Bibliothek

Notizen: Monofunctionalized Dendrons of Different Generations - as Reagents for the Introduction of Dendritic SubstituentsIn recent years dendrimers become more and more important not only in organic chemistry. They represent a new class of molecules with unique characteristic features. But dendrimers represent not only designed molecular architecture. They stand for a new concept in chemistry. They can be used to alter the properties of already existing molecular skeletons or they can be used to transfer new properties to a classical functional unit. This means that functionalized dendrimers and dendrons (dendritic building blocks) can be regarded as reagents for the preparation of new compounds with dendritic properties. In this article the synthesis and the practical use of appropriate dendritic reagents is explained. Furthermore we introduce the new technical terms „{n} dendryl-“ for dendritic substituents of n generations and „dendriagent“ which stands for dendritic reagents. Moreover we give a short outlook on future developments.

Notizen: The bis(acetone) complex of tetramethyl rac-3,3,7,7-tetramethyl-trans-5-palladatricyclo[4.1.0.02,4]heptane-1,2,4,6-tetracarboxylate rac-1a was crystallized and investigated by X-ray structure analysis. Unlike in complexes with bidendate ligands in rac-1a · 2(acetone), only a small deviation from the square planar coordination of palladium was observed. Efforts to crystallize the analogous pyridine, acetonitrile and benzonitrile complexes failed; but the labile complexes rac-1a · 2([D5]pyridine) and rac-1a · 2([D3] acetonitrile) as well as rac-1a · 2([D6]acetone) could be characterized by 1H and 13C NMR spectra and a fast ligand exchange was proven by nmr. Then the ability of different 1,2-disubstituted cyclopropenes to form trans-5-pallada-tricyclo[4.1.0.02,4] heptanes 1 was investigated. Only the diesters 5c-e lead to PTHs, with a diester possessing sterically demanding substituents in 3-position of the cyclopropene and with other substituents in 1- respectively 2-position of the cyclopropene either the cyclopropene-formation or the PTH-formation failed.

Notizen: The synthesis and stereochemical characteristics of pyrrolidino-, isoquinolino- and indolo-enaminones 2-11 are reported. The inhibition of cyclooxygenase was determined in a bovine thrombocyte intact cell assay and that of 5-lipoxygenase using intact bovine polymorphonuclear leucocytes. Except compound 2c′ which is a well-balanced dual inhibitor of both enzymes, all other enaminone derivatives are weak inhibitors of both cyclooxygenase and 5-lipoxygenase. Structure-activity relationships of the enaminones in relation to known anti-inflammatory drugs are discussed.

Notizen: Reactivity and Selectivity in the Oxidation of Styrene Derivatives. IV. Studies on the Oxidation of Substituted β,β-DimethylstyrenesThe liquid phase oxidation of substitued (p-MeO-, p-Cl-, m-CF3-) 2-aryl-3-methyl-but-2-enes, of 1,1-diphenyl-2-methyl-propene, of 1-ethoxy-2-methyl-1-phenyl-propene and of 9-isopropylidene-fluorene with pure oxygen was investigated in chlorobenzene solution and in presence of cumene and of cumene hydroperoxide in the temperature range 65-125 °C. The product yields were determined gaschromatographically. The differences of the activation energies of epoxide formation and the parallel reactions were calculated. They amount to 19-48 kJ/mol. The epoxide selectivity increases with increasing temperature and increasing concentration of olefin. The relative chain propagation constants (kpC—C) were determined by competitive oxidation with cumene. The kpC—C values of substitued β,β-dimethylstyrenes can be correlated by a LFE-relationship with the ionisation energies of the olefins.

Notizen: A new synthesis of sodium cyanodithioformate 1 and the disodium salt of cis-1,2-dicyanoethylene-1,2-dithiol 2 is reported. The key step involves a nucleophilic thiolation with elemental sulfur starting from a substituted acetonitrile 4. This method may serve as a cyanide- and carbondisulfide-free alternative in the preparation of the title compounds.

Notizen: 2,3,4,5,6-Penta-O-acetyl-D-galactonic acid chloride (1a) and D-gluconic acid chloride (1b), respectively, react with alkyl acetoacetates and benzoylacetates 2, respectively, to yield derivatives 3 of diuloses with an alkoxycarbonyl group in the branch. Decarboalkoxylation of these compounds gives 1,3-didesoxy-nono-2,4-diuloses 4a,b and 2-deoxy-octo-1,3-diuloses 4c, respectively. Compound 4a and diazomethane react to furnish the corresponding methyl enol ether 5a and 5b.

Notizen: Orthoamides. LI. Push-Pull-Butadienes and Heterocycles from Alkyne Carboxylic Acid Orthoamides and CH2-acidic CompoundsThe acetylides 4b, 4f react with N,N,N′,N′,N″,N″-hexamethylguanidiniumchloride (5) to give the orthoamides 6b, 6f, resp. From CH2-acidic compounds and the orthoamides 6a, c, e can be obtained the push-pull-substituted butadienes 8a-8aj. The 2,3,5-trimethyl-thiadiazolium salt 9 does not condense with 6e, as other CH2-acidic compounds do, instead the vinylogous guanidinium salt 10a is produced. On heating, the ketenaminals 8d, aa cyclize to give the pyridone-carbonitriles 11a, b, resp. From 4-amino-coumarins 12 and the orthocarboxylic acid amideacetals 13a, b and the ketenaminal 16 resp., the amidines 14a-c and the heterocyclic compounds 15a-c resp., are formed. The enamines 17a-c, 19a, b react with the orthoamides 6a-f to give the pyridine derivatives 18a-1, 20a-h and 21a, b, resp. Analogously, from 6-aminouracil 22 and 6a, b, e, f are formed the pure 7-dimethylaminopyrido[2,3-d] pyrimidines 23a, b or mixtures of compounds 23c, d and the isomeric 4-dimethylamino-pyrido[2,3-d]pyrimidines 24a, b resp., which can be separated via their salts 25a,b/26a,b. The heterocyclic compounds 30a-d, 32a,b can be prepared from the pyrazole derivatives 28, 31 resp. and the orthoamides 6a-f.

Notizen: Reductive dimerization of dodecylthio substituted 1,2-dithiole-3-thiones 6a-b and trithion-dithiacrown ethers 10a-c with triethyl phosphite furnished bis- and tetrakis (dodecylthio), and bis(dithiacrown ether) substituted thiodesaurines (E)-11a-b and (E)-12a-c. The stereochemistry of bis(dithia[15]crown-5)-thiodesaurine (E)-12b has been determined by X-ray crystallographic analysis.

Notizen: Formaldehyde-O-oxide and Colchicine: An Elegant Route to the AllocolchicinesTropone is a structural unit of numerous natural products i.e. imerubrine, harringtonolide and colchicine (2). It is of interest to study the selectivity of formaldehyde-O-oxide (1) with respect to these polyfunctional tropone derivatives. We report about the reactions of 1 with colchicine (2) and the colchicine derivatives 5, 8, 11, 14, 17, 20 under ozone free conditions. The fragmentation of the spiroozonides 3, 6, 9, 12, 15, 18, 21 via the activated complexes 3a, 6a, 9a, 12a, 15a, 18a, 21a opens up an elegant route to the allocolchicines 4, 7, 10, 13, 16, 19.

Notizen: 4,5-Disubstituted N-phenyl-isothiazolium salts 1 with active 5-methyl group react under the influence of anilines to form 3,4-disubstituted isothiazolium salts 3. The influence of donor and acceptor substituents in the 2-phenyl group of 1a-h and in the anilines 2 on the ring transformation were studied. The structure of the new salts was confirmed by X-ray analysis. The 3-hydroperoxy-2,3-dihydro-isothiazole 1,1-dioxides (12a,d) and the isothiazole-3(2H)-one 1,1-dioxides (14a,d) are obtained by oxidation of salts 3 with H2O2.

Notizen: Ortho-, meta- and para-xylenes 1, 13a, 13b and 13c, with donor and acceptor substituents at the α- and α′ positions, lead to a remarkable variety of intermediates and reaction products after deprotonation of the benzylic proton. Thus, the reaction of para-(cyanomethyl)dialkyl[(methylthio)phenylmethylene]ammonium tetrafluoroborates 13a and 13b with sodium hydride affords the para-quinodimethanes 14a and 14b. Poly(meta-phenylenevinylene) 14c can be obtained when starting from 13c. We report the synthesis of para-quinodimethanes 14a and 14b and poly(meta-phenylenevinylene) 14c and describe a successive approach towards meta-phenylenevinylenes of definite length 16b and 17b starting from 12d. Moreover, we compare the stability and reactivity of para-quinodimethane 14a and 14b with those of the ortho-quinodimethane 2 and we focus on the characterization of the resulting donor and acceptor substituted compounds.

Notizen: By the reaction of N-acylthioureas 7 with 1,3-dichloroacetone 9 2-dialkylamino-5-chloroacetyl-thiazoles 11 are available. These compounds react with thioureas or arylthioamides under heterocyclisation to give bis-(2-dialkylamino-5-thiazolyl)-ketones 13, 2-aryl-4-(2-dialkylamino-5-thiazolyl)-thiazoles 14, or 2-dialkylamino-4-(2-dialkylamino-5-thiazolyl)-thiazoles 15, resp., from which the last-mentioned compound exhibit a high reactivity towards several electrophilic reagents. Thus, deeply colored cyanovinyl, arylazo, and arylmethine substituted bisthiazole dyes 17, 18, and 19, resp., have been formed.

Notizen: Reductive cyclization of the 1-hydroxy-3-(3-oxoalkyl)-9,10-anthraquinones 2, 9 and 10 yields the angularly condensed cyclopenta[a]anthraquinones 3, 21 and 22a under neutral conditions (DMF/Na2S2O4). By contrast, the linear cyclopenta[b]anthraquinone 23 is isolated from 10 applying the usual alkaline Marschalk conditions (aqueous methanol, NaOH, Na2S2O4). The linearly condensed 5,12-naphthacenequinones 24-28 of different degree of saturation are obtained in good combined yield from the corresponding 1-hydroxy-3-(4-oxoalkyl)-9,10-anthraquinones 19 and 20 under the conditions of the Marschalk reaction.

Notizen: A Novel Synthetic Route to Open-Chained and Cyclic OligoetherketonesOligoetherketones of the structure 2a,b can be generated by repetitive insertion reactions of terminal biscarbenoids 4a,b, into the O—H bonds of diols like 5. The formation of the corresponding ring systems 7a and the involved carbene dimerization leading to 8b are processes which compete with the linear polyinsertion. A related one-component reaction can be performed with ω-hydroxy-1-diazo-2-alkanones (13a-c → 14a-c).

Notizen: Copper-catalyzed alkoxycarbonylcarbene transfer from methyl or tert-butyl diazoacetate to acyclic enaminoesters 6a,b and enaminocarboxanilide 13 yields vicinal push-pullsubstituted cyclopropanes 7a,b,8, and 14. In contact with dry silica gel, the latter compounds undergo facile ring-opening leading to enaminoesters 9, 10, and 15. Treatment with aqueous acid transforms 9 and 10 into 2-acylsuccinates 11 and 12, and 15 into pyrrolinone 16. Methoxycarbonylcarbene transfer to enaminoketones 1a-c does not yield isolable cyclopropanes, but after hydrolytic work-up α-acyl-γ-ketoesters 2a-c are obtained.

Notizen: Synthesis of Ether-bridged, Polycyclic Mono- and Bipyridines by Domino ReactionsOn the basis of iminium salt chemistry, an inexpensive one-pot reaction provides novel ether-bridged, polycyclic mono-and bipyridines. This domino reaction sequence succeeds using chromanone derivatives and β-amino ketone hydrochlorides (or free mannich bases) in the presence of ammonium acetate. The strategy offers a great flexibility in the design of new structures of this type (5a-b, 6a-c and 8) and underlines the efficiency of domino reactions.

Notizen: Amphiphilic and Mesogenic Carbohydrates. 10. Change of the Type of the Mesophase by Variation of the Acyl Chain of Amphiphilic Tetradecyl (N-acylamino)-2-deoxy-1-thio-β-D-glucopyranosidesThe homologous amphiphilic tetradecyl-2-(N-alkanoylamino)-2-deoxy-1-thio-β-D-glucopyranosides 5a-f were synthesized from the 2-(N-alkanoylamino)-2-deoxy-D-glucopyranoses 1a-f via the glucosyl chlorides 2a-f, the glucosyl isothiuronium chlorides 3a-f, and the acetylated thioglucosides 4a-f. On heating the amphiphiles 5a-f form different types of liquid crystalline phases in dependence of the length of the acyl chain, i.e. 5a and 5b form smectic phases, 5d-f form columnar mesophases. Polarisation microscopy, DSC-measurements and contact preparations were used to characterise the liquid crystaline phases.

Notizen: The partially diethylamino substituted phenyl-chloromono- and -disilanes Cl2Ph(NEt2)Si(2) Cl2Ph(NEt2)2Si(3), [ClPh(NEt2)Si-]2 (7) and Cl(NEt2)PhSi—SiPh(NEt2)2 (8) were synthesized. 3 and 8 are able to react with lithium powder to form the corresponding silyllithium compounds. The resulting species were characterized in solution by 13C and 29Si NMR spectroscopy. To prove the expected substitution patterns of the silyllithium compounds some coupling reactions with chlorosilanes were carried out and the resulting new oligosilanes were characterized by means of NMR spectroscopy and MS.

Notizen: Starting with monochiral 1,2,3,4-tetrahydro-3,6-dimethyl quinoline 14a,b, (Schemes 1 and 2), we have synthsized the new chiral, symmetrical and unsymmetrical, tri- and pentamethinium streptocyanine dyes 2a, (Scheme 8), 4a, (Scheme 5), and 5a,b, (Scheme 4), resp. 9a, (Scheme 6), 10a,b, (Scheme 4), and 11a, (Scheme 7) with one or two stereogenic centers in the two heterocyclic end groups. The absolute configuration of 14a,b, and thus the absolute configuration of all monochiral polymethinium dyes derived from 14a,b, has been determined by a single-crystal X-ray analysis of its 4-bromobenzenesulfonyl derivative 17a, (Scheme 1 and Fig. 1). The UV/Vis spectroscopic and chiroptical properties of the new polymethinium dyes have been studied for the first time and compared with that of similar streptocyanine dyes synthesized earlier (Tables 1 and 2) in order to find possible correlations between chiroptical properties and molecular structure.

Notizen: The cis or trans-glycidic esters 1 or 7 give ring transformations with hydrazines affording optically active 4-hydroxypyrazolidin-3-ones 3 and 4 or 6 or 9 and 10, respectively, in different regioselectivities. 4-Hydroxypyrazolidin-3-ones 3 and 9 can serve as precursors for enantiomerically pure β-amino-α-hydroxycarboxylic acid amides 5 and 11 by hydrogenation in the presence of Raney-Ni.

Notizen: 3-Acetyl-2H-thiopyran-2-ones by [4+2]-Cycloaddition Reactions of Enaminothioketones with Acetylketene3-Acetyl-2H-thiopyran-2-ones 3 are available in a one step procedure by [4+2]-cycloaddition reactions of enaminothioketones with acetylketene.

Notizen: 1-Substituted 3-hydroxy-1H-pyrazoles 1 react with chloroform, NaOH, and aceton resp. butan-2-one O-regiospecifically to yield 2-methyl-2-[(1H-pyrazol-3-yl)oxy]-propanoic resp. -butanoic acids 14 via a dichlorocarbene (12)-dichlorooxirane (9) pathway. Chlorides 17 of 14 easily cyclize to N-acylpyrazolium salts 18/19, which quantitatively afford esters 22-26 and amides 27-29 of 14. Enantiomers of the butanoic acid 14th, obtained via their diastereomeric cholesterol esters, differ in their stimulus to peroxisome proliferation. At 140 °C pyrazolium salts 18 undergo thermolysis to bicyclic β-oxa-γ-lactams 30-32. 3-Carboxyisoalkylamino-pyrazoles similarly give 1H-β-aza-γ-lactams 34. Reactions of 14 with surplus SOCl2 result in 6-chloro- 37 resp. 7-chloro-β-oxa-γ-lactams 38 via chlorosulfinylation and extrusion of SO, and in 4,4-bispyrazolyl-sulfoxide 39. A mild introduction of additional O-functions into pyrazoles affording 4,5-dihydro-3-hydroxy-5-oxo-1H-pyrazoles 52-57 is presented. Biological effects of the new pyrazoles are protection against shock and ADP-induced thromboembolism, reduction of serum lipids and improvement of blood flow.

Notizen: Benzyl cation inititiated intramolecular cyclization reactions with conjugated C—C double bonds were performed providing rac. endo-exo isomers of 1-azabicyclo[3.2.1]octenes (2 and 3). Formation of the endo isomer 2 is favoured. Compounds 2 possess dopamine uptake inhibitory effect with an additional selective MAO-B enzyme inhibitory potential. The remarkable in vitro effects do not correspond to in vivo antidepressant activity.

Notizen: Highly Reactive Trialkylsilylation Reagents Derived from Bis(trifluoromethanesulfonyl)imide - Silylation of Functional Groups, Alkines and Reactive AromaticsThe synthesis of trialylsilyl-bis(trifluormethane-sulfonyl)imides 3 is described. Compounds 3 with bulky trialkylsilyl groups 3a,b only exist in the silatautomeric form 3a′, b′ under usual conditions, 3c in the N-trimethylsilyl structure. Despite of the bulky silyl substituents in 3a′, b′ their reactivity is higher than of trimethylsilyltriflate. Alcohols, carbonyl compounds, nitroalkanes and carboxylic acid esters are silylated in good yields, especially by the more reactive triisopropylsilyl derivative 3b′ in presence of tertiary amines. tert.-Butyl carboxylates and benzylcarboxylates are cleaved. Monosubstituted alkines and electron-rich (hetero) aromatics are carbosilylated in presence of N-ethyl-diisopropylamine.

Notizen: Dehydrotriphenylenes for the Generation of Bent Molecular RibbonsThe synthetic sequences 1 → 11 and 17 → 23a lead to highly reactive mono- and bisdienophiles whose cycloaddition processes with in situ generated isobenzofuran 13 were studied: 11 + 13 → 15 and 23a + 2×13 → 24a.

Notizen: The sequential ethylene-bridged catechol/aminophenol derivates 2-H3 and 3-H3 are potential ligands for metal-directed self-assembly processes. They are prepared via Wittig-reaction followed by a high yield reduction step with up to three simultaneous transformations.

Notizen: Ten N-alkylated lupininium derivatives 5-8 were prepared as potential enantioselective phase transfer catalysts. Compounds 5a-d, 6a-d contain four asymmetric centers (including one in the side chain) with known configuration resting on an X-ray structure. Preliminary PT catalytic experiments in several reactions gave high chemical yields but relatively disappointing enantioselectivities.

Notizen: Thermolysis of 2,3-dicyano-bicylo[2,2,1]hept-5-ene-2,3-dicarboxylic anhydride (6) at 580-590 °C or of 3,4,5,6-tetraazidophthalic anhydride (9) at 110 °C affords 3,4-dicyanomaleic anhydride (1).

Notizen: Sultones are readily prepared by intramolecular Diels-Alder reaction of vinylsulfonates in an often highly stereoselective fashion. Various methods for the synthetic elaboration of these heterocycles have been developed and applied to the total synthesis of biologically active natural products.

Notizen: 1,3-Dithienium and 1,3-Dithiolenium Salts. IX. Reactions of 1,3-Dithiane-2-ylium Tetrafluoroborates with C-Nucleophiles1,3-Dithian-2-ylium tetrafluoroborates (1), which can be easily obtained by variable methods, react in good to excellent yields with variable C-nucleophiles to new geminal disubstituted 1,3-dithianes. The latter compounds are potential precursors of interesting synthetic building blocks. Reactions are described with 2-lithio-1,3-dithianes 2, sodium cyanide 4, sodium salts of the nitro alkanes 7 and CH-acids of the type of the 1,3-dicarbonyl compounds 9. The reduction of 3-oxo-2-(2-phenyl-1,3-dithian-2-yl)-ethoxybutanoat-following a diastereoselective pathway - leads to the Cram product 11. Further presented is the crystal structure of 2-phenyl-1,3-dithiane-2-ylium tetrafluoroborate (1b).

Notizen: The addition of N-chlorophthalimide (1b) to alkenes 3 via phthalimidyl radicals introduces a chlorine atom and an imidyl moiety to vicinal C-atoms of a carbon chain. The yields depend on the substituents of the alkene 3. The regioselectivity can be explained by steric and electronic effects; differences in the behavior of the addition of N-chlorophthalimide (1b) and N-bromophthalimide (1a) can be explained by a reversible attack of the phthalimidyl radical to the double bond.

Notizen: Generation of N,N-Disubstituted Iminium Salts by Application of Silane Reagents(Dialkylamino)trimethylsilanes, halotrimethylsilanes and trimethylsilyl triflate proved to be superior reagents for a convenient access to the title compounds in an aprotic medium. In most cases, the co-formation of silylethers or disiloxanes acts as driving force. A comprehensive overview on this field, including the latest findings, is given and the significant mechanistic relationships are illuminated. The three component synthesis starting from carbonyl compounds (Scheme 3) and the two component synthesis (“latent” three component synthesis) starting from α-chloroethers (Schemes 16, 19) hold a central position. The latter method offers special advantage for the entrance into the multifunctional series, as shown by the first synthesis of vinylogous Viehe salts as preparatively useful C3-building blocks (Schemes 17, 22, 23). As an aim, this report should stimulate further progress in these areas.

Notizen: 1,3-Diaza-2-azoniaallene salts R1-N=N+=N—R2 6 represent a new functional group. 1,3-Disubstituted triazenes 8 are oxidized with tert-butyl hypochlorite to stable open-chain N-chlorotriazenes R1—N=N—NCl—R2 9, which at low temperatures with Lewis acids afford the reactive intermediates 6. The salt 6a is stable below -50 °C and was characterized by spectroscopic and analytical data. Heterocumulenes 6 behave as positively charged 1,3-dipoles undergoing cycloadditions to many different multiple bonds to furnish 1,2,3-triazolium and tetrazolium salts, e.g. to both electron-rich and electron-deficient alkenes, alkynes, to one or both double bonds of 1,3-butadienes, to carbodiimides, and cyanamides (1,3-dipolar cycloaddition with inverse electron demand). With an allene, a butatriene and a pentatetraene the 4,5-dihydro-1H-1,2,3-triazolium salts 17-19 were obtained. The constitutions of four of the products were secured by X-ray structural analyses. 4,5-Dihydro-1H-1,2,3-triazolium salts 11 and 1H-1,2,3-triazolium salts 20 are aza analogues of Arduengo's and Wanzlick's nucleophilic carbenes.

Notizen: 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.

Notizen: As a continuation of our previous studies on the synthesis and antiplatelet activity of quinolin-2(1H)-ones with an α-methylidene-γ-butyrolactone substituted at O(8), the O(6)- and N(1)-substituted isomers were synthesized and evaluated for antiplatelet activity against thrombin (Thr)-, arachidonic acid (AA)-, collagen (Col)-, and platelet-activating-factor (PAF)-induced aggregation in washed rabbit platelets. These compounds were synthesized from 6-hydroxyquinolin-2(1H)-one via alkylation and Reformatsky-type condensation (Schemes 1 and 2). All of them were found to inhibit the platelet aggregation perfectly which was induced by AA and Col. 6-Substituted isomers 5b-g exhibited very strong inhibitory activities against AA- and PAF- induced aggregation and are approximately ten times more potent than their 8-substituted counterparts. However, the 1-substituted (11a and 11b) and the 1,6-disubstituted (6) counterparts were relatively inactive. Their effects on the Ca2+-dependent vasoconstriction induced by high K+, and the phasic and tonic vasoconstrictions induced by norepinephrine (NE) in rat aorta were also evaluated. Except 5g, all of them were found to have significant inhibitory activity on the NE-induced phasic and tonic vasoconstrictions. Compounds 6 and 11b also exhibited strong inhibitory activity on high-K+ medium, Ca2+-induced vasoconstriction.

Notizen: The photolysis of N-alkylpyridinium halides 9a-e in alkaline H2O gave 6-azabicyclo[3.1.0]hexenol derivatives 10a-e. N-Substituents bearing ether, acetal, and alcohol functions were found to do not adversely influence the photochemical reaction course. The free OH groups of the N-(3-hydroxypropyl) derivative 10d were protected by benzoylation. The ensuing dibenzoate 14 underwent stereocontrolled opening of the aziridine ring on reaction with MeSH/BF3 to give a thioether 15. With benzoic acid in CHCI3, 10d gave the 4-hydroxy-5-aminocyclopent-2-enyl benzoate 11. The meso-2-aminocyclopent-4-ene-1,3-diol 12 was obtained by hydrolysis of 11. On reaction with Boc2O and NaI, the aziridine ring of 14 was converted to a bicyclic compound 17. Hydrolysis of 17 provided the trans-1,3-diol 18, the epimer of 12. Face-selective dihydroxylation of Boc-protected 12 gave a meso-aminocyclopentanetetrol 23 which was characterized upon peracetylation. Dihydroxylation of 15 provided a racemic analogue of epi-mannostatin A (26).

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: Natural free carboxylic acids from the hadromerid sponge Diacarnus levii (Kelly-Borges and Vacelet) were esterified to yield the new cyclic norditerpene peroxides ent-muqubilin benzyl ester (= (αR,3S,6R)-α,6-dimethyl-6-[(E)-4-methyl-6-(2,6,6-trimethyl-cyclohex-1-en-1-yl)hex-3-enyl]-1,2-dioxan-3-acetic acid benzyl ester; 6, diacarnoate B methyl ester(= (αS,3R,6R)-α,6-dimethyl-6-{2-(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-3-oxo-2,5,5,8a-tetramethylnaphthalen-1-yl)ethyl}-1,2-dioxan-3-acetic acid methyl ester; 9), and deoxydiacarnoate B benzyl ester (= (αS,3R,6R)-α,6-dimethyl-6-{2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2,5,5,8a-tetramethyl-1-naphthalenyl]ethyl}-1,2-dioxan-3-acetic acid benzyl ester; 10), which were isolated following extensive chromatography. The relative configuration of the peroxide/α-methylacetate moiety of 6, 9, and 10, was directly determined from their NMR spectra. The absolute configurations of the peroxide/α-methylacetate moiety was deduced from comparative 1H-NMR data of the (S)- and (R)-phenylglycine methyl ester derivatives 7 and 8 as well as 11/13 and 12/14, all obtained from a mixture of the precursors of 3, 6, and 10. The absolute configuration at the carbobicyclic moiety of enone 9 and of 10, is identical, as established by chemical interconversion, 9 and 10 belong to the normal labdane series according to empirical CD rules, applied either directly to 9 or to the parent (+)-sclareolide-derived enone 20. In contrast, molar rotation additivity rules suggest the ent-labdane configuration for 9 and 10. The epidioxides 1-3, 6, and 10 proved active in vitro against the malaria parasite Plasmodium falciparum; especially the previously isolated methyl 3-epinuapapuanoate (2) was active against a chloroquine-resistant strain, and this with a good security index.

Notizen: 3-Hydroxy-2-cyanoalk-2-enamides, and 2-cyano-2-(tetrahydrofuran-2-ylidene)- and 2-cyano-2-(tetrahydropyran-2-ylidene)acetamides with N-alkyl and N-aryl substituents have been synthesized in three steps from cyanoacetic acid. Their conformations were investigated by X-ray crystallography and 1H-NMR ROESY spectroscopy at room temperature. The enolic compounds 1-3 adopt an extended conformation stabilized by a strong intramolecular O—H … O=C bond both in the solid state and in (D6)DMSO solution. In contrast, the structure of the cyclic derivatives 5a,b-8a,b is solvent-dependent. In the solid state and in CDCl3 solution, the compounds adopt an extended conformation of type I or III, while, in (D6)DMSO solution, their structures undergo time-dependent (Z)/(E)-isomerization structures (of type II or IV). This observation is compatible with a dipolar transition state of rotation. The kinetics of the isomerization are controlled by the N-substituent, the N-(t-Bu) derivatives 7a and 7b having the highest barrier of rotation around the C=C bond. The whole body of experimental evidence together with the results of molecular-mechanics calculations with I-IV, indicate that, in DMSO, two (E)/(Z)-isomers with two conformations are present, and that they undergo interconversion at room temperature with four different constants. The very fast exchange rates kI,II and kIII,IV in the NMR time-scale might be responsible for the detection of only two isomers.

Notizen: A new acylated dimeric secoiridoid glycoside, seemannoside A (2), has been isolated from the aerial parts of Lisianthius seemannii (GRISEB) O. KUNTZE (Gentianaceae). The structure was established by spectroscopic analysis (UV, MS, 1H- and 13C-NMR, and 2D-NMR experiments) and chemical reactions as (E-4′-O-p-coumaroyl)lisianthioside. The structure of the (Z)-isomer (seemannoside B, 3), also present in the plant, was confirmed by LC/UV/1H-NMR analysis. The active principle, 6, responsible for the antifungal activity of the apolar extract against Cladosporium cucumerinum, has been isolated. Its structure has been established by NMR spectroscopy and X-ray crystallographic analysis as a rare type of aglycone monoterpene dimer.

Notizen: Asymmetric Diels-Alder reaction of the pentadienoic and hexadienoic acids 2a,b with the chiral chloronitroso derivative 3 gave the primary adducts 4a,b with good-to-excellent enantioselectivity. Subsequent as- or trans-dihydroxylation and hydrogenolytic cleavage of the N—O bond led to the 5-amino-5-deoxypentono-δ-lactams 13a, 14, 15a, and 16 in the D-ribose, L-arabinose, D-xylose, and L-lyxose series, respectively, and to the 5-amino-5,6-dideoxyhexono-δ-lactams 13b and 15b in the D-allose and D-glucose series, respectively.

Notizen: 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.

Notizen: The photoisomerization behavior of three mono[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines, 1, 2, and 3, and three bis[(E)-3-(4-hydroxyphenyl)prop-2-enoyl]spermidines, 4, 5, and 6, are investigated. The synthetic product (E)-1 could be almost quantitatively (〉 96%) converted into its isomer (Z)-1 under UV light irradiation. In the cases of (E)-2 and (E)-3, a mixture of (E)/(Z) ca. 1:2 was obtained, when the same conditions were applied. The comparison of their UV spectra provides the possible explanation for these different behaviors. Furthermore, it was noticed that the (Z) → (E) isomerization of the C=C bond took place during the purification by reverse-phase high-performance liquid chromatography (RP-HPLC), and the (E)/(Z)-mixture is thus inseparable. The same feature could be observed during the isolation of the (Z,Z)-N,N′-bis[3-(4-hydroxyphenyl)prop-2-enoyl]-spermidines, (Z,Z)-4, (Z,Z)-5, and (Z,Z)-6. Nevertheless, the fractions of (Z,Z)-5 and (Z,Z)-6 were in almost pure state collected, and their 1-NMR spectra are presented.

Notizen: The coordination behavior of chiral binucleating ligands of type 1-4 with various transition metals has been investigated. 1H-NMR Titration experiments with zinc(II) salts gave detailed structural information about the structure of the resulting zinc complexes. Ligand 1 forms an unusual C3-symmetric dinuclear zinc complex [Zn2CIL3] (8a) which was characterized by X-ray crystallography. Treatment of complex 8a with various carboxylic acids resulted in ligand-exchange reactions. With ligand 2, a hydroxo-bridged dinuclear copper complex 15 was synthesized and its structure elucidated by X-ray analysis. Solution studies UV and 1H-NMR spectroscopy of the reaction of ligand 3 with ZnII and NII salts revealed the formation of dimeric species of the type [M2X4L2]. Ligand 4 formed well-defined dinuclear complexes with NiII and CuII salts of which the corresponding NiII complex [Ni2(AcO)2(ClO4)2L] (22a) was characterized by crystal-structure analysis.

Notizen: Why Pentose- and Not Hexose-Nucleic Acids? Purine-Purine Pairing in homo-DNA: Guanine,Isoguanine, 2,6-Diaminopurine, and XanthineThis paper concludes the series of reports in this journal [1-4] on the chemistry of homo-DNA, the constitutionally simplifie dmodel system of hexopyranosyl-(6′ → 4′)-oligonucleotide systems stidued in our laboratory as potentially natural-nucleic-acid alternatives in the context of a chemical aetiology of nucleic-acid structure. The report describes the synthesis and pairing properties of homo-DNA oligonucleotides which contain as nucleobases exclusively purines, and gives, together with part III of the series [3], a survey of what we know today about purine-purine pairingin homo-DNA. In addition, the paper discusses those aspects of the chemistry of homo-DNA which, we think, influence the way how some of the structural features of DNA (and RNA) are to be interpreted on a qualitative level.Purine-purine pairing occurs in the homo-DNA domain in great variety. Most prominent is a novel tridentate Watson-Crick pair between guanine and isoguanine, as well as one between 2,6-diaminopurine and xanthinone, both giving rise to very stable duplexes containing the all-purine strands in antiparallel orientation. For the guanine-isoguanine pair, constitutional assignment is based on temperature-dependent UV and CD spectroscopy of various guanine- and isoguanine-containg duplexes in comparison with duplexes known to be paired in the reverse guanine is replaced by 7-carbauguanine. Isoguanine and 2,6-diaminopurine also have the capability of self-pariring in the reverse-Hoogsteen mode, as previously observed for adenine and guanine [3]. In this type of pairing, the interchangeably. Fig. 36 provides an overall survey of the relative strength of pairing in all possible purine-purine combinations.Watson-Crick pairing of isoguanine with guanine demands the former to participate in its 3H-tautomeric form; hitherto this specific tautomer had not been considered in the pairing chemistry of isoguanine. Whereas (cumulative) purine-purine pairing in DNA (reverse-Hoogsten or Hoogsteen) seems to occur in triplexes and tetrapalexes only, its occurrence in duplexes in a characteristic feature of homo-DNA chemistry. The occurrence of purine-purine Watson-Crick base pairs is probably a consequence of homo-DNA's quasi-linear ladder structure [1][4]. In a double helix, the distance between the two sugar C-atoms, on which a base pair is anchored, is expected to be constrained by the dimensions of the helix; in a linear duplex, however, there would be no restrictions with regard to base-pair length. Homo-DNA's ladder-like model also allows one to recognize one of the reasons why nucleic-acid duplexes prefer to pair in antiparallel, rather than parallel strand orientation: in homo-DNA duplexes, (averaged) backbone and base pair axes are strongly inclined toward one another [4]; the stronger this inclination, the higher the preference for antiparallel strand orientation is expected to be (Fig. 16).In retrospect, homo-DNA turns out to be one of the first artificial oligonucleotide systems (cf. Footnote 65) to demonstrate in a comprehensive way that informational base pairing involving purines and pyrimidines is not a capability unique to ribofuranosyl systems. Stability and helical shape of pairing complexes are not necessary conditions of one another; it is the potential for extensive conformational cooperativity of hte backbone structure with respect to the constellational demands of base pairing and base stacking that determines whether or nor a given type of base-carrying backbone structure is an informational pairing system. From the viewpoint of the chemical aetiology of nucleic-acid structure, which inspired our investigations on hexopyranosyl-(6′ → 4′)-oligonucleotide systems in the first place, the work on homo-DNA is only an extensive model study, because homo-DNA is not to be considered a potential natural-nucleic-acid altenratie. In retrospect, it seems fortunate that the model study was carried out, because without it we could hardly have comprehended the pairing behavior of the proper nucleic-acid alternatives which we have studied later and which will be discussed in Part VI of this series.The English footnotes to Fig. 1-49 provide an extension of this summary.

Notizen: ‘Fully chiral’ dendrimers, containing a stereogenic center at each and every branching point, have been prepared using a chiral core triol with aromatic elongating units (cf. 27) and chiral branch diols (cf. 8, 12, and 24) as building blocks. The biggest dendrimer prepared is of the 4th generation (33: 46 building blocks, 93 stereogenic centers, 1028 possible stereoisomers), and has been obtained by a convergent growth approach in 32 steps starting from the biopolymer poly[(R)-3-hydroxybutanoic acid] (P(3-HB)). All compounds were shown to be monodisperse by MALDI-TOF mass spectrometry. Spin-lattice relaxation-time (T1) measurements and size-exclusion chromatography show typical features of structurally related achiral dendrimers. The influence of the chiral building blocks on the shape of the whole dendrimer has been investigated by chiroptical measurements: the specific rotation can be considered as average of all chiroptical properties of its constituent chiral units, independent of the solvent, the concentration, and the temperature. On the other hand, regularity in the circular dichroism (CD) spectra is completely lost with variation of the solvent (cf. Fig. 13).

Notizen: 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.

Notizen: The synthesis of a series of chiral enantiomerically pure C2-symmetric binucleating ligands is reported. Ligands of type 1-4, which consist of a phenolic or heterocyclic unit bridging two chiral dihydrooxazole rings. are readily accessible from chiral amino alcohols. Ligands 5a and 5b are composed of a cyclic urea or thiourea unit, respectively, and two 3,4-dihydro-2H-pyrrole rings containing a stereogenic center next to the N-atom. Compounds of this type are readily assembled from ethane-1,2-diamine and an imidothioic ester derived from pyroglutamic acid. These new ligands, which can coordinate two metals in close proximity to each other, are of interest regarding possible applications in asymmetric catalysis.

Notizen: Stability constants have been measured for a series of ligands based on a 2,2′-(pyridine-2,6-diyl)bis[1H-benzimidazole] unit which forms dinuclear double-stranded helical complexes with copper(I). Variation of different structural parameters confirms the importance of the coordinate bond, the stacking interactions, and the weakly bridging pyridine units observed by X-ray crystallography. The stabilities of the complexes depend strongly on the solvent, and in MeCN, which is a good solvent for copper(I), the complexes are less stable and assemble in a stepwise manner. The interconversion of the enantiomers may be followed by 1H-NMR and takes place on a millisecond time scale around room temperature. The trends in lability are similar to those found for the stability of the complexes.

Notizen: Oligodeoxyribonucleotides containing 7-deaza-2′-deoxy-8-methylguanosine (m8c7Gd; 2b) were prepared. For this purpose, the phosphonate 3a and the phosphoramidite 3b were synthesized and employed in solidphase oligodeoxyribonucleotide synthesis. The structures and the thermodynamic data of duplex formation of oligodeoxyribonucleotides containing 2b were investigated by temperature-dependent CD and UV spectra and compared with those containing 7-deaza-2′-deoxy-7-methylguanosine (m7c7Gd) or 7-deaza-2′-deoxy-guanosine (c7Gd; 2a). In general, compound 2b reduces the duplex stability. In case of the sequence d(m8c7G-C)4 (18), the B → Z transition was facilitated by the incorporation of 2b. Moreover, a single 7-deaza-8-methylguanine residue present in an oligodeoxyribonucleotide tract of guanine residues destabilizes the dG quadruplex significantly. This destabilization is more pronounced than in the case of 7-deazaguanine or 7-deaza-7-methyl-guanine.

Notizen: 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).

Notizen: 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.

Notizen: The new, axially chiral bis(4,5-dihydrooxazoles) 4 have been synthesized in a straightforward manner, starting from the substituted, racemic 1,1′-biphenyl-2,2′-dicarboxylic acids 1 and optically active amino alcohols 2. The adducts were resolved by medium-performance liquid chromatography (MPLC; see Scheme 1). Formation of Cu1 complexes of 4 was followed by 1H-NMR spectroscopy. The catalytic behavior of these complexes has been investigated by asymmetric cyclopropanation of styrene with ethyl diazoacetate. Beside the influence of steric factors, a significant electronic effect on asymmetric induction could also be observed (see Scheme 2 and Table).

Notizen: The synthesis of the enantiomerically pure, bridgehead-functionalized bicyclo[3.2.1]octanes 11 and 16, containing a conformationally fixed trihydroxypropyl (aminodihydroxypropyl) unit, as well as the X-ray structure of 11 are described. These compounds are of interest as sugar surrogates in the preparation of DNA analogs. Compounds 11 and 16 became available in 10 and 12 steps, respectively, and in an overall yield of 11 and 4% from D-arabinose via a highly stereoselective pinacol coupling as the key step.

Notizen: Absolute rate constants and their Arrhenius parameters are obtained for the addition of a cyclic malonyl radical derived from Meldrum's acid to 20 mono- or 1,1-disubstituted alkenes in (±)-propylene oxide and for the addition of the open-chain di(tert-butyl)malonyl radical to six mono- or 1,1-disubstituted alkenes in 1,1,2-trichloro-1,2,2-trifluoroethane by time-resolved electron spin resonance spectroscopy. At room temperature, the radicals add at the unsubstituted C-atoms with rate constants ranging from 1.1. 105 M-1S-1 (acrolein) to 2.4. 106 M-1S-1 (1,1-diphenylethene). The frequency factors are in the narrow ranges of log (A/M-1S-1) = 8.7 ± 0.1 for the cyclic and log (A/M-1S-1) = 8.2 ± 0.2 for the open-chain malonyl species, whereas the activation energies vary from 12.9 kJ/mol (1,1-diphenylethene) to 21.7 kJ/mol (acrylonitrile). They correlate with the alkene ionization potentials and, more weakly, with the reaction enthalpy. No correlation was found between the activation energies and the alkene electron affinities. Hence, the results confirm and quantify the electrophilic nature of malonyl radicals in addition reactions.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: An asymmetric synthesis of (-)-(4R)-dihydroisomyricoidine (28), a 13-membered amino lactam of type A, was performed by a diastereoselective Michael addition between the spermidine derivative 3 and the commercially available optically active ethyl carboxylate 4, and the cyclization of the resulting ω-amino acid 7 using diethyl phosphorocyanidate ((EtO)2POCN), followed by a Wittig reaction to introduce the (Z)-side chain. Some side reactions are also discussed.

Notizen: New derivatives of campholenaldehyde (= 2-(2,2,3-trimethylcyclopent-3-enyl)ethanal bearing two cyclopropane moieties were synthesized, and the structure of the stereoisomer responsible for its exceptionally strong, diffusive, and natural sandalwood-oil scent, ((1S,2S)-1-methyl-2-{[1S,3R,5R)-1,2,2-trimethylbicyclo[3.1.0]hex-3-yl]methyl}cyclopropyl)methanol (13a), was elucidated.

Notizen: Titanium-dioxide surfaces have been glycosylated with the benzyl-, 4-fluorobenzyl-, and acetyl-protected diazirines 1-3. The modified TiO2 surfaces were characterized by contact-angle measurement, X-ray photoelectron spectroscopy (XPES), and time-of-flight secondary-ion mass spectrometry (ToF-SIMS). The main by-products of the glucosidation (mostly azines and trehaloses) were identified. Their physisorption slightly reduces the efficiency of the glucosidation by 1 mM solution of 1 or 2 in CH2Cl2, but this influence is neutralized by repeating the glucosidation, or by using a 100 mM solution of the diazirines. The immobilized, acetylated glucosyl moieties were deacetylated in situ. Calculations based on the XPES peaks of Ti 2p and F 1s for the TiO2 surface modified with 2 indicated 1.5 ± 0.9 immobilized glucosyl moieties per nm2.

Notizen: A Chemotaxonomic survey for biologically active compounds from Malaysian Calophyllum species led to the findings of the four new benzoylcoumarins 1a, 2, 3, and 4a (including the unusual prenylated 6-benzoylcoumann 1a), two uncommon coumarins 5 and 6a with a pyran-4-one moiety fused at C(6) and C(7), and compounds 7a, 9, and 10, all isolated from the bark of C. teysmannii var. inophylloide. Their structures were determined by spectroscopic analysis and chemical transformations. X-Ray crystal-structure determination of 2 provided information on the conformational preferences of substituents in this class of coumarins. The syntheses of the cytotoxic calanone (7a) and of some related coumarins are described.

Notizen: The heme-thiolate protein chloroperoxidase (CPO) catalyzes the chlorination of activated C—H bonds. A reaction mechanism is proposed for this enzymatic transformation (Scheme 1), and a new iron(III) porphyrinate complex 13 is synthesized containing pentafluorophenyl groups at two meso-positions and a thiophenolato ligand coordinating to the Fe-atom (Schemes 2 and 3). Due to the presence of the electron-withdrawing substituents, the catalyst 13 is appreciably resistant to oxidants (HOCl) and chlorinates, e.g., monochlorodimedone (5), with turnover numbers up to 1530. The redox potential of 13, E0 = - 134 mV, and the Soret band (λmax 448 nm) of the CO adduct of the reduced state of 13 are close to the corresponding values of the enzyme CPO.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: The [4 + 2] cycloadduct 17 of 2,3-dimethylidene-1,2,3,4-tetrahydro-1,4-methanonaphthalene and 4-phenyl-4H-1,2,4-triazole-3,5-dione (PTAD) was subjected to a triplet-sensitized di-π-methane rearrangement. Hydrolysis of the resulting urazol 18 gave the hydrocarbon 7. Hydrolysis of 18 at lower base concentrations led to isomeric stable semicarbazides 24 and 25, which were submitted NiO2 or MnO2 oxidation, to give the target compound 7, and oxidation products 26 and 27.

Notizen: The difference between the strong inhibition of retaining β-glucosidases by the tetrazole 1 and the weak inhibition by the triazole 3 has been explained by the protonation by the enzymic catalytic acid of N(3) of 1, replaced by CH in 3. One also expects a contribution to the inhibition from the charge-dipole interaction between the enzymic catalytic nucleophile and the azole ring. The extent of this contribution was estimated from the calculated, distance-dependent heats of formation of the acetate-azole complexes. The calculations were validated by comparison of the charge-dipole interaction between phosphate and the inhibitors 1 and 3 in the glycogen phosphorylase b (GPb)-azole-phosphate complexes, as derived from differences in the Ki values for 1 and 3, while the structural invariance of the complexes was demonstrated by X-ray analysis. The difference between the charge-dipole interactions of (dihydrogen) phosphate and 1 or 3 as derived from Δ Ki is 1.1 kcal mol-1, while the calculated difference is 1.3 kcal mol-1. The calculated difference for the interaction of 1 or 3 with acetate, representing the catalytic nucleophile in β-glycosidases, is 2.0 kcal mol-1, while the differences of the binding energies as derived from the Ki values for the inhibition by 1 or 3 of different β-glycosidases range from 2.4 to 5.3 5 kcal mol-1. The calculated difference for 1 and the imidazole 6 is 2.5 kcal mol-1 in favour of 1, whereas the Ki-derived difference is 3.7 kcal mol-1 in favour of 6, equal to the calculated difference between 1 and the protonated imidazole 6. Thus, protonation by the catalytic acid and the charge-dipole interaction with the catalytic nucleophile contribute cooperatively to the binding of inhibitors possessing a trigonal anomeric centre bonded to a heteroatom.

Notizen: Described are the preparation of nanocrystals and the synthesis of molecules that may be covalently or noncovalently assembled in solution to yield heterosupermolecules possessing a well-defined heterosupramolecular function. Also described are preparative and synthetic methods that yield organized assemblies of heterosupermolecules possessing an addressable heterosupramolecular function. Finally, the development of these synthetic strategies to permit the covalent and noncovalent assembly and organization of a wide range of condensed phase and molecular components is outlined.

Notizen: For a comparison with the corresponding α- and β-hexapeptides H-(Val-Ala-Leu)2-OH (A) and H-(β-HVal-β-HAla-β-HLeu)2-OH (B), we have now prepared the corresponding γ-hexapeptide 1 built from the homochirally similar (S)-4-aminobutanoic acid, (R)-4-amino-5-methylhexanoic acid, and (R)-4-amino-6-methylheptanoic acid. The precursors were prepared either by double Arndt-Eistert homologation of the protected amino acids Boc-Val-OH, Boc-Ala-OH, and Boc-Leu-OH (Schemes 1 and 2), or by the superior route involving olefination/hydrogenation of the corresponding aldehydes (Boc-valinal, Boc-alaninal, and Boc-leucinal; Scheme 3). Conventional peptide-coupling methodology (EDC/HOBt) furnished the γ-hexapeptide 1 (through the intermediate γ-di- and γ-tripeptide derivatives 9-11). Analysis of NMR measurements in (D5)pyridine and CD3OH solution (COSY, TOCSY, HSQC, HMBC, ROESY) reveals that the γ-hexapeptide 1 adopts a right-handed helical structure ((P)-2.61 helix of ca. 5-Å pitch, containing 14-membered H-bonded rings) which is to be compared with the left-handed helix of the corresponding β-peptide B ((M)-31 helix of 5-Å pitch, 14-membered H-bonded rings) and with the familiar right-handed, so-called α-helix of α-peptides ((P)-3.61 helix of 5.4-Å pitch, 13-membered rings). Like the helix sense, the helix dipole reverses when going from α-, (N + → C) to β-(C + → N) to γ-peptides (N + → C). The surprising difference between the natural α-, and the analogous β- and γ-peptides is that the helix stability increases upon homologation of the residues.

Notizen: 7-O-Substituted analogs of deaminodeoxycolchinol thiomethyl ether were synthesized and evaluated for their inhibitory effects on tubulin polymerization in vitro. Ketone 9, a key compound in this study, was derived from thiocolchicone 6 by reaction with aniline. Reaction of compound 6 with MeNH2 or BuNH2 gave tetracyclic lactams 7 and 8, respectively. Optically active alcohols 11a and 11b were obtained from racemic 11 by chemical resolution including a separation of the comphanate diastereoisomers 12a and 12b, followed by basic hydrolysis. The (aR,7R)-configuration of 12b was verified by X-ray crystallographic analysis. Almost all racemic and optically active 7-O-acyl or 7-O-aroyl compounds had strong inhibitory effects on the tubulin polymerization reaction, with IC50 values from 1.7 to 5.1 μM. A few agents, such as the lactams 7 and 8, the camphanates 12a and 12b, the cyclohexanecarboxylates 19a and 19b, and, most notably, the (7S)-benzoate 15a, had negligible effects on polymerization, yielding IC50 values greater than 40μM. Ketone 9 showed strong inhibition of tubulin polymerization comparable to that of thiocolchicone (6). Optically active alcohol 11a and acyl esters 13a and 14a with a (7S)-configuration were more active than the (7R)-esters 13b and 14b. However, the esters 15a-17a with a (7S)-configuration were less active than the (7R)-isomers 15b-17b, in which the (7R)-benzoate 15b was at least 15-fold more inhibitory than the (7S)-isomer 15a. For the most part, the agents causing strongest inhibition of polymerization also caused the greatest inhibition of [3H]colchicine binding. NMR and optical rotatory data indicate that, in polar solvents, the equilibrium in esters with a 7-O-aroyl substituent, i.e., 15a,b, 16a,b, and 17a,b, is reversed from (aS) to (aR) or from (aR) to (aS), as compared to nonpolar solvents.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: 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.

Notizen: (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).

Notizen: 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.