement the X-ray investigations on biological steroid complexes in enhancing the understanding of the principles governing selective molecular recognition of steroids.

Notes: Methyl (E)-2-(acetylamino)-3-cyanoprop-2-enoate (2a), and its 2-benzoyl analog 2b ere prepared from the corresponding methyl (Z)-2-(acylamino)-3-(dimethylamino)propenoates 1 Multifunctional compounds 2 are versatile synthons for preparation of polysubstituted heterocyclic systems such as pyrroles 4, pyrimidines 5 and 6, pyridazines 7, pyrazoles 8, 9, and 11, and isoxazoles 10.

Notes: Oxy anions 3 generated from 1,2-dihydrocyclobutabenzen-1-ones 1 through addition of a charged nucleophile or from 1-hydroxy-1,2-dihydrocyclobutabenzenes 2 by deprotonation with base lead to stable products through distal and/or proximal cleavage of the strained four-membered ring via benzyl carbanion 4 and/or aryl carbanion 5. A systematic study of this process reveals the relative stability of the two isomeric carbanions 4 and 5 as a key factor in determining the course of the ring-cleavage reaction. While benzyl carbanions 4 can be trapped with carbon electrophiles, attempts at trapping aryl carbanions 5 with electrophiles other than H+ failed. In protic solvents, the magnesium salt of the tertiary alcohol 2 shows an increased rate of proximal cleavage as compared to its alkali salts. From this, we conclude that, in contrast to benzyl carbanions 4, free aryl carbanions 5 are of transient existence only. Proximal C,C-bond cleavage seems to occur either through protonation of 5 from a fast, reversible equilibrium 3⇌5 in which 3 strongly predominates, or in protic solvents possibly even through a rate-limiting protonation of 3 at the aromatic C-atom, bypassing free anion 5 altogether. Thus, additional factors other than just the relative stability of isomeric carbanions 4 and 5 are of importance in determining the regiochemistry of the base-induced C,C-bond cleavage in ketones 1 and in alcohols 2.

Notes: The decomposition of diazo ester 2b with chiral RhII catalysts proceeded via intramolecular aromatic carbenoid insertion to the racemic pyrrole derivative 5b in 72% yield. In contrast, the benzoylated precursor 16 afforded no ketorolac 1b when exposed to RhII. Methyl 2-diazo-4-phenylbutyrate (19), in turn, reacted, by 1,2-hydrogen migration rather than by aromatic substitution, to 20.

Notes: In this study, we compared the lipophilicity of O-glucuronides and their aglycones. Distribution coefficients (log D) and P values of neutral species (log P) were determined by centrifugal partition chromatography (CPC) in octanol/buffer systems. Two-phase potentiometry was also used to measure the log P value of some lipophilic solutes. The experimentally determined global influence of glucuronidation on lipophilicity, obtained as the difference (decrement) log P(glucuronide) - log P(aglycone), was found to be -1.30 ± 0.16 (n = 4) for glucuronides of alcohols (methyl, menthyl, neomenthyl, and chloramphenicol O-glucuronide). The mean decrement was -2.06 ± 0.31 (n = 9) for glucuronides of phenols (phenyl, p-nitrophenyl, 1-naphthyl, 6-bromo-2-naphthyl, 4-methylumbelliferyl, 3-coumarinyl, phenolphthalein, 4′-benzophenonyl O-glucuronide, and diflunisal phenolic glucuronide). For the acylglucuronide of diflunisal and its rearrangement isomers, the mean decrement was -1.80 ± 0.08 (n = 4; range -1.7 to -1.9). Differences in through-bond proximity effects as parametrized in the CLOGP algorithm seem to account for much of this difference. Conformational factors may also play a role, although it appears modest and unassessable for the glucuronides investigated here. The results imply that in vivo glucuronidation should have a stronger influence on the excretion of phenols than on that of alcohols.

Notes: To check if the strong inhibition of N-acetyl-β-D-glucosaminidase by the tetrazole 8 and the imidazoles 9 and 10 correlates with the presence of a heteroatom corresponding to the glycosidic O-atom, we prepared the GlcNAc-derived pyrroles (tetrahydroindolizines) 18, 19, 27, 28, 34, and 35, lacking such a heteroatom. For this. the glucose-derived pyrroles 11-13 were treated with a Lewis acid in the presence of trimethylsilyl azide. Conditions of kinetic control favored the formation of the gluco-azides 14, 23, and 30, while thermodynamic control favoured the manno-azides 20, 29, and 36. Reduction of the azides 14, 20, 23, 30, and 36 by Pd/C-catalyzed hydrogenolysis or, better, with propanedithiol and Et3N, followed by acetylation or trifluoroacetylation and hydrogenolytic debenzylation, gave the deprotected acetamido- and trifluoroacetamido-pyrroles 18, 19, 22, 27, 28, 34, 35 40, and 41. As compared to the tetrazole 8 and the imidazole 9, the pyrroles 18, 19, 27, 28, 34, and 35 are only modest inhibitors of N-acetyl-β-D-glucosaminidase from bovine kidney (Ki values between 10 and 75 μM). indicating the necessity of a heteroatom at the glycosidic position. Ki Values between 100 and 160 μM for the inhibition of N-acetyl-β-D-glucosaminidase from jack beans were determined for the pyrroles 19, 34, and 35. The trifluoroacetamides inhibited both enzymes about twice as strongly as the corresponding acetamides.

Notes: Pirlindole is an antidepressant drug. It acts principally as reversible inhibitor of monoamine oxidase-A (RIMA) and appears relatively potent in comparison with reference drugs. Pirlindole possesses stereogenic center but is generally used as racemate. In this work, the first preparative resolution of its enantiomeric couple is described. Whereas selective crystallization of salts of chiral acid failed, two asymmetric synthetic pathways were also examined; however, without success. Finally separation and isolation of enantiomers of pirlindole was completed by using the derivatization method coupled with preparative HPLC. Optical purity of each isomer was determined by chiral HPLC. The specific rotation of each antipode was also determined.

Notes: The synthesis of new ‘bridged’ β-cyclodextrin (β-CD) ‘dimers’ 7-12 was successfully achieved by two one-pot reactions from β-CD (3) and 6A-azido-6A-deoxy-β-CD (4). The ‘phosphine imine’ reaction was shown to be a superior approach compared to the Mitsunobu reaction as coupling strategy for the preparation of these ‘dimers’. NMR Data, along with molecular-modelling calculations, suggest a ‘helical-like’ arrangement for the phenanthroline-diyl-linked ‘dimer’ derivative 9. Complexation properties of 9 were established by UV-VIS-spectrophotometric titration toward four metals. Among them CuII or EuIII ions were complexed selectively by 9, but no complexation occurred with LaIII and ZnII. In addition a specific and interesting esterase activity toward the phosphodiester bond of bis(4-nitrophenyl) phosphate anion was found in the case of the CuII complex of 9.

Notes: Three new derivatives of vitamin B12 with a pyrrole head group attached to the corrin ring have been prepared. Ligand-exchange reactions and reduction provided reactive CoIII and CoII complexes. Their electro-chemical properties and their potential for fixation at the surface of electrodes by electropolymerization were studied.

Notes: The kinetics of isomerization of deuterium and hydrogen oxoperoxonitrate, ONOOD and ONOOH, respectively, to trioxonitrate(1-), NO3-, and a deuteron or proton have been studied. Analysis of the pH-rate profiles result in a normal equilibrium isotope effect (KH/KD) of 3.3. The kinetic deuterium isotope effect for the isomerization reaction is 1.6 ± 0.2 between 5 and 55°. The activation enthalpies of isomerization of ONOOD and ONOOH are identical within the error of the measurement, 86.2 ± 0.5 and 86.5 ± 0.5 kJmol-1, respectively. A secondary kinetic isotope effect of 1.6 is compatible with a mechanism of isomerization where the terminal peroxide O-atom shifts to the N-atom.

Notes: The acid-catalyzed hydrolysis of (3S,5R,6S,3′S,5′R)-5,6-epoxycapsanthin (5) led to (3S,5R,6R,3′S,5′R)-(7) and (3S,5R,6S,3′S,5′R)-capsokarpoxanthin (8). In addition, (3S,5R,8R,3′S,5′R)- (9), (3S,5R,8S,3′S,5′R)-capsochrome (10), and (3S,5R,6R,3′S,5′R)-3,6-epoxycapsanthin (6) afforded (3S,5S,6R,3′S,5′R)-capsokarpoxanthin (12) (3S,5S,8S,3′S,5′R)- (13) and (3S,5S,8R,3′S,5′S)-capsochrome (14) as well as (3S,5S,6R,3′S,5′R)-3,6-epoxyepicapsanthin (15). Compounds 5-15 were isolated in crystalline form and characterized by their UV/VIS, CD, 1H- and 13C-NMR, and mass spectra.

Notes: Blood-protein adducts are used as dosimeter for modifications of macromolecules in the target organs where the disease develops. The functional groups of cysteine, tyrosine, serine, lysine, tryptophan, histidine and N-terminal amino acids are potential reaction sites for isocyanates. Especially the N-terminal amino acids, valine and aspartic acid of hemoglobin and albumin, respectively, are reactive towards electrophilic xenobiotics. To develop methods for the quantification of such blood-protein adducts, we treated 4-chlorophenyl isocyanate (1) with the tripeptide L-valyl-glycyl-glycine (2a) and with single amino acids yielding N-[(4-chlorophenyl)carbamoyl]valyl-glycyl-glycine (3a), N-[(4-chlorophenyl)carbamoyl]valine (3b), N-[(4-chlorophenyl)carbamoyl]aspartic acid (3c), N-(4-chlorophenyl)carbamoyl glutamic acid (3d), N-acetyl-S-[(4-chlorophenyl)carbamoyl]cysteine (3e), and N-acetyl-O-[(4-chlorophenyl)carbamoyl]serine (3f), Nα-acetyl-Nε-[(4-chlorophenyl)carbamoyl]lysine (3g). For several chemicals, it was shown that blood-protein adducts are good dosimeters of exposure and dosimeters for the target dose. The hydrolysis of the N-terminal adducts of isocyanates release hydantoins which can be separated from the rest of the protein and analyzed using GC/MS or HPLC. This was achieved with 3a. The released hydantoin could be analyzed using GC/MS. We propose to analyze the N-terminal adducts of isocyanates with blood protein to distinguish between arenamine and arylisocyanate exposure.

Notes: The synthesis of 3H-naphtho[2,1-b]pyrans 9-21 linked to a thiophene moiety is described. Two different synthetic approaches were applied to prepare these novel functionalized compounds, and their spectrokinetic properties in solution are reported.

Notes: The synthesis of oligonucleotides containing 2′-deoxy-5-methylisocytidine and 2′-deoxyisoguanosine using phosphoramidite chemistry in solid-phase oligonucleotide synthesis is described. Supporting previous observations, the N,N-diisobutylformamidine moiety was found to be a far superior protecting group than N-benzoyl for 2′-deoxy-5-methylisocytidine. 2′-Deoxy-N2-[(diisobutylamino)methylidene]-5′-(4,4′-dimethoxytityl)-5-methylisocytidine 3′-(2-cyanoethyl diisopropylphosphoramidite) (1c) incorporated multiple consecutive residues during a standard automated synthesis protocol with a coupling efficiency 〉 99% according to dimethoxytrityl release. Extending coupling times of the standard protocol to ≥ 600s using 2′-deoxy-N6-[(diisobutylamino)methylidene]-5′-O-(dimethoxytrityl)-O2-(diphenylcarbamoyl)isoguanosine, 3′-(2-cyanoethyl diisopropylphosphoramidite) (7e) led to successful incorporation of multiple consecutive 2′-deoxyisoguanosine bases with a coupling efficiency 〉 97% according to dimethoxytrityl release.

Notes: Studies towards the synthesis of a chiral primary α-phosphinoalkanamine 1a are reported. O-Activated. N-carbamate-protected phenylalaninol 3a did not undergo SN reaction with KPPh2: instead, after N-deprotonation, intramolecular substitution led to formation of the aziridine derivative 5a (Scheme 2). N-Phthalimido-protected, O-activated phenylalaninol 3b also underwent an intramolecular process on treatment with KPPh2, i.e., an unusual aryl-acyliminium cyclization furnishing the (epoxymethano)isoindolo[1,2-a]isoquinolinone 7 (Scheme 3). In a reaction with KPPh2, the N,N-dibenzyl-protected and activated phenylalaninol 3d finally yielded the intermolecular SN reaction product 2a (Scheme 4). However, debenzylation by catalytic hydrogenation turned out to be impossible.

Notes: Selective NMR decoupling and nuclear Overhauser effect (NOE) experiments with phycocyanobilin (PCB) show proton-proton interactions between the terminal rings A and D, viz. the chiral C(2) methine center and the ethyl substituent at C(18), as a result of the helical conformation of this open-chain tetrapyrrole in solution. Quantitative NOE measurements and a combination of force-field and semiempirical calculations (FSC) afford inter-proton distances across the helical gap of 4.2-4.6 (NOE) and 3.2-4.2 A° (FSC). The NOE and FSC, in conjuction with a qualitative evaluation of the steric interactions in the two optimized helices, suggest furthermore that, in solution, the helix M is somewhat more stable than P. The coexistence of at least two diastereoisomers is corroborated also by the circular dichroism (CD) spectra of PCB in MeOH/EtOH which point to a temperature-dependent equilibrium in solution, and by a considerable increase of this CD upon changing the solvent from the achiral alcohols to ethyl (-)-(S)-lactate which reflects a selective solvent-induced CD differentiating between diastereoisomers.

Notes: Enantiomerically pure β-amino-acid derivatives with the side chains of Ala, Val, and Leu in the 2- or 3-position (β2- and β3-amino acids, resp.), as well as with substituents in both the 2- and 3-positions (β2,3-amino acids, of like-configuration) have been prepared (compounds 8-17) and incorporated (by stepwise synthesis and fragment coupling, intermediates 24-34) into β-hexa-, β-hepta-, and β-dodecapeptides (1-17). The new and some of the previously prepared β-peptides (35-39) showed NH/ND exchange rates (in MeOH at room temperature) with τ1/2 values of up to 60 days, unrivalled by short chain α-peptides. All β-peptides 1-7 were designed to be able to attain the previously described 31-helical structure (Figs. 1 and 2). CD Measurements (Fig. 4), indicating a new secondary structure of certain β-peptides constructed of β2- and β3-amino acids, were confirmed by detailed NMR solution-structure analyses: a β2-heptapeptide (2c) and a β2,3-hexapeptide (7c) have the 31-helical structure (Figs. 6 and 7), while to a β2/β3-hexapeptide (4) with alternating substitution pattern H-(β2-Xaa-β3-Xaa)3-OH a novel, unusual helical structure (in (D5)pyridine, Fig. 8; and in CD3OH, Figs. 9 and 10) was assigned, with a central ten-membered and two terminal twelve-membered H-bonded rings, and with C=O and N—H bonds pointing alternatively up and down along the axis of the helix (Fig. 11). Thus, for the first time, two types of β-peptide turns have been identified in solution. Hydrophobic interactions of and hindrance to solvent accessibility by the aliphatic side chains are discussed as possible factors influencing the relative stability of the two types of helices.

Notes: Tetraepoxy[22]annulene(2.2.2.0): a Tetraepoxy-Bridged Neutral Aromatic [22]Annulene of a New TypeWe describe the synthesis of tetraepoxy[22]annulene(2.2.2.0) 4, the first aromatic annulene of type B by a cyclizing twofold Wittig reaction of 2,2′-bifuran-5,5′-dicarbaldehyde (5) and the bis[phosphonium] salt 8. The configuration of 4, mainly determined by NMR spectroscopy is (Z,E,Z). According to the UV/VIS spectrum and the 1H-NMR data, the electronic situation in 4 is quite different from that of tetraepoxy[22]annulene(3.0.3.0) 2 and tetraepoxy[22]annulene(2.1.2.1) 3. According to variable-temperature 1H-NMR spectroscopy, 4 is a highly dynamic system, where the (E)-double bond rotates around the adjacent σ-bonds. At ca. -130°, this dynamic process is frozen, and 4 appears as a diatropic aromatic system; the free activation energy of the rotation ΔG≠ is ca. 8.75 kcal/mol.

Notes: In the center of the immune system, there are major histocompatibility (MHC) protein/nonapeptide complexes which are recognized by T cell. The nonapeptides consist of three regions, an N-terminal one containing three amino-acid residues with a mandatory arginine in position 2, a C-terminal one with a lysine or arginine in position 9, and a central, variable one of five residues (cf. Fig. 1). We have now synthesized the first conjugates (1-4) of oligopeptides with oligo[(R)-3-hydroxybutanoates] (OHB) as analogs of MHC-binding peptides. Of the approaches chosen (Scheme 1), a fragment coupling of a hydroxy-butanoyl-amido ester (17 and 19) with an [(aminoalkanoyl)oxy]butanoyl chloride (27; Scheme 3), followed by two peptide-coupling steps (Scheme 4), turned out to be most efficient. The conjugates H-Gln-Arg-Leu-(HB)3,4-Lys-OH (1 and 2) and H-Ala-Arg-Leu-(HB)3,4-Lys-OH (3 and 4) were thus obtained in pure form. The conjugates 1 and 2 with N-terminal glutamine have a tendency to undergo cyclization with formation of a pyroglutamate residue (ef. Fig. 2). CD Measurements at different temperatures and so-called epitope-stabilization assays show that the complexes of the conjugates 2 and 4, containing four HB units, with the HLA-B27 class-I-MHC protein are more stable than those of a model nonapeptide (C50 values of 2.25 and 1.60 μM vs. 10 μM), while the conjugates 1 and 3 with three HB units incorporated form less stable complexes (C50 values of 30 and 21 μM). The tetra(hydroxybutanoate)-peptide conjugates 2 and 4 are the first nonapeptide analogs for which the modification of the central part leads to increased affinities for a class-I-MHC protein, as compared to a model nonapeptide.

Notes: 6-Epikarpoxanthin ((all-E,3S,5R,6S,3′R)-5,-6-dihydro-β,β-carotene-3,5,6,3′-tetrol, 5), 5,6-diepikarpoxanthin ((all-E,3S,5S,6S,3′R)-5,6-β,β-carotene-3,5,6,3′-tetrol, 13), 5,6-diepilatoxanthin ((all-E,3S,5S,6S,3′S5′R,6′S)-5,6′-epoxy-5,6,5′,6′-tetrahydro-β,β-carotene-3,5,6,3′-tetrol, 14), and 5,6-diepicapsokarpoxanthin ((all-E,3S,5S,6S,3′S,5′R)-5,6-dihydro-3,5,6,3′-tetrahydroxy-β,κ-caroten-6′-one, 15) were isolated from red spice paprika (Capsicum annuum var. longum) and characterized by their UV/VIS, CD, 1H- and 13C-NMR, and mass spectra. Our investigations demonstrate that the configuration of the 3,5,6-trihydroxy-5,6-dihydro-β-end group may differ depending on the biological source.

Notes: The X-ray analyses of (η3-allyl){4-benzyl-2-[2-(diphenylphosphino-κP)phenyl]-4,5-dihydro-4-4-methyloxazole-κN}palladium(II) hexafluorophosphate (5) and the analogous [Pd(η3-1,3-diphenylallyl)] complex 6 are presented. A comparison with the (η3-allyl)- and (η-1,3-diphenylallyl)palladium complexes 2 and 3, respectively, containing the 4-monosubstituted 4,5-dihydro-2-(phosphinoaryl)oxazole ligand 1a reveals important structural differences (Fig. 3). 1H-NMR Spectroscopic investigation confirm that the 4,4-disubstituted 4,5-dihydro-2-(phosphinoaryl)oxazole ligand 4 of 5 and 6 shows the same conformation in solution as in the solid state (Table 2). The application of ligand (S)-4 in the Pd-catalyzed allylic substitution demonstrates a configurational relationship between the orientation of the allyl ligand in the intermediate (cf. complex 6) and the absolute configuration of the allylic-substitution product (Table 3).

Notes: Some new (2′-5′)triadenylates 13-16, containing at the 2′-terminal end 3′-fluoro-2′,3′-dideoxyadenosine derivatives, have been synthesized by the phosphotriester method. The selectively blocked nucleosides 2, 4, 5, and 7, were synthesized from the corresponding unprotected nucleosides 1, 3, and 6. The synthesized trimers 13, and 14 were 4- and 8-fold, respectively, more stable towards phosphodiesterase from Crotalus durissus than the natural trimer 17. In comparison to trimer 17 the new compounds 13-15 inhibit HIV-1 reverse transcriptase (RT) activity, and 15 and 16 the HIV-1 induced syncytia formation 2-3 fold whereas none of 13-16 can improve R Nase L activity.

Notes: The first asymmetric α-alkylations of lithiated sulfonamides bearing the chirality information within the amine moiety under high asymmetric inductions (de 83-95%) are described. Racemization-free acidic hydrolysis led to the title compounds 11 in acceptable overall yields and with high enantiomeric purity (ee 91- ≥ 98%; Scheme 2). As a novel chiral auxiliary, the primary amine (S,S)-or (R,R)-2 was synthesized employing the classical Erlenmeyer phenylserine synthesis (Scheme 1).

Notes: This theoretical study focuses on two indole derivatives, melatonin (1) and carvedilol (8), with the objective of improving our understanding of the molecular mechanisms underlying their radical-scavenging activity. Quantum-mechanical calculations were carried out using the AM1 semi-empirical method, some results being confirmed by ab initio (3-21G) calculations. The quantum-chemical descriptor Δ Hox (relative adiabatic oxidation potential) and the shape of the SOMO (singly occupied molecular orbital) indicate that the stabilization of its radical cation can partially explain the well-documented antioxidant efficacy of melatonin. This stablization may result from electrostatic interactions and from a hyperconjugative effect existing in a family of conformers of the melatonin radical cation having the side chain almost perpendicular to the plane of the aromatic rings. Furthermore, 6-hydroxymelatonin (7) appears to be a better free-radical scavenger than melatonin (1) in agreement with experimental results. According to the theoretical parameters Δ Hox and Δ Habs (relative bond dissociation enthalpy), carvedilol (8) is not a good antioxidant, in contrast to its ring-hydroxylated metabolites whose powerful antioxidant effects are explained by the formation of an oxyl radical stabilized by delocalization over the carbazole nucleus.

Notes: The reaction of α-nitro ketones to the corresponding α-hydroxy ketones under basic aqueous conditions, a novel transformation, was studied. The investigation revealed that the reaction is only possible with α-nitro ketones that are CH-acidic in the α′-position and readily deprotonated under the reaction conditions. The NO2/OH exchange was established to proceed with retention of configuration at the stereogenic center, and labeling experiments have shown that the OH O-atom originates, to a great extent, from the solvent. In particular, the stereochemical course of the reaction and the incorporation of external nucleophiles led us to propose a mechanism that involves neighboring-group participation. The product formation is explained by a double SN2 reaction, which proceeds via a Favorskii-like cyclopropanone intermediate.

Notes: We report on the synthesis of a receptor 4 for β,β-carotene (1), and on the binding interaction between the two which yields inclusion complex 5. The cyclodextrin ‘dimer’ 4 was obtained via condensation of the corresponding 4,4′-(porphyrin-5,15-diyl)bis phenol 8 with 6A-deoxy-6A-iodo-β-cyclodextrin (6) in the presence of Cs2CO3. Fluorescence studies of the binding interaction between ‘dimer’ 4 and β,β-carotene (1) gave a binding constant Ka of (2.4 ± 0.1) · 106 M-1.

Notes: The lithium enolate of (±)-6-endo-chloro-5-exo-(phenylseleno)-7-oxabicyclo[2.2.1]heptan-2-one (16) added to furan-2-carboxaldehyde giving a single aldol 19 (Schemes 1 and 2) that was converted with high stereoselectivity into (±)-(1RS,3SR,4SR,5RS,6SR)-5-exo-{(RS)-[(tert-butyl)dimethylsilyloxy](furan-2-yl)methyl}-6-endo-(methoxymethoxy)-2-oxo-7-oxabicyclo[2.2.1]hept-3-exo-yl 4-bromobenzenesulfonate (46). Highly regioselective Baeyer-Villiger oxidation of 46 provided the corresponding β-DL-altrofuranurono-6,1-lactone 49, the methanolysis of which gave (±)-methyl 1,5-anhydro-3-{(SR)-[(tert-butyl)dimethylsiloxy](furan-2-yl)methyl}-3-deoxy-2-O-(methoxymethyl)-α-DL-galactofuranuronate (51). Reduction of 51 followed by protection furnished (±)-1,4-anhydro-3-{(SR)-[(tert-butyl)dimethylsilyoxy](furan-2-yl)methyl}-3-deoxy-2,6-bis-O-(methoxymethyl)-α-DL-galactopyranose (54). Clean oxidation of the furan unit in (54). Clean oxidation of the furan unit in 54 was possible with dimethyldioxirane, giving the corresponding (Z)-4-oxoenal 59 that was converted into pyrroles such as (±)-1,4-anhydro-3-{(SR)-[(tert-butyl)dimethylsilyloxy](1-benzyl-1 H-pyrrol-2-yl)methyl}-3-deoxy-2,6-bis-O-(methoxymethyl)-α-DL-galactopyranose (58; Scheme 5), or into pyrrolidin-3,4-diols by dihydroxylation of (±)-1,4-anhydro-3-{(1′RS,2′RS,Z)-1′-[(tert-butyl)-dimethylsilyloxy]-2′,5′-bis[(methylsulfonyl)oxy]pent-3′-enyl}-3-deoxy-2,6-bis-O-(methoxymethyl)-α-DL-galactopyranose (70; Schemes 6 and 7). After adequate protection (→ 70), selective displacement of one of the mesylate moieties with LiN3, followed by hydrogenation of the corresponding primary azide and intramolecular substitution, led to four protected, stereoisomeric C-linked imino disaccharides (Scheme 7); the latter were deprotected under acidic conditions to give (±)-3-deoxy-3-[(1′SR)-2′,5′-dideoxy-2′,5′-imino-α-LD-ribitol-1′-C-yl]-DL-galactose (3), (±)-3-deoxy-3-[(1′SR)-2′,5′-dideoxy-2′,5′-imino-α-DL-arabinitol-1′-C-yl]-DL-galactose (4), (±)-3-deoxy-3-[(1′SR)-2′,5′-dideoxy-2′,5′-imino-β-DL-ribitol-1′-C-yl]-DL-galactose (5), and (±)-3-deoxy-3-[(1′SR)-2′,5′-dideoxy-2′,5′-imino-β-DL-arabinitol-1′-C-yl]-DL-galactose (6). These unprotected C-linked imino disaccharides were more stable as ammonium chlorides in H2O. Neutralization of 4 · HCl, followed by NaBH4 reduction, gave (±)-(1RS,2SR,6SR,7RS,8RS,8aSR)-1,2,3,5,6,7,8,8a-octahydro-7-[(1SR,2SR)-1,2,3-trihydroxypropyl]indolizine-1,2,6,8-tetrol (14), a new octahydroindolizinepolyol (Scheme 8). Methyl glycosides of C-linked imino disaccharides 3-6 were also obtained, such as (±)-methyl 3-deoxy-3-[(1′SR)-2′,5′-dideoxy-2′,5′-imino-α-LD-ribitol-1′-C-yl]-β-DL-galactofuranoside (7), (±)-methyl 3-deoxy-3-[(1′SR)-2′,5′-dideoxy-2′,5′-imino-β-LD-arabinitol-1′-C-yl]-β-DL-galactofuranoside (8) and -α-DL-galactofuranoside (9), (±)-methyl 3-deoxy-3-[(1′SR)-2′,5′-dideoxy-2′,5′-imino-α-DL-arabinitol-1′-C-yl]-β-DL-galactofuranoside (11) and -α-DL-galactopyranoside (10), and (±)-methyl 3-deoxy-3-[(1′SR)-2′,5′-dideoxy-2′,5′-imino-β-DL-ribitol-1′-C-yl]-β-DL-galactofuranoside (13) and -α-DL-galactopyranoside (12). All these new C-linked imino disaccharides can be obtained in their enantiomerically pure form either starting with enantiomerically pure 7-oxabicyclo[2.2.1]heptain-2-one derivatives (‘naked sugars of the first generation’) or using the method of Johnson and Zeller applied to the racemic protected aldol 3-exo-{[(tert-butyl)dimethylsiloxy](furan-2-yl)methyl}-6-endo-chloro-5-exo-(phenylseleno)-7-oxabicyclo[2.2.1]heptan-2-one (22; see Scheme 2). The unprotected C-linked imino disaccharides 3-13 and octahydroindolzinetetrol 14 were tested for their inhibitory activity toward 25 commercially available glycohydrolases. Only compound 3 which mimics the mannopyranosyl-cation intermediate during the hydrolysis of an α-mannopyranosyl-(1 → 3)-galactose has a weak, but specific α-mannosidase inhibitory activity.

Notes: Je umfangreicher ein Laboratoriumsbetrieb wird, um so mehr ergibt sich die Notwendigkeit einer Verwaltung des vorhandenen Chemikalienbestandes. Wer sich schon einmal mit diesem Datenbankproblem auseinandersetzten mußte, weiß, daß die Anforderungen zu komplex sind, als das man sie mit einfachen, vorgefertigten Datenbanktools erledigen könnte. Schließlich geht es weniger darum, den wissenschaftlichen Namen, die Summenformel und vielleicht auch noch eine firmeninterne Kennzeichnung zu speichern--einen Nutzen bringt das System erst, wenn eine mengenmäßige Erfassung in Verbindung mit den unterschiedlichen Lagerorten stattfindet. Bei der Nachbestellung hilft auch eine Verknüpfung mit den für die Beschaffung notwendigen Händlerinformationen. Durch die Angabe eines Mindestvorrats können zur Neige gehende Substanzen rechtzeitig nachbestellt werden, da es die Datenbank erlaubt, gezielt nach Artikeln zu suchen, die nicht mehr in ausreichender Menge vorhanden sind. Sicherheitsinformationen sowie Angaben über die physikalischen Eigenschaften der Substanz vervollständigen die Einträge, und auch die gängigen Synonyme sollten der Datenbank bekannt sein.

Notes: Asbestos minerals are naturally occurring fibrous silicates. From the structural chemistry point of view they belong to two different classes: The group of serpentines, to which the primarily used chrysotil (white asbestos) belongs, consists of curled up layer silicates. On the other hand in the amphiboles (for example blue asbestos (crocidolite)), which belong to the band silicates, the fibrous form is pre-formed in their silicon-oxygen partial structure. The characteristic properties of asbestos (its fibrous form, thermal and chemical inertness, good electric and thermal insulation, spinability…) led to extensive application of the mineral fibers in nearly all fields of engineering and everyday life. Because of the health effects of asbestos dust - fibrogene and cancerogene diseases - the application of asbestos containing products will cease with the end of this century. The search for substitute materials (especially fibers) is currently an area of interest in material sciences.

Notes: The high selectivity makes transition metal catalyzed reactions valuable for organic synthesis. Although very effective, not all of them are also efficient. This circumstance is illustrated by the small number of homogeneous metal-catalyzed reactions that is used in industrial production processes compared to heterogeneous catalysis. Using important examples of the field, criteria and measures are discussed that can be used to evaluate the efficiency of homogeneous metal-catalyzed processes. While the concept of atom economy shows the efficiency of a transformation only if very small amounts of catalyst are needed, turn over numbers give the efficiency of the catalyst itself.

Notes: The belgian chemist Paul Havrez (1838-1875) proposed two highly symmetrical, space-filling models for the benzene molecule, only a few months after Kekulé's seminal proposal of a cyclic benzene structure. One of these models is characterized by the revolutionary assumption of equal 3/2 bonds between all neighbouring carbon atoms, in sharp contrast to Kekulé's formula with alternating double and single bonds. With Considerable hind-sight, Havrez's model could be considered as a forerunner of the benzene structure with delocalized π bonds.

Notes: Seit schnelle und gut ausgerüstete Arbeitsplatzrechner aus keinem Bereich der Wissenschaft und Lehre mehr wegzudenken sind, ist auch Molecular Modelling nicht länger eine Domäne der Großrechner, der theoretisch arbeitenden Chemiker und auch nicht mehr erst ab der Diplomarbeit zugänglich. Oxford Molecular Ltd. kommt mit seinem Programm CAChe 3.11 dieser Entwicklung entgegen. Dieses leistungsstarke und methodenreiche Programmpaket, das speziell auf die Bedürfnisse praktisch arbeitender Wissenschaftler zugeschnitten ist, kann ohne zeitraubende und mühselige Einarbeitung in die Bedienung oder „graue“ Theorie von jedem leicht angewendet werden. Sicher, ohne ein Minimalwissen in Computerchemie wird man auch mit CAChe unliebsame Überraschungen erleben. CAChe sieht die Rechenchemie aber mit den Augen des Praktikers im Labor, der Zusatzinformationen zu seinen Molekülen wünscht, und nimmt ihn begleitend und beratend an die Hand.

Notes: A widespread legend concerning the famous Austrian physicist Josef Loschmidt claims that he proposed the cyclic structure of the benezene nucleus five years before August Kekulé. However, we point out, as did others before us, that this claim is not supported by the very detailed and precise account Loschmidt provides for the assumptions underlying his benzene formula, and that the origin of the legend must be due to a difficult to understand misinterpretation of this formula.

Notes: Recently, very interesting findings have been revealed in wine, and scientific research on some well known natural ingredients has shown that they possess previously unknown positive significance for the wine consumer. On the one hand residues of crop protection agents (special botryticides with carbodiimide structure, the insecticide Orthene®) are dealt with, then an atypical aging flavor (2-aminoacetophenone), and some novel principles and flavors, and finally the occurrence of mycotoxines (Ochratoxin A) as consequence of low hygiene in wine making, are reported. On the other hand Resveratrol, a phytoalexin, displays cancer chemopreventive activities, and has been found as well in German wines in varying quantities.

Notes: In recent years, a nova1 class of pharmaceuticals has been developed which bind in a predictable way to certain nucleic acid target sequences aiming at selective inhibition of expression of disease-causing genes. The chemical structure of these so-called antisense oligonucleotide compounds must be altered relative to their natural models to render them stable under in vivo conditions and to allow their penetration to the site of action inside cells. In this article, the principle of antisense oligonucleotide function, the structure of antisense oligonucleotide analogues, the different strategies for improvement of their biological potency, and selected reports on successful in vivo studies and first clinical investigations using these antisense oligonucleotides are discussed.